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{
"abstract": "OBJECTIVE\nTo report a case of herpes zoster ophthalmicus (HZO) reactivation after recombinant zoster vaccination.\n\n\nMETHODS\nA 78-year-old woman, with a history of HZO 20 years ago, was referred for progressive corneal thinning in her left eye that started 1 week after her second dose of recombinant zoster vaccination.\n\n\nRESULTS\nAt presentation, visual acuity was counting fingers. Corneal sensation was markedly decreased. Slit lamp examination revealed a temporal paracentral epithelial defect 1.5 × 2.0 mm in size with 40% thinning and surrounding stromal inflammation suggestive of stromal keratitis with ulceration. The patient was started on oral valacyclovir, topical erythromycin ointment, and hourly topical lubrication. A bandage contact lens was placed and was replaced 1 week later with self-retained cryopreserved amniotic membrane ring. The ring was removed in the following week when the thinned area was epithelialized with no further evidence of stromal lysis.\n\n\nCONCLUSIONS\nHZO reactivation after recombinant zoster vaccination is uncommon but possible. Ophthalmologists should remain aware of potential risks of zoster vaccination and take special precautions in patients with HZO history.",
"affiliations": "Division of Cornea, Cataract and External Eye Diseases, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD.",
"authors": "Jabbour|Samir|S|;Shekhawat|Nakul S|NS|;Chen|Ariel|A|;Woreta|Fasika A|FA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D053061:Herpes Zoster Vaccine; D004917:Erythromycin; D000077483:Valacyclovir; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000002537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "40(2)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D004917:Erythromycin; D015828:Eye Infections, Viral; D005260:Female; D006563:Herpes Zoster Ophthalmicus; D053061:Herpes Zoster Vaccine; D014645:Herpesvirus 3, Human; D006801:Humans; D007117:Immunization, Secondary; D000085343:Latent Infection; D000077266:Moxifloxacin; D014611:Vaccination; D000077483:Valacyclovir; D014775:Virus Activation; D014792:Visual Acuity",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "248-250",
"pmc": null,
"pmid": "32947398",
"pubdate": "2021-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Presumed Herpes Zoster Ophthalmicus Reactivation Following Recombinant Zoster Vaccination.",
"title_normalized": "presumed herpes zoster ophthalmicus reactivation following recombinant zoster vaccination"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2020GSK191053",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RECOMBINANT VARICELLA ZOSTER VIRUS (VZV) GLYCOPROTEIN E"... |
{
"abstract": "OBJECTIVE\nElderly acute myelocytic leukemia (AML) patients have limited treatment options because they poorly tolerate standard-dose chemotherapy. The present article describes our experience with ultra-low-dose decitabine combined with infusion of autologous cytokine-induced killer (CIK) cells for 2 elderly patients with myelodysplastic syndrome-transformed AML.\n\n\nMETHODS\nDecitabine (10 mg) was given on days 1 to 5, and CIK cells on day 14 with 2 to 8 × 10(9) cells per infusion.\n\n\nRESULTS\nThe therapeutic regimen resulted in marked hematologic recovery and was associated with better than expected survival in both cases.\n\n\nCONCLUSIONS\nOur experience suggests that the combination therapy is safe and effective for elderly patients with myelodysplastic syndrome-transformed AML.",
"affiliations": "Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, China; Department of Hematology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China.;Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, China.;Department of Pharmacy, the Second Artillery General Hospital, Beijing, China.;Department of Geriatric Laboratory Medicine, Chinese PLA General Hospital, Beijing, China.;Institute of Otorhinolaryngology, Chinese PLA General Hospital, Beijing, China.;Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, China.;Department of Medicine, Chinese PLA No. 202 Hospital, Shenyang, Liaoning, China.;Institute of Genomics, Chinese Academy of Sciences, Beijing, China.;Department of Oncology, Dandong Second Hospital, Shenyang, Liaoning, China.;Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, China.;Department of Hematology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China.;Department of Hematology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China.;Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing, China. Electronic address: luxuechun@126.com.",
"authors": "Wang|Haitao|H|;Yang|Bo|B|;Chi|Xiaohua|X|;Cai|Lili|L|;Yu|Ruili|R|;Zhu|Hongli|H|;Tuo|Shuai|S|;Zhang|Feng|F|;Wang|Xuanchi|X|;Yang|Yang|Y|;Wu|Xiaoxiong|X|;Li|Songwei|S|;Lu|Xuechun|X|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D000077209:Decitabine; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0149-2918",
"issue": "36(7)",
"journal": "Clinical therapeutics",
"keywords": "AML; CIK cells; MDS; acute myelocytic leukemia; cytokine-induced killer cells; decitabine; elderly; myelodysplastic syndrome",
"medline_ta": "Clin Ther",
"mesh_terms": "D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D014408:Biomarkers, Tumor; D003131:Combined Modality Therapy; D055612:Cytokine-Induced Killer Cells; D000077209:Decitabine; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009190:Myelodysplastic Syndromes; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "7706726",
"other_id": null,
"pages": "1104-11",
"pmc": null,
"pmid": "24986484",
"pubdate": "2014-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ultra-low-dose decitabine combined with autologous cytokine-induced killer cells for elderly patients with acute myeloid leukemia transformed from myelodysplastic syndrome.",
"title_normalized": "ultra low dose decitabine combined with autologous cytokine induced killer cells for elderly patients with acute myeloid leukemia transformed from myelodysplastic syndrome"
} | [
{
"companynumb": "CN-CLINIGEN GROUP PLC/ CLINIGEN HEALTHCARE LTD-CN-CLGN-20-00458",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DECITABINE"
},
... |
{
"abstract": "BACKGROUND\nOritavancin is a novel lipoglycopeptide approved for acute bacterial skin and skin structure infections. The pharmacokinetic profile and convenient one-time dosing make oritavancin an enticing option for other serious Gram-positive infections requiring prolonged treatment courses. Unfortunately, data for using oritavancin in these populations are limited.\n\n\nMETHODS\nWe report ten cases of oritavancin use for invasive Gram-positive infections in our health system, and provide a review of the currently available literature regarding oritavancin therapy for invasive infections.\n\n\nRESULTS\nAmong the ten patients who received oritavancin, the most common infection was methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia (n = 5, 50%). Other indications for oritavancin use included methicillin-resistant S. aureus (MRSA) bursitis (n = 1, 10%), group B streptococcal bacteremia with native tricuspid valve infective endocarditis (n = 1, 10%), coagulase-negative staphylococcal bacteremia (n = 1, 10%), MSSA deep tissue infection (n = 1, 10%), and enterococcal bacteremia (n = 1, 10%). Oritavancin was well tolerated, and 7/10 (70%) patients were successfully treated.\n\n\nCONCLUSIONS\nOritavancin is a potential option for patients with invasive Gram-positive infections. Further study is warranted.",
"affiliations": "Moses Cone Hospital, Cone Health, Greensboro, NC, USA.;Moses Cone Hospital, Cone Health, Greensboro, NC, USA.;Moses Cone Hospital, Cone Health, Greensboro, NC, USA.;Moses Cone Hospital, Cone Health, Greensboro, NC, USA.;Moses Cone Hospital, Cone Health, Greensboro, NC, USA. jsmith5@highpoint.edu.",
"authors": "Stewart|Cassie L|CL|;Turner|Michelle S|MS|;Frens|Jeremy J|JJ|;Snider|Cynthia B|CB|;Smith|Jordan R|JR|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40121-017-0156-z",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n28386776\n156\n10.1007/s40121-017-0156-z\nCase Series\nReal-World Experience with Oritavancin Therapy in Invasive Gram-Positive Infections\nStewart Cassie L. 1\nTurner Michelle S. 1\nFrens Jeremy J. 1\nSnider Cynthia B. 1\nSmith Jordan R. jsmith5@highpoint.edu\n\n12\n1 0000 0004 0406 6699 grid.416127.7 Moses Cone Hospital, Cone Health, Greensboro, NC USA\n2 0000 0000 9902 8484 grid.256969.7 Fred Wilson School of Pharmacy, High Point University, High Point, NC USA\n6 4 2017\n6 4 2017\n6 2017\n6 2 277289\n16 2 2017\n© The Author(s) 2017\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nIntroduction\n\nOritavancin is a novel lipoglycopeptide approved for acute bacterial skin and skin structure infections. The pharmacokinetic profile and convenient one-time dosing make oritavancin an enticing option for other serious Gram-positive infections requiring prolonged treatment courses. Unfortunately, data for using oritavancin in these populations are limited.\n\nMethods\n\nWe report ten cases of oritavancin use for invasive Gram-positive infections in our health system, and provide a review of the currently available literature regarding oritavancin therapy for invasive infections.\n\nResults\n\nAmong the ten patients who received oritavancin, the most common infection was methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia (n = 5, 50%). Other indications for oritavancin use included methicillin-resistant S. aureus (MRSA) bursitis (n = 1, 10%), group B streptococcal bacteremia with native tricuspid valve infective endocarditis (n = 1, 10%), coagulase-negative staphylococcal bacteremia (n = 1, 10%), MSSA deep tissue infection (n = 1, 10%), and enterococcal bacteremia (n = 1, 10%). Oritavancin was well tolerated, and 7/10 (70%) patients were successfully treated.\n\nConclusion\n\nOritavancin is a potential option for patients with invasive Gram-positive infections. Further study is warranted.\n\nKeywords\n\nBacteremia\nExtended duration\nLipoglycopeptide\nOPAT\nOutpatient parenteral antimicrobial therapy\nStaphylococci\nStaphylococcus aureus\nissue-copyright-statement© Springer Healthcare 2017\n==== Body\nIntroduction\n\nGram-positive pathogens are a leading cause of serious community-acquired and healthcare-associated infections [1]. Staphylococcus aureus is the most common pathogen isolated among healthcare-associated infections, and in the United States, roughly half of all S. aureus isolated from the bloodstream are now resistant to methicillin [2]. Methicillin-resistant S. aureus (MRSA) is independently associated with increased morbidity and mortality [3, 4]. Bloodstream infections with S. aureus are rife with complications such as osteomyelitis and endocarditis, and treatment courses tend to involve daily, intravenous (IV) antibiotic administration and last 6 weeks or more, which is a challenge for both patients and providers [5]. Enterococci, another group of frequently isolated hospital-acquired pathogens, can also cause serious and potentially resistant infections [2]. Over the past several decades, mutations in the vanA and vanB genes have caused vancomycin-resistant strains of Enterococcus faecalis and E. faecium to emerge. The prevalence of vancomycin-resistant enterococci has increased substantially over the last several years, and treatment options are limited [2].\n\nVancomycin has been a mainstay of therapy for Gram-positive infections, especially MRSA, but long-term outpatient parenteral antimicrobial therapy (OPAT) with vancomycin is complicated due to frequent dosing and the need for therapeutic drug monitoring to prevent potential toxicities [6]. Some patients are not candidates for prolonged intravenous antibiotics, including those likely to abuse a vascular access system and those unable to adhere to an OPAT regimen [7]. Furthermore, approximately 10% of OPAT regimens must be stopped prematurely due to adverse reactions, which may complicate the course of treatment and require a longer treatment duration with other antibiotics [7]. Treatment of Gram-positive infections, especially with S. aureus, presents a clinical challenge in need of creative therapeutic approaches.\n\nOritavancin is a novel lipoglycopeptide approved by the Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) [8]. It is structurally similar to vancomycin, but possesses an additional hydrophobic tail that alters both its pharmacokinetic and antimicrobial properties [9]. It possesses three distinct mechanisms of action, inhibiting both transpeptidation and transglycosylation, causing disruption of cell wall synthesis, and also disrupting the cell membrane through membrane binding of its hydrophobic tail [9]. Unlike many other agents approved for ABSSSIs, oritavancin is given as a one-time dose of 1200 mg IV infused over 3 h. The single dose is sufficient for ABSSSIs due to the initial peak serum concentration of 140 mg/L and prolonged terminal half-life, which ranges from 245 to 393 h (~10–17 days) [10, 11]. Pharmacokinetic data demonstrate that, on average, oritavancin maintains concentrations in several body compartments above the MIC90 threshold for at least a month from initial dosing [10]. Oritavancin is active against a variety of Gram-positive species, and surveillance data from 2008 to 2012 of over 9000 S. aureus isolates demonstrate a minimum inhibitory concentration (MIC)90 of only 0.06 mg/L [12]. Among the 205 isolates with vancomycin MICs of 2 mg/L and the 100 isolates with daptomycin MICs of ≥1 mg/L within this study, the oritavancin MIC90 was 0.12 mg/L, and only 13 of these 305 (4%) isolates possessed oritavancin MICs >0.12 mg/L, the current FDA breakpoint for susceptibility [12]. From 2013 to 2014, when oritavancin was tested against 780 invasive community-acquired and 218 invasive healthcare-associated S. aureus isolates from blood culture specimens, all S. aureus were susceptible to oritavancin and the MIC50/90 values were 0.03/0.06 mg/L, respectively [13]. These MICs were consistent regardless of oxacillin susceptibility or multi-drug resistance phenotypes. Nearly all isolates were susceptible to vancomycin, daptomycin, and linezolid, but oritavancin MIC50 and MIC90 values were eightfold lower than daptomycin and 16- to 32-fold lower than vancomycin or linezolid [13]. Oritavancin has also shown potent in vitro activity against methicillin-resistant coagulase-negative staphylococci (CoNS) with MIC50 and MIC90 of 0.06 and 0.12 mg/L, respectively [14]. Oritavancin also possesses in vitro activity against enterococci, achieving a MIC90 of 0.06 mg/L against VRE in one surveillance study [15]. Although this agent is currently indicated solely for ABSSSIs, the therapeutic potential for disease states necessitating prolonged therapy, such as Gram-positive bacteremia and endocarditis, is enticing.\n\nOur health system has used oritavancin in several cases of invasive Gram-positive infections where IV antibiotics were not considered a safe option, the patient refused IV antibiotic therapy, or antibiotics such as cefazolin, vancomycin, or daptomycin were not feasible. Currently, oritavancin is not on our health system’s formulary, and the infectious diseases (ID) physicians are the only providers prescribing oritavancin. Here, we document several cases in an effort to describe the efficacy and safety of oritavancin for serious Gram-positive indications other than ABSSSIs, and provide a review of the current available literature regarding off-label oritavancin therapy.\n\nMethods\n\nStudy Design and Population\n\nThis was a retrospective, observational chart review of adult (≥18 years of age) patients using electronic medical records at Cone Health, a 1254-bed, five-hospital healthcare system based in Greensboro, North Carolina, USA. Eligible patients received at least one dose of oritavancin for an indication other than ABSSSI from April to December 2015. April was chosen as the first month included in the study, because it was the first month that a dose of oritavancin was ordered in our health system. Patients were identified by VigiLanz™ decision support software.\n\nCompliance with Ethics Guidelines\n\nThis was a retrospective study reviewing chart data, therefore no new studies with human or animal subjects were performed by any of the authors. A waiver of informed consent was obtained from the Cone Health Institutional Review Board.\n\nData Collection\n\nPatient demographics, comorbid conditions, primary infection site, microbiological data, antimicrobial therapy employed in treatment, length of hospital stay, and overall clinical outcome as judged by the investigators were collected. With respect to oritavancin, the indication, number of doses administered, and adverse effects were collected.\n\nSafety Assessment\n\nSafety data included adverse event reporting by the prescribing physician and follow-up with patients after oritavancin administration.\n\nDefinitions\n\nPatient outcomes were categorized as clinical cure or failure. Clinical cure was defined as resolution of all clinical signs and symptoms of infection, which included resolution of fever, normalization of white blood cell count and erythrocyte sedimentation rate, with no additional infection-related hospital admissions, no additional antibiotic therapy required for the indication initially treated with oritavancin, and infection clearance with sterile blood cultures where indicated. Failure was defined as worsening of current infection or new/recurrent signs and symptoms of infection requiring either a change or addition of antibiotic therapy. Patients lost to follow-up were classified as not clinically evaluable.\n\nResults\n\nA total of ten patients received off-label oritavancin during the pre-specified study period at our health system. Table 1 summarizes the clinical course and outcomes for all patients. The median patient age was 46 (range 29–66) years. The most common infection leading to off-label use of oritavancin was methicillin-susceptible S. aureus (MSSA) bacteremia (n = 5, 50%). Other indications included MRSA bursitis (n = 1, 10%), group B streptococcal bacteremia with native tricuspid valve endocarditis (n = 1, 10%), coagulase-negative staphylococcal bacteremia (n = 1, 10%), MSSA deep tissue infection (n = 1, 10%), and enterococcal bacteremia (n = 1, 10%). All but one patient received a one-time 1200-mg dose of oritavancin. There were a number of antibiotics used prior to initiation of oritavancin therapy, the most common being vancomycin (9 patients, 90%) and cefazolin (6 patients, 60%). All patients received oritavancin following different courses of standard antibiotic therapy for continued clearance of the initial infection. Safety data revealed that oritavancin was generally well tolerated. One patient developed nausea during administration of oritavancin that quickly resolved after the infusion was completed. Another patient, who received three doses of oritavancin, experienced hearing loss documented by an audiologist, a heretofore unseen reaction to oritavancin. However, this patient also recently completed a course of vancomycin therapy. Contact was attempted with all patients after receiving oritavancin by either follow-up in our outpatient infectious diseases clinic or by telephone. Seven patients (70%) were clinically cured of their initial infection after receiving oritavancin, two patients (20%) failed oritavancin therapy, and one patient (10%) was unable to be contacted for follow-upTable 1 Antibiotic course and clinical outcomes for patients receiving oritavancin therapy\n\nPatient\tAge\tSex\tOritavancin indication\tDuration of antibiotics used before oritavancin\tReason for oritavancin selection\tNumber of oritavancin doses\tOritavancin adverse events\tClinical outcome\tLength of stay (days)\t\n1\t57\tM\tMSSA CLABSI\tCefazolin (1 day)\n\nVancomycin (4 days)\n\n\tRefused OPAT\t1\tNausea\tC\t20\t\n2\t53\tM\tMSSA bacteremia and wound infection\tCefazolin (5 days)\n\nDaptomycin (1 dose)\n\nPiperacillin-tazobactam (2 days)\n\nVancomycin (2 days)\n\n\tRefused OPAT\t1\tNone\tC\t7\t\n3\t26\tF\tMSSA bacteremia, iliopsoas abscess, and sacral joint osteomyelitis\tCefazolin (7 days)\n\nPiperacillin-tazobactam (3 days)\n\nVancomycin (4 days)\n\n\tHistory of IVDU\t1\tNone\tF\t8\t\n4\t53\tF\tMSSA bacteremia and psoas abscess\tCefazolin (18 days)\n\nPiperacillin-tazobactam (2 days)\n\nVancomycin (4 days)\n\n\tHistory of IVDU\t1\tNone\tNCE\t8\t\n5\t31\tM\tMSSA bacteremia\tCefazolin (7 days)\n\nVancomycin (4 days)\n\n\tHistory of noncompliance with OPAT\t1\tNone\tC\t9\t\n6\t41\tM\tCoNS bacteremia\tVancomycin (3 days)\tDesire to avoid OPAT\t1\tNone\tC\t10\t\n7\t38\tF\tGroup B Streptococcus bacteremia with native tricuspid valve endocarditis and right shoulder myositis\tCeftriaxone (4 days)\n\nVancomycin (3 days)\n\n\tHistory of IVDU\t1\tNone\tF\t6\t\n8\t29\tF\tEnterococcus spp. bacteremia\tAmpicillin (5 days)\tHistory of IVDU\t1\tNone\tC\t5\t\n9\t63\tM\tMRSA bursitis\tCefazolin (1 day)\n\nVancomycin (7 days)\n\n\tDesire to avoid OPAT\t1\tNausea\tC\t9\t\n10\t66\tF\tMSSA deep tissue infection\tVancomycin (6 weeks)\n\nClindamycin (20 weeks)\n\n\tMultiple antibiotic allergies\t3\tHearing loss\tC\tn/a\t\nC cure, F failure, MSSA methicillin-susceptible Staphylococcus aureus, CoNS coagulase-negative Staphylococcus, OPAT outpatient parenteral antimicrobial therapy, IVDU intravenous drug use, NCE not clinically evaluable, CLABSI central-line associated bloodstream infection\n\nCase Reports\n\nThe ten patients who received oritavancin are discussed below.\n\nPatient 1\n\nA 57-year-old male with a history of rheumatic heart disease status post-aortic and mitral valve replacement, severe congestive heart failure, and chronic kidney disease was admitted with shortness of breath, bilateral lower extremity edema, and abdominal distention. Due to bleeding complications and loss of central line access, he had a peripherally inserted central catheter (PICC) placed during his treatment course. One week later, he complained of intense pain, swelling, and redness around the PICC placement site. The PICC line was removed, blood and catheter tip cultures were obtained, and he was started on vancomycin. Preliminary blood cultures revealed S. aureus. An ID physician consultation was sought, where cefazolin was added in addition to vancomycin. After susceptibilities revealed MSSA (resistant to penicillin), the patient’s regimen was narrowed to cefazolin. A transesophageal echocardiogram (TEE) was obtained which revealed no evidence of infective endocarditis on his native or prosthetic valves. Due to complications he experienced with his central line and PICC, he was reluctant to have a second PICC line placed again for OPAT. He received one dose of oritavancin after 1 day of cefazolin and 4 days of vancomycin, and after repeat blood cultures had been negative for 48 h. He was discharged the next day, and at follow-up in our outpatient ID clinic, a third set of blood cultures was collected and remained sterile, approximately 22 days after his oritavancin dose.\n\nPatient 2\n\nA 53-year-old male with an extensive history including paraplegia, chronic ischial decubitus ulcers with osteomyelitis, chronic left knee ulcers with osteomyelitis, epididymitis, and recurrent staphylococcal and streptococcal bacteremia was admitted with severe scrotal drainage and edema. He was septic on admission and started on broad spectrum antibiotics with vancomycin and piperacillin-tazobactam. Urine cultures drawn on admission were positive for Klebsiella pneumoniae (resistant to ampicillin and intermediate to nitrofurantoin), and blood cultures drawn on admission were positive for MSSA (susceptible to all antibiotics tested). ID was consulted, and after 2 days of vancomycin and piperacillin-tazobactam, he received a one-time dose of daptomycin but was ultimately switched to cefazolin monotherapy. A transthoracic echocardiogram (TTE) revealed no evidence of vegetations, and he refused to have a TEE performed. He has a history of noncompliance and refusal of IV antibiotics and again refused IV antibiotics and placement into a skilled nursing facility on this admission. Due to this, the ID physician prescribed a dose of oritavancin after he received 5 days of cefazolin and after repeat blood cultures were negative. He was scheduled to have another dose of oritavancin 2 weeks after his first dose, but failed to show up to his appointments at our infusion center or ID clinic. Upon contact with the patient after discharge, he noted traveling to New York to receive a skin flap for his chronic decubitus ulcers, but no hospital admissions, no further infections, and no other antibiotics needed after the one-time oritavancin dose.\n\nPatient 3\n\nA 26-year-old female with active intravenous drug use (IVDU) and no other concomitant medical conditions was admitted with fever, chills, and acute low back pain. Blood cultures obtained on admission were positive for MSSA (resistant to penicillin). Imaging of her lumbar spine and pelvis revealed that she had an iliopsoas abscess and sacroiliac joint infection. Aspirate of the iliopsoas abscess was also culture positive for MSSA. Dual therapy was initiated with vancomycin and cefazolin, which was subsequently narrowed to cefazolin when susceptibility data became available. Her TEE was negative for endocarditis, as well as her repeat blood cultures on cefazolin. She was determined to not be a candidate for OPAT due to active IVDU. She received one dose of oritavancin once negative blood cultures were finalized and was discharged on oral clindamycin. At outpatient follow-up 6 weeks after discharge, she reported non-adherence to oral clindamycin due to inability to afford medication, and complained of continued hip pain, night sweats, fever, and chills. Antibiotics were re-instituted at this time, with a 1-month course of cephalexin and plans for repeat imaging. Three weeks into her cephalexin course, she presented to our emergency department (ED) where she reported increased hip pain and fevers. Repeat imaging showed worsening sacroiliac infection with surrounding osteomyelitis. The orthopedic surgeon consultation recommended medical management rather than irrigation and debridement of her sacroiliac joint due to the location and complicated nature of her infection. She was started on a course of vancomycin, and blood cultures obtained on admission remained sterile throughout the hospitalization. Vancomycin was discontinued by ID who then recommended joint aspiration by interventional radiology. There was no growth on the joint aspiration culture, and she was discharged on a 3-month course of sulfamethoxazole/trimethoprim and rifampin. She was scheduled for a follow-up in our outpatient ID clinic 2–3 weeks after discharge but was lost to follow-up. She subsequently returned back to our ED 2 months after her last hospitalization with intense hip pain and fevers. Per ID, she was started on cefazolin for 6–8 weeks with a repeat MRI in 4 weeks. A TTE revealed no evidence of vegetations. Blood cultures remained sterile throughout the hospital stay, but, due to continued fevers while on antibiotics and a new systolic heart murmur found on examination, a TEE was obtained, which revealed a small aortic valve vegetation consistent with infective endocarditis. Although her subsequent blood cultures remained sterile, she most likely never cleared her sacroiliac joint infection, which was thought to be the sequelae of initial MSSA bacteremia, and nidus for development of infective endocarditis.\n\nPatient 4\n\nA 53-year-old female with active IVDU, hypertension, and bipolar disorder was admitted with a 2-week history of right hip/buttock pain surrounding the site where she injects heroin. She was started on broad spectrum antibiotics with vancomycin and piperacillin-tazobactam. Imaging of her right hip showed extensive edema surrounding the pelvis with a psoas abscess and possible early osteomyelitis. Blood cultures revealed S. aureus, so an ID consult was sought and after 2 days of vancomycin and piperacillin-tazobactam, her antibiotics were changed to vancomycin and cefazolin. A TTE revealed no evidence of vegetations, and she refused a TEE. Susceptibilities revealed MSSA (susceptible to all antibiotics tested), and her antibiotics were subsequently narrowed to cefazolin. Orthopedic surgeons did not feel surgical debridement of her right hip was necessary, and they recommended follow-up imaging in 1 month. Due to the patient’s active IVDU, she was thought not to be a candidate for OPAT. After her repeat blood cultures were negative, she was discharged to a skilled nursing facility with IV cefazolin for at least 6 weeks with follow-up in the outpatient ID clinic in 2–3 weeks. She left the skilled nursing facility against medical advice only 8 days after being discharged from the hospital with a PICC line still in place. She followed up with ID the next day in the outpatient ID clinic where she was prescribed a dose of oritavancin after approximately 18 days of cefazolin. She failed to obtain repeat imaging after her oritavancin dose. Since her dose of oritavancin, she has failed to follow-up in the ID clinic, and we were unable to reach her by telephone. She has had no other hospital admissions at our health system.\n\nPatient 5\n\nA 31-year-old male with a complicated history including Job syndrome, aspergilloma on chronic posaconazole, hypertension, anxiety, muscle spasms, and anemia was admitted with left lower leg swelling and pain. He also has an extensive infectious disease-related history including cryptococcal meningitis as an infant, multiple intrathoracic and intraabdominal infections, and recurrent MSSA and MRSA bacteremia. Imaging on admission showed possible cellulitis with no evidence of an abscess or osteomyelitis, and blood cultures revealed S. aureus. He was started on vancomycin, and a TEE revealed no evidence of vegetations. He has a history of noncompliance with outpatient antibiotic therapy with undetectable vancomycin levels, so he was deemed not a candidate for OPAT. Susceptibility data revealed MSSA (resistant to clindamycin and erythromycin), and he was prescribed a dose of oritavancin after receiving 4 days of vancomycin and 7 days of cefazolin and after repeat blood cultures were negative. Repeat blood cultures 9 days after his oritavancin dose were also negative.\n\nPatient 6\n\nA 41-year-old male with a history of chronic back pain, pseudoseizures, vertebral osteomyelitis with group B streptococcal infection, fungemia, depression, and polysubstance abuse was admitted with back pain and suicidal thoughts. Blood cultures obtained on admission were positive for coagulase-negative Staphylococcus (resistant to clindamycin, erythromycin, levofloxacin, oxacillin, penicillin, rifampin, tetracycline, and trimethoprim-sulfamethoxazole; susceptible to gentamicin and vancomycin only). The patient was started on vancomycin. After repeat blood cultures had been negative for 72 h and a TTE was negative for endocarditis, the patient was given a one-time dose of oritavancin after 3 days of vancomycin to preclude any need for OPAT due to the patient’s extensive psychiatric history. Per ID, no follow-up was needed in the outpatient ID clinic. Upon follow-up with the patient by phone call, he denied any additional infection-related hospital admissions or antibiotics needed for his infection.\n\nPatient 7\n\nA 38-year-old female with active IVDU and no other chronic medical conditions was admitted with diaphoresis, right index finger pain, and shoulder pain. Imaging of her right shoulder showed myositis without evidence of abscess, and blood cultures on admission revealed Streptococcus agalactiae (resistant to clindamycin and erythromycin). Her initial work-up with TTE revealed that she had native tricuspid valve infective endocarditis. She was started on intravenous vancomycin therapy and subsequently narrowed to intravenous ceftriaxone. An evaluation by cardiothoracic surgery recommended medical management only due to lack of evidence of right-sided heart failure or tricuspid regurgitation. She was deemed to not be a candidate for OPAT due to active IVDU. The ID physician prescribed one dose of oritavancin prior to discharge after 3 days of vancomycin and 4 days of ceftriaxone, and after repeat blood cultures had been negative for 48 h. Upon contact with the patient after discharge, she revealed that she had moved out of state and subsequently required valve replacement surgery 3 months after her oritavancin dose. Due to the need for surgical intervention and hospital readmission, she was deemed a clinical failure.\n\nPatient 8\n\nA 29-year-old female with active IVDU and no other chronic medical conditions was admitted with a left hand abscess. Her hand infection had started over 4 weeks prior to hospital admission, where she had an incision and drainage by a local orthopedic surgeon in the ambulatory setting. Upon admission, the patient received incision and drainage procedure of her left hand abscess with specimen sent for culture. Her wound culture isolated microaerophilic streptococcus, and she was discharged after surgery with oral doxycycline. One day after discharge, one of two blood cultures obtained during her admission grew Enterococcus species, and she was contacted to return to the hospital. She was readmitted for enterococcal bacteremia but also complained of fever, chills, and continued hand pain. The enterococcus isolate from blood cultures was vancomycin- and ampicillin-sensitive; thus, the patient was initiated with intravenous ampicillin. A TEE was negative for endocarditis. Given her ongoing IVDU, there was concern she would abuse her PICC line needed for OPAT. She wanted to leave against medical advice, so her ID physician prescribed one dose of oritavancin after 5 days of ampicillin and after repeat blood cultures had been negative for 48 h. She did not keep her follow-up ID appointment. On a follow-up phone call, she denied any other hospital admissions for the infection and any other antibiotic use after oritavancin.\n\nPatient 9\n\nA 63-year-old male with a history of hypertension was admitted with a 1-week history of left knee pain. Imaging revealed soft tissue swelling with septic prepatellar bursitis. Knee aspiration was performed in the emergency department yielding gross purulence, and he was started on vancomycin. Orthopedic surgery initially elected to treat the patient with antibiotics only, but he spiked a high fever and had continued leukocytosis despite antibiotics, so incision and drainage of the knee was performed. Cultures of the aspirate grew MRSA (resistant to erythromycin, oxacillin, and penicillin), and the initial plan was to continue IV antibiotic therapy with vancomycin while hospitalized and transition to oral doxycycline on discharge for a total of 3 weeks of antibiotics. He required another incision and drainage with closure 5 days after his first surgery. At that time, it was decided by ID to give him a one-time dose of oritavancin to preclude any need for antibiotics post-discharge, and after he had received 1 day of cefazolin and 7 days of vancomycin. He did endorse severe nausea while the oritavancin dose was infusing that quickly resolved after completion. When he followed-up in our outpatient ID clinic 4 months after his hospitalization, his infection had resolved with no further symptoms, drainage, or need for further antibiotics or hospitalizations.\n\nPatient 10\n\nA 66-year-old female with a history of hypertension, depression, previous MRSA infection, gastric bypass, and gastroesophageal reflux disease sustained a complicated work-related injury, which included right wrist and humerus fracture managed by open reduction and internal fixation. Post-operative day 10, she developed a deep shoulder joint abscess with MSSA (susceptible to all antibiotics tested) requiring a second surgery with irrigation and debridement and hardware removal. She was treated initially with a 6-week course of intravenous vancomycin followed by oral clindamycin. Her shoulder infection showed improvement after 5 weeks of clindamycin, but then she was found to have developed a massive left thigh hematoma that required surgical evacuation with debridement of necrotic tissue and wound vacuum placement. She was continued on oral clindamycin for an additional 7 weeks due to suspected staphylococcal infection. She required multiple surgical debridements, and antibiotics were stopped since the wound bed appeared to be healing with no signs of infection. After 4 weeks of being off antibiotics, the patient’s leg wound appeared to have increasing induration and drainage, thus clindamycin was reinitiated. MSSA was isolated from a wound culture obtained at this time, and susceptibilities now revealed clindamycin resistance. Oritavancin was chosen to treat her deep tissue infection since the patient reported allergies to cephalexin (anaphylaxis), tetracyclines (anaphylaxis), and sulfa antibiotics (hives), which limited antibiotic treatment selection. She received one dose of oritavancin after 20 weeks of clindamycin and tolerated the dose without difficulty. On follow-up, she was deemed to have a suboptimal response to her first dose of oritavancin by evidence of continued wound drainage and elevated erythrocyte sedimentation rate (ESR), thus a second dose was administered, which was 19 days after receiving the first dose. During a follow-up visit, the patient reported new-onset hearing loss and was referred for audiology testing. She had received her final dose of oritavancin 14 days after her second dose for a total of three doses in a 33-day period. Evaluation by audiology was conducted after she received her third dose where the patient was diagnosed with moderate high frequency sensorineural hearing loss. At outpatient follow-up 3 weeks after her third oritavancin dose, she was clinically cured and her inflammatory markers had normalized. The patient reported some mild improvement in hearing loss but still had tinnitus.\n\nDiscussion and Review of Literature\n\nInvasive Gram-positive infections, especially with S. aureus, are associated with high morbidity and mortality and often lead to complications, such as infective endocarditis [2]. Alternative options with convenient dosing, ideal pharmacokinetics, and desirable safety profiles are needed for patients who cannot tolerate or use outpatient intravenous antibiotics, such as vancomycin. Oritavancin is a novel lipoglycopeptide that is currently FDA-approved for treatment of ABSSSIs. Its convenient one-time dosing and long half-life, low MICs for Gram-positive organisms, and absence of a need for therapeutic drug monitoring make it an appealing choice for other serious Gram-positive infections. This case series describes the outcomes of patients treated with oritavancin for off-label indications that could not be managed with standard therapy. These cases supplement the limited available data demonstrating the use of oritavancin in patients with Gram-positive infections other than ABSSSIs.\n\nTwo patients who received oritavancin for invasive Gram-positive infections failed therapy. Patient 3 illustrated a complex course receiving multiple antibiotics for her sacroiliac septic arthritis and osteomyelitis. After her oritavancin dose, she was eventually readmitted several times for worsening infection. She reported noncompliance with several outpatient antibiotic regimens due to inability to afford medication, which could have caused re-seeding of her joint infection into her bloodstream and eventually causing endocarditis. Another explanation could be that the initial TEE obtained on her first admission was a false negative. The patient eventually had irrigation and debridement of her hip 6 months after her initial infection with placement of antibiotic beads and was continued on chronic suppressive therapy with cephalexin.\n\nPatient 7 was also deemed an oritavancin failure. She had evidence of a large tricuspid valve vegetation on initial TTE. Due to no evidence of right-sided heart failure or tricuspid valve regurgitation, cardiothoracic surgery decided on medical management only. She was discharged in stable condition after her one-time dose of oritavancin. She never followed-up in our outpatient ID clinic, but on a follow-up phone call, she revealed that she had moved away and become sick again requiring readmission to a hospital. During that hospitalization, she required heart valve replacement due to ongoing endocarditis and her deteriorating condition.\n\nPatient 10, who received 6 weeks of IV vancomycin followed by three doses of oritavancin, developed high-frequency hearing loss. Although not common, vancomycin has been associated with ototoxicity. According to a case series by Mellor et al., two patients who received vancomycin developed tinnitus and vertigo that quickly resolved after discontinuation of vancomycin [16]. To date, there have been no case reports of ototoxicity with oritavancin therapy. Our patient did not have previous audiology testing before receiving antibiotics. She noticed intermittent ringing in her ears possibly during her vancomycin therapy, but did not mention this to her physician until after the first oritavancin dose. We are not sure if her hearing loss was due to her initial vancomycin, her subsequent oritavancin, or simply age-related. The audiology report also states that it is difficult to say if it is due to antibiotic therapy, but the onset of symptoms during therapy is curious. The patient also revealed that the ringing in her ears still persists 8 months after her last oritavancin dose. This could potentially be a serious adverse event associated with multiple doses of oritavancin.\n\nIn addition to our case series, oritavancin has been used clinically in a number of scenarios and also possesses some impressive in vivo data. To date, it has been demonstrated that the single oritavancin dose is convenient for treatment of Gram-positive infections. The SIMPLIFI trial included 302 patients and evaluated different dosing strategies for oritavancin—a one-time dose of 1200 mg, a 200-mg daily dose for 3–7 days, or infrequent dosing which consisted of an 800-mg dose with the option of an additional 400-mg dose on day 5 [17]. The results demonstrated that the one-time front-loading dose of 1200 mg and the infrequent dosing strategy was as efficacious and safe as daily administration in treating ABSSSIs caused by Gram-positive infections, including MRSA. Similar to ABSSSIs, the one-time dose of oritavancin for complicated invasive infections, such as endocarditis and bacteremia, would allow patients to receive adequate treatment before discharge and would ensure adherence.\n\nTo date, there are limited data on oritavancin use in serious systemic infections. In the SOLO I trial that evaluated the efficacy and safety of a single dose of oritavancin compared to a 7- to 10-day course of vancomycin, only 3.8% of patients in the oritavancin arm and 1.9% of patients in the vancomycin arm had positive blood cultures [18]. Likewise, in the SOLO II trial, which also evaluated oritavancin efficacy and safety versus vancomycin, only 2% of patients in each the oritavancin and vancomycin arm had positive blood cultures secondary to their ABSSSI infection [19]. In both these pivotal trials, oritavancin was shown to be non-inferior to vancomycin in treatment of ABSSSIs, but there was no mention on outcomes for the few patients who also had bacteremia. These results suggest that more data are needed to determine the efficacy and outcomes of oritavancin in invasive infections due to Gram-positive bacteremia.\n\nA case report published in late 2015 described a 73-year-old male who had vancomycin-resistant Enterococcus faecium prosthetic valve endocarditis that was treated with a prolonged course of oritavancin [20]. In this complicated case, the patient received multiple antibiotics for his recurrent VRE bacteremia, including daptomycin, tigecycline, linezolid, and gentamicin, but these were poorly tolerated with associated anorexia, nausea, thrombocytopenia, hyperlactatemia, and altered mental status. The patient was eventually treated with oritavancin 1200 mg every other day for three doses then once weekly for 6 weeks after susceptibility testing of the VRE isolate showed an oritavancin MIC of 0.5 mg/L. After discontinuation of the other antibiotics and continuation of the oritavancin, the anorexia, altered mental status, and platelet count returned to baseline. Blood cultures remained negative throughout his initial course of oritavancin, but 8 days after completion of oritavancin, his blood cultures again grew VRE. Oritavancin was reinitiated at a dose of 1200 mg twice weekly. The patient underwent an aortic and mitral valve replacement, and the surgical culture from the prosthetic aortic valve grew VRE, and the mitral valve culture had evidence of healing endocarditis. He continued twice-weekly infusions of oritavancin for 10 weeks with no return of positive blood cultures, but at the 10-week follow-up visit he experienced elevated liver function tests (LFTs) and oritavancin was stopped. His LFTs returned to baseline 11 months after oritavancin completion. This case report shows potential for oritavancin therapy in invasive infections, such as VRE endocarditis [20]. This case also emphasizes the need for more studies evaluating different dosing strategies for oritavancin therapy in invasive Gram-positive infections.\n\nOritavancin has been used on a case-by-case basis by our ID physicians as an alternative in patients who would otherwise have required long courses of treatment for serious infections, and who may not have completed those courses due to individual circumstances. This medication can potentially have a niche in this difficult-to-treat patient population, and the one-time infusion of oritavancin ensures compliance with treatment. However, it cannot be ignored that the two patients who failed oritavancin therapy had complicated infections such as osteomyelitis and endocarditis, two serious diseases states where a long-acting antibiotic, such as oritavancin, would be desirable. Furthermore, a potential limitation to this case series is the fact that none of the patients received oritavancin monotherapy. Since all the patients received standard of care, and some patients received suppressive oral therapy post-oritavancin dose, it is difficult to say that the clinical cures in this case series are strictly due to oritavancin itself. Moreover, one ethical issue is discharging patients who have potential compliance issues with one dose of oritavancin for an infection requiring many weeks of antibiotics. This could lead to loss of follow-up and inappropriate duration of therapy for a complicated, serious infection. With this in consideration, the ID physicians at our institution felt it was better to give these patients an antibiotic that we knew would last at least a few weeks instead of no treatment at all.\n\nConclusion\n\nIn conclusion, given the limited data available regarding oritavancin therapy in complicated Gram-positive infections, this series suggests promising outcomes in disease states such as S. aureus and enterococcal bacteremia. Normally, the standard of care is several weeks of IV antibiotics. Unfortunately, there are situations, such as those described in this report, where delivering this standard of care is not possible. Additional data and literature are needed on the outcomes of patients treated with oritavancin for indications other than ABSSSIs before oritavancin can be routinely recommended.\n\nAcknowledgements\n\nNo funding or sponsorship was received for this study or publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.\n\nDisclosures\n\nCassie L. Stewart, Jeremy J. Frens, Michelle S. Turner, Jordan R. Smith, and Cynthia B. Snider have no disclosures or conflicts of interest.\n\nCompliance with Ethics Guidelines\n\nThis was a retrospective study reviewing chart data therefore no new studies with human or animal subjects were performed by any of the authors. A waiver of informed consent was obtained from the Cone Health Institutional Review Board.\n\nData Availability\n\nThe datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/3708F0602569295B.\n==== Refs\nReferences\n\n1. Menichetti F Current and emerging serious Gram-positive infections Clin Microbiol Infect 2005 11 Suppl 3 22 28 10.1111/j.1469-0691.2005.01138.x 15811021\n2. Sievert DM Ricks P Edwards JR Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010 Infect Control Hosp Epidemiol 2013 34 1 14 10.1086/668770 23221186\n3. Cosgrove SE Sakoulas G Perencevich EN Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis Clin Infect Dis 2003 36 53 59 10.1086/345476 12491202\n4. van Hal SJ Jensen SO Vaska VL Predictors of mortality in Staphylococcus aureus bacteremia Clin Microbiol Rev 2012 25 362 386 10.1128/CMR.05022-11 22491776\n5. Liu C Bayer A Cosgrove SE Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children Clin Infect Dis 2011 52 e18 e55 10.1093/cid/ciq146 21208910\n6. Rybak M Lomaestro B Rotschafer JC Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists Am J Health Syst Pharm 2009 66 82 98 10.2146/ajhp080434 19106348\n7. Tice AD Rehm SJ Dalovisio JR Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines Clin Infect Dis 2004 38 1651 1672 10.1086/420939 15227610\n8. Corey GR Good S Jiang H Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of Gram-positive acute bacterial skin and skin structure infections: the SOLO II Noninferiority Study Clin Infect Dis. 2015 60 254 262 10.1093/cid/ciu778 25294250\n9. Smith JR Yim J Raut A Oritavancin combinations with beta-lactams against multidrug-resistant Staphylococcus aureus and vancomycin-resistant enterococci Antimicrob Agents Chemother 2016 60 2352 2358 10.1128/AAC.03006-15 26833159\n10. Rubino CM Bhavnani SM Moeck G Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials Antimicrob Agents Chemother 2015 59 3365 3372 10.1128/AAC.00176-15 25824211\n11. Rubino CM Van Wart SA Bhavnani SM Oritavancin population pharmacokinetics in healthy subjects and patients with complicated skin and skin structure infections or bacteremia Antimicrob Agents Chemother 2009 53 4422 4428 10.1128/AAC.00231-09 19635952\n12. Mendes RE Sader HS Flamm RK Oritavancin activity against Staphylococcus aureus causing invasive infections in U.S. and European hospitals: a 5-year international surveillance program Antimicrob Agents Chemother 2014 58 2921 2924 10.1128/AAC.02482-13 24550323\n13. Duncan LR Sader HS Flamm RK Oritavancin in vitro activity against contemporary Staphylococcus aureus isolates responsible for invasive community- and healthcare-associated infections among patients in the United States (2013–2014) Diagn Microbiol Infect Dis 2016 86 303 306 10.1016/j.diagmicrobio.2016.07.025 27543378\n14. Morrissey I Seifert H Canton R Activity of oritavancin against methicillin-resistant staphylococci, vancomycin-resistant enterococci and beta-haemolytic streptococci collected from western European countries in 2011 J Antimicrob Chemother 2013 68 164 167 10.1093/jac/dks344 22941898\n15. Mendes RE Woosley LN Farrell DJ Oritavancin activity against vancomycin-susceptible and vancomycin-resistant Enterococci with molecularly characterized glycopeptide resistance genes recovered from bacteremic patients, 2009–2010 Antimicrob Agents Chemother 2012 56 1639 1642 10.1128/AAC.06067-11 22183169\n16. Mellor JA Kingdom J Cafferkey M Vancomycin ototoxicity in patients with normal renal function Br J Audiol 1984 18 179 180 10.3109/03005368409078946 6487853\n17. Dunbar LM Milata J McClure T Comparison of the efficacy and safety of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the SIMPLIFI trial Antimicrob Agents Chemother 2011 55 3476 3484 10.1128/AAC.00029-11 21537018\n18. Corey GR Kabler H Mehra P Single-dose oritavancin in the treatment of acute bacterial skin infections N Engl J Med 2014 370 2180 2190 10.1056/NEJMoa1310422 24897083\n19. Corey GR Good S Jiang H Single-dose oritavancin versus 7–10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study Clin Infect Dis 2015 60 254 262 10.1093/cid/ciu778 25294250\n20. Johnson JA Feeney ER Kubiak DW Prolonged use of oritavancin for vancomycin-resistant Enterococcus faecium prosthetic valve endocarditis Open Forum Infect Dis. 2015 2 ofv156 10.1093/ofid/ofv156 26677455\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2193-6382",
"issue": "6(2)",
"journal": "Infectious diseases and therapy",
"keywords": "Bacteremia; Extended duration; Lipoglycopeptide; OPAT; Outpatient parenteral antimicrobial therapy; Staphylococci; Staphylococcus aureus",
"medline_ta": "Infect Dis Ther",
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"pages": "277-289",
"pmc": null,
"pmid": "28386776",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "26677455;22941898;24897083;27543378;19106348;15811021;25294250;21537018;21208910;26833159;24550323;12491202;25824211;22183169;15227610;22491776;23221186;19635952;6487853",
"title": "Real-World Experience with Oritavancin Therapy in Invasive Gram-Positive Infections.",
"title_normalized": "real world experience with oritavancin therapy in invasive gram positive infections"
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"abstract": "BACKGROUND\nTakotsubo syndrome (TTS), also known as stress cardiomyopathy, apical ballooning syndrome and broken heart syndrome, is characterized by acute-onset chest pain, electrocardiographic (ECG) abnormalities and reversible left ventricular (LV) disfunction in the absence of a culprit obstructive lesion in the coronary arteries; therefore, myocardial infarction is the most important differential diagnosis. Usually induced by emotional/physical stress, its treatment consists in hemodynamic support until complete and spontaneous recovery occurs, which is generally achieved within a few days to weeks. Cervical malignancies are an important public health issue in low/middle-income countries and, in the setting of locally advanced disease, concurrent chemoradiation followed by brachytherapy is considered the standard treatment, harboring curative potential.\n\n\nMETHODS\nWe report a case of a 38-year-old woman who underwent concurrent chemoradiotherapy and developed cardiopulmonary arrest in ventricular fibrillation during a brachytherapy session. Complementary tests disclosed altered ECG and cardiac biomarkers, no evidence of coronary artery obstruction, as well as LV disfunction consistent with TTS on echocardiogram and cardiac MRI. After few days of supportive therapy, complete recovery of heart function was observed.\n\n\nCONCLUSIONS\nEspecially for cancer patients, who usually experience intense emotional/physical stress intrinsically associated with their diagnosis and aggressive treatments, considering TTS as a differential diagnosis is warranted. Intracavitary brachytherapy procedure may represent a trigger for TTS.",
"affiliations": "Oncology Center, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, 01308-050, São Paulo, Brazil. Aline.cristini@hotmail.com.;Oncology Center, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, 01308-050, São Paulo, Brazil.;Oncology Center, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, 01308-050, São Paulo, Brazil.;Cardiology Center, Hospital Sírio-Libanês, São Paulo, Brazil.;Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil.;Oncology Center, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, 01308-050, São Paulo, Brazil.",
"authors": "Vieira|Aline Cristini|AC|;Ribeiro|Mauricio Fernando Silva Almeida|MFSA|;Lima|Julianne|J|;Filho|Jacob Sessim|JS|;de Andrade Carvalho|Heloisa|H|;Mano|Max Senna|MS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40959-020-00082-8",
"fulltext": "\n==== Front\nCardiooncology\nCardiooncology\nCardio-oncology\n2057-3804 BioMed Central London \n\n82\n10.1186/s40959-020-00082-8\nShort Communication\nTakotsubo syndrome induced by brachytherapy in a patient with endocervical adenocarcinoma\nVieira Aline Cristini Aline.cristini@hotmail.com 1 Ribeiro Mauricio Fernando Silva Almeida 1 Lima Julianne 1 Filho Jacob Sessim 2 de Andrade Carvalho Heloisa 34 Mano Max Senna 1 1 grid.413471.40000 0000 9080 8521Oncology Center, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, 01308-050 São Paulo, Brazil \n2 grid.413471.40000 0000 9080 8521Cardiology Center, Hospital Sírio-Libanês, São Paulo, Brazil \n3 grid.413471.40000 0000 9080 8521Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil \n4 grid.11899.380000 0004 1937 0722Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil \n5 12 2020 \n5 12 2020 \n2020 \n6 305 9 2020 22 10 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nTakotsubo syndrome (TTS), also known as stress cardiomyopathy, apical ballooning syndrome and broken heart syndrome, is characterized by acute-onset chest pain, electrocardiographic (ECG) abnormalities and reversible left ventricular (LV) disfunction in the absence of a culprit obstructive lesion in the coronary arteries; therefore, myocardial infarction is the most important differential diagnosis. Usually induced by emotional/physical stress, its treatment consists in hemodynamic support until complete and spontaneous recovery occurs, which is generally achieved within a few days to weeks. Cervical malignancies are an important public health issue in low/middle-income countries and, in the setting of locally advanced disease, concurrent chemoradiation followed by brachytherapy is considered the standard treatment, harboring curative potential.\n\nCase report\nWe report a case of a 38-year-old woman who underwent concurrent chemoradiotherapy and developed cardiopulmonary arrest in ventricular fibrillation during a brachytherapy session. Complementary tests disclosed altered ECG and cardiac biomarkers, no evidence of coronary artery obstruction, as well as LV disfunction consistent with TTS on echocardiogram and cardiac MRI. After few days of supportive therapy, complete recovery of heart function was observed.\n\nConclusions\nEspecially for cancer patients, who usually experience intense emotional/physical stress intrinsically associated with their diagnosis and aggressive treatments, considering TTS as a differential diagnosis is warranted. Intracavitary brachytherapy procedure may represent a trigger for TTS.\n\nKeywords\nTakotsuboBrachytherapyEndocervical adenocarcinomaHeart failureStress cardiomyopathyBroken heart syndromeissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nTakotsubo syndrome (TTS), also known as stress cardiomyopathy, apical ballooning syndrome and broken heart syndrome, is an acute and transient left ventricular (LV) myocardial dysfunction, which can occur in the setting of a severe psychological or physical stress event, most often occurring 1 to 5 days before [1]. TTS’s clinical presentation might be indistinguishable from an acute coronary syndrome (ACS) with respect to symptoms, electrocardiographic (ECG) changes and biomarkers. Since its first report in 1990 by Sato et al. [2]. TTS remains with no reliable non-invasive diagnostic approach, leaving coronary angiography with left ventriculography as the gold standard diagnostic tool to reject or to ratify this diagnosis to this days [3, 4]. Typically, it occurs in postmenopausal women with few cardiovascular risk factors [1, 3–5].\n\nThe exact pathophysiology of TTS is still unknown [6]. Besides anecdotal case reports describing the occurrence of TTS in the setting of malignancy and chemotherapy, the role of chemotherapy and tumor in the development of TTS with regard to physical and emotional stress remains unclear [7]. It has been suggested that the treatment of the malignancy itself is associated with the development of TTS [8].\n\nHerein we describe a case of a 38-year-old female patient without history of cardiovascular disorder who developed TTS during a brachytherapy session to treat an endocervical adenocarcinoma.\n\nCase report\nA 38-year-old female presented with an abnormal pap smear in January 2018 without local or systemic manifestations. A biopsy was performed and the patient was diagnosed with endocervical adenocarcinoma. A staging magnetic resonance imaging (MRI) of the pelvis and a positron emission tomography – computed tomography (PET-CT) were performed, which showed a hypermetabolic bulky lesion arising from uterine cervix (SUV max: 23.0), without parametrial, bladder, rectal involvement, or distant metastasis. Clinical staging based on International Federation of Gynecology and Obstetrics (FIGO) classified the disease in FIGO IIA1.\n\nThe patient started chemoradiotherapy with cisplatin 40 mg/m2 weekly, and high dose-rate brachytherapy starting in the fourth week of external beam irradiation. At the end of the third session (four brachytherapy sessions programmed), during applicator removal, although under anesthesia, the patient developed a ventricular tachycardia with pulse, followed by cardiopulmonary arrest in ventricular fibrillation. After two minutes of cardiopulmonary resuscitation, return of spontaneous circulation was achieved, and the patient was admitted to an intensive care unit.\n\nDuring the investigation, ECG showed ST-segment elevation in lead II and in AVF, and prolonged QT interval of 470 msec. There was a rise in the levels of serum creatine kinase-MB (CKMB) level to 10.4 ng/mL (normal limit: < 5.0 ng/mL), serum troponin-I level was 2.04 ng/ml (normal limit: < 0.16 ng/ml) and natriuretic peptide B levels (BNP) to 233 pg/mL (normal limit: < 100 pg/mL). Transthoracic echocardiogram showed marked LV dysfunction, with akinesia of all apical and middle segments of LV wall, with estimated LV ejection fraction (LVEF) of 30% (Fig. 1). The coronary angiography demonstrated no obstructive lesions in the coronary arteries and moderate hypokinesia of the anterior and inferior apical segments of LV wall (Fig. 2). Holter showed rare and isolated polymorphic ventricular premature beats and signs of heart dysautonomia with parasympathetic depression and adrenergic predominance. A cardiac MRI was performed seven days after the event showing circumferential mid-ventricle hypokinesia associated with LV systolic dysfunction, however with a significant improvement of the global LV contractility (Fig. 3a and b), absence of myocardial fibrosis in the late gadolinium enhancement sequences (Fig. 3c), signs of myocardial edema in the LV wall in T2-weighted sequences and moderate pericardial effusion (Fig. 3d), suggestive with Takotsubo cardiomyopathy.\nFig. 1 Apical 4 chambers view showing akinesia of the mid-apical segments of the inferior septal and anterolateral walls, determining apical ballooning (arrows). LA: Left Atrial. LV: Left Ventricle. RA: Right Atrial. RV: Right Ventricle\n\nFig. 2 Cineangiocoronariography showing absent of significant obstructive atherosclerotic lesions. Left coronary in right anterior cranial oblique incidence (a). Right coronary in left anterior cranial oblique incidence (b). Cardiac ventriculography demonstrating mid left ventricular segments hypokinesia (arrows). Left ventricle in max diastole (c) and in max systole (d) in right oblique incidence.\n\nFig. 3 Cine cardiac magnetic resonance images showing a 3-chamber view of the left ventricle in end diastole (a) and in end systole (b) demonstrating a circumferential mid-ventricle hypokinesia with greater intensity in the anteroseptal segment (arrows). (c) image shows late gadolinium enhancement sequence showing a 4-chamber view of the heart without any sign of myocardial fibrosis. (d) Cine cardiac magnetic resonance sequence demonstrating diffuse pericardium effusion of moderate intensity (arrows). (e) Short-tau inversion-recovery (STIR) sequence, a T2-weighted sequence used to assess myocardial edema, demonstrating the presence of hypersignal in the middle segments of the anterior, septal and lateral walls (arrows) which indicates the presence of myocardial edema in these segments\n\n\n\nTreatment with carvedilol 3.125 mg twice daily and enalapril 2.5 mg twice daily (titrating the dose up to the maximum dose tolerated by the patient) was initiated. The levels of troponin-I returned to the normal range after 4 days, CKMB levels after 6 days and BNP in 12 days. Fifteen days after the event, the patient presented with chest pain, and pericarditis was diagnosed. Repeat echocardiogram after 12 days of the TTS event, showed remarkable improvement in LV function, with LVEF of 68%, preserved biventricular function and small pericardial effusion. The patient was treated with Ibuprofen 800 mg three times per day and Colchicine 0.5 mg twice daily for three months, with good response and no signs of recurrence. The cardiac MRI was repeated two months later, showing a preserved biventricular contractility, a physiological pericardial effusion, and no late gadolinium enhancement suggestive of myocardial fibrosis. Once complete cardiac recovery was achieved, she was able to resume brachytherapy, and the remaining application was performed 15 days later as an inpatient condition and under rigorous monitoring, uneventfully. The total cancer treatment time was 64 days.\n\nThe patient received further adjuvant treatment with cisplatin 50 mg/m2 plus gemcitabine 100 mg/m2, with discontinuation after one cycle due to severe myelotoxicity. Further, she continued her therapy with carvedilol and enalapril for approximately 6 months when she spontaneously decided to interrupt the treatment. The patient remains in follow-up with sustained complete response from the cancer as demonstrated by pelvic MRI and clinical examination performed every six months for two years until the time that this manuscript was submitted to publication.\n\nDiscussion\nThis report illustrates the case of a young patient with locally advanced endocervical adenocarcinoma, FIGO stage IIA1, that was recommended to treatment with concurrent chemoradiotherapy and presented TTS followed by cardiorespiratory arrest induced during brachytherapy.\n\nTTS is clinically an acute myocardial infarction-like cardiomyopathy without a culprit coronary artery lesion [3]. Approximately 80–90% of cases occur in postmenopausal women and classically TTS has been linked to emotional stress due to excessive release of catecholamines as mechanism of response [1, 9, 10]. Although the patient in this case outwardly displayed very little anxiety about her diagnosis and treatment approach, it is possible that she felt a heightened degree of internal emotional stress that may have contributed to the development of TTS. It is also possible that she presented some degree of pain during applicator removal at the end of the third brachytherapy session, due to anesthesia superficialization, which could have triggered a cardiomyopathy induced by the release of several inflammatory cytokines and metabolites related to this physical distress. Of note, a small vaginal laceration was observed after the applicator removal.\n\nAn important subject of our case is the differential diagnosis with myocarditis. The presence of pericardial effusion is not part of the diagnosis of TTS and it is very common in patients with myocarditis. The absence of late gadolinium enhancement by cardiac RMI may also be present in patients with myocarditis, especially in the initial days. However, the cardiac MRI performed 2 months later to the event did not demonstrate any sign of myocardial fibrosis, which helped to rule out the hypothesis of myocarditis.\n\nThe relationship between malignancy and TTS is particularly interesting from an epidemiologic, mechanistic and outcome standpoint as both malignancy and chemotherapy have been associated with TTS [11]. The overall long-term mortality of TTS patients with malignant disease is significantly increased and the prevalence of cancer in patients with TTS is high, considerably exceeding that in the normal population [12]. One of the hypothesis is that cancer and TTS share similar triggering mechanisms, which consist in activation of the sympathetic nervous system [8, 13]. Therefore, TTS patients with cancer should be considered a high-risk subgroup with respect to their increased mortality rate.\n\nEndothelial dysfunction in epicardial and microvascular coronary arteries occurs frequently in patients with cancer, especially during and after systemic chemotherapy or radiotherapy of the heart region, which might be a predisposing factor for the developement of TTS [1, 3, 14] Mediastinal radiotherapy can induce heart disease, such as coronary obstruction, stenosis or regurgitation due to valvular fibrosis, cardiomyopathy and pericardial constriction and inflammation [15]. Though cisplatin remains the cornerstone of endocervical carcinoma stage IIA1 treatment chemotherapy and a standard of care, however it is also related to some other rare side effects like vasculitis, cardiomyopathy and vascular thrombosis. Cisplatin inducing cardiomyopathy and thromboembolic phenomena can be explained by several mechanisms, some of which are endovascular injury with intimal fibrosis, decreased activation of protein C, hypomagnesaemia and myocardial fiber apoptosis [11]. Previous usage of cisplatin might have contributed for the development of myocardial dysfunction in our patient.\n\nAlthough, so far there is limited data on TTS induced by radiotherapy and no reports on brachytherapy-induced cardiomyopathy. In fact, brachytherapy by itself is painless. However, applicators placement and removal may present only mild discomfort or severe pain according to the different procedures (molds, intracavitary procedures, interstitial implants), and the use of sedation or anesthesia is properly indicated. TTS in the context of intracavitary gynecological brachytherapy procedure, not the radiation delivery, could have been triggered by the unweighted pain experienced by our patient during applicator removal. This case may represent a warning for intracavitary gynecological brachytherapy procedures, since in many facilities in our country it is performed only with sedation, or even without any sedation or analgesia.\n\nAlthough most patients with TTS experience complete cardiac function recovery, the complication rates can be compared to those found in patients with acute coronary syndrome [13]. Patients who survive an acute episode typically recover systolic function within 1 to 4 weeks [1, 3]. Our patient recovered the systolic function within 2 weeks.\n\nConclusions\nTTS appears to occur more frequently than was previously thought. Increased awareness of the existence of this syndrome and knowledge of its risk factors are gaining importance in recent years. Further research is required to investigate the interplay of malignancies, its treatments and TTS, which might be helpful to elucidate the pathophysiological mechanism of this cardiomyopathy. To the best of our knowledge, we are herein reporting the second case of TTS arising in the setting of radiation therapy and the first for brachytherapy.\n\nAbbreviations\nTTSTakotsubo syndrome\n\nECGElectrocardiographic\n\nLVLeft ventricle\n\nCKMBcreatine kinase-MB\n\nACSAcute coronary syndrome\n\nMRIMagnetic resonance imaging\n\nLVEFLeft ventricular ejection fraction\n\nPET-CTPositron Emission Tomography – Computed Tomography\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors' contributions\nAll authors contributed significantly to the manuscript. All authors provided critique and feedback on the manuscript. All authors read and approved the final version of the manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nThis case report was approved by the ethics committee of the Hospital Sírio-Libanês, São Paulo, Brazil.\n\nConsent for publication\nThe patient provided consent and gave permission to have her case, as well as relevant related workup and diagnostic images, presented in the medical literature.\n\nCompeting interests\nThe authors declare that they have no potential conflicts of interest related to this publication.\n==== Refs\nReferences\n1. Medina de Chazal H Del Buono MG Keyser-Marcus L Stress Cardiomyopathy Diagnosis and Treatment J Am Coll Cardiol 2018 72 16 1955 71 10.1016/j.jacc.2018.07.072 30309474 \n2. Sato H. Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm. In: Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure. Kagakuhyoronsha Publishing Co; 1990:56–64.\n3. Ghadri J-R Wittstein IS Prasad A International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology Eur Heart J 2018 39 22 2032 46 10.1093/eurheartj/ehy076 29850871 \n4. Ghadri J-R Wittstein IS Prasad A International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management Eur Heart J 2018 39 22 2047 62 10.1093/eurheartj/ehy077 29850820 \n5. Ueyama T Kasamatsu K Hano T Tsuruo Y Ishikura F Catecholamines and Estrogen Are Involved in the Pathogenesis of Emotional Stress-induced Acute Heart Attack Ann N Y Acad Sci 2008 1148 1 479 85 10.1196/annals.1410.079 19120144 \n6. Ghadri JR Ruschitzka F Lüscher TF Templin C Takotsubo cardiomyopathy: still much more to learn Heart 2014 100 22 1804 12 10.1136/heartjnl-2013-304691 24711482 \n7. Toyooka S Akagi S Furukawa M Takotsubo cardiomyopathy associated with pulmonary resections after induction chemoradiotherapy for non-small cell lung cancer Gen Thorac Cardiovasc Surg 2012 60 9 599 602 10.1007/s11748-012-0058-7 22610162 \n8. Munoz E Iliescu G Vejpongsa P Takotsubo Stress Cardiomyopathy J Am Coll Cardiol 2016 68 10 1143 4 10.1016/j.jacc.2016.06.027 27585514 \n9. Ghadri JR Kato K Cammann VL Long-Term Prognosis of Patients With Takotsubo Syndrome J Am Coll Cardiol 2018 72 8 874 82 10.1016/j.jacc.2018.06.016 30115226 \n10. Sharkey SW Windenburg DC Lesser JR Natural History and Expansive Clinical Profile of Stress (Tako-Tsubo) Cardiomyopathy J Am Coll Cardiol 2010 55 4 333 41 10.1016/j.jacc.2009.08.057 20117439 \n11. Ozturk MA, Ozveren O, Cinar V, Erdik B, Oyan B. Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction. Blood Coagulation & Fibrinolysis. 2013;24(1):90–4. 10.1097/MBC.0b013e3283597605.\n12. Burgdorf C, Kurowski V, Bonnemeier H, Schunkert H, Radke PW. Long-term prognosis of the transient left ventricular dysfunction syndrome (Tako-Tsubo cardiomyopathy): Focus on malignancies. European Journal of Heart Failure. 2008;10(10):1015-1019. 10.1016/j.ejheart.2008.07.008.\n13. Cammann VL, Sarcon A, Ding KJ, et al. Clinical Features and Outcomes of Patients With Malignancy and Takotsubo Syndrome: Observations From the International Takotsubo Registry. JAHA. 2019;8(15). 10.1161/JAHA.118.010881.\n14. Han X, Zhou Y, Liu W. Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy. npj Precision Oncology. 2017;1(1). 10.1038/s41698-017-0034-x.\n15. Modi S, Baig W. Radiotherapy-induced Tako-tsubo Cardiomyopathy. Clinical Oncology. 2009;21(4):361-362. 10.1016/j.clon.2009.01.005.\n\n",
"fulltext_license": "CC BY",
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"issue": "6(1)",
"journal": "Cardio-oncology (London, England)",
"keywords": "Brachytherapy; Broken heart syndrome; Endocervical adenocarcinoma; Heart failure; Stress cardiomyopathy; Takotsubo",
"medline_ta": "Cardiooncology",
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"title": "Takotsubo syndrome induced by brachytherapy in a patient with endocervical adenocarcinoma.",
"title_normalized": "takotsubo syndrome induced by brachytherapy in a patient with endocervical adenocarcinoma"
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"abstract": "BACKGROUND\nVancomycin has only rarely been implicated as a cause of thrombocytopenia, and there is only limited evidence that this complication is caused by immune mechanisms. We conducted a study to determine whether thrombocytopenia is caused by vancomycin-dependent antibodies in patients being treated with vancomycin.\n\n\nMETHODS\nWe identified and characterized vancomycin-dependent, platelet-reactive antibodies in patients who had been referred for testing during a 5-year period because of a clinical suspicion of vancomycin-induced thrombocytopenia. We obtained clinical information about the patients from their referring physicians.\n\n\nRESULTS\nDrug-dependent, platelet-reactive antibodies of the IgG class, the IgM class, or both were identified in 34 patients, and clinical follow-up information was obtained from 29 of these patients. The mean nadir platelet count in these patients was 13,600 per cubic millimeter, and severe bleeding occurred in 10 patients (34%). Platelet levels returned to baseline in all 26 surviving patients after vancomycin was stopped. In 15 patients, the drug was continued for 1 to 14 days while other possible causes of thrombocytopenia were investigated. Vancomycin-dependent antibodies were not found in 25 patients who had been given vancomycin and in whom thrombocytopenia did not develop.\n\n\nCONCLUSIONS\nSevere bleeding can occur in patients with vancomycin-induced immune thrombocytopenia. The detection of vancomycin-dependent antiplatelet antibodies in patients receiving the antibiotic in whom thrombocytopenia develops, and the absence of antibodies in patients given the drug in whom platelet counts remain stable, indicate that these antibodies are the cause of the thrombocytopenia.",
"affiliations": "Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.",
"authors": "Von Drygalski|Annette|A|;Curtis|Brian R|BR|;Bougie|Daniel W|DW|;McFarland|Janice G|JG|;Ahl|Scott|S|;Limbu|Indra|I|;Baker|Kelty R|KR|;Aster|Richard H|RH|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000906:Antibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D014640:Vancomycin",
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"medline_ta": "N Engl J Med",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D000906:Antibodies; D001792:Blood Platelets; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D012016:Reference Values; D013921:Thrombocytopenia; D014640:Vancomycin",
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"references": null,
"title": "Vancomycin-induced immune thrombocytopenia.",
"title_normalized": "vancomycin induced immune thrombocytopenia"
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"abstract": "Background and aims - Description of two cases of rare intravascular large B-cell lymphoma and secondary T-cell lymphoma diagnosed postmortem, that manifested clinically as longitudinally extensive transverse myelitis (LETM). We discuss causes of diagnostic difficulties, deceptive radiological and histological investigations, and outline diagnostic procedures based on our and previously reported cases. Case reports - Our first case, a 48-year-old female was admitted to the neurological department due to paraparesis. MRI suggested LETM, but the treatments were ineffective. She died after four weeks because of pneumonia and untreatable polyserositis. Pathological examination revealed intravascular large B-cell lymphoma (IVL). Our second case, a 61-year-old man presented with headache and paraparesis. MRI showed small bitemporal lesions and lesions suggesting LETM. Diagnostic investigations were unsuccessful, including tests for possible lymphoma (CSF flow cytometry and muscle biopsy for suspected IVL). Chest CT showed focal inflammation in a small area of the lung, and adrenal adenoma. Brain biopsy sample from the affected temporal area suggested T-cell mediated lymphocytic (paraneoplastic or viral) meningoencephalitis and excluded diffuse large B-cell lymphoma. The symptoms worsened, and the patient died in the sixth week of disease. The pathological examination of the presumed adenoma in the adrenal gland, the pancreatic tail and the lung lesions revealed peripheral T-cell lymphoma, as did the brain and spinal cord lesions. Even at histological examination, the T-cell lymphoma had the misleading appearance of inflammatory condition as did the MRI. Conclusion - Lymphoma can manifest as LETM. In cases of etiologically unclear atypical LETM in patients older than 40 years, a random skin biopsy (with subcutaneous adipose tissue) from the thigh and from the abdomen is strongly recommended as soon as possible. This may detect IVL and provide the possibility of prompt chemotherapy. In case of suspicion of lymphoma, parallel examination of the CSF by flow cytometry is also recommended. If skin biopsy is negative but lymphoma suspicion remains high, biopsy from other sites (bone marrow, lymph nodes or adrenal gland lesion) or from a simultaneously existing cerebral lesion is suggested, to exclude or prove diffuse large B-cell lymphoma, IVL, or a rare T-cell lymphoma.",
"affiliations": "Department of Pathology, Markusovszky University Teaching Hospital, Szombathely.;Department of Neurology, Markusovszky University Teaching Hospital, Szombathely.;Department of Neurology, Markusovszky University Teaching Hospital, Szombathely.;Department of Radiology, Markusovszky University Teaching Hospital, Szombathely.;1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest.;Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.;Department of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.;Department of Pathology, Markusovszky University Teaching Hospital, Szombathely.",
"authors": "Tolvaj|Balázs|B|;Hahn|Katalin|K|;Nagy|Zsuzsanna|Z|;Vadvári|Árpád|Á|;Csomor|Judit|J|;Gelpi|Ellen|E|;Illes|Zsolt|Z|;Garzuly|Ferenc|F|",
"chemical_list": null,
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"issue": "73(7-08)",
"journal": "Ideggyogyaszati szemle",
"keywords": "LETM; intravascular lymphoma; longitudinally extensive transverse myelitis; primary CNS lymphoma; secondary peripheral T-cell lymphoma; spinal cord lymphoma",
"medline_ta": "Ideggyogy Sz",
"mesh_terms": "D001706:Biopsy; D001921:Brain; D017809:Fatal Outcome; D005260:Female; D006261:Headache; D006801:Humans; D008223:Lymphoma; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009188:Myelitis, Transverse; D020335:Paraparesis",
"nlm_unique_id": "17510500R",
"other_id": null,
"pages": "275-285",
"pmc": null,
"pmid": "32750245",
"pubdate": "2020-07-30",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Life threatening rare lymphomas presenting as longitudinally extensive transverse myelitis: a diagnostic challenge.",
"title_normalized": "life threatening rare lymphomas presenting as longitudinally extensive transverse myelitis a diagnostic challenge"
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"companynumb": "HU-BEH-2020121035",
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"abstract": "BACKGROUND\nSuccessful spontaneous pregnancy in a kidney graft recipient is regarded as a sign of full recovery. The crucial factors determining positive outcome are optimizing time of conception and multidisciplinary team care. However, there are only a few reports dealing with in vitro fertilization (IVF) outcomes in organ recipients.\n\n\nMETHODS\nA 34-year-old living donor kidney recipient with primary infertility due to bilateral tubal obstruction was referred to our clinic. Transfer of 2 embryos was conducted after a long stimulation protocol with GnRH and rFSH, and a viable singleton pregnancy was confirmed by subsequent ultrasound examination. Pregnancy complications were: chronic hypertension, fetal intrauterine growth restriction, and severe anemia requiring blood transfusions and erythropoietin treatment. In the 34th week of gestation the patient presented with worsening of blood pressure control. A male newborn, 1810 grams weight and 10 points Apgar score was delivered by cesarean section. Although our patient was qualified for the IVF program with signs of suboptimal graft function, it was stable during the ovarian stimulation protocol. Fortunately, in the second half of the pregnancy only mild creatinine rise and proteinuria <1 g/day were observed.\n\n\nCONCLUSIONS\nIVF may be a good treatment option in female kidney graft recipients. It does not necessarily lead to graft function deterioration and it provides multidisciplinary specialized care, allowing for delivery of a healthy newborn.",
"affiliations": "1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Medical University of Warsaw, Warsaw, Poland.;1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland.;Clinical Department of Internal Medicine, Nephrology and Transplantology, Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland.;First Department of Obstetrics and Gynecology, Medical University of Warsaw, Warszawa, Poland.",
"authors": "Pietrzak|Bronisława|B|;Mazanowska|Natalia|N|;Kociszewska-Najman|Bożena|B|;Szymusik|Iwona|I|;Grzechocińska|Barbara|B|;Pazik|Joanna|J|;Jabiry-Zieniewicz|Zoulikha|Z|;Popow|Anna|A|;Wielgos|Mirosław|M|",
"chemical_list": null,
"country": "United States",
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"issn_linking": "1425-9524",
"issue": "20()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D005307:Fertilization in Vitro; D005317:Fetal Growth Retardation; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D007247:Infertility, Female; D016030:Kidney Transplantation; D011247:Pregnancy; D011256:Pregnancy Outcome; D066027:Transplant Recipients",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "338-41",
"pmc": null,
"pmid": "26076906",
"pubdate": "2015-06-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Successful Pregnancy Outcome after In Vitro Fertilization in a Kidney Graft Recipient: A Case Report and Literature Review.",
"title_normalized": "successful pregnancy outcome after in vitro fertilization in a kidney graft recipient a case report and literature review"
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"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "The authors describe the first case of drug rash with eosinophilia and systemic symptoms syndrome caused by hydroxychloroquine treatment in a male patient affected by seronegative arthritis.",
"affiliations": "Department of General Medicine, Sacro Cuore Hospital, Via Sempreboni 5, Negrar, VR, Italy. reumatologia@sacrocuore.it",
"authors": "Volpe|Alessandro|A|;Marchetta|Antonio|A|;Caramaschi|Paola|P|;Biasi|Domenico|D|;Bambara|Lisa Maria|LM|;Arcaro|Guido|G|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-007-0772-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "27(4)",
"journal": "Clinical rheumatology",
"keywords": null,
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D018501:Antirheumatic Agents; D001168:Arthritis; D004802:Eosinophilia; D005076:Exanthema; D005334:Fever; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D013577:Syndrome",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "537-9",
"pmc": null,
"pmid": "17952481",
"pubdate": "2008-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9069593;17075280;17381452;15349041;17300272;16882184;16964632",
"title": "Hydroxychloroquine-induced DRESS syndrome.",
"title_normalized": "hydroxychloroquine induced dress syndrome"
} | [
{
"companynumb": "IT-IPCA LABORATORIES LIMITED-IPC201703-000277",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},
... |
{
"abstract": "Neuroleptic malignant syndrome (NMS) is a possible cause of fever of unknown origin (FUO) and is a potentially fatal adverse effect of various drugs, especially of neuroleptics. First generation antipsychotics, such as received by the patient described in this article, are more likely to cause NMS than second generation antipsychotics. The key symptoms are the development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication. Malignant catatonia (MC) is an important differential diagnosis of NMS. While neuroleptics can trigger NMS and must be immediately discontinued if NMS occurs, neuroleptic therapy represents the first line treatment for MC. This article describes the case of a patient with schizoaffective disorder where initially the diagnosis of NMS was not clear. Eventually, fever and a markedly elevated serum creatine kinase (CK) led to the correct diagnosis and the appropriate therapy with dantrolene, bromocriptine and amantadine. Furthermore, a thorough review of the currently available literature on NMS is provided.",
"affiliations": "Klinik für Anästhesiologie und operative Intensivmedizin, Klinikum der Universität Witten/Herdecke mit Sitz in Köln, Kliniken der Stadt Köln gGmbH, Krankenhaus Merheim, Ostmerheimerstr. 200, 51109, Köln, Deutschland, ChackupurakalR@kliniken-koeln.de.",
"authors": "Chackupurakal|R|R|;Wild|U|U|;Kamm|M|M|;Wappler|F|F|;Reske|D|D|;Sakka|S G|SG|",
"chemical_list": "D014150:Antipsychotic Agents; D015415:Biomarkers; D003402:Creatine Kinase",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00101-015-0046-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2417",
"issue": "64(7)",
"journal": "Der Anaesthesist",
"keywords": null,
"medline_ta": "Anaesthesist",
"mesh_terms": "D014150:Antipsychotic Agents; D015415:Biomarkers; D002389:Catatonia; D003402:Creatine Kinase; D003937:Diagnosis, Differential; D005335:Fever of Unknown Origin; D006801:Humans; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D011618:Psychotic Disorders",
"nlm_unique_id": "0370525",
"other_id": null,
"pages": "527-31",
"pmc": null,
"pmid": "26122200",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": "13734791;2888445;19837825;1751888;6133848;21206810;25578944;1349827;3941310;19933965;10798826;3615574;20306454;17541044;24006163;23194104;2899358;22475734;22854034;18480098",
"title": "Neuroleptic malignant syndrome : Rare cause of fever of unknown origin.",
"title_normalized": "neuroleptic malignant syndrome rare cause of fever of unknown origin"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE INC.-DE2015GSK127880",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional"... |
{
"abstract": "Hyperinfection caused by Strongyloides stercoralis in iatrogenically immunosuppressed patients is becoming more frequently observed. Here, we review the relevant literature and present a recent case of hyperinfection syndrome of S stercoralis in a patient chronically treated with systemic corticosteroids and methotrexate for dermatomyositis. The patient was born in Guatemala but no history of Strongyloides infection was documented. Disseminated Strongyloides is often associated with the immunocompromised state and is commonly seen with cutaneous lesions, respiratory failure, and sepsis. In this patient, a protracted course of progressive muscle weakness and multiple hospital stays for respiratory distress led to acute respiratory failure, septic shock, and rapid physical decline. A few days preceding his death, the patient developed petechiae and multiple purpuric macules and patches over the abdomen and thighs. Histologic review of skin biopsy specimens demonstrated multiple intravascular and interstitial filariform larvae. Dermatologists should be aware of patient populations at risk for infection with S stercoralis and be able to make this diagnosis to initiate earlier treatment of hyperinfection and dissemination.",
"affiliations": "Department of Dermatology, St Joseph Mercy Hospital, Ypsilanti, Michigan, USA.",
"authors": "Basile|Amy|A|;Simzar|Soheil|S|;Bentow|Jason|J|;Antelo|Fernando|F|;Shitabata|Paul|P|;Peng|Shi-Kaung|SK|;Craft|Noah|N|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2009.09.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "63(5)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": null,
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000818:Animals; D001706:Biopsy; D003882:Dermatomyositis; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D015163:Superinfection",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "896-902",
"pmc": null,
"pmid": "20172622",
"pubdate": "2010-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated Strongyloides stercoralis: hyperinfection during medical immunosuppression.",
"title_normalized": "disseminated strongyloides stercoralis hyperinfection during medical immunosuppression"
} | [
{
"companynumb": "US-PFIZER INC-2018165319",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPanobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.\n\n\nMETHODS\nFollowing a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.\n\n\nRESULTS\nMost common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).\n\n\nCONCLUSIONS\nPanobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.",
"affiliations": "1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Nuclear Medicine, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;HELIOS Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Berlin, Germany.;1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;HELIOS Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Berlin, Germany.;1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;Novartis Pharma GmbH, Nuremberg, Germany.;Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University Duisburg-Essen, Essen, Germany.;1] Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany [2] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;HELIOS Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Berlin, Germany.",
"authors": "Bauer|S|S|;Hilger|R A|RA|;Mühlenberg|T|T|;Grabellus|F|F|;Nagarajah|J|J|;Hoiczyk|M|M|;Reichardt|A|A|;Ahrens|M|M|;Reichardt|P|P|;Grunewald|S|S|;Scheulen|M E|ME|;Pustowka|A|A|;Bock|E|E|;Schuler|M|M|;Pink|D|D|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000077767:Panobinostat",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2013.826",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201382610.1038/bjc.2013.82624434430Clinical StudyPhase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors Panobinostat and imatinib in refractory GISTBauer S 12*Hilger R A 2Mühlenberg T 12Grabellus F 13Nagarajah J 14Hoiczyk M 12Reichardt A 5Ahrens M 12Reichardt P 5Grunewald S 12Scheulen M E 2Pustowka A 6Bock E 7Schuler M 12Pink D 51 Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany2 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany3 Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany4 Department of Nuclear Medicine, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany5 HELIOS Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Berlin, Germany6 Novartis Pharma GmbH, Nuremberg, Germany7 Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University Duisburg-Essen, Essen, Germany* E-mail: sebastian.bauer@uk-essen.de04 03 2014 16 01 2014 110 5 1155 1162 11 09 2013 13 11 2013 16 12 2013 Copyright © 2014 Cancer Research UK2014Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Background:\nPanobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.\n\nMethods:\nFollowing a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a ‘3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.\n\nResults:\nMost common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).\n\nConclusion:\nPanobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.\n\nGISTimatinib resistancehistonedeacetylase inhibitorsKITtargeted therapyLBH589panobinostat\n==== Body\nActivating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA) represent the key oncogenic events in gastrointestinal stromal tumors (GIST) (Hirota et al, 1998; Heinrich et al, 2003). Imatinib mesylate (IM) is a small molecule inhibitor of KIT and PDGFRA that provides long-lasting responses in most patients (82–86%), with a median overall survival of 5 years (Verweij et al, 2004; Blanke et al, 2008a, 2008b). Despite long-lasting responses, most patients eventually acquire resistance and progress. Salvage treatments such as sunitinib and regorafenib may still achieve objective remissions (7% and 4.5%), but median time to progression is only in the range of 6 months (Demetri et al, 2006, 2012). Therefore, alternative treatment strategies for IM-resistant GIST are needed.\n\nPanobinostat (LBH589) is a novel cinnamic hydroxamic acid inhibitor of histone deacetylases (HDACi), which is active on HDAC class I and II isoforms at nanomolar concentrations (Geng et al, 2006). Inhibition of HDACs has been effective in several human cancers, in particular haematologic malignancies, in clinical trials (Giles et al, 2006). Since 2006, two HDACi, vorinostat (SAHA) and romidepsin, have received FDA approval for the treatment of advanced cutaneous T-cell lymphoma (Mann et al, 2007; Xu et al, 2007; Whittaker et al, 2010). We have preclinically evaluated the activity of different classes of HDACi in GIST. The pan-HDACi panobinostat (LBH589) potently inhibited the growth of GIST cell lines in vitro (IC50 values between 80 and 100 nM) (Mühlenberg et al, 2009). Interestingly, panobinostat activity was only seen in KIT-positive GIST models indicating target specificity. This was mediated by transcriptional repression of KIT and by acetylation and subsequent inhibition of heat-shock protein 90 (HSP90), a critical chaperone protein for KIT stabilisation and non-histone client of HDAC6 (Mühlenberg et al, 2009). Additive antitumoral efficacy of panobinostat and IM was observed in IM-resistant GIST models in vitro and in vivo (Floris et al, 2009a).\n\nAgainst this background, we conducted a phase I study of panobinostat in combination with IM for treatment of patients with metastatic GIST who had progressed on IM and sunitinib.\n\nPatients and methods\nPatients\nPatients with metastatic GIST (aged 18 years and older) refractory to IM and sunitinib were enrolled in the trial following written informed consent. Additional main inclusion criteria were Eastern Cooperative Oncology Group performance score 2 or lower, absolute neutrophil count 1500 per litre, platelets 100 000 per litre, serum transaminase activity <2.5 × ULN, total bilirubin <1.5 × ULN, serum creatinine <1.5 × ULN or a creatinine clearance of ⩾60 ml min−1, fasting serum cholesterol ⩽350 mg dl−1, triglycerides ⩽300 mg dl−1, proteinuria ⩽1 g in 24 h, no prior thromboembolic disease, no history of haematemesis or haemoptysis. Patients with a history of cardiac disease (congestive heart failure (> New York Heart Association class 2), active coronary artery disease, cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, uncontrolled hypertension; myocardial infarction less than 6 month before study entry) were excluded. There was no limit on the number of previous anticancer regimens. The institutional review boards of both sites approved the study. A central pathology review that included KIT and PDGFRA mutational testing was performed for all patients from archival tissue by one of the investigators (FG).\n\nStudy design and treatment\nWTZ-GIST-09-01 was an open-label, single-arm, bicentric phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with IM. In addition, the study assessed the safety, tolerability, activity, pharmacokinetics and pharmacodynamic activity of the combination. Given a low risk of QTc prolongation, a strict ECG screen at baseline and during treatment was incorporated in the protocol. To obtain a preliminary signal for clinical activity, a prespecified expansion of the MTD cohort to a maximum of nine patients was implemented. IM was administered orally at a dose of 400 mg once daily. As patients may respond to an imatinib rechallenge (http://meetinglibrary.asco.org/content/116140-132), the baseline FDG-PET scan was performed following a 7-day run-in phase, and escalating doses of panobinostat (three times per week for 3 out of 4 weeks) were added. One treatment cycle consisted of 29 days. The dose escalation for panobinostat followed the strict traditional escalation rule (STER). Using STER, patients are treated in cohorts of three, each receiving the same dose. If no DLT occurs, the next cohort of three will receive the next higher dose. If one DLT occurs, the cohort is expanded to three other patients. If two or more DLTs occur, escalation stops and the dose is de-escalated to the next lower level (Chin and Lee, 2008). We selected 20 mg as the starting dose following the discussion with the panobinostat development team from Novartis, based on the existing data on combination trials with panobinostat (Drappatz et al, 2012). WTZ-GIST-09-01 (EudraCT number: 2009-011417-24; German Clinical Trials Register: DRKS00000657) was approved by the institutional ethics committees of the two participating centers and the German Federal Regulatory Drug Agency (BfArM; 4035954).\n\nDose-limiting toxicities\nDLTs were defined from the safety profile of cycle 1 for each dose level. At dose level 1, panobinostat 20 mg was given as a three-times-per-week (MWF schedule) oral dose for 3 out of 4 weeks. Panobinostat doses were increased by 10 mg if no DLT emerged. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 3.0). Haematological DLTs were defined as ⩾CTCAE grade 3 neutropenia lasting for >7 days, CTCAE grade 3 thrombocytopenia lasting for >7 days, CTCAE grade 4 thrombocytopenia and neutropenic fever (ANC (including bands) <1.0 × 109 l−1, fever ⩾38.5 °C). Non-haematologic DLT was defined as any grade 3 or 4 toxicity occurring during cycle 1.\n\nPharmacokinetics and biomarkers\nBlood sampling for pharmacokinetic (PK) and pharmacodynamic (PD) studies was performed on day 1, 8, 15, 22 and 29. For PK analyses, blood was withdrawn into EDTA tubes and centrifuged immediately at 2000 × g for 10 min at 4 °C. For extraction of panobinostat and IM, 400 μl plasma was mixed with 600 μl acetonitrile. Free IM, N-desmethyl-IM (CGP074588) and panobinostat were measured by liquid chromatography coupled to a photodiode array (LC/PDA) spectrometer (Acquity Ultra Performance LC system, Waters GmbH, Eschborn, Germany). Pharmacokinetics were calculated using the TOPFIT 2.0 software (Thomae GmbH, Biberach, Germany). A concentration/time plot for IM and desmethyl-IM was generated. The pharmacokinetics of IM and desmethyl-IM have been described by a two-compartment distribution.\n\nAcetylation of histone H3 in peripheral blood mononuclear cells (PBMNC) was assessed as a PD marker of panobinostat activity in vivo. Protein lysates were prepared from PBMNC and subjected to electrophoresis and immunoblotting as previously described (Rubin et al, 2001; Duensing et al, 2004). Changes in protein expression were visualised by chemiluminescence and captured and quantified using a FUJI LAS3000 system with Science Lab 2001 ImageGauge 4.0 software (Fujifilm Medial Systems, Stamford, CT, USA). To identify the lowest plasma level of panobinostat that would induce acetylation, PBMNC from two healthy volunteers were incubated ex vivo with increasing concentrations of panobinostat. In addition, IM-sensitive GIST-T1 (exon 11-mutant) cells and the highly IM-resistant subline GIST-T1-juke (exon 11 and exon 17 D816E double mutant) were incubated in vitro with panobinostat at concentrations that were achieved in study patients as confirmed by our PK analyses.\n\nEvaluation of clinical activity\nFull-dose CT scans were performed at least 14 days before randomisation and at least every 56 days. Metabolic imaging studies were conducted at baseline after the run-in period with IM (day 7) before administration of the first dose of panobinostat to exclude metabolic effects by IM rechallenge. All patients were instructed to fast for 6 h before intravenous administration of 18 F-FDG (median: 273 MBq, range: 250–450 MBq). Patients with a blood glucose level exceeding 150 mg dl−1 were not included in the study. Whole-body PET/CT scans were obtained using a PET/CT system (mCT; Siemens Molecular Imaging, Eschborn, Germany) after a median of 65 min (range: 50–80 min) post injection of 18F-FDG.\n\nPET scans were repeated on day 29 of the first cycle. In case of clinical progression, a full-dose PET-CT was performed instead. Metabolic response was defined according to the EORTC-PET Study Group criteria; radiologic response was evaluated per RECIST. Patients with clinical, radiological and/or metabolic response or disease stabilisation were continued on trial medication until progression. In the follow-up phase of the study, CT scans were repeated every 56 days.\n\nResults\nPatient characteristics\nIn all, 12 patients (median 56 years, range 34–74) with metastatic GIST were enrolled at two sarcoma centers. All patients were eligible and evaluable for toxicity. Patients had been heavily pretreated with a median of five treatment lines (range 3–11) before study entry. Clinical and epidemiological data and treatment outcome of the study patients are summarised in Table 1.\n\nSafety\nAll patients experienced at least one adverse event (AE), the majority of AEs were graded mild. The most common AEs were thrombocytopenia (92%), fatigue (67%), creatinine elevation (58%), nausea (50%), anaemia (42%), diarrhoea (42%) and vomiting (33% Table 2). The majority of events (thrombocytopenia, nausea, diarrhoea) occurred in the third week of panobinostat treatment, but quickly resolved during week 4, in which no panobinostat was given. Although AE grades 3 or 4 were uncommon, the MWF schedule for 3 weeks was associated with severe thrombocytopenia, which was the dose-limiting toxicity at dose level 2 (30 mg panobinostat). Grade 3 and 4 toxicities that were clearly attributable to study treatments were thrombocytopenia, neutropenia and nausea. After panobinostat rechallenge (3 patients at panobinostat 30 mg, 1 patient at 20 mg) at reduced dose, thrombocytopenia was <grade III except for one patient (grade 3) in cycle 2. This resolved after further dose reduction. There were no treatment-related deaths, but one patient died of progressive disease shortly after discontinuation of treatment.\n\nPharmacokinetics\nPlasma concentrations of IM, desmethyl-IM (IM-metabolite) and panobinostat were determined in 14 treatment courses from 12 patients. Results are summarised in Table 3. The mean peak concentrations (Cmax) of panobinostat were 12.6, 16.6 and 15.6 ng ml−1 (Days 1, 8 and 15) at dose level 1 (n=8), which was declared the MTD (Table 3, Figure 1A). Because of low plasma concentrations of panobinostat, only the Cmax was calculated. The lower limit of detection for panobinostat in plasma was 2 ng ml−1, and the lower limit of quantification was 4 ng ml−1. The mean Cmax for IM was 2068 ng ml−1 during the 7-day run-in period, which was not significantly different from the Cmax of 2564 ng ml−1 during combination therapy (P=0185, t-test). Mean IM trough levels during the run-in period and during combination therapy amounted 1085 ng ml−1 and 1290 ng ml−1 (P=0.125). The terminal half-life for IM in the presence of panobinostat was 20.5 h, whereas the terminal half-life of IM alone is approximately 18 h (Peng et al, 2005). Actual plasma levels for desmethyl-IM, the main metabolite of IM, were as predicted, thus making a pharmacodynamic interaction of panobinostat on IM metabolism highly unlikely (Figure 1B).\n\nPharmacodynamic biomarkers for target inhibition in vivo\nWe assessed the acetylation of histone H3 (H3) in PBMNCs obtained from five patients treated at dose level 1 (MTD) as a pharmacodynamic biomarker for the activity of panobinostat (Figure 1C). Peak H3 acetylation was observed between 4 and 8 h following the first oral dose of panobinostat in four of five patients. H3 acetylation was maintained for 24 h in three patients and decreased at later time points in most patients (not shown). H3 acetylation correlated with detectable plasma levels of panobinostat, although not quantitatively (Figure 1C).\n\nTo corroborate these findings, we incubated PBMNCs from healthy donors with panobinostat ex vivo for 8 h. At concentrations of 5 ng ml−1 and above, H3 acetylation became detectable (Figure 2A). Time course experiments with GIST-T1 cells (IM-sensitive cell line) confirmed that H3 acetylation persisted for 8 h after removal of panobinostat and completely disappeared within 24 h (Figure 2B). Incubating GIST-T1 cells and IM-resistant GIST-T1 (KIT D816E mutant) with panobinostat and IM at those concentrations clinically achieved in study patients treated at the MTD (Cmax and ½ Cmax) demonstrated complete inhibition of KIT phosphorylation (Figure 2C).\n\nClinical activity\nNo objective responses per RECIST were observed (8 SD, 3 PD). Most patients had extensive metastatic disease, and a decrease in size or change of density was rarely seen in single lesions. Changes in metabolic activity of tumour lesions were assessed by comparing the individual patients' 18FDG-PET scans obtained at the end of the IM run-in with those obtained on day 29 of cycle 1. Eleven patients were evaluable for PET response, and one patient treated at dose level 1 achieved a metabolic partial response (mPR) as defined by EORTC-PET Study Group criteria (Young et al, 1999). Another seven patients exhibited metabolic disease stabilisation, and three patients had metabolically progressive disease (Figure 3A). The median treatment duration was 6 weeks. The patient achieving a mPR was treated for 17 weeks (Table 1; Figure 3B). He had been diagnosed with metastatic disease 6 years before study enrolment and already received imatinib, sunitinib, nilotinib, imatinib rechallenge, radiation therapy to the large tumour bulk and sorafenib. We attribute his disease stabilisation to the panobinostat addition as he was treated with imatinib at 800 mg qd−1 before the study and enrolled into the trial due to progressive disease at that dose.\n\nDiscussion\nIn spite of the vast improvement in the treatment of metastatic GIST since the introduction of IM, most patients eventually develop resistance and progress. The mortality of IM-resistant GIST patients amounts 10% per year, which highlights the need for effective salvage treatments (Blanke et al, 2008a). Secondary mutations of the KIT kinase domain are the major mechanism of resistance to IM and sunitinib (Heinrich et al, 2006), thus providing an opportunity for the development of better KIT inhibitors. However, the genomic heterogeneity of these resistance mutations poses a pharmacological challenge to develop selective KIT inhibitors that inhibit all possible mutations (Wardelmann et al, 2005). In contrast to ATP-competitive drugs, such as IM, sunitinib or regorafenib, allosteric KIT inhibitors exhibited an improved capability to inhibit various secondary KIT mutations including those affecting exon 17 (for example, point mutations of D816). However, the clinical utility of these compounds still remains to be proven (Heinrich et al, 2010).\n\nModulating the KIT chaperone heat-shock protein 90 (HSP90) is an alternative strategy to overcome IM resistance in GIST. Pharmacologic HSP90 inhibitors effectively inhibit KIT in vitro at concentrations that can be achieved in patients regardless of secondary KIT mutations (Bauer et al, 2006; Wagner et al, 2008). Unfortunately, encouraging results from early clinical trials were followed by unexpected toxicities, which were observed in the subsequent phase III trial (Demetri et al, 2010). Hence, the therapeutic potential of HSP90 inhibitors in the treatment of GIST remains unclear and is subject of ongoing clinical trials. Recently, HDACi such as SAHA or panobinostat were shown to have potent antitumoral activity in GIST models in vitro and in vivo (Mühlenberg et al, 2009; Floris et al, 2009b). Mechanistically, HDACi in part act by indirect inhibition of KIT via acetylation and functional inhibition of HSP90 and by transcriptional repression of KIT itself (Mühlenberg et al, 2009; Floris et al, 2009b). Combining HDACi with IM further enhanced the activity, which was even observed in IM-resistant GIST models (Mühlenberg et al, 2009; Floris et al, 2009b). These findings provided the rationale for the present phase I study. Here we aimed to identify a feasible dose and schedule for combination therapy of GIST with panobinostat and IM. We further explored pharmacodynamic effects of plasma levels of both drugs, which could be achieved in the clinic.\n\nDose levels of the trial were chosen based on clinical and pharmacological considerations. Notably, the MTD had to be defined after only 2 dose levels following a classical ‘3 plus 3' design. The dose-limiting toxicity at dose level 2 (30 mg panobinostat and 400 mg IM) was thrombocytopenia, which correlated well with DLTs seen in other phase I trials with panobinostat (Fukutomi et al, 2012; Morita et al, 2012). Although most of the latter trials targeted malignancies affecting the bone marrow, haematotoxicity also is important in GIST, a cancer not known for common bone marrow involvement. Notably, haematologic toxicity, especially in the third week of panobinostat, requiring dose interruptions was still observed at the MTD in subsequent cycles. In this combination trial, we did not observe additional toxicities as compared with panobinostat or IM monotherapy trials in patients with other types of cancer (Fukutomi et al, 2012). Common toxicities included fatigue, nausea, changes in appetite or dysgeusia. These toxicities peaked during the third week of combination therapy. Notably, severe hepatotoxicity, as seen with ansamycin-based HSP90 inhibitors in GIST, did not occur. On the basis of the literature, panobinostat and IM could have a two-way pharmacokinetic interaction. CYP3A4 appears to be the main enzyme responsible for the oxidative metabolism of panobinostat in human liver microsomes. Panobinostat itself has been found to be a weak inhibitor of CYP2D6 and a weak inhibitor of CYP3A4/5. In contrast, IM is a potent inhibitor of CYP3A4 and may increase substrate levels 2- to 3.5-fold (Hamberg et al, 2011; Filppula et al, 2012). In the present trial, we observed an increase of the mean Cmax of IM by 23%. This is suggestive of an interaction. However, because of the limited number of patients, these findings did not reach statistical significance. Fukutomi et al (2012) recently reported Cmax plasma levels for panobinostat monotherapy of 10 ng /ml−1 when given at a dose of 20 mg thrice weekly . Panobinostat Cmax levels in our combination study ranged from 13 to 16 ng ml−1, which may hint at an increase in exposure of panobinostat resulting from the coadministration of IM. This could not be formally proven as the study design did not provide a period of panobinostat monotherapy for comparison. Nonetheless, we did not find evidence for a disproportionately strong interaction.\n\nWith regard to clinical activity, we did not observe objective radiographic responses but did observe evidence of metabolic inhibition and prolonged disease stabilisation in some patients, which is noteworthy in the light of a median of five previous treatment lines. Importantly, in vivo inhibition of HDAC in PBMNCs from study patients was demonstrated using histone H3 acetylation as a pharmacodynamic biomarker. Moreover, our correlative ex vivo and in vitro studies confirmed that target inhibition of HDACs and KIT can be achieved at plasma levels of panobinostat and IM (Cmax and ½ Cmax), which were observed in the present trial. Notably, at these concentrations, panobinostat and IM inhibited the notorious KIT D816E mutation, which is known to confer cross-resistance to IM, sunitinib, sorafenib and regorafenib in GIST (Heinrich et al, 2012; and data not shown).\n\nIn the present trial, panobinostat plasma levels were below the lowest level of quantification 24 h after the first dose. This situation was recapitulated in our preclinical models by removing panobinostat from the media from responding cells, resulting in complete reactivation of KIT signalling within 24 h. As KIT activation drives the disease, these findings would beg for a continuous treatment schedule, as used with direct KIT inhibitors such as IM. Notably, continuous panobinostat treatment for 32 h resulted in reactivation of KIT phosphorylation (Figure 2B).\n\nWe believe that these data are particularly relevant, as it shows that HDAC inhibitors may require disease-specific dosing schedules. In GIST, HDACi exert the antitumoral effect via HSP90 acetylation rather than on a complex epigenetic ‘reprogramming' as in lymphomas. Dosing intervals should therefore be short enough to prevent the GIST cell to fully reactivate its KIT-driven cell cycle machinery.\n\nWith regard to the optimal duration of panobinostat treatment, the experience from the PANORAMA-1 trial in multiple myeloma has shown that panobinostat for three consecutive weeks is associated with unacceptable toxicity, as we have seen in our trial. Panobinostat 20 mg (thrice weekly) in a 2 week on ora 1 week off schedule has substantially reduced the rate of grade 3 thrombocytopenia in the combination trial in myeloma (personal communication Novartis) and improved the tolerability, which would be the blueprint for future studies in GIST.\n\nIn conclusion, the present schedule of panobinostat in combination with IM is tolerated in heavily pretreated patients with metastatic GIST but future studies should use a 2 week on or 1 week off schedule to improve the tolerability. Haematological toxicity represents the dose-limiting toxicity. Target inhibition was achieved at the MTD, and limited evidence for metabolic tumour inhibition was observed. Acetylation of histone H3 in PBMNCs correlated with measurable panobinostat levels and seems to be a valuable biomarker. On the basis of our correlative studies, additive effects can be expected with IM and panobinostat, and KIT inhibition may even be achieved in exon 17-mutant GIST. These findings warrant further clinical exploration of HDAC inhibitors in combination with KIT inhibitors.\n\nWe thank the teams of the Sarcoma Center at the West German Cancer Center, Essen and the Sarcoma Center Berlin/Brandenburg for their dedicated clinical care. We also wish to acknowledge the contributions of Julia Ketzer, Claudia Ose, Sarah Rauhut, Edel Ó Halloran and Simone Micheel. This study was supported by a research grant from Novartis; SB holds a Max Eder Fellowship of the Deutsche Krebshilfe (No. 109757) and received funds from the Life Raft Group Research Initiative; the West German Cancer Center is supported by a National Oncology Center of Excellence grant of the Deutsche Krebshilfe.\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.\n\nThis work has in part been presented at the 2012 Annual Meeting of the American Society of Clinical Oncology, Chicago, May 31-June 4.\n\nThe authors declare no conflict of interest.\n\nFigure 1 Pharmakokinetic studies and biomarker analyses. (A) Cmax diagram for panobinostat at day 1 (first dose panobinostat), day 8 and day 15. The black lines within the boxes indicate the median values, the red lines the mean values. (B) Calculated fit curves for IM and d-desmethyl IM. (C) Immunoblot analyses for acetylated histone H3 from lysates of PBMNCs taken at various time points from selected patients with corresponding panobinostat plasma levels. LLQ=lower level of quantification.\n\nFigure 2 Preclinical revalidation of clinical biomarkers and tumour-specific target inhibition. (A) Immunoblot analyses for acetylated histone H3 from lysates of PBMNCS from healthy volunteers incubated ex vivo with increasing concentrations of panobinostat. (B) Immunoblot analysis of GIST-T1 cells treated with panobinostat (Pan, 50 nm) for 8 h following a time course after withdrawal of treatment (WD). Continuous treatment with panobinostat at 16 h and 32 h are shown in the right columns. (C) Immunoblot analyses of imatinib-sensitive GIST-T1 and imatinib-resistant GIST-T1R treated with IM, panobinostat or with IM and panobinostat combined.\n\nFigure 3 Clinical activity of panobinostat and imatinib in GIST. (A) Water fall plot of the relative change in SUV of baseline scans compared with the scans at the end of cycle 1. (B) FDG-PET-CT images of a patient with advanced metastatic GIST at baseline after imatinib run-in (left) and after 3 weeks panobinostat (right) resulting in a partial metabolic remission.\n\nTable 1 Patient characteristics\nPat\tDose level\tAge\tSex\t# Pretreatments\tType of pretreatment\tGene, exon\tPrimary mutation\tECOG\tPET-response\tRECIST\tDays on study treatment\t\n101\t20\t34\tm\t11\tIM, SU, other\tKIT exon 11, Exon 17\tDel E554-V559; D820Y\t0\tmPD\tPD\t25\t\n102\t20\t41\tm\t5\tIM, SU, Nilo, Sora, other\tPDGFR Exon 12\tDel V559-P573; D820G\t0\tmPR\tSD\t116\t\n103\t30\t60\tm\t4\tIM, SU, Dasa, Nilo\tPDGFR Exon 18\tD842V\t0\tmSD\tPD\t12\t\n104\t30\t38\tw\t5\tIM, SU, Nilo, Sora, other\tKIT exon 9\tduplication A502 and Y503; Y823D\t \tmPD\tSD\t26\t\n106\t20 Extension\t75\tw\t4\tIM, SU, Nilo, Sora\t—\tNA\t1\tmSD\tSD\t35\t\n107\t20 Extension\t38\tm\t4\tIM, SU, Nilo, other\tKIT intron 10/exon 11\tK550–558dela\t0\tmPD\t—\t18\t\n108\t20 Extension\t55\tm\t5\tIM, SU, other\tKIT, Exon 11\tK558-V559insP\t0\tmSD\tSD\t \t\n201\t20\t56\tm\t3\tIM, SU, other\tKIT, Exon 13\tK642E\t0\tmSD\tSD\t74\t\n202\t30\t54\tw\t4\tIM, SU, other\tc-KIT Exon 11\tDel K558\t1\tmSD\tSD\t65\t\n203\t30\t74\tw\t5\tIM, SU, Sora, other\t—\tExon 11 wt, other exons not analysed\t1\t—\tPD\t86\t\n204\t20\t63\tw\t8\tIM, SU,Nilo, Sora, other\tKIT, Exon 9\tDuplication A502 and Y503\t1\tmSD\tSD\t51\t\n205\t20\t69\tm\t10\tIM, SU, Nilo, Sora, other\tKIT, Exon 11\tY553-K558delinsW\t1\tmSD\tSD\t72\t\nAbbreviations: IM=imatinib; mPD=metabolic progressive disease; mPR=metabolic partial response; mSD=metabolic stable disease; NA=not applicable; Nilo=nilotinib; Sora=Sorafenib; SU=sunitinib.\n\na Mutational analysis kindly provided by Professor Stephan Dirnhofer, Basel.\n\nTable 2 Summary of adverse events (>10% relative frequency)\n \t \tNo. of patients\t\nToxicity\tDose level panobinostat\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tTotal\t%\t\nThrombocytopenia\t20 mg\t3\t1\t1\t1\t6\t11\t91.7\t\n \t30mg\t——\t—\t3\t2\t5\t \t \t\nFatigue\t20 mg\t3\t3\t—\t—\t6\t8\t66.7\t\n \t30 mg\t—\t2\t—\t—\t2\t \t \t\nCreatinine\t20 mg\t2\t2\t1\t—\t5\t7\t58.3\t\n \t30 mg\t1\t1\t—\t—\t2\t \t \t\nNausea\t20 mg\t1\t1\t—\t—\t2\t6\t50.0\t\n \t30 mg\t1\t2\t1\t—\t4\t \t \t\nAnaemia\t20 mg\t—\t3\t—\t—\t3\t5\t41.7\t\n \t30 mg\t—\t2\t—\t—\t2\t \t \t\nDiarrhoea\t20 mg\t3\t1\t—\t—\t4\t5\t41.7\t\n \t30 mg\t1\t—\t—\t—\t1\t \t \t\nVomiting\t20 mg\t—\t1\t—\t—\t1\t4\t33.3\t\n \t30 mg\t2\t1\t—\t—\t3\t \t \t\nDizziness\t20 mg\t2\t—\t—\t—\t2\t3\t25.0\t\n \t30 mg\t1\t—\t—\t—\t1\t \t \t\nDyspepsia\t20 mg\t2\t—\t—\t—\t2\t3\t25.0\t\n \t30 mg\t1\t—\t—\t—\t1\t \t \t\nHypothyroidism\t20 mg\t3\t—\t—\t—\t3\t3\t25.0\t\n \t30 mg\t—\t—\t—\t—\t0\t \t \t\nMuscle spasms\t20 mg\t1\t1\t—\t—\t2\t3\t25.0\t\n \t30 mg\t—\t1\t—\t—\t1\t \t \t\nOedema\t20 mg\t2\t—\t—\t—\t2\t3\t25.0\t\n \t30 mg\t1\t—\t—\t—\t1\t \t \t\nWeight loss\t20 mg\t1\t1\t—\t—\t2\t3\t25.0\t\n \t30 mg\t—\t1\t—\t—\t1\t \t \t\nChills\t20 mg\t1\t1\t—\t—\t2\t2\t16.7\t\n \t30 mg\t—\t—\t—\t—\t0\t \t \t\nConstipation\t20 mg\t1\t—\t—\t—\t1\t2\t16.7\t\n \t30 mg\t1\t—\t—\t—\t1\t \t \t\nDry mouth\t20 mg\t2\t—\t—\t—\t2\t2\t16.7\t\n \t30 mg\t—\t—\t—\t—\t0\t \t \t\nDry skin\t20 mg\t1\t—\t—\t—\t1\t2\t16.7\t\n \t30 mg\t1\t—\t—\t—\t1\t \t \t\nDysgeusia\t20 mg\t2\t—\t—\t—\t2\t2\t16.7\t\n \t30 mg\t—\t—\t—\t—\t0\t \t \t\nHeadache\t20 mg\t1\t—\t—\t—\t1\t2\t16.7\t\n \t30 mg\t—\t1\t—\t—\t1\t \t \t\nLymphopenia\t20 mg\t—\t—\t1\t—\t1\t2\t16.7\t\n \t30 mg\t—\t1\t—\t—\t1\t \t \t\nNeutropenia\t20 mg\t—\t—\t—\t1\t1\t2\t16.7\t\n \t30 mg\t—\t1\t—\t—\t1\t \t \t\nThe highest grade per patient that occurred within the core study (cycle 1) or consecutive cycles as graded by NCI-CTCAE toxicity criteria (version 3.0).\n\nTable 3 Summary of pharmacokinetic analyses for IM and panobinostat\nPK parameter\tConcentration (ng ml−1) (± s.e.m.)\tConcentration (±s.e.m.)\t\nPanobinostat Cmax (mean) at 20 mg\t\nD1\t12.6 (±3.6)\t36.1 nM (±10.3 nM)\t\nD8\t16.6 (±2.3)\t47.5 nM (±16.6 nM)\t\nD15\t15.6 (±3.8)\t44.6 nM (±10.9 nM)\t\nIM Cmax (mean): \n(P=0.185)\t2068 (±310) (without pan)\n2564 (±190) (with pan)\t3.5 μM (±0.5 μM) (without pan)\n4.3 μM (±0.3 μM) (with pan)\t\nIM terminal half-life:\t20.5 h (with pan)\t \t\nIM trough levels: (mean)\n(P=0.125)\t1085 (±480) (without pan)\n1290 (±440) (with pan)\t1.8 μM (±0.8 μM) (without pan)\n2.2 μM (±0.7 μM) (with pan)\n==== Refs\nBauer S Yu LK Demetri GD Fletcher JA 2006 Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor Cancer Res 66 (189153 9161 16982758 \nBlanke CD Demetri GD Von Mehren M Heinrich MC Eisenberg B Fletcher JA Corless CL Fletcher CD Roberts PJ Heinz D Wehre E Nikolova Z Joensuu H 2008 Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT J Clin Oncol 26 (4620 625 18235121 \nBlanke CD Rankin C Demetri GD Ryan CW Von Mehren M Benjamin 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"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "110(5)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D005260:Female; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids; D000068877:Imatinib Mesylate; D007211:Indoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077767:Panobinostat; D010879:Piperazines; D011743:Pyrimidines",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1155-62",
"pmc": null,
"pmid": "24434430",
"pubdate": "2014-03-04",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16899611;15007386;19509176;16954519;18235121;20697094;16982758;23177515;17145876;18235122;21964801;22014153;9438854;15451219;22665524;10673991;21484248;11719439;17046465;21706316;17962618;12522257;16122278;21984064;19706776;17694093;15811621",
"title": "Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors.",
"title_normalized": "phase i study of panobinostat and imatinib in patients with treatment refractory metastatic gastrointestinal stromal tumors"
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"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-137028",
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"abstract": "Chronic HIV infection leads to increased risk of non-Hodgkin B-cell lymphoma. However, only few recent data are available about their current management and prognosis in HIV-infected children since the advent highly active antiretroviral therapy (HAART). This multicenter retrospective study describes the 12 cases of B-cell non-Hodgkin lymphoma diagnosed in HIV-infected children in France between 1996 and 2009. All children had moderate to severe immunosuppression and high viral load at the time of diagnosis. Nine children had extracerebral primary sites and 3 had a primary central nervous system lymphoma. Eight patients had Burkitt lymphoma; 4 had diffuse large B-cell lymphoma. Concomitantly with HAART, all children with extracerebral lymphoma received intensive chemotherapy according to LMB protocol, those with primary central nervous system lymphoma received high-dose methotrexate. No toxicity-related deaths occurred. Ten patients entered complete remission (CR), 2 died of tumor progression despite a second line of therapy. No relapses occurred after CR (median follow-up, 72 mo). Thus, prognosis of patients unresponsive to first-line lymphoma treatment remains poor, but relapse seems to be rare when CR is achieved. Children without severe comorbidities can tolerate intensive chemotherapy with a mandatory HAART treatment, taking into account drug interactions.",
"affiliations": "Service d'Onco-Hématologie Pédiatrique, Hôpital A. Trousseau, France.",
"authors": "Godot|Cécile|C|;Patte|Catherine|C|;Blanche|Stéphane|S|;Rohrlich|Pierre|P|;Dollfus|Catherine|C|;Tabone|Marie-Dominique|MD|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab",
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"issue": "34(7)",
"journal": "Journal of pediatric hematology/oncology",
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"mesh_terms": "D000293:Adolescent; D058846:Antibodies, Monoclonal, Murine-Derived; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007223:Infant; D016483:Lymphoma, AIDS-Related; D016393:Lymphoma, B-Cell; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D000069283:Rituximab",
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"pubdate": "2012-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Characteristics and prognosis of B-cell lymphoma in HIV-infected children in the HAART era.",
"title_normalized": "characteristics and prognosis of b cell lymphoma in hiv infected children in the haart era"
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"abstract": "COVID-19 is the disease caused by SARS-CoV-2 that portends both a relatively high mortality rate as well as high rate of intensive care admission amongst all age groups; however effective therapy remains poorly characterized. Post-transplant patients are especially high risk and underrepresented in the literature. In these patients, cytokine release may play a significant role in the development of acute respiratory distress syndrome, raising the hypothesis that interleukin-6 inhibitors such as tocilizumab may be of benefit. Here, we describe two high-risk post-transplant patients who were treated with single-dose tocilizumab after intubation for moderate acute respiratory distress syndrome secondary to confirmed COVID-19 infection. Both patients recovered rapidly and were successfully extubated and discharged from the hospital without need for supplemental oxygen shortly thereafter, and their clinical improvement correlated with response in interleukin-6 levels. Tocilizumab appears to hold promise for critically ill COVID-19 patients who require mechanical ventilation when given shortly after intubation.",
"affiliations": "Division of Internal Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States.;Division of Internal Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States.;Division of Internal Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States.;Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States.",
"authors": "Ladna|M|M|;Villanueva|F L|FL|;Maharrey|P B|PB|;Lascano|J|J|",
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"doi": "10.1016/j.rmcr.2020.101319",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(20)30533-5\n10.1016/j.rmcr.2020.101319\n101319\nCase Report\nPost-transplant patients with COVID-19 associated acute respiratory distress syndrome, a role for Tociluzumab: A case series\nLadna M. michael.ladna@medicine.ufl.edu\na∗\nVillanueva F.L. a\nMaharrey P.B. a\nLascano J. b\na Division of Internal Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States\nb Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States\n∗ Corresponding author. Division of Internal Medicine, Department of Medicine, 1600 SW Archer Rd, Gainesville, FL, 32610, United States. michael.ladna@medicine.ufl.edu\n09 12 2020\n2021\n09 12 2020\n32 1013196 8 2020\n3 12 2020\n7 12 2020\nPublished by Elsevier Ltd.\n2020\n\nThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nCOVID-19 is the disease caused by SARS-CoV-2 that portends both a relatively high mortality rate as well as high rate of intensive care admission amongst all age groups; however effective therapy remains poorly characterized. Post-transplant patients are especially high risk and underrepresented in the literature. In these patients, cytokine release may play a significant role in the development of acute respiratory distress syndrome, raising the hypothesis that interleukin-6 inhibitors such as tocilizumab may be of benefit. Here, we describe two high-risk post-transplant patients who were treated with single-dose tocilizumab after intubation for moderate acute respiratory distress syndrome secondary to confirmed COVID-19 infection. Both patients recovered rapidly and were successfully extubated and discharged from the hospital without need for supplemental oxygen shortly thereafter, and their clinical improvement correlated with response in interleukin-6 levels. Tocilizumab appears to hold promise for critically ill COVID-19 patients who require mechanical ventilation when given shortly after intubation.\n\nKeywords\n\nCOVID-19\nAcute respiratory distress syndrome\nTocilizumab\nRespiratory failure\nCritical care\nAbbreviations\n\nLIST, ARDS\nacute respiratory distress syndrome, COVID-19\ncoronavirus disease of 2019, CT\ncomputerized tomography, IL\ninterleukin, CAR-T cell: chimeric antigen receptor T-cell\n==== Body\n1 Introduction\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel beta coronavirus which originated in Wuhan, China in 2019. This virus causes coronavirus disease of 2019 (COVID-19). SARS-CoV-2 has a high virulence, no vaccine, no antiviral treatment, and relatively high mortality of 1.8–3.4%. Disease severity of COVID-19 necessitating admission to intensive care units is estimated at 5–11.5% amongst all age groups [1]. The United States is at particularly high risk for SARS-CoV-2-related mortality due to high prevalence of risk factors for poor outcomes, which include age greater than 65, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, history of tobacco use, and chronic obstructive pulmonary disease [[2], [3], [4]]. Transplant patients are likely at higher risk given immunosuppression and underrepresented in current literature.\n\nSeveral treatments are being actively investigated including hydroxychloroquine and azithromycin combination therapy, lopinavir/ritonavir, and remdesivir. These agents have shown antiviral activity against SARS-CoV-2 in vitro [[5], [6], [7]] as well as promise in humans [8,9], though this data is limited. Utility of these agents is likely limited to early disease since they theoretically function as antiviral; late complications of COVID-19 include acute respiratory distress syndrome (ARDS), which may be a result of cytokine storm. Cytokine storm is triggered by release of interferon gamma by T-cells which leads to release of tumor necrosis factor alpha, IL-6, and IL-10 by macrophages which can go on to cause significant lung injury and ARDS, as well as distributive shock and multisystem organ failure [10]. Studies have already shown that lopinavir/ritonavir did not have significant benefit when used late in disease course for varying severities of COVID-19, including ARDS [11,12].\n\nMortality of late stage ARDS secondary to COVID-19 is high, with studies showing mortality from 48% up to 90% once intubated and placed on mechanical ventilation, which is significantly higher than mortality associated with intubation for other viral pneumonias which is around 22% [13,14]. The reason for this higher mortality could be related to cytokine storm as critically ill COVID-19 patients have cytokine profiles resembling macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis with significant elevations in IL-1B, IL-2, IL-6, IL-17, IL-8 and tumor necrosis factor [15], with similar serologic markers such as elevated ferritin, elevated liver enzymes, and coagulopathies [16]. Presence of cytokine storm is further supported by significant proportion of COVID-19 patients who are intubated and requiring vasopressors for distributive shock despite no evidence of bacterial superinfection [17]. Thus, an effective therapy is in dire need.\n\nIL-6 inhibitors such as tocilizumab and siltuximab/sarilumab have shown benefit in treatment of cytokine storm in chimeric antigen receptor T-cell patients. These agents have also shown promise for treatment of ARDS in severely ill COVID-19 patients via suppression of cytokine storm [18]. We present two critically ill post-transplant patients, each requiring intubation and mechanical ventilation for severe COVID-19 disease who were treated with single-dose tocilizumab and experienced rapid subsequent improvement at a large tertiary referral center in Gainesville, Florida, United States.\n\n2 Case 1\n\nCase 1 is a 50-year-old male with past medical history of coronary artery disease, nonischemic cardiomyopathy, type 2 diabetes mellitus, essential hypertension, and prior stroke who recently underwent kidney and heart transplant in February 2020. His post-transplant course was complicated with upper respiratory symptoms about one month after transplant, and his nasopharyngeal nucleic acid amplification test for SARS-CoV-2 returned positive. During that admission, he did not require supplemental oxygen, and was discharged home to complete a total five-day course of hydroxychloroquine. Three days after discharge, he presented to the emergency department for severe dyspnea. While being evaluated in the emergency department, he experienced rapid and profound hypoxic respiratory decompensation requiring intubation and mechanical ventilation. Initial lab work was significant for IL-6 level of 45 pg/mL, ferritin of 648 ng/mL, LDH of 426 U/L, D-Dimer of 4.84 UG/mL, high-sensitivity CRP of 74.9 mg/L. These elevated markers of inflammation and cell death were consistent with potential cytokine storm. Admission chest radiograph showed significant burden of bilateral airspace opacities (Fig. 1). He was given 400 mg of tocilizumab on his first hospital day, approximately 5 hours after intubation. He was also started on broad spectrum antibiotics (vancomycin and cefepime), azithromycin 500 mg daily, and hydroxychloroquine 200 mg twice a day. His transplant immunosuppression with tacrolimus was continued, he was started on stress dose hydrocortisone 50mg every 6 hours and his mycophenolate was held per International Society for Heart and Lung Transplantation guidelines for moderate-severe COVID-19 ARDS [19]. Due to progressively worsening hypoxia and ARDS (pAO2:FiO2 ratio of 117), he was started on inhaled epoprostenol and subsequently underwent brief neuromuscular blockade with cisatracurium for 4 h on his first hospital night. He continued to improve clinically in the subsequent days with supportive care and lung-protective ventilation per ARDSNet protocol [20], associated with rapid improvement in the airspace opacities seen on admission chest radiograph on repeat on his fourth hospital day (Fig. 2). He did not require proning or vasopressive support during his hospitalization. He was weaned off inhaled epoprostenol on his fifth hospital day, extubated on his seventh hospital day, and was discharged home without supplemental oxygen requirement on his eleventh hospital day. His IL-6 level peaked at 303 pg/mL and decreased to 21 pg/mL on the date of discharge.Fig. 1 Chest radiograph of Case 1 on day of admission which shows bilateral multifocal airspace opacities.\n\nFig. 1\n\nFig. 2 Chest radiograph of Case 1 on hospital day 8 post-extubation which shows improvement in multifocal airspace opacities.\n\nFig. 2\n\n3 Case 2\n\nCase 2 is a 67-year-old male with past medical history of chronic hepatitis B complicated by hepatocellular carcinoma status post orthotopic liver transplant in September 2016, with repeat orthotopic Roux-en-Y liver transplant with pyloric exclusion in November of 2016, history of cryptococcus pneumonia with documented clearance after 28 days of fluconazole in 2018, hypertension, and type 2 diabetes mellitus who presented to the emergency department for one week of fever and dyspnea, and he was admitted to the medical intensive care unit due to acute hypoxic respiratory failure requiring intubation and mechanical ventilation. Admission chest radiograph showed multifocal airspace opacities (Fig. 3), and computerized tomography (CT) of the chest on day of admission showed multifocal mixed ground glass opacities and dense consolidations throughout bilateral lungs (Fig. 4). Initial arterial blood gas showed a pAO2:FiO2 ratio of 116, consistent with moderate ARDS. His nasopharyngeal nucleic acid amplification test for SARS-CoV-2 returned positive. His initial lab work was notable for IL-6 level of 31 pg/mL, ferritin of 320.4 ng/mL, LDH of 321 U/L, D-Dimer of 3.25 UG/mL, high-sensitivity CRP of 244 mg/L, which suggested a high level of inflammation and cell death consistent with potential cytokine storm. He was started on broad spectrum antibiotics (vancomycin and piperacillin/tazobactam), azithromycin 500 mg daily, and hydroxychloroquine 400 mg twice a day for one day followed by 200 mg twice a day. His home oral hydrocortisone for underlying adrenal insufficiency was continued and he did not require stress dose steroids. He was given single 400 mg dose of tocilizumab on his first hospital day, approximately 5 h after intubation, after which transplant hepatology recommended holding home mycophenolate mofetil and tacrolimus given potent immunosuppressive effects of tocilizumab. He was extubated on his second hospital day, and chest radiograph afterwards showed improvement in the multifocal airspace disease (Fig. 5). Tacrolimus was started seven days after administration of tocilizumab. He did not require neuromuscular blockade, vasopressive support, or proning during his hospitalization. He continued to improve and was discharged home on his eighth hospital day without supplemental oxygen requirement. His IL-6 level peaked at 318 pg/mL and decreased to 78 pg/mL on the date of discharge. His mycophenolate was restarted two weeks after administration of tocilizumab.Fig. 3 Chest radiograph of Case 2 on day of admission which shows bilateral multifocal airspace opacities.\n\nFig. 3\n\nFig. 4 Axial CT chest on day of admission with multifocal mixed ground glass and dense consolidations throughout bilateral lungs.\n\nFig. 4\n\nFig. 5 Chest radiograph of Case 2 on hospital day 4 with slight improvement in multifocal airspace opacities.\n\nFig. 5\n\n4 Discussion\n\nWe have presented two successful cases of single-dose tocilizumab use in critically ill post-transplant patients with moderate COVID-19 ARDS.\n\nAlthough both patients had rapid improvement with tocilizumab, there are several unique factors. Notably, both patients were already immunosuppressed prior to hospitalization due to their post-transplant status, theoretically causing their respective immune systems to be less able to mount a strong cytokine release in the setting of COVID-19. This could perhaps explain how our cases differ from the results of the study by Lou et al. in Wuhan, China which showed that single-dose tocilizumab often failed to improve disease activity in those who were critically ill, who often needed multiple doses of tocilizumab due to persistently elevated IL-6 levels even when given in conjunction with high-dose glucocorticoids [18]. Both of our patients had a peak IL-6 level over 300 pg/mL during their hospitalization which subsequently trended downward prior to discharge. This particular population of post-transplant patients with severe COVID-19 is underrepresented in current literature and provides a unique perspective in use of novel therapies.\n\nOf note, both patients were also treated with hydroxychloroquine and azithromycin since treatment took part prior to recent studies that revealed no benefit to COVID-19 patients when treated with hydroxychloroquine [21] with or without azithromycin [22]. In fact, some studies found an increase in adverse events for group treated with hydroxychloroquine [21]. Despite confounding factors and limitations, the rapid improvement seen in both patients is both promising and reassuring given that COVID-19 patients who require intubation typically require prolonged mechanical ventilation for average of 10 days [4]. Both patients also have several comorbidities, notably history of solid organ transplant on immunosuppression, and advanced age which puts them in higher risk for extended mechanical ventilation duration and mortality from COVID-19. The therapeutic window for IL-6 inhibitors such as tocilizumab is likely quite narrow. These agents must be given just before or immediately at onset of ARDS and cytokine storm, which tends to occur at day 7–10 of illness, and only in the minority of patients who experience rapid deterioration requiring admission to intensive care for mechanical ventilation (approximately 5–10% of all patients) [1]. Once ARDS has fully evolved, inhibition of immune system would likely do little to help remove proteinaceous fluid in alveoli, thus long mechanical ventilation and admission in the intensive care setting is to be expected.\n\nMoving forward, further randomized controlled trials are necessary to support the findings we report. Given the robust response, we recommend consideration of tocilizumab, especially if other IL-6 inhibitors/blockers are not available, to critically ill patients with confirmed COVID-19 who require intubation for hypoxic respiratory failure with evidence of bilateral ground glass opacities on chest radiograph or CT, as aggressive empiric early treatment will likely have most impact on preventing ARDS and thus decreasing mortality.\n\nFunding sources\n\nThis research did not receive any grant support.\n\nAuthor contributions\n\nML, FLV, and PBM had full access to both cases in this study and drafted the original manuscript, and JL provided critical revision. ML, FLV, PBM, and JL were involved in the conception of the project and the approval of the final manuscript, and they will take responsibility for the integrity and accuracy of the data presented.\n\nDeclaration of competing interest\n\nThe authors have no conflicts of interest to disclose.\n\nAcknowledgements\n\nML, FLV, and PBM had full access to both cases in this study and drafted the original manuscript, and JL provided critical revision. ML, FLV, PBM, and JL were involved in the conception of the project and the approval of the final manuscript, and they will take responsibility for the integrity and accuracy of the data presented.\n==== Refs\nReferences\n\n1 Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19)—United States, February 12–March 16, 2020 2020 Center for Disease Control (CDC)\n2 Wu C. Chen X. Cai Y. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China JAMA Internal Medicine 180 7 2020 934 943 32167524\n3 Zhou F. Yu T. Du R. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Lancet 395 10229 2020 1054 1062 32171076\n4 Grasselli G. Zangrillo A. Zanella A. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region Italy. JAMA. 323 16 2020 1574 1581 32250385\n5 Gordon C.J. Tchesnokov E.P. Feng J.Y. Porter D.P. Götte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus J. Biol. Chem. 295 15 2020 4773 4779 32094225\n6 Yao X. Ye F. Zhang M. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) 2020 Clinical Infectious Diseases\n7 Yao T.T. Qian J.D. Zhu W.Y. Wang Y. Wang G.Q. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus—a possible reference for coronavirus disease‐19 treatment option J. Med. Virol. 92 6 2020 556 563 32104907\n8 Gautret P. Lagier J.-C. Parola P. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Int. J. Antimicrob. Agents 56 1 2020 105949\n9 Grein J. Ohmagari N. Shin D. Compassionate use of remdesivir for patients with severe covid-19 N. Engl. J. Med. 382 24 2020 2327 2336 32275812\n10 Wang Z. Han W. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy Biomarker Research 6 1 2018 4 29387417\n11 Que T. Wong V. Yuen K. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study Hong Kong Med. J. 9 6 2003 399 406 14660806\n12 Cao B. Wang Y. Wen D. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19 N. Engl. J. Med. 382 19 2020 1787 1799 32187464\n13 ICNARC report on COVID-19 in critical care Intensive Care National Audit & Research Centre (ICNARC) 2020 April 4\n14 Wang Y. Lu X. Chen H. Clinical course and outcomes of 344 intensive care patients with COVID-19 Am. J. Respir. Crit. Care Med. ja 2020\n15 Wan S. Yi Q. Fan S. Characteristics of Lymphocyte Subsets and Cytokines in Peripheral Blood of 123 Hospitalized Patients with 2019 Novel Coronavirus Pneumonia (NCP) 2020 medRxiv\n16 McGonagle D. Sharif K. O'Regan A. Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease Autoimmun. Rev. 2020 102537\n17 Bhatraju P.K. Ghassemieh B.J. Nichols M. Covid-19 in critically ill patients in the Seattle region—case series N. Engl. J. Med. 382 21 2020 2012 2022 32227758\n18 Luo P. Liu Y. Qiu L. Liu X. Liu D. Li J. Tocilizumab treatment in COVID‐19: a single center experience J. Med. Virol. 92 7 2020 814 818 32253759\n19 Guidance from the international society of heart and lung transplantation regarding the SARS CoV-2 pandemic https://ishlt.org/ishlt/media/documents/SARS-CoV-2_-Guidance-for-Cardiothoracic-Transplant-and-VAD-centers.pdf 2020\n20 Brower R.G. Matthay M.A. Morris A. Schoenfeld D. Thompson B.T. Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome N. Engl. J. Med. 342 18 2000 1301 1308 10793162\n21 Tang W. Cao Z. Han M. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial BMJ 369 2020 m1849 10.1136/bmj.m1849 32409561\n22 Molina J.M. Delaugerre C. Le Goff J. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection Med. Maladies Infect. 50 4 2020 384 10.1016/j.medmal.2020.03.006\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2213-0071",
"issue": "32()",
"journal": "Respiratory medicine case reports",
"keywords": "Acute respiratory distress syndrome; COVID-19; Critical care; LIST, ARDS; Respiratory failure; Tocilizumab; acute respiratory distress syndrome, COVID-19; computerized tomography, IL; coronavirus disease of 2019, CT; interleukin, CAR-T cell: chimeric antigen receptor T-cell",
"medline_ta": "Respir Med Case Rep",
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"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101319",
"pmc": null,
"pmid": "33318918",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "14660806;10793162;32250385;32150618;32171076;32253759;32094225;32240719;32104907;32251717;32167524;32267160;32205204;32409561;32187464;29387417;32275812;32227758",
"title": "Post-transplant patients with COVID-19 associated acute respiratory distress syndrome, a role for Tociluzumab: A case series.",
"title_normalized": "post transplant patients with covid 19 associated acute respiratory distress syndrome a role for tociluzumab a case series"
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"abstract": "BACKGROUND\nMicafungin, an antifungal echinocandin, has been indicated for pediatric patients with invasive fungal infection (IFI) in Japan and Europe. Its efficacy in immunocompromised pediatric patients with IFI, however, has not been fully investigated.\n\n\nMETHODS\nThe safety and efficacy of micafungin as an antifungal therapy were analyzed in nine consecutive severe immunocompromised patients with IFI.\n\n\nRESULTS\nThree patients with proven or probable Candida infections had complete response to micafungin therapy. Of the other six patients with proven, probable or possible Aspergillus infection, four had complete response and one had partial response to micafungin treatment. No severe adverse events were observed.\n\n\nCONCLUSIONS\nIn this small series, micafungin was effective for IFI caused by both Candida and Aspergillus species and no severe adverse events were observed in these immunocompromised patients.",
"affiliations": "Department of Developmental Medicine, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Pediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.;Department of Pediatrics, Ikeda City Hospital, Ikeda, Japan.;Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Pediatrics, Higashitoyonakawatanabe Hospital, Osaka, Japan.;Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Developmental Medicine, Osaka University Graduate School of Medicine, Suita, Japan.",
"authors": "Hashii|Yoshiko|Y|;Kusuki|Shigenori|S|;Takizawa|Sachiko|S|;Tokimasa|Sadao|S|;Ohta|Hideaki|H|;Hara|Junichi|J|;Ozono|Keiichi|K|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin",
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"issue": "56(6)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "immunocompromised host; invasive fungal infection; micafungin; pediatric patient",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D001228:Aspergillosis; D002177:Candidiasis; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D054714:Echinocandins; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D055666:Lipopeptides; D008297:Male; D000077551:Micafungin; D016896:Treatment Outcome",
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"title": "Efficacy of micafungin in pediatric immunocompromised patients with invasive fungal infection.",
"title_normalized": "efficacy of micafungin in pediatric immunocompromised patients with invasive fungal infection"
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"abstract": "Two immunocompromised patients with relapsing gastrointestinal infection with relatively resistant Salmonella infantis were cured with prolonged ertapenem followed by encapsulated fecal transplant.",
"affiliations": "Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts.;Division of Infectious Diseases, Brigham and Womens Hospital, Boston, Massachusetts.;Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts.;Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts.;Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts.",
"authors": "Torres Soto|Mariam|M|;Hammond|Sarah|S|;Elshaboury|Ramy H|RH|;Johnson|Jacob|J|;Hohmann|Elizabeth L|EL|",
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"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n30648128\n10.1093/ofid/ofy334\nofy334\nID Case\nRecurrent Relatively Resistant Salmonella infantis Infection in 2 Immunocompromised Hosts Cleared With Prolonged Antibiotics and Fecal Microbiota Transplantation\nTorres Soto Mariam 1 Hammond Sarah 2 Elshaboury Ramy H 1 Johnson Jacob 1 Hohmann Elizabeth L 1 1 \nDivision of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts\n\n2 \nDivision of Infectious Diseases, Brigham and Womens Hospital, Boston, Massachusetts\n\nCorrespondence: M. Torres Soto, BA, MA, Jackson 518, 55 Fruit St., Boston, MA 02114 (mtorressoto@mgh.harvard.edu).\n1 2019 \n14 12 2018 \n14 12 2018 \n6 1 ofy33412 11 2018 11 12 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2018This 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\nTwo immunocompromised patients with relapsing gastrointestinal infection with relatively resistant Salmonella infantis were cured with prolonged ertapenem followed by encapsulated fecal transplant.\n\nchronic carriagefecal transplantFMTSalmonella\n==== Body\nNontyphoidal salmonellae are hardy organisms that may be difficult to eradicate in compromised hosts, including those with AIDS, cancer, hemoglobinopathies, and organ transplants. Salmonellae may persist in the reticuloendotheial system and in the biliary, urinary, and intestinal tracts, particularly in the setting of anatomic or immunological abnormalities. The median duration of salmonella shedding in normal adults after intestinal infection is 5 weeks [1]. Intestinal colonization resistance and elimination of enteric pathogens is a complex process influenced by host, pathogen, and the microbiome [2]. A Finnish report discusses new indications for fecal microbiota transplant (FMT), including 2 apparently healthy food handlers with prolonged, asymptomatic shedding of salmonella not eradicated by antibiotics alone [3]. Here we report 2 immunocompromised hosts with persistent symptomatic infection with Salmonella infantis, who were ultimately cured with a combination of ertapenem and capsulized FMT.\n\nPATIENT 1\nThe patient was a 60-year-old man with chronic lymphocytic leukemia (CLL) last treated 8 years earlier, with slowly progressive recurrent nodal disease. He had intermittent neutropenia and CLL-related hypogammaglobulinemia treated with monthly intravenous immunoglobulin (IVIg), and he presented to the emergency department with several weeks of worsening diarrhea and a day of fever. The patient had no suspicious ingestions or travel. The patient’s baseline absolute neutrophil counts were 200–2500 for several years, and renal function was normal. An abdominal computed tomography (CT) scan showed pancolitis. He was admitted to the hospital for assessment and supportive care. Stool testing for Clostridium difficile was negative, but stool cultures grew salmonella group C1, eventually identified as S. infantis resistant to ceftriaxone and trimethoprim-sulfamethoxazole, intermediate to ciprofloxacin, and susceptible to ceftazidime (Table 1). He was discharged home on a 14-day course of ciprofloxacin (500 mg twice daily), which was later extended, based on the intermediate susceptibility to ciprofloxacin. A blood culture collected on day 14 of therapy was negative, and the patient reported feeling back to his baseline after 19 days, so ciprofloxacin was stopped.\n\nTable 1. Antimicrobial Susceptibilities for Salmonella infantis Isolates\n\nAntibiotic\tPatient 1\tPatient 2\t\nAmpicillin\tR (6)\tR (>32)\t\nCeftriaxone\tR (>256)\tR (>64)\t\nCiprofloxacin\tI (0.125)\tI (0.250)\t\nCeftazidime\tS (<2)\tND\t\nErtapenem\tS (31 mm)\tS (<0.5 E-test)\t\nTrimethoprim/sulfa\tR (6)\tR (>320)\t\nAzithromycin\tS (16 E-test)\tS (4 E-test)\t\nNumbers are minimum inhibitory concentrations by VITEK; mm corresponds to Kirby-Bauer disk testing, E-test where noted.\n\nAbbreviation: ND, not done.\n\nAbout 2 weeks after stopping ciprofloxacin, he developed fever and explosive diarrhea. He was found to be neutropenic, and a repeat CT scan of the abdomen again demonstrated pancolitis. He was admitted to the hospital. Blood cultures were negative, but a stool culture again grew salmonella with the same resistance pattern. He was treated with ceftazidime and his symptoms improved, but he developed a diffuse rash within a few days. Additional resistance testing was performed, including antibiotics for which there are no defined breakpoints. The minimum inhibitory concentration (MIC) for azithromycin by E-test was 16 mcg/mL, and the Kirby-Bauer disc diameter for ertapenem was 31 mm; intravenous (IV) ertapenem was administered. Fever and diarrhea improved, though he continued to have 3–4 loose bowel movements per day. He was discharged home on a 6-week course of ertapenem. During his antibiotic course, he developed intermittent neutropenia treated with filgrastim, and he continued to have loose stools and malaise. His absolute neutrophil count was 0.60 K/uL at the time he was admitted with relapsed salmonella; the lowest neutrophil count seen during the illness was 0.21 K/uL after he has been treated with IV ertapenem for several weeks. He was intermittently supported with granulocyte-colony stimulating factor (G-CSF) to treat neutropenia during his clinical course while ill with salmonella and during IV ertapenem therapy. A repeat CT scan of the abdomen obtained near the end of the ertapenem course showed resolution of colitis and no biliary abnormalities. Because of concerns that his hypogammaglobulinemia, underlying CLL, and initial treatment with ciprofloxacin could put him at risk for further salmonella recurrence, the patient was referred for FMT. Four days after the ertapenem stopped, the patient was treated with frozen, encapsulated FMT, 15 capsules on each of 2 successive days [4], under single patient treatment IND 17745. Loose stools and malaise resolved promptly. A stool culture collected just before FMT was negative for salmonellae; no normal (aerobic) flora were present. Subsequent stool culture 18 days after FMT showed normal (aerobic) flora present and was negative for salmonella (with enrichment).\n\nAfter FMT his absolute neutrophil count (ANC) improved and he no longer required G-CSF support, he was not neutropenic at 4-month follow-up (ANC 1.760 K/uL). IgA was measured during his initial hospitalization for salmonella infection and was low, at 13 mg/dL, and had been low during much of his prolonged CLL history. Notably, at baseline, when he came into care in our medical system, he had a normal IgA level (>10 years before the current illness). He was receiving standard IVIg therapy with Gammunex-C, which is a product that is not IgA-free. The patient was seen in an infectious diseases clinic 4 months after FMT and remains without relapse more than a year later.\n\nPATIENT 2\nA 48-year-old woman with chronic arthropathy on rituximab for 4 years presented to her primary care provider with fever, abdominal pain, and diarrhea for 6 days after a trip to the Dominican Republic. Her traveling companion had a similar illness, but symptoms resolved without treatment. Her last dose of rituximab had been 6 months earlier. She had undergone revision endoscopic sinus surgery approximately 10 weeks before her trip and had received two 10-day courses of oral clindamycin for symptoms of postoperative sinusitis, the last ending 14 days before the trip. She also had a 7-day course of oral prednisone around this time, as well as sulfasalazine (4g/d) and hydroxychloroquine (300 mg/d). Abdominal CT scan showed diffuse colonic wall thickening with mucosal hyperenhancement and fluid in the colon, suggesting proctocolitis of inflammatory or infectious etiology. C. difficile testing was negative, but a stool culture grew salmonella group C1, ultimately identified as S. infantis with intermediate sensitivity to ciprofloxacin (Table 1).\n\nShe was started on a 14-day regimen of ciprofloxacin at an outside hospital (500 mg twice daily, subsequently increased to 750 mg when resistance patterns were known). Diarrhea improved modestly, but 8 days after completing the antibiotic, she experienced worsening diarrhea and fever, necessitating hospitalization. Blood cultures were negative, a stool culture came back positive for salmonella C1 (azithromycin MIC by E-test = 4) (Table 1), scant normal (aerobic) flora were present, and colonoscopy showed mild diffuse colitis. A 14-day regimen of azithromycin was recommended, her diarrhea resolved, and she was followed for 2 months clinically, at which point she was deemed “cleared” to resume rituximab therapy, which had been deferred.\n\nTwo weeks after stopping azithromycin, she had the first of 2 planned rituximab infusions; 1 day after the infusion, diarrhea and fever to 102ºF recurred. She was hospitalized and started on IV meropenem. After 5 days, she was transitioned to azithromycin (500 mg given orally/by mouth daily for 10 days, then 250 mg daily) for a total duration of therapy of 4 weeks. Azithomycin was chosen for high intracellular concentrations and acceptable, unchanged MIC. Consideration was also given to administering IVIg. Serum IgG and IgA were just below the lower limit of the normal range, so this was deferred in favor of FMT, as the primary site of infection seemed to be within the gastrointestinal (GI) lumen and the patient was not documented to be bacteremic. Abdominal CT done during the previous admission was reviewed with consideration of biliary abnormalities, but none were seen. An right-upper quadrant ultrasound was normal. One week after stopping azithromycin, she received frozen, encapsulated FMT (15 capsules on each of 2 successive days) under single patient treatment IND 18238. The patient felt well and returned to work.\n\nFifteen days later, she presented again with diarrhea, abdominal pain, fever to 102°F, and stool culture again showing salmonella C1 with the same resistance pattern. She was started on a 4-week regimen of IV ertapenem (1 g daily). Serum immunoglobulins were in the low-normal range. Her diarrhea resolved within 2 weeks, but she did not feel entirely well. Four days after completing ertapenem, she received frozen, encapsulated FMT (15 capsules on each of 3 successive days; same donor as used previously). Stool culture with enrichment that was done before FMT revealed that normal (aerobic) flora were present and was negative for enteric pathogens. Rituximab was deferred for 3 months after the second FMT. Diarrhea resolved, and she reported normal bowel habits and an improved sense of well-being within 7 days. She was contacted 2 months after FMT treatment and reported feeling back to baseline.\n\nDISCUSSION\nBoth patients ultimately cleared symptomatic salmonella intestinal infection after a long course of a carbapenem and FMT. Both patients were initially suspected to have C. difficile infection, highlighting the need for additional testing for enteric pathogens in compromised hosts. Both patients were treated with a fluoroquinolone empirically by generalists and initially improved. Though fluoroquinolones at higher doses are an accepted treatment option for typhoidal salmonellae with intermediate resistance [5], this has not been formally studied in nontyphoidal intestinal infection in compromised hosts and may not be advisable. We were surprised by the second patient’s relapse after 1 month of azithromycin followed by FMT. Although there are no formal breakpoints for azithromycin, a study using broth microdilution proposed a value of <16 mcg/mL as “sensitive” [6]. Additionally, studies show that intracellular levels of azithromycin are ~100-fold higher than serum levels [7], and thus advantageous in situations where reticuloendothelial persistence is likely. One wonders if the anti-inflammatory effects of macrolides might inhibit clearance in compromised hosts; this has not been studied at the mucosal surface. Neither patient was documented to be bacteremic or to have signs or symptoms of an extraintestinal focus of infection. Biliary abnormalities were absent in both, and we hypothesize that they both had ongoing luminal intestinal carriage of the organism. Perhaps intestinal carriage is better treated by carbapenems than by azithromycin; limited data show that both penetrate colorectal tissues [8–10]. The degree to which FMT contributed to cure is unknown, but both patients had absent or scant normal (aerobic) flora initially and reported normalized GI function after FMT. The effect of FMT is likely multifactorial; host, flora, and pathogen probably contribute to gastrointestinal “colonization resistance.” For example, normal flora has a protective role in clearing S. enterica from the mouse gut [11], and butyrate derived from normal flora suppresses expression of salmonella invasion genes [12]. FMT has been recommended for patients with multiple recurrent C. difficile infections by both the Infectious Diseases Society of America and American College of Gastroenterology, has been demonstrated to decrease the burden of resistant organisms in the human intestine [13–15], and may be of value in selected immunocompromised hosts with other persistent intestinal infections.\n\nAcknowledgments\n\nAuthor contributions. Mariam Torres Soto was involved in the drafting of the manuscript. Sarah Hammond, Ramy H. Elshaboury, and Jacob Johnson were involved in the critical revision of the manuscript. Elizabeth Hohmann was involved with the report concept and critical revision of the manuscript.\n\n\nPotential conflicts of interest. There are no potential conflicts of interest to disclose and no funding sources to declare. All authors: no reported conflicts of interest. 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. \nBuchwald DS , Blaser MJ \nA review of human salmonellosis: II. Duration of excretion following infection with nontyphi salmonella\n. Rev Infect Dis 1984 ; 6 :345 –56\n.6377442 \n2. \nKim S , Covington A , Pamer EG \nThe intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens\n. Immunol Rev 2017 ; 279 :90 –105\n.28856737 \n3. \nLahtinen P , Mattila E , Anttila VJ , et al. \nFaecal microbiota transplantation in patients with Clostridium difficile and significant comorbidities as well as in patients with new indications: a case series\n. World J Gastroenterol 2017 ; 23 :7174 –84\n.29093626 \n4. \nYoungster I , Mahabamunuge J , Systrom HK , et al. \nOral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection\n. BMC Med 2016 ; 14 :1–4 .26728489 \n5. \nParry CM , Vinh H , Chinh NT , et al. \nThe influence of reduced susceptibility to fluoroquinolones in Salmonella enterica serovar typhi on the clinical response to ofloxacin therapy\n. PLoS Negl Trop Dis 2011 ; 5 :1–8 .\n6. \nSjölund-Karlsson M , Joyce K , Blickenstaff K , et al. \nAntimicrobial susceptibility to azithromycin among Salmonella enterica isolates from the United States\n. Antimicrob Agents Chemother 2011 ; 55 :3985 –9\n.21690279 \n7. \nPanteix G , Guillaumond B , Harf R , et al. \nIn-vitro concentration of azithromycin in human phagocytic cells\n. J Antimicrob Chemother 1993 ; 31 (Suppl E ):1 –4\n.\n8. \nErttmann M , Krausse R , Ullmann U \nPharmacokinetics of imipenem in patients undergoing major colon surgery\n. Infection 1990 ; 18 :367 –71\n.2076910 \n9. \nKong FYS , Rupasinghe TW , Simpson JA , et al \nPharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men\n. PLoS One 2017 ; 12 :1–14. \n10. \nWittau M , Scheele J , Bulitta JB , et al. \nPharmacokinetics of ertapenem in colorectal tissue\n. Chemotherapy 2011 ; 57 :437 –48\n.22189340 \n11. \nEndt K , Stecher B , Chaffron S , et al. \nThe microbiota mediates pathogen clearance from the gut lumen after non-typhoidal salmonella diarrhea\n. PLoS Pathog 2010 ; 6 :e1001097 .20844578 \n12. \nBäumler AJ , Sperandio V \nInteractions between the microbiota and pathogenic bacteria in the gut\n. Nature 2016 ; 535 :85 –93\n.27383983 \n13. \nBilinski J , Grzesiowski P , Sorensen N , et al. \nFecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study\n. Clin Infect Dis 2017 ; 65 :364 –70\n.28369341 \n14. \nDavido B , Batista R , Michelon H , et al. \nIs faecal microbiota transplantation an option to eradicate highly drug-resistant enteric bacteria carriage\n? J Hosp Infect 2017 ; 95 :433 –7\n.28237504 \n15. \nWei Y , Jianfeng G , Weiming Z , et al \nFecal microbiota transplantation restores dysbiosis in patients with methicillin resistant Staphylococcus aureus enterocolitis\n. BMC Infect Dis 2015 ; 15:1–8 .\n\n",
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"title": "Recurrent Relatively Resistant Salmonella infantis Infection in 2 Immunocompromised Hosts Cleared With Prolonged Antibiotics and Fecal Microbiota Transplantation.",
"title_normalized": "recurrent relatively resistant salmonella infantis infection in 2 immunocompromised hosts cleared with prolonged antibiotics and fecal microbiota transplantation"
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"abstract": "As methadone use increases, the potential for methadone-induced cardiotoxicity (MIC) may rise. We describe a case of acute right ventricular (RV) failure leading to cardiogenic shock after methadone overdose. This presentation was followed by full RV recovery. This previously undescribed presentation highlights the challenges involved with MIC, its diagnosis and its management.",
"affiliations": "Division of Hospital Medicine, University of Florida College of Medicine, Gainesville, Florida, USA mohamad.taha@medicine.ufl.edu.;Division of Hospital Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Hospital Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Hospital Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.",
"authors": "Taha|Mohamad Badie|MB|http://orcid.org/0000-0002-9975-1220;Dasa|Osama|O|;Al-Ani|Mohammad|M|;Taha|Omar B|OB|;Radhakrishnan|Nila S|NS|;Ahmed|Mustafa M|MM|",
"chemical_list": "D000996:Antitussive Agents; D008691:Methadone",
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"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; clinical diagnostic tests; heart failure; toxicology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000996:Antitussive Agents; D066126:Cardiotoxicity; D062787:Drug Overdose; D005260:Female; D006333:Heart Failure; D006801:Humans; D008691:Methadone; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D016278:Ventricular Function, Right",
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"pubdate": "2020-11-02",
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"title": "Acute right ventricular failure: a novel presentation of methadone-induced cardiotoxicity.",
"title_normalized": "acute right ventricular failure a novel presentation of methadone induced cardiotoxicity"
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"abstract": "BACKGROUND\nStandard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma.\n\n\nMETHODS\nIn this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1-21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m(2) as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786.\n\n\nRESULTS\n110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83-95). Complete responses occurred in 65 (63%, 95% CI 53-72) and partial responses in 28 patients (27%, 19-37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]).\n\n\nCONCLUSIONS\nLenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress.\n\n\nBACKGROUND\nCelgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant.",
"affiliations": "Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: nfowler@mdanderson.org.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Fowler|Nathan H|NH|;Davis|R Eric|RE|;Rawal|Seema|S|;Nastoupil|Loretta|L|;Hagemeister|Fredrick B|FB|;McLaughlin|Peter|P|;Kwak|Larry W|LW|;Romaguera|Jorge E|JE|;Fanale|Michelle A|MA|;Fayad|Luis E|LE|;Westin|Jason R|JR|;Shah|Jatin|J|;Orlowski|Robert Z|RZ|;Wang|Michael|M|;Turturro|Francesco|F|;Oki|Yasuhiro|Y|;Claret|Linda C|LC|;Feng|Lei|L|;Baladandayuthapani|Veerabhadran|V|;Muzzafar|Tariq|T|;Tsai|Kenneth Y|KY|;Samaniego|Felipe|F|;Neelapu|Sattva S|SS|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D013792:Thalidomide; D000077269:Lenalidomide",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008224:Lymphoma, Follicular; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D000069283:Rituximab; D013792:Thalidomide; D016896:Treatment Outcome",
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"pubdate": "2014-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10561185;16199517;18628480;7746977;19786615;9699230;21544854;19245430;15126323;18662969;22881386;15657404;21725050;23530110;24292625;16123223;17242397;22677155;9060552;21189385;21228334;19565649;22010965;24292623;8558211;23545991;22888354;22698399;17995965;9166827;22899582;23433739;24436409;11309499;18687642;24328678;16569772;11133748;18606983;23001911",
"title": "Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial.",
"title_normalized": "safety and activity of lenalidomide and rituximab in untreated indolent lymphoma an open label phase 2 trial"
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... |
{
"abstract": "OBJECTIVE\nTo understand patient perspective regarding recommended changes in the 2015 American Thyroid Association (ATA) guidelines. Specifically, in regard to active surveillance (AS) of some small differentiated thyroid cancer (DTC), performance of less extensive surgery for low-risk DTC, and more selective administration of radioactive iodine (RAI).\n\n\nMETHODS\nAn online survey was disseminated to thyroid cancer patient advocacy organizations and members of the ATA to distribute to the patients. Data were collected on demographic and treatment information, and patient experience with DTC. Patients were asked \"what if\" scenarios on core topics, including AS, extent of surgery, and indications for RAI.\n\n\nRESULTS\nSurvey responses were analyzed from 1546 patients with DTC: 1478 (96%) had a total thyroidectomy, and 1167 (76%) underwent RAI. If there was no change in the overall cancer outcome, 606 (39%) of respondents would have considered lobectomy over total thyroidectomy, 536 (35%) would have opted for AS, and 638 (41%) would have chosen to forego RAI. Moreover, (774/1217) 64% of respondents wanted more time with their clinicians when making decisions about the extent of surgery. A total of 621/1167 of patients experienced significant side effects with RAI, and 351/1167 of patients felt that the risks of treatment were not well explained. 1237/1546 (80%) of patients felt that AS would not be overly burdensome, and quality of life was the main reason cited for choosing AS.\n\n\nCONCLUSIONS\nPatient perspective regarding choice in the management of low-risk DTC varies widely, and a large proportion of DTC patients would change aspects of their care if oncologic outcomes were equivalent.",
"affiliations": "Massachusetts General Hospital Institute for Technology Assessment, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: clubitz@mgh.harvard.edu.;Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University, Nashville, Tennessee.;Massachusetts General Hospital Institute for Technology Assessment, Boston, Massachusetts.;Massachusetts General Hospital Institute for Technology Assessment, Boston, Massachusetts.;Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle Cancer Care Alliance, Seattle, Washington.;Department of Surgery, University of California San Francisco, San Francisco, California.;Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Lubitz|Carrie C|CC|;Kiernan|Colleen M|CM|;Toumi|Asmae|A|;Zhan|Tiannan|T|;Roth|Mara Y|MY|;Sosa|Julie A|JA|;Tuttle|R Michael|RM|;Grubbs|Elizabeth G|EG|",
"chemical_list": "D007457:Iodine Radioisotopes",
"country": "United States",
"delete": false,
"doi": "10.1016/j.eprac.2021.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-891X",
"issue": "27(5)",
"journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists",
"keywords": "active surveillance; decision-making; patient perspective; radioactive iodine; survivorship; thyroid cancer",
"medline_ta": "Endocr Pract",
"mesh_terms": "D006801:Humans; D007457:Iodine Radioisotopes; D011788:Quality of Life; D013964:Thyroid Neoplasms; D013965:Thyroidectomy",
"nlm_unique_id": "9607439",
"other_id": null,
"pages": "383-389",
"pmc": null,
"pmid": "33840638",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patient Perspectives on the Extent of Surgery and Radioactive Iodine Treatment for Low-Risk Differentiated Thyroid Cancer.",
"title_normalized": "patient perspectives on the extent of surgery and radioactive iodine treatment for low risk differentiated thyroid cancer"
} | [
{
"companynumb": "US-CURIUM-2021000320",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM IODIDE I-131"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCytomegaly remains one of the most common infectious complications in organ transplant recipients, and the course of the infection may have a negative effect on survival of the transplant and recipient.\n\n\nMETHODS\nWe describe the case of a 32-year-old female patient who received a second kidney transplant from a cadaveric donor in July 2012, treated successfully with ganciclovir for primary CMV infection in August 2012 and then re-treated from November due to re-infection. The viral load at the start of re-treatment was 6 million copies. In view of ganciclovir treatment failure, Sando immunoglobulins were administered. Subsequently, when CMV viral load increased to 18 million copies, a decision was made to use combination treatment with leflunomide and ganciclovir. Immunosuppressive treatment was also modified by administering everolimus in view of its potential antiviral activity. Seizures, pancytopenia, diabetes, diarrhoea, and (probably) drug-induced liver damage and cholangitis were observed in the course of treatment. At 3 months of hospitalization, the patient was discharged home with viral load of 8000 copies. As treatment continuation, she received valganciclovir at the full therapeutic dose in view of very good kidney function (creatinine 0.7 mg/dl). The patient was re-hospitalized after 10 days due to fever and cough. Due to abnormal liver function test results and negative serum markers of viral hepatitis, HCV RNA was tested, with a positive result (above 10^8 copies). Subsequently, decline in clinical status, overhydration, increasing creatinine levels, hepatic failure signs, and renewed CMV DNA increase to 520 000 copies were observed. Despite intensive treatment, the patient died of multi-organ failure.\n\n\nCONCLUSIONS\nThe case described illustrates the difficulties in the treatment of CMV infection and its possible dramatic complications.",
"affiliations": "Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.;Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine and Nephrology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.",
"authors": "Miszewska-Szyszkowska|Dorota|D|;Mikołajczyk|Natalia|N|;Komuda-Leszek|Ewa|E|;Wieczorek-Godlewska|Renata|R|;Świder|Robert|R|;Dęborska-Materkowska|Dominika|D|;Szmidt|Jacek|J|;Durlik|Magdalena|M|",
"chemical_list": "D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D007555:Isoxazoles; D000077339:Leflunomide; D015774:Ganciclovir",
"country": "United States",
"delete": false,
"doi": "10.12659/AOT.892076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1425-9524",
"issue": "20()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D002761:Cholangitis; D003586:Cytomegalovirus Infections; D003924:Diabetes Mellitus, Type 2; D017809:Fatal Outcome; D005260:Female; D015774:Ganciclovir; D006526:Hepatitis C; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007555:Isoxazoles; D016030:Kidney Transplantation; D000077339:Leflunomide; D009102:Multiple Organ Failure; D010198:Pancytopenia; D012086:Reoperation; D012640:Seizures; D066027:Transplant Recipients; D019562:Viral Load",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "169-74",
"pmc": null,
"pmid": "25813912",
"pubdate": "2015-03-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe cytomegalovirus infection in a second kidney transplant recipient treated with ganciclovir, leflunomide, and immunoglobulins, with complications including seizures, acute HCV infection, drug-induced pancytopenia, diabetes, cholangitis, and multi-organ failure with fatal outcome: a case report.",
"title_normalized": "severe cytomegalovirus infection in a second kidney transplant recipient treated with ganciclovir leflunomide and immunoglobulins with complications including seizures acute hcv infection drug induced pancytopenia diabetes cholangitis and multi organ failure with fatal outcome a case report"
} | [
{
"companynumb": "PHHY2015PL056974",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Ewing sarcoma of the thoracic spine and chest wall is frequently treated with concurrent chemotherapy and radiation therapy (RT). Treatment-related acute esophagitis can lead to hospitalization and treatment delays. The aim of this study was to analyze the incidence, risk factors, and management of esophagitis in pediatric patients with Ewing sarcoma of the thoracic region.\n\n\n\nWe conducted a single-institution retrospective review of patients treated over a 10-year period. Medical records were reviewed for patient and treatment characteristics associated with Common Terminology Criteria for Adverse Events grade 2 or higher esophagitis. RT plans were also reviewed and various esophageal dose metrics were analyzed.\n\n\n\nTwelve of 37 patients (32%) developed acute esophagitis. Neutropenia was associated with an increased risk of esophagitis (60% vs. 14%; P < 0.01). RT significantly contributed to its incidence when maximum esophageal dose was >47 Gy (69% vs. 5%; P < 0.0001) and esophageal D5cm3 was >15 Gy (67% vs. 9%; P < 0.001). All 12 patients with esophagitis were managed with oral opioid analgesics. Nine patients with persistent symptoms received subsequent fluconazole for empiric fungal treatment and each had a decreased need for opioid analgesics within 2-5 days.\n\n\n\nApproximately one-third of patients with Ewing sarcoma of the thoracic region will develop acute esophagitis. An esophageal D5cm3 dose < 15 Gy and maximal esophageal dose < 47 Gy may keep the rate of acute esophagitis under 5%. However, the association with neutropenia and consistent response to antifungal therapy suggest chemotherapy-associated toxicity and an infectious component as part of the process.",
"affiliations": "Division of Hematology/Oncology, Nemours Children's Specialty Care, Jacksonville, Florida.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.;Division of Hematology/Oncology, Nemours Children's Specialty Care, Jacksonville, Florida.;Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida.",
"authors": "Agarwal|Vibhuti|V|0000-0001-8769-0232;Logie|Natalie|N|;Morris|Christopher G|CG|;Bradley|Julie A|JA|;Rotondo|Ronny L|RL|;Bradfield|Scott M|SM|;Indelicato|Daniel J|DJ|0000-0001-5765-1873",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "65(6)",
"journal": "Pediatric blood & cancer",
"keywords": "Ewing sarcoma; disease management; esophagitis; radiation therapy; thorax",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D004941:Esophagitis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D012512:Sarcoma, Ewing; D015996:Survival Rate; D013899:Thoracic Neoplasms; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27006",
"pmc": null,
"pmid": "29431250",
"pubdate": "2018-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Esophagitis associated with multimodality management of pediatric Ewing sarcoma of thorax.",
"title_normalized": "esophagitis associated with multimodality management of pediatric ewing sarcoma of thorax"
} | [
{
"companynumb": "US-TEVA-2018-US-905537",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
... |
{
"abstract": "Poor cosmetic results following cervical laminectomy and fusion (CLF) are rarely considered in assessing surgical complications. Atrophy from muscle denervation and posterior bone loss may result in a sunken appearance; relative tension may lead to wide, unsightly scars. Paraspinal muscle flaps are routinely employed by plastic surgeons for closure of wound infection and dehiscence.\n\n\n\nTo assess clinical and cosmetic results of CLF with/without a paraspinal muscle flap closure technique.\n\n\n\nA retrospectively collected cohort analysis was undertaken for a 12-yr period in CLF patients. During the study period, a paraspinal muscle flap closure technique was adopted. Wounds were inspected for scar width and depth using a scale devised to categorize the posterior neck contour. Minimum follow-up was 12 mo.\n\n\n\nOf 159 patients, 94 wounds were evaluated of which 34 had muscle flap closure. There were no differences in age, sex, body mass index, mJOA scores, diabetes status, or number of spinal levels treated. Mean follow-up was 18.6 (12-48) and 49.8 (12-130) mo in the muscle flap and conventional closure groups respectively; contour scores were 1.20 vs 2.65 (P < .00001) and scar width was 2.8 vs 4.9 mm (P < .0001). No patient had a wound complication in the muscle flap group and 4 (7%) in the conventional closure group.\n\n\n\nParaspinal muscle flap closure of CLF improved cosmetic appearance in terms of wound contour and scar width. Further investigation is needed to determine any effect upon wound infection and dehiscence rates.",
"affiliations": "Department of Surgery, Maimonides Medical Center, Brooklyn, New York.;Department of Orthopedic Surgery, Maimonides Medical Center, Brooklyn, New York.;Department of Neurological Surgery, Montefiore Medical Center, Bronx, New York.;Department of Surgery, Maimonides Medical Center, Brooklyn, New York.",
"authors": "Weinstein|Gila R|GR|;Komlos|Daniel|D|;Haranhalli|Neil|N|;Houten|John K|JK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ons/opy245",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2332-4252",
"issue": "17(1)",
"journal": "Operative neurosurgery (Hagerstown, Md.)",
"keywords": "Cervical laminectomy and fusion; Cosmetic; Muscle flap; Outcome; Plastic surgery; Wound closure; Wound infection",
"medline_ta": "Oper Neurosurg (Hagerstown)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007796:Laminectomy; D008297:Male; D008875:Middle Aged; D064170:Paraspinal Muscles; D017060:Patient Satisfaction; D011183:Postoperative Complications; D012189:Retrospective Studies; D013123:Spinal Fusion; D013524:Surgical Flaps; D016896:Treatment Outcome; D058106:Wound Closure Techniques",
"nlm_unique_id": "101635417",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "30202986",
"pubdate": "2019-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Improved Cosmetic Outcome With Bilateral Paraspinal Muscle Flap Closure Following Cervical Laminectomy and Fusion.",
"title_normalized": "improved cosmetic outcome with bilateral paraspinal muscle flap closure following cervical laminectomy and fusion"
} | [
{
"companynumb": "US-JNJFOC-20190914730",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nIn this case report we attempt to emphasize the unfamiliar link between trazodone and relapse of psychotic symptoms.\n\n\nMETHODS\nCase report and literature review of relevant papers.\n\n\nRESULTS\nWe report a case of a 78-year-old woman with an established diagnosis of paranoid schizophrenia who has experienced an exacerbation of positive psychotic symptoms following initiation of 50 mg dailydose of trazodone. We noted that psychotic symptoms abated following discontinuation of trazodone.\n\n\nCONCLUSIONS\nTrazodone use in patients in remission from schizophrenia may be associated with relapse of psychotic symptoms and caution is required.",
"affiliations": "1Millmount Community Mental Health Services,St Vincent's Hospital Fairview,Dublin,Ireland.;2Millmount Community Mental Health Services,St Vincent's Hospital Fairview,Dublin,Ireland.",
"authors": "Osman|M|M|;Kilduff|M|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/ipm.2014.67",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0790-9667",
"issue": "32(4)",
"journal": "Irish journal of psychological medicine",
"keywords": "Psychotic disorders; recurrence; schizophrenia; sleep initiation and maintenance disorders; trazodone",
"medline_ta": "Ir J Psychol Med",
"mesh_terms": null,
"nlm_unique_id": "8900208",
"other_id": null,
"pages": "337-339",
"pmc": null,
"pmid": "30185249",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Trazodone and exacerbation of psychotic symptoms: an unfamiliar link.",
"title_normalized": "trazodone and exacerbation of psychotic symptoms an unfamiliar link"
} | [
{
"companynumb": "IE-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-109293",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAZODONE HYDROCHLORIDE"
},
... |
{
"abstract": "A 51-year-old man was hospitalised for severe hyponatremia. Initial history and physical examination suggested hypovolemia, and he was treated with normal saline at 100 mL/hour. After several days, his hyponatremia failed to improve, and then worsened without resolution of presenting ataxia and fatigue. He had no new complaints including no cough or orthopnea. He had no jugular venous distention or oedema, and his lungs were clear to auscultation. Point-of-care ultrasound was used, revealing a distended inferior vena cava, pulmonary oedema and pleural effusion, suggesting hypervolemia. Based on ultrasound findings, we treated with 60 mg oral torsemide two times per day. Hyponatremia resolved without complication within 48 hours. In this case, physical examination failed to recognise volume status change from hypovolemic to hypervolemic, increasing hospitalisation and morbidity. The point-of-care ultrasound proved to be an accurate tool for proper volume evaluation, and may be used as an adjunct to physical examination for hyponatremic patients.",
"affiliations": "Department of Internal Medicine, University of South Carolina School of Medicine Greenville Campus, Greenville, South Carolina, USA.;Department of Internal Medicine, Prisma Health, Greenville, South Carolina, USA anielrao@gmail.com.",
"authors": "Evins|Connor|C|;Rao|Aniel|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235304",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(6)",
"journal": "BMJ case reports",
"keywords": "fluid electrolyte and acid-base disturbances; general practice / family medicine; ultrasonography",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001810:Blood Volume; D003324:Coronary Artery Disease; D003951:Diagnostic Errors; D006333:Heart Failure; D006801:Humans; D007010:Hyponatremia; D008297:Male; D008875:Middle Aged; D010808:Physical Examination; D000067716:Point-of-Care Testing; D014463:Ultrasonography; D014883:Water-Electrolyte Imbalance",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32595119",
"pubdate": "2020-06-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Point-of-care ultrasound to evaluate volume status in severe hyponatremia.",
"title_normalized": "point of care ultrasound to evaluate volume status in severe hyponatremia"
} | [
{
"companynumb": "US-TEVA-2020-US-1812734",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "A 63-year-old man who presented with asymptomatic gross hematuria was referred to our hospital. Left ureteral tumor (cT3N0M0) was diagnosed and left nephroureterectomy was performed. Pathological examination revealed urothelial carcinoma and small cell carcinoma with local invasion (pT3). The patient was treated with three cycles of adjuvant chemotherapy with gemcitabine and cisplatin. Three months after the chemotherapy, cystoscopy showed an intravesical recurrence of the tumor. Transurethral resection was performed and histopathological examination revealed small cell carcinoma (pT1). We recommended a cystectomy and neoadjuvant chemotherapy with etoposide and carboplatin according to the standard care of small cell carcinoma of bladder. However, the patient refused to undergo cystectomy and desired to preserve his bladder. Therefore, after two cycles of chemotherapy with etoposide and carboplatin, transurethral resection was performed to examine the presence of the residual tumor instead of immediate cystectomy. Because of no residual tumor, another two cycles of chemotherapy were added instead of a cystectomy. There is no evidence of recurrence seven months after the chemotherapy.",
"affiliations": "The Department of Urology, Kinki Central Hospital of Mutual Aid Association of Public Teachers.;The Department of Urology, Kinki Central Hospital of Mutual Aid Association of Public Teachers.;The Department of Urology, Kinki Central Hospital of Mutual Aid Association of Public Teachers.;The Department of Urology, Kinki Central Hospital of Mutual Aid Association of Public Teachers.;The Department of Pathology, Kinki Central Hospital of Mutual Aid Association of Public Teachers.",
"authors": "Ueda|Norichika|N|;Kobayashi|Yasuyuki|Y|;Arai|Hiroki|H|;Honda|Masahito|M|;Yoshida|Kyotaro|K|",
"chemical_list": "D005047:Etoposide; D016190:Carboplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "62(2)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D018288:Carcinoma, Small Cell; D005047:Etoposide; D006801:Humans; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D012008:Recurrence; D014516:Ureteral Neoplasms; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "93-7",
"pmc": null,
"pmid": "27018413",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Intravesical Recurrence of Small Cell Carcinoma of the Ureter: A Case Report.",
"title_normalized": "intravesical recurrence of small cell carcinoma of the ureter a case report"
} | [
{
"companynumb": "JP-CIPLA LTD.-2017JP13351",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "This case involved a 69-year-old woman who had been taking tamoxifen for 5 years after breast cancer surgery. She was referred to our clinic for endometrial cancer screening when tamoxifen was first prescribed. Subsequently, transvaginal ultrasonography and endometrial cytology were performed every 6 months. Despite these regular examinations, stage IVb papillary serous carcinoma was detected 8 months after the end of tamoxifen administration. Total abdominal hysterectomy was performed, but only a small polyp was seen upon macroscopic examination of the uterus. However, papillary serous carcinoma was found microscopically in almost all lymphovascular spaces in the uterus from the endometrium to the serosa. On the surface of the polyp, only endometrial intraepithelial carcinoma with positive immunostaining for p53 was detected. Chemotherapy, including a platinum compound, was administrated, but unfortunately it was ineffective and the patient died of her disease 14 months after the operation.",
"affiliations": "Department of Obstetrics and Gynecology, Osaka Police Hospital, Osaka, Japan.",
"authors": "Maenaka|Takahide|T|;Egawa-Takata|Tomomi|T|;Hisamoto|Koji|K|;Kunishige|Ichiro|I|;Nishio|Yukihiro|Y|;Tsujimoto|Masahiko|M|",
"chemical_list": "D004965:Estrogen Antagonists; D013629:Tamoxifen",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12317",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "40(5)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "cytology; endometrial; serous carcinoma; tamoxifen; uterine neoplasms",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000368:Aged; D018283:Cystadenocarcinoma, Papillary; D018284:Cystadenocarcinoma, Serous; D004965:Estrogen Antagonists; D005260:Female; D006801:Humans; D013629:Tamoxifen; D014594:Uterine Neoplasms",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1450-4",
"pmc": null,
"pmid": "24606575",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of uterine papillary serous carcinoma following tamoxifen treatment that could not be diagnosed during screening.",
"title_normalized": "case of uterine papillary serous carcinoma following tamoxifen treatment that could not be diagnosed during screening"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1000331",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": null,
... |
{
"abstract": "Tuberculosis (TB) is one of the leading causes of death worldwide, particularly in low- and middle-income countries. The global rates and numbers of drug resistant TB are rising. With increasing globalization, the spread of drug-resistant strains of TB has become a mounting global public health concern. We present a case of a young man previously treated for multi-drug resistant (MDR) TB in India who presented with neurological symptoms and central nervous system TB in the United States. His case highlights unique diagnostic and treatment challenges that are likely to become more commonplace with the increase of patients infected with drug-resistant TB and complicated extrapulmonary disease.",
"affiliations": "Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, AIDS Program, 135 College St, New Haven, CT 06510, United States.;Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, AIDS Program, 135 College St, New Haven, CT 06510, United States.;Connecticut Department of Public Health, 410 Capitol Avenue, Hartford, CT 06134, United States.;Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, AIDS Program, 135 College St, New Haven, CT 06510, United States.;Yale School of Medicine, Department of Pathology, 333 Cedar St, New Haven, CT 06510, United States.;Yale School of Medicine, Department of Radiology, 333 Cedar St, New Haven, CT 06510, United States.;Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, AIDS Program, 135 College St, New Haven, CT 06510, United States.",
"authors": "Kaplan|Samantha R|SR|;Topal|Jeffrey|J|;Sosa|Lynn|L|;Malinis|Maricar|M|;Huttner|Anita|A|;Malhotra|Ajay|A|;Friedland|Gerald|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jctube.2017.12.004",
"fulltext": "\n==== Front\nJ Clin Tuberc Other Mycobact DisJ Clin Tuberc Other Mycobact DisJournal of Clinical Tuberculosis and Other Mycobacterial Diseases2405-5794Elsevier S2405-5794(17)30042-610.1016/j.jctube.2017.12.004ArticleA patient with central nervous system tuberculomas and a history of disseminated multi-drug-resistant tuberculosis Kaplan Samantha R. aTopal Jeffrey aSosa Lynn bMalinis Maricar aHuttner Anita cMalhotra Ajay dFriedland Gerald gerald.friedland@yale.edua⁎a Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, AIDS Program, 135 College St, New Haven, CT 06510, United Statesb Connecticut Department of Public Health, 410 Capitol Avenue, Hartford, CT 06134, United Statesc Yale School of Medicine, Department of Pathology, 333 Cedar St, New Haven, CT 06510, United Statesd Yale School of Medicine, Department of Radiology, 333 Cedar St, New Haven, CT 06510, United States⁎ Corresponding author. gerald.friedland@yale.edu06 12 2017 1 2018 06 12 2017 10 9 16 16 6 2017 1 12 2017 4 12 2017 © 2017 Published by Elsevier Ltd.2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tuberculosis (TB) is one of the leading causes of death worldwide, particularly in low- and middle-income countries. The global rates and numbers of drug resistant TB are rising. With increasing globalization, the spread of drug-resistant strains of TB has become a mounting global public health concern. We present a case of a young man previously treated for multi-drug resistant (MDR) TB in India who presented with neurological symptoms and central nervous system TB in the United States. His case highlights unique diagnostic and treatment challenges that are likely to become more commonplace with the increase of patients infected with drug-resistant TB and complicated extrapulmonary disease.\n\nKeywords\nTuberculosis (TB)Multi-drug resistant tuberculosis (MDR-TB)Extensively drug-resistant tuberculosis (XDR-TB)Central nervous system (CNS) TBTuberculomaBedaquilineAbbreviations\nAFB, acid-fast bacilliBAL, bronchoalveolar lavageCNS, central nervous systemCSF, cerebrospinal fluidCT, computerized tomographyDOT, directly observed therapyDST, drug susceptibility testingFDA, Food and Drug AdministrationIV, intravenousLUL, left upper lobeMDR-TB, multidrug-resistant tuberculosisMRI, magnetic resonance imagingTB, tuberculosisWHO, World Health OrganizationXDR-TB, extensively drug-resistant tuberculosis\n==== Body\n1 Introduction\nTuberculosis (TB) remains one of the top ten causes of death worldwide. In 2015, an estimated 10.4 million people worldwide developed TB and 1.8 million died; over 95% of these deaths occurred in low- and middle-income countries [1]. Resistance to standard anti-TB regimens is becoming widespread in the form of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. MDR-TB is defined as resistance to isoniazid and rifampin, two of the most potent first-line TB drugs; XDR-TB is resistance to isoniazid, rifampin, the fluoroquinolones, as well as any of the second line injectable agents [1]. Globally, MDR-TB and XDR–TB notifications are both increasing. There were an estimated 480,000 people globally who developed MDR-TB in 2015; the largest numbers of these cases were reported in India, China, and Russia, and 9.5% of MDR cases met the definition of XDR-TB [1]. While TB most commonly infects the lungs, TB can occur in any organ in the body, including the central nervous system (CNS). CNS TB occurs in approximately 1% of patients with TB disease and is associated with major morbidity and mortality.\n\nWe present a complicated case of CNS TB in a young man with a history of previously treated MDR-TB. The diagnosis and treatment of this patient presented unique challenges to the treatment team. While MDR and XDR-TB are presently uncommon in patients treated in the United States, rising numbers of cases of drug resistant TB globally and increasing globalization and international travel raise concerns that such cases could be encountered more frequently both in the US and worldwide.\n\n2 Case history and presentation\nThe patient's TB history is illustrated in Fig. 1 and Table 1 and is summarized here. The patient is a 28-year-old man from India who moved to the United States to attend university in 2004. In 2009, he developed night sweats, fever, weight loss, and cough. He returned to India shortly afterwards, where he was diagnosed with pulmonary and extrapulmonary TB with cervical lymphadenitis. Initial drug susceptibility testing from a lymph node aspirate revealed resistance to pyrazinamide. He was initially treated with a reportedly standard regimen (records not available) but his symptoms did not improve. Two months after start of treatment, he was diagnosed with disseminated TB involving the lungs, spine, and lymph nodes, and required surgery for stabilization of the spine. He was presumed to have MDR-TB, and was started on an empiric eight-drug regimen; bronchoscopy mycobacterial culture was also taken as this time (Table 1). The patient admitted to missing doses of the TB medications during the first two weeks of treatment due to medication-induced nausea and vomiting, but tolerated the regimen thereafter. Four months after his initial presentation, the diagnosis of MDR-TB was microbiologically confirmed; TB drug susceptibility testing (DST) from the initial bronchoscopy revealed resistance to isoniazid, rifampicin, pyrazinamide, ofloxacin, and streptomycin (Table 1). Based on these results, he was changed to a seven -drug regimen, omitting pyrazinamide, rifampin, and moxifloxacin, and adding clofazimine and p-aminosalicylic acid (Table 1, Fig. 1), which he completed after 18 months; directly observed therapy (DOT) was not provided. In 2011, four months after completion of TB therapy with this regimen, while still in India, symptoms including fever, night sweats, weight loss, and fatigue recurred. Bronchoscopy was repeated but cultures were negative for M. tuberculosis. He was empirically treated with his previous seven-drug regimen for an additional 24 months (Table 1, Fig. 1). The patient reported adherence to the treatment, supported by later direct confirmation in conversation with his treating physician in India; however, DOT was again not provided. By September 2013, he had successfully completed his second course of treatment for MDR-TB, for a total of 46 months of therapy, and returned to the United States.Fig. 1 Case narrative timeline.\n\nFig 1Table 1 Categories of antituberculous drugs and patient's TB treatment and drug susceptibility testing history, adapted from the 2016 WHO TB Treatment Guidelines [2].\n\nTable 1WHO classification\t\tDrug\tPresumptive MDR regimen, 2009 (4 months, pre-DST)\tMDR regimen (2 courses)a\tTotal # of months from previous regimens\tResistant on previous DST?\t# Of months in “XDR” regimenb\t\nFirst-line agents (drug-sensitive TB)\t\tIsoniazid\tx\tx\t46\tx\t\t\n\t\tRifampin\tx\t\t4\tx\t\t\n\t\tEthambutol\tx\tx\t46\t\t\t\n\t\tPyrazinamide\tx\t\t4\tx\t\t\nGroup A: fluoroquinolones\t\tLevofloxacin\t\t\t0\t\t\t\n\t\tMoxifloxacin\tx\t\t1\t\t24\t\n\t\tGatifloxacin\t\t\t0\t\t\t\n\t\t(Ofloxacin)\t\t\t0\tx\t\t\nGroup B: Second-line injectable agents\t\tAmikacin\t\t\t0\t\t\t\n\t\tCapreomycin\t\t\t0\t\t24\t\n\t\tKanamycin\tx\tx\t8\t\t\t\n\t\t(Streptomycin)\t\t\t0\tx\t\t\nGroup C: Other core second-line agents\t\tEthionamide/Protionamide\tx\tx\t43\t\t\t\n\t\tCycloserine/Terizidone\tX\tx\t43\t\t\t\n\t\tLinezolid\t\t\t0\t\t24\t\n\t\tClofazimine\t\tx\t42\t\t\t\nGroup D: Add-on agents\tD1\tPyrazinamide\tx\t\t4\tx\t15c\t\n\t\tEthambutol\tx\tx\t46\t\t\t\n\t\tHigh-dose isoniazid\tx\tx\t46\tx\t15c\t\n\tD2\tBedaquiline\t\t\t0\t\t18\t\n\t\tDelamanid\t\t\t0\t\t\t\n\tD3\tp-aminosalicylic acid\t\tx\t42\t\t\t\n\t\tImipenem-cilastatin\t\t\t0\t\t\t\n\t\tMeropenem\t\t\t0\t\t24\t\n\t\tAmoxicillin-clavulanate\t\t\t0\t\t24\t\n\t\t(Thioacetazone)\t\t\t0\t\t\t\nDST: drug susceptibility testing; MDR: multi-drug resistant; TB: tuberculosis; WHO: World Health Organization; XDR: extensively-drug resistant.\n\na Prescribed in 2009 and 2011, before some of the agents in this table were available.\n\nb Prescribed in 2014, before some of the agents in this table were available.\n\nc Added seven months into treatment course for increased CNS penetration.\n\n\n\nThe patient was well until February 2014, when he collapsed at work with a seizure. A brain magnetic resonance imaging (MRI) scan revealed two enhancing lesions, one in the superior left frontal lobe measuring 9 × 7 × 7 mm and one in the medulla oblongata measuring 5 × 5 × 6 mm; each demonstrated mild to moderate ring enhancement and edema. A lumbar puncture was negative for M. tuberculosis using polymerase chain reaction (PCR) testing. Mycobacterial culture was not performed. Serologies for HIV, syphilis, toxoplasmosis, brucella, echinococcus, cysticercosis, and B. burgdorferi were negative. Excision of the frontal lobe lesion for pathological and microbiological diagnosis was recommended.\n\nA repeat MRI in June 2014 showed an interval increase in vasogenic edema around the lesion in the medulla oblongata when compared with imaging from three months prior (Fig. 2A–C). He underwent left craniotomy with removal of a yellowish granular firm mass lesion from his frontal lobe. Pathology of the brain lesion revealed tuberculous abscess with multiple granulomas at varying stages including several caseating granulomas, surrounded by numerous lymphocytic and macrophage inflammatory cells as indicated on stains for T cell, B cell, and macrophage markers (CD3, CD20, and CD68) (Fig. 3). The specimen stained positive for acid-fast bacilli (AFB). Nucleic acid amplification testing (GeneXpert®) was positive for M. tuberculosis and rifampin resistance. Mycobacterial and fungal cultures were negative after eight weeks of incubation.Fig. 2 Serial MRIs of medulla lesion. (A) June 2014: pre-treatment. T2 sagittal. Arrow points to location of lesion in the medulla (B) June 2014: pre-treatment. T2 sagittal, enlarged (C) June 2014: pre-treatment, T2 axial (D) October 2014: two months into treatment, T2 axial (E) March 2015: seven months into treatment, T2 axial (F) July 2016: at completion of treatment course, T2 axial. This image shows similar size lesion compared with pre-treatment, but marked diminution of edema around lesion. (All images are Spin Echo T2 WI without contrast).\n\nFig 2Fig. 3 Pathology from frontal lobe lesion (A and B). The hematoxylin & eosin stained biopsy samples show several granulomas, including one granuloma with necrotic center ('caseating necrosis’, arrow in B). Numerous inflammatory cells are present throughout the biopsy, (C) demonstrates CD68 positive macrophages and (D) shows CD3 positive T-lymphocytes.\n\nFig 3\n\nThe patient was admitted in July 2014 for further workup and treatment. On admission, he denied fever, chills, weight loss, cough, hemoptysis, chest pain, urinary symptoms, nausea, vomiting, diarrhea, or constipation. His surgical scar was well healed. His mental status was normal, neurologic examination was non-focal, and the remainder of the physical examination was unremarkable. Complete blood count (CBC) was normal except for a mild leukocytosis (14,300), likely due to the patient being on steroids prescribed after his neurosurgery. Other routine blood tests (complete metabolic panel including liver function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), thyroid stimulating hormone (TSH)) were within normal limits.\n\n3 Further imaging and microbiologic studies\nThe patient underwent a chest computerized tomography (CT) scan that revealed calcified lung nodules consistent with prior granulomatous disease. An abdominal/pelvis CT demonstrated scattered calcified granulomas and non-enlarged calcified peritoneal lymph nodes also suggestive of prior granulomatous disease. Post-operative changes were seen at the site of his previous spinal surgery (T8-T12).\n\nSix induced sputum specimens were negative for AFB and culture for M. tuberculosis was negative after eight weeks of incubation. GeneXpert® was negative on three specimens. Urine and blood mycobacterial cultures were also negative. Bronchoscopy with bronchoalveolar lavage (BAL) and biopsy of a heavily calcified granuloma in the left upper lobe (LUL) were performed, which showed mild chronic inflammation and no granulomas. AFB stains of both specimens were negative and cultures of both samples were reported as no growth. A repeat brain MRI post-surgery indicated the medulla lesion similar in appearance to the previous scan, with no interval change in edema.\n\nFormalin fixed paraffin embedded brain tissue was sent to the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia to amplify any M. tuberculosis genetic material (DNA) present and test for common resistance mutations to TB medications; however, the sample was small and did not contain a sufficient amount of genetic material for amplification.\n\n4 Treatment course and follow-up\nGiven the radiological and pathological interpretations, the patient was diagnosed with probable active CNS TB disease with tuberculoma formation. In light of his documented history of prolonged treatment for extrapulmonary MDR-TB, lack of current positive cultures, and inability to obtain current TB drug susceptibilities, combined with the precarious location of the lesion in his brainstem, he was started on an empiric TB drug regimen. The regimen was chosen after review of medical records obtained from India and extensive discussions with local clinicians, the Connecticut Department of Public Health, and national TB experts (Table 1). This regimen consisted of moxifloxacin 400 mg orally daily, capreomycin 1000 mg intravenous (IV) daily, linezolid 600 mg orally daily, bedaquiline (provided through the Connecticut Department of Public Health) loading dose 400 mg orally daily × 14 days, then 200 mg orally three times per week, meropenem 2 g IV every eight hours, and amoxicillin-clavulanate 500 mg/125 mg orally every eight hours. A dexamethasone taper (starting at 2 mg orally every six hours) was also initiated due to concerns for worsening edema surrounding the medulla lesion.\n\nThe patient remained hospitalized for four weeks to ensure medication adherence and tolerance and to arrange support services including a visiting nurse for intravenous therapy monitoring and case management including DOT by the local health department. He lived with a very supportive family, who provided strong social support and were educated about and involved in his care and medication adherence. Drug safety monitoring was employed, given the wide array of possible adverse effects with this regimen. Daily electrocardiograms were performed to monitor QTc prolongation for bedaquiline and moxifloxacin use while in hospital and weekly to monthly thereafter. Renal function, electrolytes, and baseline and follow-up audiology exams were performed to monitor for capreomycin toxicity. Weekly CBC was performed while on linezolid. Liver function tests were also monitored for hepatotoxicity.\n\nThe patient was followed in the Infectious Disease outpatient clinic every six to eight weeks for the 24-month duration of his treatment. The local health department also saw him 3–5 times per week at home for DOT and medication monitoring, including toxicity assessment. Meropenem administration was carefully monitored and the patient learned to self-administer it every eight hours via a CADD® pump, carried in a backpack for continuous infusion. His CNS lesion was monitored by serial MRI examinations every two to three months, with assessment of the size of the medulla lesion and surrounding edema. He completed his first course of bedaquiline and other drugs after six months of treatment without incident. Dexamethasone dose was gradually tapered from 2 mg daily to 1 mg every other day. At seven months into treatment, MRI results indicated re-demonstration of a ring-enhancing lesion of the dorsal medulla, which was slightly larger in size measuring 7 × 6 mm compared to pre-treatment lesion of 5 × 4 mm. The peripheral rim enhancement was also thicker than on the prior exam. In addition, there was interval increase in peri-lesional edema (Fig. 2E). His regimen was re-evaluated with input from local and national TB experts. Drug resistance or lack of sufficient drug potency within the central nervous system was a concern, but it was concluded that the most likely explanation for the increase in edema was a tapering of the dexamethasone dose from daily to every other day dosing with possible paradoxical reaction (immune reconstitution) after several months of therapy. As a result, the dexamethasone dose was increased again to daily dosing (1 mg), and the anti-TB drug regimen was also revised: bedaquiline was restarted, with loading dose 400 mg orally daily × 14 days, then 200 mg three times per week. Isoniazid 600 mg orally daily (with vitamin B6 100 mg) and pyrazinamide 2000 mg orally daily were also added because of their favorable CSF penetrative properties. Meropenem 2 g IV every eight hours, amoxicillin-clavulanate 500 mg/125 mg orally every eight hours, linezolid 600 mg orally daily, and moxifloxacin 400 mg orally daily were maintained. DOT was also increased at this time to once per day, including weekends, either in person or by internet-based video (FaceTime®) methods.\n\nHe continued the regimen for a total of 24 months and completed treatment on August 20, 2016. He has remained clinically stable for nine months after treatment completion, without return of seizures or neurologic sequelae. MRI at time of treatment completion showed the stable 7 mm peripherally enhancing lesion at the ponto-medullary junction, unchanged in size, with no new lesions identified. There was minimal edema, markedly decreased back to the level of the prior scans (Fig. 2F). He tolerated his complicated treatment course well, experiencing surprisingly minimal toxicity from this regimen, apart from moderate bilateral peripheral neuropathy in his feet felt to be due to linezolid, which responded to gabapentin. Through the course of the treatment, he remained optimistic, and he and his family were fully engaged in decision-making and the arduous treatment course. He was also able to work as a math tutor and accountant during the latter half of his treatment. His treatment course was complicated, however, by weight gain, general deconditioning, fatigue, and avascular necrosis of the left hip (which has since required a total hip replacement), all likely attributable to long-term steroid use. He will continue to follow up at the infectious disease outpatient clinic for an additional two years after his treatment completion date.\n\n5 Discussion\nThis case of a young man with a history of multidrug-resistant TB who presented with a seizure and CNS lesions posed an array of complex diagnostic and therapeutic challenges. The first challenge in caring for this patient was to determine whether he had an active tuberculoma or CNS brain abscess. His previously complicated history of confirmed extrapulmonary MDR-TB in India, with prolonged MDR-TB therapy, did not include CNS disease. His clinical presentation was with a seizure, without other more usual systemic signs or symptoms of active TB disease. Under our care, two lesions were seen on MRI with surrounding edema, and tissue obtained at brain biopsy was AFB positive and positive on nucleic acid amplification testing (GeneXpert®) for M. tuberculosis and rifampin resistance. However, TB culture was negative. The reason for this discrepancy between the positive AFB stain and GeneXpert® results and the negative culture is not clear. One possibility is that the organisms seen on stain and detected on PCR were actually dead as both Xpert and AFB stain will pick up dead as well as live organisms. Alternatively, there may have been a falsely negative culture result for technical reasons.\n\nFurther, multiple pulmonary specimens were also culture negative for TB. The location of the patient's lesion in the medulla oblongata within the brainstem was further challenging diagnostically, as confirmation via biopsy of the lesion itself was contraindicated because of its anatomic location. We therefore had to rely on the use of radiologic imaging and interpretation of the pathology of tissue obtained from a coexisting frontal lobe lesion to make the diagnosis of active CNS TB disease. Other reported studies have used radiological diagnosis using MRI and CT for tuberculomas and to assess their activity; notably, lesions are frequently surrounded by a halo of contiguous vasogenic white matter edema, the amount of which is thought to be inversely proportional to the maturity and activity of the lesion [3], [4]. In this case, the edema surrounding the patient's medulla lesion on MRI led neuroradiologists to conclude that the lesion was most likely active, particularly given the interval increase in edema when compared with the MRI from three months prior (Fig. 2A–C).\n\nHistopathological findings of caseating granulomas and multinucleated giant cells and inflammatory cells as indicated on stains for T cell, B cell, and macrophage markers (CD3, CD20, CD68,) in the patient's frontal lobe brain specimen also strongly supported the diagnosis of active disease (Fig. 3). A retrospective study of 23 patients with CNS tuberculomas found caseating granulomas and epithelioid histiocytes on pathology but AFBs were not usually seen [5]. In another study of 17 cases of intramedullary tuberculomas of the spinal cord, similar pathological findings of well circumscribed masses with caseating granulomas were present, but AFB were seen in less than half the cases, with only one culture-positive specimen [6]. A case study of a patient with a tuberculoma in the medulla oblongata, similar to this patient, showed a granulomatous lesion containing multinucleated giant cells and inflammatory cells with caseous necrosis [7]. In the present case, we were able to employ the GeneXpert® test on the frontal lobe specimen, which was positive for both M. tuberculosis and rifampin resistance. The World Health Organization has summarized information on the use of GeneXpert® for extrapulmonary TB tissue specimens and affirms its utility in individual cases, but does not make a general recommendation for this use as data is limited. However, available limited data suggests that the use of GeneXpert® on tissue samples has high sensitivity and specificity in detecting M. tuberculosis organisms, including in brain tissue [8], [9], [10]. This was helpful in confirming the diagnosis but not whether the lesion was active or not. Although these findings were from the frontal lobe and not the medulla lesion, we assumed that the patient had active TB disease within the medulla based on these characteristic pathologic and radiologic findings, despite the negative culture. Given the mortality of CNS tuberculoma without treatment is estimated between 35–85%, and the precarious location of the lesion in question and its likely activity, we concluded that there was sufficient urgency to treat this patient empirically and aggressively [7], [11].\n\nA second challenge in the management of this patient, given his previous extensive and prolonged treatment for MDR-TB, was constructing an effective treatment regimen. We were fortunate to be in contact with his treating physician in India and have access to his previous files, including his available drug resistance reports and type and duration of treatment regimens. Although guidelines exist for MDR and XDR-TB treatment, treatment is often based on expert opinion and tailored to individual patients, particularly for extrapulmonary disease, as was the case for this patient [12]. The drugs for which resistance was known and those used extensively before treatment relapse left an extremely limited array of drugs from which to choose (Table 1). These recommendations generally apply to both pulmonary and extra-pulmonary MDR/XDR-TB, but recommendations for treatment of CNS MDR or XDR-TB are further problematic because of limited data on CNS penetration and a lack of evidence of clinical success for many of the recommended medications. Among first-line agents, classic CNS-penetrating drugs used successfully in other tuberculoma cases include isoniazid, rifampin, ethambutol, and pyrazinamide [5], [6], [13], but available previous resistance data and previous treatment history for this patient indicated likely resistance to these agents. Second-line TB drugs with good CNS penetration include ethionamide, cycloserine, later generation fluoroquinolones (e.g. moxifloxacin), and linezolid [11], [14], [15], [16]. Newly developed and available bedaquiline was an obvious choice; however, there were no data on the CNS penetration of bedaquiline. While drug susceptibility tests could not be obtained presently, previous resistance information was available for some of the drugs, and it was assumed that the patient was probably resistant to the medications that he received during his previous treatment courses (Table 1).\n\nAt the time of the decision to initiate treatment in this patient, we recognized that there were only three truly new agents available for him: bedaquiline, linezolid, and meropenem/amoxicillin-clavulanate (solely for clavulanate, which is not available as a single agent in the United States). In addition, moxifloxacin was prescribed despite his brief treatment history with this drug, given its favorable CNS penetration and that it has shown to be a predictor of successful outcomes in XDR-TB [17], including in a prospective study of heavily pre-treated patients with MDR-TB in the private sector in Mumbai, India, where the patient likely acquired his initial infection [18]. Furthermore, although there was reported resistance to streptomycin and ofloxacin, and previous use of kanamycin, we chose to administer capreomycin in addition to moxifloxacin, recognizing that class cross-resistance was possible.\n\nBedaquiline was, at the time, the newest TB medication and the first new anti-TB drug in 40 years. Bedaquiline inhibits mycobacterial ATP synthase and has been approved by the United States Food and Drug Administration (FDA) and the World Health Organization for use in drug-resistant TB [2], [19]. Bedaquiline has been shown to effect more rapid sputum culture conversion in both MDR and XDR-TB patients [20], [21], [22], [23], [24], and there are ongoing studies indicating its effectiveness in treating pulmonary XDR-TB in combination with other new drugs [25]. There is very limited information and a lack of formal research regarding bedaquiline CNS penetration and pharmacokinetics. We located a single case report in which multiple CSF measurements of bedaquiline were completed in a patient being treated for TB meningitis. In this case study, bedaquiline was not detected in the CSF [26]. Information on how this may relate to the penetration of the drug into a brain abscess is similarly limited. In this case, with such limited therapeutic options and available information and an extremely dangerous clinical scenario, we felt justified to aggressively treat with bedaquiline. We recognize a critical need to develop more information on the CNS penetration of most of the older TB drugs and bedaquiline and other newer drugs in the future. While bedaquiline is normally prescribed for 24 weeks, our patient underwent an 18-month regimen without adverse effects. To our knowledge, this is one of the longest administered bedaquiline regimens in the United States.\n\nMeropenem combined with clavulanate has been shown to be effective against XDR and MDR strains in vitro, demonstrating that the specific beta-lactamase of M. tuberculosis can be overcome with an effective beta lactamase inhibitor such as clavulanate [27], [28], [29], [30], [31], [32]. From limited experience, effectiveness of this regimen in combination with linezolid has also been shown in patients with MDR and XDR [29], [33], [34], adding to the evidence for linezolid's effectiveness in achieving culture conversion in XDR patients [35]. As meropenem is only available in an intravenous formulation, administration of this drug required the use of a CADD® pump and the patient's ability to perform home IV therapy. We recognize that this may not be a feasible solution for every patient. Of note, although he tolerated his antituberculosis medications well and without major toxicities, the patient had mild residual neuropathy at the time of completion of treatment, attributable to linezolid.\n\nMonitoring the response to TB treatment requires documentation of negative smear and culture. Current international guidelines recommend continuing therapy for a minimum of 24 months after culture conversion for XDR-TB [36]. In some circumstances, particularly if resistance patterns are known, more prolonged therapy may be beneficial [37], [38]. Because our patient did not have a positive culture and his lesion was inaccessible to sample, it was not possible to use microbiological criteria to determine exactly when to end treatment. We elected to treat for 24 months, with careful radiologic and clinical monitoring and continued follow-up after treatment completion.\n\nAn additional challenge was the use of steroids to treat this patient. Although still controversial, reviews suggest that steroids are effective in reducing mortality for all forms of TB [39]. There is more general agreement that steroids are of benefit in reducing mortality and focal neurological deficits in patients with tuberculous meningitis [40], [41]. There has also been some evidence suggesting that corticosteroids are effective in managing cerebral edema and symptoms related to tuberculomas, but data are limited and based solely on anecdotes and case reports [11], [42]. However, because of the persistent and recurring edema noted on the patient's MRI scans and the location of the lesion in a high-risk area of his brainstem, we felt obliged to add dexamethasone, with very gradual taper, to his regimen. As noted, this unfortunately resulted in his only serious medication toxicity, aseptic necrosis of the left hip.\n\nClose collaboration between clinical medicine and public health colleagues was vital to the successful treatment of this patient. The state public health department facilitated discussion of this patient on a national conference call between clinical and public health TB experts to come to a consensus on the best treatment regimen for the patient and then again when the patient's brain lesions appeared worse on imaging. This resulted in a change in the regimen that the patient ultimately completed. The state public health department procured bedaquiline and received permission for its continued use beyond the recommended 24-week course, and facilitated local health department DOT and monitoring of the patient's medication supply and symptoms. The use of live internet-based video DOT (via HIPAA compliant FaceTime® on the patient's iPhone®) facilitated interaction with the patient on a daily basis (including weekends), even if the patient travelled or a public health staff member was away. Such methodology has been used effectively and efficiently in other settings [43], [44], [45]. In addition to the medical care received, critical to the therapeutic success were the patient's supportive home setting and his own stamina and resilience.\n\n6 Conclusions\nIn summary, this case outlines the difficult diagnostic and therapeutic challenges and decisions made in a non-immunocompromised young man from India with previous extensive treatment for MDR-TB and presumed CNS XDR-TB. While the case represents a rare TB presentation, the issues discussed in diagnosing and treating this patient have broader relevance. There is mounting evidence of growing numbers of drug-resistant TB cases globally, and transmitted primary drug-resistant TB is increasingly more common than resistance due to inadequate or unsuccessful TB treatment [12], [46], [47], [48], [49], [50]. As drug-resistant TB strains spread throughout populous countries such as India and China, as well as countries of the former Soviet Union and sub-Saharan Africa, and extend to lower prevalence areas such as the United States, using second and third-line regimens in combination with newer drugs will become increasingly commonplace. This case illustrates not only complexities of diagnosis and treatment, but also the continuing need for an array of new effective TB agents and rigorous documentation of their effectiveness in the clinical setting. In addition, further experience is needed in their use in managing not only pulmonary but also extrapulmonary drug-susceptible and drug-resistant TB. Finally, we note that this case illustrates the greater issue of increasing TB and drug resistant TB as a global public health emergency at a time when, paradoxically, cases are declining in the United States. In an era of globalization and continuing disparities of health and resources that underlie the spread of TB, we acknowledge the need to support global TB efforts to prevent the spread of drug-resistant TB, and to maintain TB expertise and patient supportive services in the United States.\n\nAcknowledgments\nWe acknowledge the assistance of many colleagues at Yale New Haven Hospital in the management of this patient, including Katrin Sadigh MD (Internal Medicine) and Hao Feng MD (Internal Medicine). We would also like to acknowledge Danielle Orcutt (CT DPH), Patricia Carey (CT DPH), Darleen Hoffler (CT DPH), and Dr. Zarir Udwadia, Mumbai, India.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n==== Refs\nReferences\n1 World Health Organization Tuberculosis fact sheet 2016 19 October Available from: http://www.who.int/mediacentre/factsheets/fs104/en/ 2016 \n2 World Health Organization WHO treatment guidelines for drug-resistant tuberculosis: 2016 update 2016 World Health Organization \n3 Bernaerts A Vanhoenacker FM Parizel PM Van Goethem JW Van Altena R Laridon A Tuberculosis of the central nervous system: overview of neuroradiological findings Eur Radiol 13 8 2003 1876 1890 12942288 \n4 Donmez FY Coskun M Guven G Medulla oblongata tuberculoma mimicking metastasis presenting with stroke-like symptoms Neurol Sci. 30 2009 349 352 19495558 \n5 Bayindir C Mete O Bilgic B Retrospective study of 23 pathologically proven cases of central nervous system tuberculomas Clin Neurol Neurosurg 108 4 2006 353 357 16644403 \n6 MacDonell AH Baird RW Bronze MS Intramedullary tuberculomas of the spinal cord: case report and review Rev Infectious Dis 12 3 1990 432 439 2193350 \n7 Gulsen S Caner H Tuberculoma in the medulla oblongata and medulla spinalis: two case reports Balkan Med J 30 4 2013 442 445 25207157 \n8 Miller MB Popowitch EB Backlund MG Ager EP Performance of Xpert MTB/RIF RUO assay and IS6110 real-time PCR for Mycobacterium tuberculosis detection in clinical samples J Clin Microbiol 49 10 2011 3458 3462 21849695 \n9 Scott LE Beylis N Nicol M Nkuna G Molapo S Berrie L Diagnostic accuracy of Xpert MTB/RIF for extrapulmonary tuberculosis specimens: establishing a laboratory testing algorithm for South Africa J Clin Microbiol 52 6 2014 1818 1823 24622091 \n10 World Health Organization. Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children: policy update. 2013.\n11 Thwaites G FIsher M Hemingway C Scott G Solomon T Innes J British infection society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children J Infect 59 2009 167 187 19643501 \n12 Dheda K Gumbo T Maartens G Dooley KE McNerney R Murray M The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis Lancet Respir Med 5 4 2017 291 360 \n13 Gropper MR Schulder M Sharan AD Cho ES Central nervous system tuberculosis: medical management and surgical indications Surg Neurol 44 4 1995 378 384 Discussion 84-5 8553259 \n14 Daley CL Caminero JA Management of multidrug resistant tuberculosis Semin Respir Crit Care Med 34 2013 44 59 23460005 \n15 Sun F Ruan Q Wang J Chen S Jin J Shao L Linezolid manifests a rapid and dramatic therapeutic effect for patients with life-threatening tuberculous meningitis Antimicrob Agents Chemother 58 10 2014 6297 6301 25092692 \n16 Nau R Sörgel F Eiffert H Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections Clin Microbiol Rev 23 4 2010 858 883 20930076 \n17 Jacobson KR Tierney DB Jeon CY Mitnick CD Murray MB Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis Clin Infect Dis 51 1 2010 6 14 20504231 \n18 Udwadia Z, Moharil G. Multidrug-resistant-tuberculosis treatment in the Indian private sector: results from a tertiary referral private hospital in Mumbai. Lung India.\n19 Bedaquiline: drug information [Internet]. 2017 [cited 4 April 2017].\n20 Diacon AH Donald PR Pym A Grobusch M Patientia RF Mahanyele R Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance Antimicrob Agents Chemother 56 6 2012 3271 3276 22391540 \n21 Pym AS Diacon AH Tang SJ Conradie F Danilovits M Chuchottaworn C Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis Eur Respir J 47 2 2016 564 574 26647431 \n22 Ndjeka N Conradie F Schnippel K Hughes J Bantubani N Ferreira H Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysis Int J Tuberculosis Lung Dis 19 8 2015 979 985 \n23 Guglielmetti L Le Du D Jachym M Henry B Martin D Caumes E Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort Clin Infect Dis 60 2 2015 188 194 25320286 \n24 Diacon AH Pym A Grobusch M Patientia R Rustomjee R Page-Shipp L The diarylquinoline TMC207 for multidrug-resistant tuberculosis N Engl J Med 360 23 2009 2397 2405 19494215 \n25 Conradie F Diacon AH Everitt D Mendel C van Niekerk C Howell P The NIX-TB trial of pretomanid, bedaquiline, and linezolid to treat XDR-TB Conference on retroviruses and opportunistic infections (CROI); Seattle, WA 2017 \n26 Akkerman OW Odish OF Bolhuis MS de Lange WC Kremer HP Luijckx GJ Pharmacokinetics of Bedaquiline in cerebrospinal fluid and serum in multidrug-resistant tuberculous meningitis Clin Infect Dis 62 4 2016 523 524 26534926 \n27 Kurz SG Bonomo RA Reappraising the use of beta-lactams to treat tuberculosis Expert Rev Anti Infect Ther 10 9 2012 999 1006 23106275 \n28 Hugonnet JE Tremblay LW Boshoff HI Barry 3rd CE Blanchard JS Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis Science 323 5918 2009 1215 1218 (New York, NY) 19251630 \n29 Dauby N Muylle I Mouchet F Sergysels R Payen MC Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis Pediatr Infect Dis J 30 9 2011 812 813 21378593 \n30 Davies Forsman L Giske CG Bruchfeld J Schon T Jureen P Angeby K Meropenem-clavulanic acid has high in vitro activity against multidrug-resistant mycobacterium tuberculosis Antimicrob Agents Chemother 59 6 2015 3630 3632 25824227 \n31 England K Boshoff HIM Arora K Weiner D Dayao E Schimel D Meropenem-clavulanic acid shows activity against mycobacterium tuberculosis in vivo Antimicrob Agents Chemother 56 6 2012 3384 3387 22450968 \n32 Diacon AH van der Merwe L Barnard M von Groote-Bidlingmaier F Lange C Garcia-Basteiro AL B-lactams against tuberculosis – new trick for an old dog? N Engl J Med 2016 \n33 De Lorenzo S Alffenaar JW Sotgiu G Centis R D'Ambrosio L Tiberi S Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB Eur Respir J 41 6 2013 1386 1392 22997218 \n34 Tiberi S Payen MC Sotgiu G D'Ambrosio L Alarcon Guizado V Alffenaar JW Effectiveness and safety of meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB Eur Respir J 47 4 2016 1235 1243 26965290 \n35 Lee M Lee J Carroll MW Choi H Min S Song T Linezolid for treatment of chronic extensively drug-resistant tuberculosis N Engl J Med 367 16 2012 1508 1518 23075177 \n36 Curry International Tuberculosis Center and California Department of Public Health Drug-resistant tuberculosis: a survival guide for clinicians 3rd ed. 2016 \n37 Ahmad Khan F Gelmanova IY Franke MF Atwood S Zemlyanaya NA Unakova IA Aggressive regimens reduce risk of recurrence after successful treatment of MDR-TB Clin Infect Dis 63 2 2016 214 220 27161772 \n38 Yuen CM Kurbatova EV Tupasi T Caoili JC Van Der Walt M Kvasnovsky C Association between regimen composition and treatment response in patients with multidrug-resistant tuberculosis: a prospective cohort study PLoS Med 12 12 2015 e1001932 \n39 Critchley JA Young F Orton L Garner P Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis Lancet Infect Dis 13 3 2013 223 237 23369413 \n40 Prasad K Singh MB Corticosteroids for managing tuberculous meningitis Cochrane Database Syst Rev 1 2008 Cd002244 \n41 Kadhiravan T Deepanjali S Role of corticosteroids in the treatment of tuberculosis: an evidence-based update Indian J Chest Dis Allied Sci 52 2010 153 158 20949734 \n42 Afghani B Lieberman JM Paradoxical enlargement or development of intracranial tuberculomas during therapy: case report and review Clin Infect Dis 19 6 1994 1092 1099 7888539 \n43 Chuck C Robinson E Macaraig M Alexander M Burzynski J Enhancing management of tuberculosis treatment with video directly observed therapy in New York city Int J Tuberculosis Lung Dis 20 5 2016 588 593 \n44 Story A Garfein RS Hayward A Rusovich V Dadu A Soltan V Monitoring therapy compliance of tuberculosis patients by using video-enabled electronic devices Emerg Infect Dis 22 3 2016 538 540 26891363 \n45 Garfein RS Collins K Munoz F Moser K Cerecer-Callu P Raab F Feasibility of tuberculosis treatment monitoring by video directly observed therapy: a binational pilot study Int J Tuberculosis Lung Dis 19 9 2015 1057 1064 \n46 Shah NS Auld SC Brust JC Mathema B Ismail N Moodley P Transmission of extensively drug-resistant tuberculosis in South Africa N Engl J Med 376 3 2017 243 253 28099825 \n47 Moro ML Gori A Errante I Infuso A Franzetti F Sodano L An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian multidrug-resistant tuberculosis outbreak study group Aids. 12 9 1998 1095 1102 9662207 \n48 Ritacco V Di Lonardo M Reniero A Ambroggi M Barrera L Dambrosi A Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires J Infect Dis 176 3 1997 637 642 9291309 \n49 Pearson ML Jereb JA Frieden TR Crawford JT Davis BJ Dooley SW Nosocomial transmission of multidrug-resistant mycobacterium tuberculosis. A risk to patients and health care workers Ann Internal Med 117 3 1992 191 196 1352093 \n50 O'Donnell MR Jarand J Loveday M HIgh incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers Ann Intern Med 153 8 2010 516 522 20956708\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2405-5794",
"issue": "10()",
"journal": "Journal of clinical tuberculosis and other mycobacterial diseases",
"keywords": "AFB, acid-fast bacilli; BAL, bronchoalveolar lavage; Bedaquiline; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computerized tomography; Central nervous system (CNS) TB; DOT, directly observed therapy; DST, drug susceptibility testing; Extensively drug-resistant tuberculosis (XDR-TB); FDA, Food and Drug Administration; IV, intravenous; LUL, left upper lobe; MDR-TB, multidrug-resistant tuberculosis; MRI, magnetic resonance imaging; Multi-drug resistant tuberculosis (MDR-TB); TB, tuberculosis; Tuberculoma; Tuberculosis (TB); WHO, World Health Organization; XDR-TB, extensively drug-resistant tuberculosis",
"medline_ta": "J Clin Tuberc Other Mycobact Dis",
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"nlm_unique_id": "101682877",
"other_id": null,
"pages": "9-16",
"pmc": null,
"pmid": "31720380",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": "22450968;26162365;9291309;18254003;22391540;26534926;26260824;9662207;8553259;22997218;25207157;25378840;20504231;27433841;23369413;19643501;28099825;27161772;19495558;20949734;1352093;21849695;23075177;24622091;7888539;12942288;2193350;23106275;26714320;25320286;20956708;25092692;19494215;20930076;16644403;21378593;26891363;26965290;27084810;19251630;25824227;23460005;26647431",
"title": "A patient with central nervous system tuberculomas and a history of disseminated multi-drug-resistant tuberculosis.",
"title_normalized": "a patient with central nervous system tuberculomas and a history of disseminated multi drug resistant tuberculosis"
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"abstract": "Molecular portraits of numerous tumors have flooded oncologists with vast amounts of data. In parallel, effective inhibitors of central pathways have shown great clinical benefit. Together, this promises potential clinical benefits to otherwise end-stage cancer patients. Here, we report a clinical service offering mutation detection of archived samples using the ion Ampliseq cancer panel coupled with clinical consultation.A multidisciplinary think tank consisting of oncologists, molecular-biologists, genetic counselors, and pathologists discussed 67 heavily pretreated, advanced cancer patient cases, taking into account mutations identified using ion Ampliseq cancer panel, medical history, and relevant literature.The team generated a treatment plan, targeting specific mutations, for 41 out of 64 cases. Three patients died before results were available. For 32 patients, the treating oncologists chose not to include the panel recommendation in the treatment plan for various reasons. Nine patients were treated as recommended by the panel, 5 with clinical benefit, and 4 with disease progression.This study suggests that routine use of massive parallel tumor sequencing is feasible and can judiciously affect treatment decisions when coupled with multidisciplinary team-based decision making. Administration of personalized based therapies at an earlier stage of disease, expansion of genetic alterations examined, and increased availability of targeted therapies may lead to further improvement in the clinical outcome of metastatic cancer patients.",
"affiliations": "Sharett Institute of Oncology Leslie and Michael Gaffin Center for Oncology, Departments of Oncology and Neurology, Hebrew University-Hadassah Medical Center Department of Pediatrics, Hadassah Medical Center, Division of Pediatric Hematology and Oncology Lautenberg Center for Immunology, IMRIC, The Hebrew University-Hadassah Medical School Department of Pathology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.",
"authors": "Zick|Aviad|A|;Peretz|Tamar|T|;Lotem|Michal|M|;Hubert|Ayala|A|;Katz|Daniela|D|;Temper|Mark|M|;Rottenberg|Yakir|Y|;Uziely|Beatrice|B|;Nechushtan|Hovav|H|;Meirovitz|Amichai|A|;Sonnenblick|Amir|A|;Sapir|Eli|E|;Edelman|David|D|;Goldberg|Yael|Y|;Lossos|Alexander|A|;Rosenberg|Shai|S|;Fried|Iris|I|;Finklstein|Ruth|R|;Pikarsky|Eli|E|;Goldshmidt|Hanoch|H|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1097/MD.0000000000006931",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28514312MD-D-16-0665710.1097/MD.0000000000006931069315700Research ArticleObservational StudyTreatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients Zick Aviad MD, PhDa∗Peretz Tamar MDaLotem Michal MDaHubert Ayala MDaKatz Daniela MDaTemper Mark MDaRottenberg Yakir MD, MPHaUziely Beatrice MD, MPHaNechushtan Hovav MD, PhDaMeirovitz Amichai MDaSonnenblick Amir MD, PhDaSapir Eli MDaEdelman David MDaGoldberg Yael MDaLossos Alexander MDbRosenberg Shai MD, PhDbFried Iris MDcFinklstein Ruth MScdPikarsky Eli MD, PhDdeGoldshmidt Hanoch PhDeLi. Jianfeng a Sharett Institute of Oncologyb Leslie and Michael Gaffin Center for Oncology, Departments of Oncology and Neurology, Hebrew University-Hadassah Medical Centerc Department of Pediatrics, Hadassah Medical Center, Division of Pediatric Hematology and Oncologyd Lautenberg Center for Immunology, IMRIC, The Hebrew University-Hadassah Medical Schoole Department of Pathology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.∗ Correspondence: Aviad Zick, Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel (e-mail: aviadz@hadassah.org.il).5 2017 19 5 2017 96 20 e69311 12 2016 26 3 2017 24 4 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nMolecular portraits of numerous tumors have flooded oncologists with vast amounts of data. In parallel, effective inhibitors of central pathways have shown great clinical benefit. Together, this promises potential clinical benefits to otherwise end-stage cancer patients. Here, we report a clinical service offering mutation detection of archived samples using the ion Ampliseq cancer panel coupled with clinical consultation.\n\nA multidisciplinary think tank consisting of oncologists, molecular-biologists, genetic counselors, and pathologists discussed 67 heavily pretreated, advanced cancer patient cases, taking into account mutations identified using ion Ampliseq cancer panel, medical history, and relevant literature.\n\nThe team generated a treatment plan, targeting specific mutations, for 41 out of 64 cases. Three patients died before results were available. For 32 patients, the treating oncologists chose not to include the panel recommendation in the treatment plan for various reasons. Nine patients were treated as recommended by the panel, 5 with clinical benefit, and 4 with disease progression.\n\nThis study suggests that routine use of massive parallel tumor sequencing is feasible and can judiciously affect treatment decisions when coupled with multidisciplinary team-based decision making. Administration of personalized based therapies at an earlier stage of disease, expansion of genetic alterations examined, and increased availability of targeted therapies may lead to further improvement in the clinical outcome of metastatic cancer patients.\n\nKeywords\nDNAhigh-throughput nucleotide sequencingmutationneoplasmsprecision medicineOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nIn recent years, molecular profiles of tumors such as breast,[1,2] prostate,[3] colon,[4] lung,[5] ovary,[6] and glioblastoma[7] have been reported. In parallel, inhibitors of molecular pathways are commonly used in oncological practice including inhibitors of ABL1,[8] Adenylyl cyclase,[9] ALK,[10] BRAF,[11,12] CDK4/6,[13] DNMT,[14] EGFR,[15–18] HER2,[19–22] JAK,[23] KIT,[24] MEK,[25] mTOR,[26] RET,[5] ROS,[27] SMO,[28] VEGF,[29,30] and VEGFR.[31,32] Some of these inhibitors have shown clinical activity in diverse organs—HER2 inhibition in HER2-positive breast[22] and gastric tumors;[33] CKIT inhibition in gastrointestinal stroma tumor[24] and melanoma,[34] and mTOR inhibition in renal cell carcinoma,[35] Astrocytoma,[26] pancreatic neuroendocrine tumors,[36] and ER-positive breast cancer.[37] These reports, in conjunction with phase II,[38] phase I[39] and case reports[40] where patients derived clinical benefit from pathway inhibition, provide the clinical rationale for testing mutations in tumor samples and utilizing mutation analysis to choose a pathway inhibitor to treat patients. Several academic institutions[41,42] and commercial companies[43,44] offer a molecular profiling service[41,42] that hundreds of cancer patients in Israel have chosen to utilize, indicating an unmet need.\n\nIn this report, we describe a comprehensive molecular service based in an academic hospital setting. We detail the validation of the molecular technique, patient population and mutations found, as well as the decision-making process, clinical decisions taken by the molecular oncology forum and clinical outcome.\n\n2 Methods\n2.1 Patient population\nPatients were referred by their treating physician, at their discretion after a detailed discussion with the patient where the possible benefits and expected limitations were carefully reviewed prior to ordering this service. The clinical service included mutation detection, data analysis, and panel treatment recommendation. Patients receiving off-label treatment signed an informed consent (29c) that was approved by the head of the Hadassah Medical Center ethics (Helsinki) committee prior to treatment.\n\n2.2 Molecular profiling\nFormalin fixed paraffin embedded (FFPE) tissue was examined by a pathologist to identify the region for sampling and percentage of tumor cells in the analyzed region. DNA was extracted using QIamp DNA FFPE Tissue Kit and the Ion Ampliseq cancer panel was applied. Up to 4 samples were loaded on a 314 chip (10 million bases (Mb)capacity) or up to 8 samples were loaded on a 316 chip (100 Mb capacity) and run on an Ion Torrent Personal Genome Machine (PGM) System. Mutations were identified by the Ion Variant caller as previously described.[43] The V1 panel amplifies 13,311 bp in ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, FLT3, GNAS, HNF1A, HRAS, IDH1, JAK2/3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NMP1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB11, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53 and VHL. The V2 panel amplifies 22,027 bp in the same genes and also in EZH2, GNA11, GNAQ, and IDH2. Sanger sequencing was performed as previously described.\n\n2.3 Data interpretation\nAll variants were (manually) visualized using the integrative genome viewer.[44] Noncoding and synonymous variants were not investigated further. All variants with allelic fraction of 100% ± 3% or 50% ± 3% were perceived as potential germ line changes. If a variant was previously identified, in the study population, as a known germline variant, it was appraised as such. All others were perceived as somatic changes. Nonsynonymous somatic variants were examined using the COSMIC database,[45] and variants not identified in the database were not further evaluated. The variants identified in COSMIC were investigated by a literature review initiated by references found in the COSMIC database. A report including a summary of the case, the variant caller report, and review of the literature was sent to the treating physician. Based on the treating physician's remarks, a revised report was sent to the molecular oncology forum members including molecular-biologists, genetic counselors, oncologists, and pathologists. Each case was presented, reviewed, and discussed to reach a consensus recommendation.\n\n2.4 FFPE-based somatic panel validation\nTo validate the test, we sequenced 20 samples, 19 of the samples tested positive for KRAS, BRAF, or EGFR and 1 sample was positive for several mutations. In 19 out of 20 samples we succeeded in generating amplified DNA amenable for massive parallel sequencing. The average number of bases read was 229 Mb per chip which resulted in average coverage of 3503X. Sanger sequencing was performed on previously unknown mutations for further validation. The previously known mutations in all samples were identified.\n\nReproducibility was tested using duplicates prepared separately from the same DNA sample. There was full concordance between variants called, a total of 14 pairs. The average difference of variant allelic fraction (i.e., the percentage of the DNA reads that are mutated) in the duplicates was 1.6% with a median of 0.5%. A sample of normal tissue was analyzed and the variations found were either 50% ± 3% or 100% ± 3%, all perceived as germline. Based on these results, a clinical service was established where each tumor sample is tested twice, and certain mutations are regarded as germline.\n\n3 Results\n3.1 Patient population\nTable 1 reports the patients’ characteristics. The median number of previous treatments is 2. The advanced stage of disease in this population is demonstrated by the fact that 3 patients died while the test was processed, in a span of weeks (Table 1). In 64 cases the test was performed on existing FFPE samples. In 3 cases where no tissue was available for testing, test-designated biopsies were performed, 2 from lung metastases, and 1 from the primary gastric tumor. DNA was extracted from the tumor primary site (n = 33), local recurrences or distant metastasis (n = 29). The tumors were either naive to chemotherapy (n = 47), or previously treated (n = 16).\n\nTable 1 Clinical characterization of patients examined.\n\n3.2 Molecular profile\nSome samples tested harbored known mutations; 3 BRAF V600E, 3 KRAS G12D, 1 KRAS G13C, and 1 IDH1 R132H were reidentified. A KRAS G12D positive case was reclassified as KRAS wild type, a KRAS negative case was reclassified as KRAS A146T positive, and a BRAF V600E negative case was reclassified as BRAF V600E positive.\n\n3.3 Clinical outcome\nOf 67 patients assessed, 3 died before results were processed. Of the remaining patients, for 23 patients no novel perceived actionable somatic mutations were detected; in 41 patients, 75 novel actionable somatic mutations were detected with a median of 1 mutation per sample (range 1–3). One sample harboring hundreds of somatic mutations is not described. Actionable mutations are listed in Table 2. Of the 41 patients with actionable mutations that led to treatment recommendations, 9 patients received the treatment recommended by the forum. In 4 patients the disease progressed, however in 5, following the recommended treatment a clinical benefit, stable disease for more than 2 months or partial response was achieved (Table 3).[46–74] In 32 patients, treatment was deferred due to a combination of reasons including availability of pathway inhibitors in clinical trials outside the country, poor clinical condition, and other available treatment options. In cases where germline mutations were suspected, genetic consultation was recommended.\n\nTable 2 Actionable mutations identified in 67 cancer patients.\n\nTable 3 Clinical outcome of patients treated as recommended.\n\n4 Discussion\nThis series of 67 metastatic cancer or brain tumor patients whose tumors were tested for actionable mutations demonstrates that in the majority of patients, actionable mutations can be identified. When the recommended treatment was applied, clinical benefit was achieved in a significant portion of the patients. This work has several limitations, including being conducted in a single institution, retrospective study, limited accessibility to pathway inhibitors, a small heterogeneous population, and lack of clear indication.\n\nA proof that such a service prolongs the life of patients in a randomized prospective study was not found.[75] The extendibility of such a proof will be hard to come by, as the paradigm in oncology is shifting from large randomized trials to highly tailored small trials,[76] and following the perception that each patient's cancer is unique and genomic characterization of the tumor can have clinical significance in treating cancer patients[76] in a patient-centered research approach.[77,78] An impetus to establishing and applying this test clinically was the ever-increasing utilization of genomic tests performed by private companies. It was felt that a service that includes a validated test followed by a discussion by a multidisciplinary forum should be established.\n\nThere is limited availability to pathway inhibitors recommended by the forum, as phase I/II trials targeting molecular pathways are currently sparsely available in Israel.[79] The recommended treatment options often include treatments that may not be covered by the health insurance, and when purchased privately, may cost thousands of dollars a month.\n\nThe small patient population described is very heterogonous as to cancer site, number of treatments, and clinical statuses. It also does not represent the general patient population as these patients were able to pay for the service and were selected at the treating physician's discretion. Patient selection could have led to deference of treatments proposed as some patients were on one hand too ill to receive treatment, or on the other hand had other treatment options. The limitations of this work mirror the realty of implementing tumor biology into day-to-day clinical practice. These include, among other things, complicated issues involving ethics, drug accessibly, and clinical indication.[80]\n\nThis study highlights the growing ethical dilemmas a treating oncologist is faced with daily,[78] and questions such as whether it is ethical to offer an unproven test or treatment to patients that are suffering from end stage cancer? Is it ethical to deny a test that may decrease suffering and prolong life? As with others,[81] in our experience, it is essential to conduct a detailed discussion with the patient where the possible benefits and expected limitations are carefully reviewed prior to ordering this service.\n\nFor all patients with an actionable mutation, a clinical trial outside of Israel could be found using www.clinicaltrials.gov.[79] This option is considered not relevant by the molecular oncology forum due to the effort and suffering of advanced stage cancer patients traveling to a foreign country and living there, the very high costs and the inherently unknown clinical benefit. As another option, the concept of suitable off-trial possibilities was opted.[81] It is clear that this treatment concept is inferior to including patients in clinical trials. As molecular characterization of tumors has been democratized, increasing access to molecular inhibitors should be the next challenge of the pharmaceutical, research, and clinical community. This approach may help solve poor accrual as once uniform clinical entities are fragmented to an assortment of rare tumors with hundreds of compounds and thousands of combinations waiting to be tested in phase I/II trials.[82]\n\nOther groups have recently published the clinical results of harnessing molecular profiling to metastatic cancer patients. A study of 1283 advanced metastatic cancer patients tested FFPE tumor tissue using targeted sequencing of hotspot regions in PIK3CA, BRAF, KRAS, NRAS, PTEN, EGFR, KIT, GNAQ and MET. Using these tests, clinical targets were found in 40% of the patients. Sixteen percent received targeted treatment with 4% of the total population achieving a clinical response. A similar group of patients who received nontargeted therapy had an inferior response rate, time to treatment failure, and overall survival.[83] In 2 studies including 109 and 423 metastatic breast cancer patients, fresh tissue biopsies were tested for amplifications and deletions using comparative genome hybridization and hot spot sequencing of AKT1 and PIK3CA. Using these tests, clinical targets were found in 50% and 46% of the patients respectively. Sixteen percent and 13% received targeted treatment; the treatment was outside a clinical trial protocol in 40% of the patients, with a total of 8% and 3% respectively achieving clinical benefit.[84,85] Another study of 11 advanced metastatic cancer patients tested fresh tissue biopsies using whole genome sequencing and whole transcriptome sequencing. Using these tests, clinical targets were found in 89% of the patients. One patient was treated according to the targets identified with a short-lived partial response.[86] Initiatives such as the AURORA trial where hundreds of metastatic breast cancer patients will be subjected to molecular characterization and treated per mutation with a pathway inhibitor[87] and the NCI-MATCH trial that aims at recruiting 2400 metastatic cancer patients who will be treated in 24 different arms based on somatic mutations identified in the tumor sample will better quantify the benefit of this approach. Molecular profiling in the NCI-MATCH is based on the Oncomine Cancer Panel assay, using AmpliSeq chemistry and the PGM sequencer. Using this assay achieved an overall sensitivity of 96.98% and 99.99% specificity in detecting mutations. High reproducibility in detecting all reportable variants was observed, with a 99.99% mean interoperator pairwise concordance.[88]\n\nOur experience is in line with these studies, putative targets are identified in most patients, and clinical benefit is achieved in modest numbers. This study suggests that routine use of massive parallel tumor sequencing is feasible and can judiciously affect treatment decisions when coupled with multidisciplinary team based decision making. Administration of personalized therapies at earlier stages of therapy, expansion of genetic alterations examined, and availability of targeted therapies may lead to further improvement in the clinical outcome of patients.\n\nAbbreviations: FFPE = formalin fixed paraffin embedded, Mb = million bases, PGM = Personal Genome Machine.\n\nAZ and TP equality contributed to this work.\n\nThis work is supported by THE ISRAEL SCIENCE FOUNDATION (Grant No. 1985/13) and the Sharett Fund.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Curtis C Shah SP Chin SF \nThe genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups . Nature \n2012 ;486 :346 –52 .22522925 \n[2] Cancer Genome Atlas N \nComprehensive molecular portraits of human breast tumours . Nature \n2012 ;490 :61 –70 .23000897 \n[3] Grasso CS Wu YM Robinson DR \nThe mutational landscape of lethal castration-resistant prostate cancer . 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"issue": "96(20)",
"journal": "Medicine",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005240:Feasibility Studies; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms; D057285:Precision Medicine; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult",
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"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
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"title": "Treatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients.",
"title_normalized": "treatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients"
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"abstract": "Plasmablastic lymphoma (PBL) is a rare AIDS-related malignancy with a poor prognosis. Little is known about this entity, and no standard treatment regimen has been defined. To establish an adequate treatment strategy, we investigated 24 cases of PBL arising in human immunodeficiency virus-positive individuals. Most of the patients were in the AIDS stage, with a median CD4 count of 67.5/µL. Lymph nodes (58 %), gastrointestinal tract (42 %), bone marrow (39 %), oral cavity (38 %), and CNS (18 %) were the most commonly involved sites. Histology findings for the following were positive at varying rates, as follows: CD10 (56 %); CD30 (39 %); CD38 (87 %); MUM-1 (91 %); CD138 (79 %); EBER (91 %); and LMP-1 (18 %). There was a marked increase in patients in 2011-12, and the cases found in that period appeared to be more aggressive, showing a higher rate of advanced-stage PBL. Fourteen cases were treated with CHOP, while the others were treated with more intensive regimens, including bortezomib and hematopoietic stem cell transplantation. The overall median survival time was 15 months. A CD4 count of >100/µL at diagnosis and attaining complete remission in the first-line chemotherapy were associated with better outcomes (P = 0.027 and 0.0016, respectively). Host immune status and chemosensitivity are associated with improved prognosis in PBL.",
"affiliations": "Department of Clinical Infectious Diseases, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan. ykoizumi@aichi-med-u.ac.jp.;Department of Infectious Diseases, Osaka National Hospital, Osaka, Osaka, Japan.;Department of Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.;Department of Infectious Diseases, Osaka National Hospital, Osaka, Osaka, Japan.;Department of Infectious Diseases, Osaka National Hospital, Osaka, Osaka, Japan.;AIDS Clinical Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan.;Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan.;Department of Hematology, National Center for Global Health and Medicine Hospital, Tokyo, Japan.;Department of Hematology and Oncology, University of Fukui Hospital, Fukui, Fukui, Japan.;Department of Infectious Diseases, Osaka National Hospital, Osaka, Osaka, Japan.;Department of Hematology, Shiga University of Medical Science, Otsu, Shiga, Japan.;Department of Hematology, Shiga University of Medical Science, Otsu, Shiga, Japan.;Division of Biostatistics, Clinical Research Center, Aichi Medical University, Nagakute, Aichi, Japan.;Department of Clinical Infectious Diseases, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.;Department of Hematology, Kawasaki Medical School, Kawasaki, Okayama, Japan.;Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.;Department of Infectious Diseases, Osaka National Hospital, Osaka, Osaka, Japan.;Department of Hematology, Nagoya Medical Center, Nagoya, Aichi, Japan.;Department of Pathology, Osaka National Hospital, Osaka, Osaka, Japan.;Department of Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.;Department of Pathology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.;Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.;Center for AIDS Research, Kumamoto University, Kumamoto, Kumamoto, Japan.",
"authors": "Koizumi|Yusuke|Y|;Uehira|Tomoko|T|;Ota|Yasunori|Y|;Ogawa|Yoshihiko|Y|;Yajima|Keishiro|K|;Tanuma|Junko|J|;Yotsumoto|Mihoko|M|;Hagiwara|Shotaro|S|;Ikegaya|Satoshi|S|;Watanabe|Dai|D|;Minamiguchi|Hitoshi|H|;Hodohara|Keiko|K|;Murotani|Kenta|K|;Mikamo|Hiroshige|H|;Wada|Hideho|H|;Ajisawa|Atsushi|A|;Shirasaka|Takuma|T|;Nagai|Hirokazu|H|;Kodama|Yoshinori|Y|;Hishima|Tsunekazu|T|;Mochizuki|Makoto|M|;Katano|Harutaka|H|;Okada|Seiji|S|",
"chemical_list": "D044966:Anti-Retroviral Agents; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-016-2082-3",
"fulltext": null,
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"issn_linking": "0925-5710",
"issue": "104(6)",
"journal": "International journal of hematology",
"keywords": "Acquired immunodeficiency syndrome; CD4; Combination antiretroviral therapy; Epstein–Barr virus; Human immunodeficiency virus; Plasmablastic lymphoma",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D018791:CD4 Lymphocyte Count; D003520:Cyclophosphamide; D004317:Doxorubicin; D020031:Epstein-Barr Virus Infections; D005260:Female; D006678:HIV; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D016483:Lymphoma, AIDS-Related; D008297:Male; D008875:Middle Aged; D000069293:Plasmablastic Lymphoma; D011241:Prednisone; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "669-681",
"pmc": null,
"pmid": "27604616",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "19220417;10561185;25612847;12857922;18756521;16199516;9028965;16327436;21856550;24453289;22642936;24407967;22899491;20202462;22180164;3024161;24300545;11999580;21486978;16414538;21752466;18389175;22510767;22752537;25293772;15223650;18787825;9242574;23880011;20823416;25408850;21447826;20167839;17094093;24528507;21483021;23509308;21593346;20138565;18939960",
"title": "Clinical and pathological aspects of human immunodeficiency virus-associated plasmablastic lymphoma: analysis of 24 cases.",
"title_normalized": "clinical and pathological aspects of human immunodeficiency virus associated plasmablastic lymphoma analysis of 24 cases"
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... |
{
"abstract": "Hemoperitoneum is a rare and potentially life-threatening complication of GIST. We reported a 54-year-old man who developed disseminated intra-abdominal recurrence from a previously resected gastrointestinal stromal tumour (GIST) of the small bowel, and the patient presented with hemoperitoneum. Emergent debulking surgery was performed. A high dose imatinib was prescribed. Despite the presence of residual disease, the patient was well clinically 8 months after the operation. Even though, there is no evidence to support the routine use of debulking surgery in the management of GIST. In our patient, disease progression after second line targeted therapy and the absence of alternative treatment options for spontaneous rupture and hemoperitoneum prompted us to treat the patient aggressively. Resection of the ruptured GIST was carried out for control of bleeding and to prevent recurrent bleeding in this patient with good surgical risks. During the treatment decision-making, the patient's general condition, the risk of surgery and the extent of dissemination were taken into consideration. In this patient who presented with spontaneous rupture of a small intestinal GIST, the novel use of targeted therapy and aggressive surgical treatment produced reasonably good survival outcome.",
"affiliations": "Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.",
"authors": "Lai|Eric C H|EC|;Chung|Kam Man|KM|;Lau|Stephanie H Y|SH|;Lau|Wan Yee|WY|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "China",
"delete": false,
"doi": "10.1007/s11684-014-0344-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2095-0217",
"issue": "9(1)",
"journal": "Frontiers of medicine",
"keywords": null,
"medline_ta": "Front Med",
"mesh_terms": "D000970:Antineoplastic Agents; D001549:Benzamides; D065426:Cytoreduction Surgical Procedures; D018450:Disease Progression; D004210:Dissection; D004305:Dose-Response Relationship, Drug; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006465:Hemoperitoneum; D006801:Humans; D000068877:Imatinib Mesylate; D007421:Intestine, Small; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010879:Piperazines; D011183:Postoperative Complications; D011743:Pyrimidines; D018570:Risk Assessment; D012422:Rupture, Spontaneous",
"nlm_unique_id": "101549428",
"other_id": null,
"pages": "108-11",
"pmc": null,
"pmid": "25001102",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18202855;23084087;24530605;18289826;18473425;22633986;24491288;19879571;24859399;23751846",
"title": "A ruptured recurrent small bowel gastrointestinal stromal tumour causing hemoperitoneum.",
"title_normalized": "a ruptured recurrent small bowel gastrointestinal stromal tumour causing hemoperitoneum"
} | [
{
"companynumb": "PHHY2015CN159606",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NILOTINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain, weight loss associated with diarrhea, and multiple inflammatory ulcerations and strictures of the small bowel. Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo. Increased levels of tumor necrosis factor-alpha (TNF-α) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder. No specific therapy has been shown to change the course of ulcerative jejunoileitis. We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies, including high dose corticosteroids and cyclosporine. The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-α monoclonal antibody, infliximab (Remicade(®)).",
"affiliations": "Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA 98101, United States.",
"authors": "Seven|Gulseren|G|;Assaad|Adel|A|;Biehl|Thomas|T|;Kozarek|Richard A|RA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v18.i36.5135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "18(36)",
"journal": "World journal of gastroenterology",
"keywords": "Biologic therapy; Infliximab; Tumor necrosis factor-alpha; Ulcerative jejunoileitis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D004751:Enteritis; D006801:Humans; D007079:Ileitis; D000069285:Infliximab; D007579:Jejunal Diseases; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha; D014456:Ulcer",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5135-7",
"pmc": null,
"pmid": "23049226",
"pubdate": "2012-09-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11875014;8899074;15879730;10994614;7524749;7797011;9250161;7959194;16489326;9550432",
"title": "Use of anti tumor necrosis factor-alpha monoclonal antibody for ulcerative jejunoileitis.",
"title_normalized": "use of anti tumor necrosis factor alpha monoclonal antibody for ulcerative jejunoileitis"
} | [
{
"companynumb": "US-TEVA-2021-US-1900120",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMINO ACIDS\\DEXTROSE\\ELECTROLYTES NOS"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo review the options for acute and maintenance pharmacological treatment of bipolar disorder in children and adolescents, including the treatment of bipolar depression and comorbid attention deficit/hyperactivity disorder (ADHD).\n\n\nMETHODS\nNarrative review of randomized clinical trials and open-label studies published from 2000 to 2012. The PubMed and PsycINFO websites were queried. Case series were included when a higher level of evidence was not available.\n\n\nRESULTS\nPublished data from randomized controlled trials (RCTs) in acute mania/hypomania with significant responses are available for lithium, topiramate, risperidone, olanzapine, and aripiprazole. Open trials of lithium and lamotrigine show that these drugs may be effective in the treatment of depressive episodes. No trials of selective serotonin reuptake inhibitors (SSRIs) have been conducted. In the treatment of comorbid ADHD, there are encouraging findings with mixed amphetamine salts and atomoxetine; conflicting results are observed with methylphenidate.\n\n\nCONCLUSIONS\nPublished RCTs of traditional mood stabilizers are scarce, but the best available evidence (results from meta-analytic regression) suggests that second-generation antipsychotics (SGAs) as a group are more effective in reducing manic symptoms. Risperidone was the only one included in head-to-head comparisons (vs. lithium and divalproex), showing superiority in terms of efficacy, but with more metabolic side effects, which were also more common in most of the SGAs. There are few studies addressing the treatment of ADHD and depression. Brazilian guidelines for the treatment of pediatric bipolar disorder should also include some SGAs (especially risperidone and aripiprazole) as first-line treatment, and these drugs should be provided by the public health services.",
"affiliations": "Program for Children and Adolescents with Bipolar Disorder (ProCAB), Universidade Federal do Rio Grande do Sul (UFRGS), Porto AlegreRS, Brazil.;Program for Children and Adolescents with Bipolar Disorder (ProCAB), Universidade Federal do Rio Grande do Sul (UFRGS), Porto AlegreRS, Brazil.;Program for Children and Adolescents with Bipolar Disorder (ProCAB), Universidade Federal do Rio Grande do Sul (UFRGS), Porto AlegreRS, Brazil.;Program for Children and Adolescents with Bipolar Disorder (ProCAB), Universidade Federal do Rio Grande do Sul (UFRGS), Porto AlegreRS, Brazil.",
"authors": "Peruzzolo|Tatiana Lauxen|TL|;Tramontina|Silzá|S|;Rohde|Luis Augusto|LA|;Zeni|Cristian Patrick|CP|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1516-4446",
"issue": "35(4)",
"journal": "Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)",
"keywords": null,
"medline_ta": "Braz J Psychiatry",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D001714:Bipolar Disorder; D002648:Child; D015897:Comorbidity; D006801:Humans; D016032:Randomized Controlled Trials as Topic",
"nlm_unique_id": "100895975",
"other_id": null,
"pages": "393-405",
"pmc": null,
"pmid": "24402215",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Pharmacotherapy of bipolar disorder in children and adolescents: an update.",
"title_normalized": "pharmacotherapy of bipolar disorder in children and adolescents an update"
} | [
{
"companynumb": "BR-JNJFOC-20170219908",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": "3",
"dru... |
{
"abstract": "The safety and efficacy of combination therapy comprising immune checkpoint inhibitors and cancer-specific peptide vaccines have not yet been established.\nA 71-year-old female metastatic renal cell carcinoma patient with multiple lung and pleural metastases. She had been treated with interferon alpha, sunitinib, axitinib, and pazopanib sequentially, but no clinical efficacy was observed. She participated in a clinical trial using cancer-specific peptide vaccine therapy. Initially no antitumor effect was observed, and vaccine therapy was ceased after two courses. But 3 months after the start of nivolumab, remarkable tumor shrinkage was observed at all metastatic sites, which resulted in almost complete response at 6 months. At 10 months, nivolumab was stopped due to cellulitis at the peptide vaccine inoculation site. Intriguingly, even after nivolumab discontinuation, complete response was maintained for more than 1 year.\nWe experienced a remarkable antitumor effect by nivolumab in a patient who was previously treated with vaccine therapy.",
"affiliations": "Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Dermatology and Plastic Surgery Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Cell Pathology Faculty of Life Sciences Kumamoto University Kumamoto Japan.;Department of Urology Kurume University School of Medicine Kurume Fukuoka Japan.;Department of Urology Faculty of Life Sciences Kumamoto University Kumamoto Japan.",
"authors": "Kurahashi|Ryoma|R|https://orcid.org/0000-0001-6972-8065;Motoshima|Takanobu|T|;Fukushima|Yumi|Y|;Murakami|Yoji|Y|;Yatsuda|Junji|J|;Yamaguchi|Takahiro|T|;Sugiyama|Yutaka|Y|;Fukushima|Satoshi|S|;Komohara|Yoshihiro|Y|;Suekane|Shigetaka|S|https://orcid.org/0000-0003-1150-2893;Kamba|Tomomi|T|https://orcid.org/0000-0002-5255-6479",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1002/iju5.12139",
"fulltext": "\n==== Front\nIJU Case Rep\nIJU Case Rep\n10.1002/(ISSN)2577-171X\nIJU5\nIJU Case Reports\n2577-171X John Wiley and Sons Inc. Hoboken \n\n10.1002/iju5.12139\nIJU512139\nCase Report\nCase Reports\nRemarkable antitumor effect of nivolumab in a patient with metastatic renal cell carcinoma previously treated with a peptide‐based vaccine\nNivolumab and peptide vaccineR Kurahashi et al.Kurahashi Ryoma https://orcid.org/0000-0001-6972-8065\n1\nrkurahashi-ncd@umin.ac.jp Motoshima Takanobu \n1\n Fukushima Yumi \n1\n Murakami Yoji \n1\n Yatsuda Junji \n1\n Yamaguchi Takahiro \n1\n Sugiyama Yutaka \n1\n Fukushima Satoshi \n2\n Komohara Yoshihiro \n3\n Suekane Shigetaka https://orcid.org/0000-0003-1150-2893\n4\n Kamba Tomomi https://orcid.org/0000-0002-5255-6479\n1\n \n1 \nDepartment of\nUrology\nFaculty of Life Sciences\nKumamoto University\nKumamoto\nJapan\n\n\n2 \nDermatology and Plastic Surgery\nFaculty of Life Sciences\nKumamoto University\nKumamoto\nJapan\n\n\n3 \nCell Pathology\nFaculty of Life Sciences\nKumamoto University\nKumamoto\nJapan\n\n\n4 \nDepartment of Urology\nKurume University School of Medicine\nKurume\nFukuoka\nJapan\n\n* Correspondence: Ryoma Kurahashi M.D., Ph.D., Department of Urology, Faculty of Life Sciences, Kumamoto University, 1‐1‐1 Honjo, Chuo‐ku, Kumamoto 860‐8556, Japan. Email: rkurahashi-ncd@umin.ac.jp\n09 1 2020 \n3 2020 \n3 2 10.1002/iju5.v3.244 48\n16 7 2019 12 12 2019 © 2020 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.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.Introduction\nThe safety and efficacy of combination therapy comprising immune checkpoint inhibitors and cancer‐specific peptide vaccines have not yet been established.\n\nCase presentation\nA 71‐year‐old female metastatic renal cell carcinoma patient with multiple lung and pleural metastases. She had been treated with interferon alpha, sunitinib, axitinib, and pazopanib sequentially, but no clinical efficacy was observed. She participated in a clinical trial using cancer‐specific peptide vaccine therapy. Initially no antitumor effect was observed, and vaccine therapy was ceased after two courses. But 3 months after the start of nivolumab, remarkable tumor shrinkage was observed at all metastatic sites, which resulted in almost complete response at 6 months. At 10 months, nivolumab was stopped due to cellulitis at the peptide vaccine inoculation site. Intriguingly, even after nivolumab discontinuation, complete response was maintained for more than 1 year.\n\nConclusion\nWe experienced a remarkable antitumor effect by nivolumab in a patient who was previously treated with vaccine therapy.\n\ncomplete responsemetastatic renal cell carcinomanivolumabpeptide vaccine source-schema-version-number2.0cover-dateMarch 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:08.06.2020\n\n\nKurahashi \nR \n, \nMotoshima \nT \n, \nFukushima \nY \n\net al\nRemarkable antitumor effect of nivolumab in a patient with metastatic renal cell carcinoma previously treated with a peptide‐based vaccine\n. IJU Case Rep . 2020 ; 3 : 44 –48\n.\n==== Body\nAbbreviations & Acronyms\nCRcomplete response\n\nEGFRepidermal growth factor receptor\n\nHLAhuman leukocyte antigen\n\nIFNαinterferon alpha\n\nirAEimmune‐related adverse event\n\nLCKlymphocyte‐specific protein tyrosine kinase\n\nmRCCmetastatic renal cell carcinoma\n\nMRP3multidrug resistance‐associated protein 3\n\nPD‐1programmed cell death‐1\n\nPD‐L1programmed cell death‐ligand 1\n\nSART2squamous cell carcinoma antigen recognized by T cells 2\n\nTILtumor infiltrating T cell\n\n\nKeynote message\nThe safety and efficacy of combination therapy comprising immune checkpoint inhibitors and cancer‐specific peptide vaccines have not yet been established. However, the combined therapy could have a synergistic effect of compensating for each other’s weakness and exert a remarkable antitumor effect.\n\n\n\n\nIntroduction\nThe treatment paradigm of mRCC has dramatically changed after the approval of anti‐PD‐1 monoclonal antibody nivolumab.1 However, there are some limitations, such as therapeutic effect is achieved in only 30% of mRCC patients and among 21% of patients experience grade 3–4 irAEs.2 Although peptide‐based vaccines enhance immunospecificity and immunogenicity against cancer, the immunosuppressive effect can be a problem.\n\nHere, we report a case that started nivolumab as a later‐line treatment for mRCC following TKIs and peptide vaccine therapy, demonstrating remarkable tumor shrinkage that resulted in CR with a minor localized irAE.\n\nCase presentation\nA 71‐year‐old woman underwent left radical nephrectomy 4 years ago. Pathological findings showed clear cell renal cell carcinoma G2 (pT3aN0M0), but 15 months after surgery multiple lung and pleural metastases occurred. Despite sequential therapy comprising IFNα, sunitinib, axitinib, and pazopanib, no clinical efficacy was observed and all drugs were discontinued due to cancer progression within 6 months.\n\nDuring pazopanib treatment, the patient participated in a clinical trial to receive a cancer‐specific peptide vaccine at her own discretion. The patient's HLA subtype was HLA‐A24, and cancer‐specific peptides such as SART2, LCK, EGFR, and MRP3 were identified in renal cell carcinoma tissue (Table 1). These cancer peptides were used to eliminate cancer cells via activation and enhancement of the exhausted immune system to improve its potential to attack cancer cells. Administration of these cancer peptides was also expected to facilitate further elimination of remaining cancer cells by the immune system, resulting in a more favorable therapeutic effect. After two courses (18 times) of vaccine therapy, no significant anti‐cancer effect was detected. The patient subsequently decided to discontinue vaccine therapy, wished to receive newly approved nivolumab and was referred to our hospital.\n\nTable 1 The immunoreactivity to SART2, LCK, EGFR, and MRP3 was activated by the peptide vaccine and it was maintained after vaccination. IgG response, as defined by FIU\n\nThe immunoreactivity of HLA‐A24 peptide subset\t\nHLA‐A24 peptides subset\tPre vaccination\tPost 1st course\tPost 2nd course\tAfter 6 months\tAfter 12 months\t\nSART2‐93\t62\t5059\t32 016\t27 842\t28 221\t\nSART3‐109\t30\t28\t19\t14\t12\t\nLok‐208\t56\t60\t171\t168\t342\t\nPAP‐213\t32\t28\t23\t15\t13\t\nEGF‐R‐800\t62\t163\t10 738\t5044\t6335\t\nMRP3‐503\t18\t419\t13 704\t7446\t11 708\t\nMRP3‐1293\t44\t52\t52\t33\t37\t\nSART2‐161\t27\t33\t36\t22\t21\t\nLck‐486\t55\t24 602\t24 724\t18 549\t20 116\t\nLck‐488\t54\t391\t393\t182\t174\t\nEZH2‐735\t42\t36\t33\t25\t24\t\nPTHrP‐102\t40\t80\t38\t25\t21\t\n \t \t \t \tIgG(FIU)\t\nJohn Wiley & Sons, LtdAfter obtaining informed consent about the possibility of severe irAEs, we started nivolumab at a dose of 3 mg/kg. Soon after the start of nivolumab, the multiple lung and pleural metastatic lesions began to shrink markedly and we finally achieved almost CR without any specific serious adverse events (Fig. 1).\n\nFigure 1 (a) Schedule of peptide vaccine administration. First course (8 doses/course): 3.0 mg/1.5 ml peptide vaccine is administrated by subcutaneous injection once per week four times, and the next four administrations are at the same dose once every 2 weeks. Second course: same dose is given once per month. (b) Chest computed tomography shows remarkable tumor shrinkage at lung and pleural metastatic sites after induction of nivolumab.\n\nTen months after the start of nivolumab administration, fever and erythema with induration over a 10‐cm area of bilateral thigh developed. Skin biopsy of the lesion was performed and pathological findings showed infiltration of a number of inflammatory cells, such as lymphocytes, plasma cells, foam cells, and epithelioid cells, resulting in a diagnosis of immune‐related cellulitis (Fig. 2). Interestingly, these skin reaction areas corresponded to peptide vaccine inoculation sites.\n\nFigure 2 (a) Erythema and induration were observed on bilateral thigh corresponded to peptide vaccine inoculation sites. (b, c) Pathological findings of skin biopsy (H&E). Infiltration of lymphocytes, plasma cells, foam cells, and epithelioid cells indicates immune‐related cellulitis. Lymphocytes that infiltrated the erythema were CD8 dominant, and PD‐L1‐ and PD‐L2‐positive cells also infiltrated around the lymphocytes. Scale bar; 100 μm.\n\nBecause this irAE occurred, we ceased nivolumab treatment and continued close follow‐up without any anti‐cancer treatment. The patient has maintained CR without any clinical symptoms for more than a year since discontinuation of nivolumab.\n\nDiscussion\nCancer vaccine therapy is one of the major immunotherapies, which induces specific anti‐cancer activity of lymphocytes through administration of specific cancer antigens.3 There are several methodologies, one of which is administering the identified cancer antigen peptide or protein with an adjuvant, and the other is transferring autologous lymphocytes that acquire tumor specificity by antigen stimulation.4, 5 In addition, another strategy is the use of an autologous cancer vaccine cell, which has been made more immunogenic by transferring a cytokine or chemokine gene.6 This treatment has had an excellent therapeutic effect for urological cancers, especially prostate cancer.7\n\n\nImmune checkpoint inhibitors targeting molecules expressed in tumor cells and immune cells have strong modification effects. PD‐1 is expressed on activated T lymphocytes and functions through a checkpoint mechanism for T lymphocyte activation.8, 9 Immune checkpoint inhibitors, including nivolumab, release immune tolerance by acting directly on these target molecules, and introduce cytotoxicity to tumor cells.10\n\n\nIn this case, there is a possibility that cancer‐specific T lymphocytes induced by cancer peptide vaccines were exhausted due to the expression of PD‐1. Such memory T‐cell exhaustion induced by the PD‐1 pathway was reactivated by nivolumab, resulting in strong and specific cytotoxicity with high‐affinity recognition of multiple cancer antigens induced by the peptide vaccine. This possibility is also supported by the skin reaction that occurred as an irAE was seen at vaccine inoculation sites. We confirmed that the infiltrating T lymphocytes are CD8‐dominant and PD‐L1‐ and PD‐L2‐positive cells infiltrating around the lymphocytes. It is highly likely that the remainder of the inoculated vaccine was later activated by nivolumab (Fig. 2). We also performed immunohistochemistry in the primary tissues. Cancer cells are all strongly positive for HLA‐class I (A/B/C), and focally positive for HLA‐DR. The density of CD8‐positive TIL was 3–10 cells/HPF in 90% area (low TIL area); however, high infiltration (more than 100 cells/HPF) of CD8‐positive TIL was seen in the HLA‐DR‐positive area. Increased numbers of PD‐1‐ and FOXP3‐positive cells were also detected in high TIL areas. PD‐L1‐positive cells and CD163‐positive M2‐like macrophages were also increased in high TIL areas (Fig. 3). Taken together, these results suggest that the induced CD8 lymphocytes may have been immunosuppressed by M2‐like macrophages such as TAM. Therefore, there were no tumor suppressive effects with peptide vaccine alone, and it seems that the antitumor effects were induced by administration of nivolumab.\n\nFigure 3 Histology of primary renal cell carcinoma. (a) Low magnification of hematoxylin and eosin (H.E.) staining and IHC of CD8 were presented. CD8‐positive TILs were focally detected. Scale bar; 500 μm. (b) H.E. and IHCs of low TIL area and high TIL area were presented. IHCs were performed using anti‐CD8 (clone C8/144B), anti‐HLA‐A/B/C (clone EMR8‐5), anti‐HLA‐DR (clone TAL1B5), anti‐PD‐L1 (clone 22C3), anti‐CD163 (clone 10D6), anti‐PD‐1 (clone EH33), and anti‐FOXP3 (clone 236A/E7) monoclonal antibodies. Scale bar; 50 μm.\n\nTherefore, cancer vaccine therapy and immune checkpoint inhibitors can be expected to have a synergistic therapeutic effect compensating for each other's weakness with completely different mechanisms, exerting an antitumor effect. In fact, Ali et al.11 reported that combination therapy comprising an immune checkpoint inhibitor and cancer‐specific vaccine showed a remarkable tumor reduction effect in a melanoma xenograft murine model. In addition, randomized clinical trials are currently underway to examine the efficacy of this combination therapy in patients with melanoma and lung cancer (Clinical Trials.gov identifiers: NCT03047928 and NCT03406715).\n\nWhen considering combination immunotherapy with immune checkpoint inhibitors and cancer‐specific vaccines, we have to pay attention to the possibility of severe irAE due to unexpected immune reactions such as excessive cytokine release leading to general inflammation.12 In this case, we started nivolumab after providing adequate information about such risks, and fortunately, there were no severe irAEs. Further study about the safety and efficacy of combined treatment comprising a peptide vaccine and immune checkpoint inhibitor is warranted.\n\nConclusion\nThis is a unique clinical case that demonstrated a remarkable antitumor effect of nivolumab following previous treatment with a cancer‐specific peptide vaccine. Combination therapy comprising an immune checkpoint inhibitor with a cancer‐specific peptide vaccine could be a promising treatment option for patients with mRCC.\n\nConflict of interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 \n\nMotzer \nRJ \n, \nEscudier \nB \n, \nMcDermott \nDF \n, et al\nCheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal‐cell carcinoma\n. N. Engl. J. Med. \n2015 ; 373 : 1803 –13\n.26406148 \n2 \n\nChen \nTW \n, \nRazak \nAR \n, \nBedard \nPL \n, \nSiu \nLL \n, \nHansen \nAR \n. A systematic review of immune‐related adverse event reporting in clinical trials of immune checkpoint inhibitors\n. Ann. Oncol. \n2015 ; 26 : 1824 –9\n.25888611 \n3 \n\nKomohara \nY \n, \nHarada \nM \n, \nArima \nY \n\net al\nIdentification of target antigens in specific immunotherapy for renal cell carcinoma\n. J. Urol. \n2007 ; 177 : 1157 –62\n.17296437 \n4 \n\nSuekane \nS \n, \nNishitani \nM \n, \nNoguchi \nM \n\net al\nPhase I trial of personalized peptide vaccination for cytokine‐refractory metastatic renal cell carcinoma patients\n. Cancer Sci. \n2007 ; 98 : 1965 –8\n.17919310 \n5 \n\nObara \nW \n, \nKanehira \nM \n, \nKatagiri \nT \n, \nKato \nR \n, \nKato \nY \n, \nTakata \nR \n. Present status and future perspective of peptide‐based vaccine therapy for urological cancer\n. Cancer Sci. \n2018 ; 109 : 550 –9\n.29345737 \n6 \n\nvan Elsas \nA \n, \nHurwitz \nAA \n, \nAllison \nJP \n. Combination immunotherapy of B16 melanoma using anti‐cytotoxic T lymphocyte‐associated antigen 4 (Ctla‐4) and granulocyte/macrophage colony‐stimulating factor (Gm‐Csf)‐producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation\n. J. Exp. Med. \n1999 ; 190 : 355 –66\n.10430624 \n7 \n\nNoguchi \nM \n, \nKoga \nN \n, \nMoriya \nF \n\net al\nSurvival analysis of multiple peptide vaccination for the selection of correlated peptides in urological cancers\n. Cancer Sci. \n2018 ; 109 : 2660 –9\n.29938870 \n8 \n\nIshida \nY \n, \nAgata \nY \n, \nShibahara \nK \n, \nHonjo \nT \n. Induced expression of PD‐1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death\n. EMBO J. \n1992 ; 11 : 3887 –95\n.1396582 \n9 \n\nIwai \nY \n, \nIshida \nM \n, \nTanaka \nY \n, \nOkazaki \nT \n, \nHonjo \nT \n, \nMinato \nN \n. Involvement of PD‐L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD‐L1 blockade\n. Proc. Natl Acad. Sci. USA \n2002 ; 99 : 12293 –7\n.12218188 \n10 \n\nIwai \nY \n, \nTerawaki \nS \n, \nHonjo \nT \n. PD‐1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells\n. Int. Immunol. \n2005 ; 17 : 133 –44\n.15611321 \n11 \n\nAli \nOA \n, \nLewin \nSA \n, \nDranoff \nG \n, \nMooney \nDJ \n. Vaccines combined with immune checkpoint antibodies promote cytotoxic T‐cell activity and tumor eradication\n. Cancer Immunol. Res. \n2016 ; 4 : 95 –100\n.26669718 \n12 \n\nPostow \nMA \n, \nSidlow \nR \n, \nHellmann \nMD \n. Immune‐related adverse events associated with immune checkpoint blockade\n. N. Engl. J. Med. \n2018 ; 378 : 158 –68\n.29320654\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2577-171X",
"issue": "3(2)",
"journal": "IJU case reports",
"keywords": "complete response; metastatic renal cell carcinoma; nivolumab; peptide vaccine",
"medline_ta": "IJU Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101764958",
"other_id": null,
"pages": "44-48",
"pmc": null,
"pmid": "32743467",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "26406148;15611321;10430624;12218188;17919310;1396582;29320654;26669718;29938870;29345737;25888611;17296437",
"title": "Remarkable antitumor effect of nivolumab in a patient with metastatic renal cell carcinoma previously treated with a peptide-based vaccine.",
"title_normalized": "remarkable antitumor effect of nivolumab in a patient with metastatic renal cell carcinoma previously treated with a peptide based vaccine"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2018-106572",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nWe report a case of intravenous drug use associated tricuspid valve endocarditis in a 28-year-old pregnant female at 26-week gestation.\n\n\nMETHODS\nPatient management required a multidisciplinary collaboration between cardiac surgery, obstetrics and gynecology, and neonatal critical care.\n\n\nRESULTS\nDespite appropriate intravenous antibiotics, the patient developed life-threatening complications and underwent planned cesarean delivery at 28 weeks 6 days gestation followed by interval tricuspid valve replacement 1 week later.\n\n\nCONCLUSIONS\nBoth the patient and her infant were successfully managed through the perioperative period.",
"affiliations": "Division of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.;Division of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology, and Reproductive Science, Yale School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology, and Reproductive Science, Yale School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology, and Reproductive Science, Yale School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology, and Reproductive Science, Yale School of Medicine, New Haven, Connecticut.;Department of Obstetrics, Gynecology, and Reproductive Science, Yale School of Medicine, New Haven, Connecticut.;Division of Cardiology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut.;Division of Cardiology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut.;Division of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.",
"authors": "Lin|Dishen|D|http://orcid.org/0000-0002-5977-6773;Mullan|Clancy W|CW|http://orcid.org/0000-0002-2774-251X;Deshmukh|Uma|U|;Bahtiyar|Mert Ozan|MO|;Hosier|Hillary|H|;Lipkind|Heather|H|;Abdel-Razeq|Sonya|S|;Ranjan|Saurabh|S|;Lancaster|Gilead|G|;Pietras|Colleen|C|",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1111/jocs.14888",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-0440",
"issue": "35(9)",
"journal": "Journal of cardiac surgery",
"keywords": "valve repair/replacement",
"medline_ta": "J Card Surg",
"mesh_terms": "D000328:Adult; D006348:Cardiac Surgical Procedures; D004696:Endocarditis; D004697:Endocarditis, Bacterial; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D004364:Pharmaceutical Preparations; D011247:Pregnancy; D014261:Tricuspid Valve",
"nlm_unique_id": "8908809",
"other_id": null,
"pages": "2392-2395",
"pmc": null,
"pmid": "32720414",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Drug use associated tricuspid valve infective endocarditis in pregnancy.",
"title_normalized": "drug use associated tricuspid valve infective endocarditis in pregnancy"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202010857",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXACILLIN SODIUM"
},
"drugadditional": "1... |
{
"abstract": "Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection.",
"affiliations": "Department of Pediatric Immunology, Hacettepe University Children's Hospital, Ankara, Turkey. Electronic address: pinar_gur3334@hotmail.com.;Department of Pediatric Immunology, Hacettepe University Children's Hospital, Ankara, Turkey.;Department of Pediatric Immunology, Hacettepe University Children's Hospital, Ankara, Turkey.;Department of Radiology, Hacettepe University Children's Hospital, Ankara, Turkey.;Department of Pathology, Hacettepe University Children's Hospital, Ankara, Turkey.;Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.;Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.;Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.;Department of Pediatric Immunology, Hacettepe University Children's Hospital, Ankara, Turkey.",
"authors": "Cetinkaya|Pinar Gur|PG|;Ayvaz|Deniz Cagdas|DC|;Karaatmaca|Betül|B|;Gocmen|Rahsan|R|;Söylemezoğlu|Figen|F|;Bainter|Wayne|W|;Chou|Janet|J|;Chatila|Talal A|TA|;Tezcan|Ilhan|I|",
"chemical_list": "D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; C476731:NLRP12 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clim.2018.01.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1521-6616",
"issue": "191()",
"journal": "Clinical immunology (Orlando, Fla.)",
"keywords": "CARD9 deficiency; Central nervous system infection; Fungal infection; NLRP12",
"medline_ta": "Clin Immunol",
"mesh_terms": "D000293:Adolescent; D053468:CARD Signaling Adaptor Proteins; D020314:Central Nervous System Fungal Infections; D018389:Codon, Nonsense; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009181:Mycoses",
"nlm_unique_id": "100883537",
"other_id": null,
"pages": "21-26",
"pmc": null,
"pmid": "29307770",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "A young girl with severe cerebral fungal infection due to card 9 deficiency.",
"title_normalized": "a young girl with severe cerebral fungal infection due to card 9 deficiency"
} | [
{
"companynumb": "TR-PFIZER INC-2019307470",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
... |
{
"abstract": "Mesenchymal stem/stromal cells (MSCs) within the bone marrow (BM) are vitally important in forming the micro-environment supporting haematopoiesis after myeloablative chemotherapy. MSCs are known to be damaged phenotypically and functionally by chemotherapy; however, to the best our knowledge, the persistence of genotoxic effects of chemotherapy on the BM micro-environment has not been studied. We therefore aimed to evaluate genotoxic effects of chemotherapy on the BM both in vitro and in vivo, using the comet and micronucleus assays, focussing on the persistence of DNA lesions that may contribute to complications in the patient. The MSC cell line (HS-5) and primary cord blood mononuclear cells (CBMNCs: a source of undamaged DNA) were exposed to the chemotherapeutic agent cyclophosphamide (CY) within a physiologically relevant in vitro model. CY treatment resulted in significant increases in CBMNC DNA damage at all time points tested (3-48 h exposure). Similarly, HS-5 cells exposed to CY exhibited significant increases in DNA damage as measured by the comet assay, with increased numbers of abnormal cells visible in the micronucleus assay. In addition, even 48 h after removal of 48-h CY treatment, DNA damage remains significantly increased in treated cells relative to controls. In patients treated with chemotherapy for haematological malignancy, highly significant increases in damaged DNA were seen in BM cells isolated from one individual 1 year after completion of therapy for acute leukaemia compared with pretreatment (P < 0.001). Similarly, two individuals treated 7 and 17 years previously with chemotherapy exhibited significant increases of damaged DNA in MSC compared with untreated age- and sex-matched controls (P < 0.05). Unlike haematopoietic cells, MSCs are not replaced following a stem cell transplant. Therefore, long-term damage to MSC may impact on engraftment of either allogeneic or autologous transplants. In addition, persistence of DNA lesions may lead to genetic instability, correlating with the significant number of chemotherapy-treated individuals who have therapy-related malignancies.",
"affiliations": "Centre for Research in Biosciences, University of the West of England, Coldharbour Lane, Bristol, UK.;School of Biomedical Sciences, University of Plymouth, Plymouth, Devon, UK.;Centre for Research in Biosciences, University of the West of England, Coldharbour Lane, Bristol, UK.;Centre for Research in Biosciences, University of the West of England, Coldharbour Lane, Bristol, UK.",
"authors": "May|Jennifer E|JE|;Donaldson|Craig|C|;Gynn|Liana|L|;Morse|H Ruth|HR|",
"chemical_list": "D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1093/mutage/gey014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0267-8357",
"issue": "33(3)",
"journal": "Mutagenesis",
"keywords": null,
"medline_ta": "Mutagenesis",
"mesh_terms": "D000368:Aged; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003520:Cyclophosphamide; D004249:DNA Damage; D005260:Female; D005312:Fetal Blood; D006410:Hematopoiesis; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D059630:Mesenchymal Stem Cells; D008875:Middle Aged; D055153:Stem Cell Niche",
"nlm_unique_id": "8707812",
"other_id": null,
"pages": "241-251",
"pmc": null,
"pmid": "30239865",
"pubdate": "2018-09-17",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Chemotherapy-induced genotoxic damage to bone marrow cells: long-term implications.",
"title_normalized": "chemotherapy induced genotoxic damage to bone marrow cells long term implications"
} | [
{
"companynumb": "GB-CONCORDIA PHARMACEUTICALS INC.-E2B_00019127",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MITOXANTRONE HYDROCHLORIDE"
},
... |
{
"abstract": "This report describes a case of drug-associated choreoathetosis in a patient receiving ciprofloxacin. A 72-year-old haemodialysis patient presented with a 4-day history of progressive weakness, restlessness and involuntary movements of all limbs. He had been prescribed ciprofloxacin 500 mg twice daily for a lower respiratory tract infection 7 days previously. He had generalised choreoathetosis affecting both upper and lower limbs. The temporal relationship with drug exposure and a dose which was on the upper limit for his renal impairment implicated ciprofloxacin as the culprit. His symptoms completely resolved within 1 week of drug withdrawal and never recurred subsequently.",
"affiliations": "Graduate Entry Medical School, University of Limerick, Limerick, Ireland. drahadabdalla@gmail.com",
"authors": "Abdalla|Ahad|A|;Ramly|Shazrul|S|;Boers|Peter|P|;Casserly|Liam|L|",
"chemical_list": "D002939:Ciprofloxacin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002939:Ciprofloxacin; D003937:Diagnosis, Differential; D020820:Dyskinesias; D006801:Humans; D008297:Male; D009128:Muscle Spasticity; D006435:Renal Dialysis; D012141:Respiratory Tract Infections",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23605987",
"pubdate": "2013-04-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15739219;3830244;2309508;11281089;8865032;10991972;9756792;15133830;11073740",
"title": "Ciprofloxacin-associated choreoathetosis in a haemodialysis patient.",
"title_normalized": "ciprofloxacin associated choreoathetosis in a haemodialysis patient"
} | [
{
"companynumb": "PHHY2013IE060773",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Patients with eating disorders (EDs) often present with psychiatric comorbidity, and functional and/or organic gastrointestinal (GI) symptomatology. Such multidiagnostic presentations can complicate diagnostic practice and treatment delivery. Here we describe an adolescent patient who presented with mixed ED, depressive, and GI symptomatology, who had received multiple contrasting diagnoses throughout treatment. We used a novel machine learning approach to classify (i) the patient's functional brain imaging during an experimental pain paradigm, and (ii) patient self-report psychological measures, to categorize the diagnostic phenotype most closely approximated by the patient. Specifically, we found that the patient's response to pain anticipation and experience within the insula and anterior cingulate cortices, and patient self-report data, were most consistent with patients with GI pain. This work is the first to demonstrate the possibility of using imaging data, alongside supervised learning models, for purposes of single patient classification in those with ED symptomatology, where diagnostic comorbidity is common.",
"affiliations": "Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States; San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States. Electronic address: irina.strigo@ucsf.edu.;Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States.;Department of Psychiatry, University of California, San Diego, San Diego, CA, United States; San Diego Veterans Affairs Medical Center, San Diego, CA, United States.;Department of Pediatrics, University of California, San Diego, San Diego, CA, United States.;Department of Pediatrics, University of California, San Diego, San Diego, CA, United States.;Department of Psychiatry, University of California, San Diego, San Diego, CA, United States.",
"authors": "Strigo|Irina A|IA|;Murray|Stuart B|SB|;Simmons|Alan N|AN|;Bernard|Rebecca S|RS|;Huang|Jeannie S|JS|;Kaye|Walter H|WH|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2017.07.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "45()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Brain response; Eating disorders; Neuroimaging; Precision treatment; fMRI",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000293:Adolescent; D002540:Cerebral Cortex; D003863:Depression; D003936:Diagnosis, Computer-Assisted; D001068:Feeding and Eating Disorders; D005260:Female; D005767:Gastrointestinal Diseases; D006179:Gyrus Cinguli; D006801:Humans; D008279:Magnetic Resonance Imaging; D010146:Pain",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "149-153",
"pmc": null,
"pmid": "28823587",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The clinical application of fMRI data in a single-patient diagnostic conundrum: Classifying brain response to experimental pain to distinguish between gastrointestinal, depressive and eating disorder symptoms.",
"title_normalized": "the clinical application of fmri data in a single patient diagnostic conundrum classifying brain response to experimental pain to distinguish between gastrointestinal depressive and eating disorder symptoms"
} | [
{
"companynumb": "US-009507513-1803USA003264",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional... |
{
"abstract": "Disseminated fusariosis is a life-threatening, invasive, opportunistic infection in immunocompromised patients, especially those with haematological malignancies. The prognosis is poor because these fungi are resistant to many of the available antifungal agents. We present a case of disseminated fusariosis caused by Fusarium proliferatum in a patient with severe aplastic anaemia complicated by a secondary infection of Aspergillus flavus, with a fatal outcome. We also review the documented Fusarium infections in immunocompromised hosts.",
"affiliations": "Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Clinical Microbiology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Pathology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.",
"authors": "Ricna|Dita|D|;Lengerova|Martina|M|;Palackova|Martina|M|;Hadrabova|Marketa|M|;Kocmanova|Iva|I|;Weinbergerova|Barbora|B|;Pavlovsky|Zdenek|Z|;Volfova|Pavlina|P|;Bouchnerova|Jana|J|;Mayer|Jiri|J|;Racil|Zdenek|Z|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "59(1)",
"journal": "Mycoses",
"keywords": "Fusarium proliferatum; PCR diagnostics; fusariosis; real-time PCR",
"medline_ta": "Mycoses",
"mesh_terms": "D000741:Anemia, Aplastic; D000935:Antifungal Agents; D001228:Aspergillosis; D001231:Aspergillus flavus; D060085:Coinfection; D017809:Fatal Outcome; D060585:Fusariosis; D005670:Fusarium; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009894:Opportunistic Infections; D014230:Triazoles; D055815:Young Adult",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "48-55",
"pmc": null,
"pmid": "26661324",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Disseminated fusariosis by Fusarium proliferatum in a patient with aplastic anaemia receiving primary posaconazole prophylaxis - case report and review of the literature.",
"title_normalized": "disseminated fusariosis by fusarium proliferatum in a patient with aplastic anaemia receiving primary posaconazole prophylaxis case report and review of the literature"
} | [
{
"companynumb": "CZ-PFIZER INC-2016006751",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nFrom a pharmacokinetic viewpoint, the use of ombitasvir/paritaprevir/ritonavir, one of the standards of care for genotype 1b chronic hepatitis C in Japan, could be possible in patients with impaired renal function. The aim of this study was to assess the efficacy and safety of this combination that have not yet been addressed in patients undergoing dialysis.\n\n\nMETHODS\nA retrospective, multicenter study evaluated the outcome of 12-week ombitasvir (non-structural protein [NS]5A inhibitor)/paritaprevir (NS3/4A protease inhibitor)/ritonavir combination therapy for dialysis patients. The primary end-point was sustained virologic response 12 weeks after therapy (SVR12).\n\n\nRESULTS\nThe subjects were 31 patients with a median age of 64 years (range, 49-85 years), including 10 cirrhotic patients. All of the 31 patients had an estimated glomerular filtration rate level <15 mL/min/1.73 m2 , defined as end-stage renal disease (ESRD). Pre-existing resistance-associated substitutions at position L31 and Y93 of the NS5A region were detected in 0% and 3.6% (1/28), respectively. The rates of rapid virologic response, end-of-treatment response, and SVR12 were 93.5% (29/31), 100% (31/31), and 96.8% (30/31), respectively. The incidence of adverse events was 35.5% (11/31). Of the 11 patients, one discontinued the treatment due to erythema multiforme and thereafter relapsed. The most frequent adverse event was pruritus (6.5%; 2/31).\n\n\nCONCLUSIONS\nThe present study suggests that ombitasvir/paritaprevir/ritonavir combination therapy is effective and safe for genotype 1b chronic hepatitis C patients undergoing dialysis due to ESRD.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.;Core Research Facilities for Basic Science, Jikei University School of Medicine, Tokyo, Japan.;Division of Gastroenterology and Hepatology, Japanese Red Cross Saitama Hospital, Saitama, Japan.;Department of Internal Medicine, Division of Hepatology and Gastroenterology, Tokyo Medical University, Ibaraki Medical Center, Ibaraki, Japan.;Department of Internal Medicine, Division of Gastroenterology, Mito Saiseikai General Hospital, Ibaraki, Japan.;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Otakanomori Hospital, Chiba, Japan.;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Seirei Sakura Citizen Hospital, Chiba, Japan.;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan.;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan.;Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.;Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.;Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.;Department of Internal Medicine, Division of Gastroenterology, Kikkoman General Hospital, Chiba, Japan.;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Internal Medicine, Division of Hepatology and Gastroenterology, Tokyo Medical University, Ibaraki Medical Center, Ibaraki, Japan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.",
"authors": "Atsukawa|Masanori|M|;Tsubota|Akihito|A|;Koushima|Yohei|Y|;Ikegami|Tadashi|T|;Watanabe|Kouji|K|;Shimada|Noritomo|N|;Sato|Shinichi|S|;Kato|Keizo|K|;Abe|Hiroshi|H|;Okubo|Tomomi|T|;Arai|Taeang|T|;Itokawa|Norio|N|;Kondo|Chisa|C|;Mikami|Shigeru|S|;Asano|Toru|T|;Chuganji|Yoshimichi|Y|;Matsuzaki|Yasushi|Y|;Iwakiri|Katsuhiko|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.12910",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "47(13)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "chronic hepatitis C; dialysis; end-stage renal disease; genotype 1b; ombitasvir/paritaprevir/ritonavir",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "1429-1437",
"pmc": null,
"pmid": "28457003",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of ombitasvir/paritaprevir/ritonavir in dialysis patients with genotype 1b chronic hepatitis C.",
"title_normalized": "efficacy and safety of ombitasvir paritaprevir ritonavir in dialysis patients with genotype 1b chronic hepatitis c"
} | [
{
"companynumb": "JP-ABBVIE-17P-087-2011198-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OMBITASVIR\\PARITAPREVIR\\RITONAVIR"
},
"d... |
{
"abstract": "Warfarin is a synthetic oral anticoagulant that crosses the placenta and can lead to a number of congenital abnormalities known as fetal warfarin syndrome. Our aim is to report on the follow-up from birth to age 8 years of a patient with fetal warfarin syndrome. He presented significant respiratory dysfunction, as well as dental and speech and language complications. The patient was the second child of a mother who took warfarin during pregnancy due to a metallic heart valve. The patient had respiratory dysfunction at birth. On physical examination, he had a hypoplastic nose, pectus excavatum, and clubbing of the fingers. Nasal fibrobronchoscopy showed upper airway obstruction due to narrowing of the nasal cavities. He underwent surgical correction with Max Pereira graft, zetaplasty, and osteotomies for the piriform aperture. At dental evaluation, he had caries and delayed eruption of the upper incisors. Speech and language assessment revealed high palate, mouth breathing, little nasal patency, and shortened upper lip. Auditory long latency and cognitive-related potential to auditory stimuli demonstrated functional changes in the cortical auditory pathways. We believe that the frequency of certain findings observed in our patient may be higher in fetal warfarin syndrome than is appreciated, since a significant number result in abortions, stillbirths, or children evaluated in the first year of life without a follow-up. Thus, a multidisciplinary approach and long-term monitoring of these patients may be necessary.",
"affiliations": "Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil.;Graduation in Nursing, UFCSPA, RS, Brazil.;Clinical Genetics, UFCSPA and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), RS, Brazil.;Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil.;Speech Language Pathology, Universidade Federal do Rio Grande do Sul (UFRGS), RS, Brazil.;Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil.;Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil.;Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil.;Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil.",
"authors": "Silveira|Daniélle B|DB|;da Rosa|Ernani B|EB|;de Mattos|Vinicius F|VF|;Goetze|Thayse B|TB|;Sleifer|Pricila|P|;Santa Maria|Fernanda D|FD|;Rosa|Rosana C M|RC|;Rosa|Rafael F M|RF|;Zen|Paulo R G|PR|",
"chemical_list": "D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.36655",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "167(6)",
"journal": "American journal of medical genetics. Part A",
"keywords": "dental anomalies; fetal warfarin syndrome; multidisciplinary approach; nasal hypoplasia; respiratory dysfunction; speech language pathology",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D001308:Auditory Perceptual Disorders; D002648:Child; D005260:Female; D005333:Fetus; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009035:Mothers; D009295:Nasal Bone; D015508:Nasal Obstruction; D010027:Osteotomy; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D014071:Tooth Abnormalities; D014859:Warfarin",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "1294-9",
"pmc": null,
"pmid": "25899236",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Importance of a multidisciplinary approach and monitoring in fetal warfarin syndrome.",
"title_normalized": "importance of a multidisciplinary approach and monitoring in fetal warfarin syndrome"
} | [
{
"companynumb": "PHHY2015BR071940",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Warfarin is the commonest anticoagulant used in today's practice; it has a very narrow therapeutics window. Under and overdosing results in various life-threatening complications. Warfarin-related nephropathy (WRN) is a rare cause of acute kidney injury (AKI) in patients on long-term anticoagulation, as a result of supratherapeutic anticoagulation. Warfarin causes AKI by inducing glomerular hemorrhage with subsequent tubular obstruction by red blood cell (RBC) casts. WRN has been associated with irreversible kidney injury and increased risk of mortality. Despite a better understanding of pathophysiology and histopathology of WRN, its preventive measures and clinical outcome are not well known. We report here the case of a 62-year-old male, who was on a long-term warfarin therapy due to chronic atrial fibrillation with a history of old ischemic stroke and dilated cardiomyopathy. He was presented with AKI and his renal biopsy was suggestive of WRN. He was managed by withholding warfarin for a few days until the therapeutic range of international normalized ratio was achieved and steroids and N-acetylcysteine (NAC) recovered. WRN is a diagnosis of exclusion; other causes of AKI must be ruled out. Renal biopsy is the gold standard for diagnosis. Patients on chronic anticoagulant therapy should be monitored periodically for the therapeutic range of anticoagulants, deterioration of renal function, and hematuria.",
"affiliations": "Consultant Nephrologist, Tata Main Hospital, Jamshedpur, Jharkhand, India.;Registrar, Tata Main Hospital, Jamshedpur, Jharkhand, India.;Sr. Registrar, Tata Main Hospital, Jamshedpur, Jharkhand, India.",
"authors": "Yadav|Prabhakar|P|;Yadav|Sonal|S|;Pathak|Saurabh|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jfmpc.jfmpc_671_19",
"fulltext": "\n==== Front\nJ Family Med Prim CareJ Family Med Prim CareJFMPCJournal of Family Medicine and Primary Care2249-48632278-7135Wolters Kluwer - Medknow India JFMPC-8-304510.4103/jfmpc.jfmpc_671_19Case ReportWarfarin: A double-edged sword Yadav Prabhakar 1Yadav Sonal 2Pathak Saurabh 31 Consultant Nephrologist, Tata Main Hospital, Jamshedpur, Jharkhand, India2 Registrar, Tata Main Hospital, Jamshedpur, Jharkhand, India3 Sr. Registrar, Tata Main Hospital, Jamshedpur, Jharkhand, IndiaAddress for correspondence: Dr. Prabhakar Yadav, A/C-16/G, Phase -11, Adarsh Nagar, Sonari, East Singhbhum, Jamshedpur - 831 011, Jharkhand, India. E-mail: prabhakar577@yahoo.in9 2019 30 9 2019 8 9 3045 3047 22 8 2019 23 8 2019 06 9 2019 Copyright: © 2019 Journal of Family Medicine and Primary Care2019This 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.Warfarin is the commonest anticoagulant used in today's practice; it has a very narrow therapeutics window. Under and overdosing results in various life-threatening complications. Warfarin-related nephropathy (WRN) is a rare cause of acute kidney injury (AKI) in patients on long-term anticoagulation, as a result of supratherapeutic anticoagulation. Warfarin causes AKI by inducing glomerular hemorrhage with subsequent tubular obstruction by red blood cell (RBC) casts. WRN has been associated with irreversible kidney injury and increased risk of mortality. Despite a better understanding of pathophysiology and histopathology of WRN, its preventive measures and clinical outcome are not well known. We report here the case of a 62-year-old male, who was on a long-term warfarin therapy due to chronic atrial fibrillation with a history of old ischemic stroke and dilated cardiomyopathy. He was presented with AKI and his renal biopsy was suggestive of WRN. He was managed by withholding warfarin for a few days until the therapeutic range of international normalized ratio was achieved and steroids and N-acetylcysteine (NAC) recovered. WRN is a diagnosis of exclusion; other causes of AKI must be ruled out. Renal biopsy is the gold standard for diagnosis. Patients on chronic anticoagulant therapy should be monitored periodically for the therapeutic range of anticoagulants, deterioration of renal function, and hematuria.\n\nAcute kidney injurywarfarinwarfarin-related nephropathy\n==== Body\nBackground\nWarfarin is the commonly used anticoagulant for preventing thrombosis in a different subset of patients. Supratherapeutic dose of warfarin results in side effects like hematuria, vasculitis, interstitial nephritis, and hemorrhage.[12] Patients on chronic warfarin therapy are at increased risk of acute kidney injury (AKI) due to many reasons such as associated comorbidities, increased risk of hemorrhage, renal ischemia, atheroembolism, and allergic acute interstitial nephritis.[1] We are reporting here a case of warfarin-related nephropathy (WRN), biopsy-proven in a 62-year-old man with chronic atrial fibrillation on long-term warfarin therapy with a history of ischemic stroke and dilated cardiomyopathy, where warfarin cannot be withheld.\n\nCase Report\nA 62-year-old male was admitted with pain in abdomen as well as decreased appetite, vomiting, and red-colored urine. He was a known case of coronary artery disease post-percutaneous transluminal coronary angioplasty (PTCA)/stent with old ischemic stroke, chronic atrial fibrillation, dilated cardiomyopathy, and type 2 diabetes mellitus. He was kept on acenocoumarol 1 mg, aspirin 75 mg, atorvastatin 10 mg, and metoprolol 25 mg twice daily. He was on regular follow-up, and his acenocoumarol was recently increased to 1 and 2 mg alternate day to achieve the therapeutic international normalized ratio (INR). His baseline creatinine was 1.2 mg/dl. There was no history of exertional dyspnea, chest pain, palpitations, skin rash, decreased urine output, burning micturition, or pyuria. On physical examination, he was well nourished, no pallor and icterus was noticed, pulse rate was 80/min, and blood pressure was 130/80 mmHg. His serum creatinine was 5.35 mg/dl and INR was 5.4, with dysmorphic red blood cell (RBC) casts in the urine [Table 1]. A provisional diagnosis of AKI was made in the background of anticoagulation and was investigated further.\n\nTable 1 Laboratory investigations\n\nInvestigations\t04/04/2018\t03/06/2018 Warfarin dose increased\t05/07/2018 On admission\t10/07/2018 Heparin switch over\t21/07/2018 Discharge\t\nHb (g/dl)\t13.7\t13.4\t13.1\t11.0\t10.1\t\nTLC (cells/mm3)\t7900\t7000\t8600\t7200\t6800\t\nPlatelets (lakh/mm3)\t1.25\t1.6\t1.79\t1.89\t2.1\t\nCreatinine (mg/dl)\t1.40\t1.3\t5.35\t3.2\t1.8\t\nBilirubin (mg/dl)\t0.8\t0.9\t1.08\t1.0\t0.91\t\nUrine routine and microscopy\tAlbumin - nil RBC and pus cell - nil\tAlbumin - nil RBC and pus cell - nil\tAlbumin - 1+RBC - plenty and dysmorphic, RBC cast+Pus cell-6-8/hpf\tAlbumin - 1+RBC - 20-25/hpf Pus - 5-6/hpf\tAlbumin - nil RBC - 6-8/hpf Pus - 3-4/hpf\t\nPT INR\t1.61\t1.3\t5.4\t1.4\t1.8\t\nANA/DSDNA\t\t\tNegative\t\t\t\nANCA\t\t\tNegative\t\t\t\nC3/C4\t\t\tNormal\t\t\t\nHB: Hemoglobin, TLC: Total leucocyte count, PT: Prothrombin time, INR: International normalized ratio, ANA: Anti nuclear antibody, ANCA: Antineutrophilic cytoplasmic antibodies, RBC: Red blood cells, DSDNA: Double-stranded DNA\n\nThe autoimmune markers were negative. 2D echocardiography showed global hypokinesia with ejection fraction of 35%. The ultrasonography showed bilateral normal-sized kidneys. Renal biopsy was planned in view of unexplained AKI after stopping acenocoumarol, suggestive of acute tubular necrosis with RBC casts and immunofluorescence studies were negative [Figure 1]. Oral N-acetylcysteine (NAC) 1200 mg twice daily as well as oral prednisolone 30 mg/day was started. The serum creatinine started improving with the above treatment; meanwhile, he was managed with low molecular heparin before being restarted back with warfarin, with target INR of 1.5–2. The serum creatinine and INR 3-month postdischarge were 1.3 and 1.8, respectively.\n\nFigure 1 Sections stained with H and E (A). RBC casts in tubules (B). Normal glomerulus (C). Acute tubular necrosis\n\nDiscussion\nWarfarin is a commonly used anticoagulant in clinical practice, used for both treatment as well as prophylaxis for prevention of arterial and venous thrombosis. WRN is defined as an increase in serum creatinine >0.3 mg/dl, occurred within 1 week of an INR >3.0 in patients on chronic warfarin therapy.[3]\n\nKapoor et al. in 2008 described the entity called WRN as a cause of AKI in patients with hematuria while on warfarin therapy.[2] Brodsky et al. described an association between anticoagulation with warfarin and INR (>3.0) and worsening renal function.[3] They published a series of nine patients who received renal biopsies over a 5-year period for unexplained AKI and hematuria during warfarin therapy.[4] They retrospectively analyzed the biopsies and found extensive erythrocytes in Bowmen's space and tubules, and occlusive RBC casts in distal tubules without Tamm–Horsfall protein and active glomerulonephritis.[4] WRN was a rare cause of AKI <1% of the total kidney biopsies reviewed by them.[4] Preexisting chronic kidney disease (CKD) doubles the incidence of WRN, 33% in CKD and 16.5% in non-CKD population.[56] Out of nine patients analyzed by them, four patients had a complete renal recovery, four became dialysis-dependent, and one developed CKD with no improvement in kidney function 2 months after biopsy.[4]\n\nMendonca et al., Golla et al., and Conjeevaram et al. reported cases of WRN from India; we are reporting here a similar case.[789]\n\nManagement of WRN in patients requiring long-term anticoagulation is ambiguous. Alternative to warfarin, other anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban are being increasingly used. However, their renal safety is not established. In the literature, dabigatran-related nephropathy was also reported.[10] The best way to prevent WRN is to avoid excessive anticoagulation, drug interactions particularly with vitamin K antagonist and antibiotics, which interferes with warfarin metabolism and increases its drug level. In our case, patient had baseline serum creatinine of 1.2 mg/dl, and after 3 months of follow-up, his creatinine was 1.3 mg/dl, that is almost complete recovery occurred.[4] Beneficial effects of steroid in WRN are not documented in studies; it may be useful due to its anti-inflammatory and antifibrotic action. Withholding of warfarin till therapeutic level attained reduces the glomerular hemorrhage and prevents further damage to renal tubules and hasten recovery of renal failure.[8]\n\nConclusion\nAKI resulting from glomerular hemorrhage and tubular obstruction by RBC cast in patients on chronic warfarin therapy is a rare but serious complication. The supratherapeutic dose of warfarin increases the risk of AKI due to glomerular hematuria. Renal biopsy may be required for confirmation of diagnosis. Elderly patients, overanticoagulation, and underlying kidney diseases are the greatest risk factors. The treatment of biopsy-proven WRN is not clear; anticoagulants should be withdrawn and its effects should be reversed by using vitamin K. There is insufficient evidence regarding additional treatment with NAC or oral glucocorticoids. Clinical outcome in these patients is worst leading to the development of CKD and dialysis requirement. Care providers involved in the clinical care of patients on long-term anticoagulation should be aware of WRN and such patients should be monitored regularly for deterioration of renal function, change in coagulation profiles, and hematuria. Better understanding of WRN, though underdiagnosed, helps clinicians in early diagnosis, prognostication, timely therapy, and prevention from developing AKI, CKD, or dialysis dependence.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Oliver T Ciaudelli B Cohen DA Anticoagulation-related nephropathy: The most common diagnosis you’ve never heard of Am J Med 2019 pii: S0002-9343(19)30233-5. doi: 10.1016/j.amjmed. 2019.02.038. [Epub ahead of print] \n2 Kapoor K Bekaii-Saab J Warfarin-induced allergic interstitial nephritis and leucocytoclastic vasculitis Intern Med J 2008 38 281 3 18380703 \n3 Brodsky S Eikelboom J Hebert LA Anticoagulant-related nephropathy J Am Soc Nephrol 2018 29 2787 93 30420420 \n4 Brodsky SV Satoskar A Chen J Nadasdy G Eagen JW Hamirani M Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: A report of 9 cases Am J Kidney Dis 2009 54 1121 6 19577348 \n5 Brodsky SV Satoskar A Hemminger J Rovin B Hebert L Ryan MS Anticoagulant-related nephropathy in kidney biopsy: A single-center report of 41 cases Kidney Med 2019 1 51 6 \n6 An JN Ahn SY Yoon C-H Youn TJ Han M-K Kim S The occurrence of warfarin-related nephropathy and effects on renal and patient outcomes in Korean patients PLoS One 2013 8 e57661 23560034 \n7 Mendonca S Gupta D Valsan A Tewari R Warfarin related acute kidney injury: A case report Indian J Nephrol 2017 27 78 80 28182051 \n8 Golla A Goli R Nagalla VK Kiran BV Raju DS Uppin MS Warfarin-related nephropathy Indian J Nephrol 2018 28 378 81 30271000 \n9 Conjeevaram A Lohia P Ravishankar GS Vankalakunti M Double whammy: Pigment nephropathy and warfarin-related nephropathy as aetiology for acute kidney injury in a patient with mechanical heart valves Open Urol Nephrol J 2019 12 41 4 \n10 Ikeda M Tanaka M Shimoda S Saita H Nishikawa S Shimada H Dabigatran-induced anticoagulant-related nephropathy with undiagnosed IgA nephropathy in a patient with normal baseline renal function CEN Case Rep 2019 1 5 30073489\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2249-4863",
"issue": "8(9)",
"journal": "Journal of family medicine and primary care",
"keywords": "Acute kidney injury; warfarin; warfarin-related nephropathy",
"medline_ta": "J Family Med Prim Care",
"mesh_terms": null,
"nlm_unique_id": "101610082",
"other_id": null,
"pages": "3045-3047",
"pmc": null,
"pmid": "31681692",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "19577348;31347098;28182051;30420420;23560034;30878544;18380703;30271000",
"title": "Warfarin: A double-edged sword.",
"title_normalized": "warfarin a double edged sword"
} | [
{
"companynumb": "IN-IPCA LABORATORIES LIMITED-IPC-2020-IN-003758",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drug... |
{
"abstract": "Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution.\nWe reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases.\nA total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%).\nNanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.",
"affiliations": "Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.;Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.",
"authors": "Kashiwada|Takeru|T|;Saito|Yoshinobu|Y|;Terasaki|Yasuhiro|Y|;Hisakane|Kakeru|K|;Takeuchi|Susumu|S|;Sugano|Teppei|T|;Miyanaga|Akihiko|A|;Noro|Rintaro|R|;Minegishi|Yuji|Y|;Seike|Masahiro|M|;Kubota|Kaoru|K|;Gemma|Akihiko|A|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyy180",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "49(2)",
"journal": "Japanese journal of clinical oncology",
"keywords": null,
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "165-173",
"pmc": null,
"pmid": "30508192",
"pubdate": "2019-02-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Interstitial lung disease associated with nanoparticle albumin-bound paclitaxel treatment in patients with lung cancer.",
"title_normalized": "interstitial lung disease associated with nanoparticle albumin bound paclitaxel treatment in patients with lung cancer"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20181204065",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Sorafenib is currently the only targeted therapy available for advanced stage hepatocellular carcinoma (HCC). Cutaneous adverse events associated with sorafenib treatment include hand-foot skin reaction, but there has been no report of drug reaction (or rash) with eosinophilia and systemic symptoms (DRESS) syndrome. Here, we report a case of 72-year-old man with HCC and alcoholic liver cirrhosis who developed skin eruptions, fever, eosinophilia, and deteriorated hepatic and renal function under sorafenib treatment. He has since successfully recovered with conservative care.",
"affiliations": "Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.;Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.",
"authors": "Kim|Dong Kyun|DK|;Lee|Sung Woo|SW|;Nam|Hwa Seong|HS|;Jeon|Dong Sub|DS|;Park|Na Rae|NR|;Nam|Young Hee|YH|;Lee|Soo Keol|SK|;Baek|Yang Hyun|YH|;Han|Sang Young|SY|;Lee|Sung Wook|SW|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/kjg.2016.67.6.337",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "67(6)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": "DRESS syndrome; Hepatocellular carcinoma; Sorafenib",
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "337-340",
"pmc": null,
"pmid": "27312836",
"pubdate": "2016-06-25",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Case of Sorafenib-induced DRESS Syndrome in Hepatocelluar Carcinoma.",
"title_normalized": "a case of sorafenib induced dress syndrome in hepatocelluar carcinoma"
} | [
{
"companynumb": "KR-BAYER-2016-123777",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Neutropenic enterocolitis is well documented in patients with leukemia or lymphoma who are recovering from the adverse effects of chemotherapy. We report two cases of probable neutropenic enterocolitis in two patients with AIDS who developed the syndrome during an episode of moderate neutropenia. To the best of our knowledge, this syndrome has not been reported previously in a patient with AIDS. Both of our patients manifested a mild form of enterocolitis that was characterized by fever, abdominal pain, and evidence of colonic edema easily recognized by computed tomography of the abdomen. Both patients were managed successfully with use of conservative measures including discontinuation of use of marrow-suppressive drugs and therapy with broad-spectrum antimicrobial agents. Neutropenic enterocolitis should be considered as a treatable cause of fever and abdominal pain in patients with AIDS.",
"affiliations": "Department of Medicine, Case Western Reserve University School of Medicine, MetroHealth Medical Center, Cleveland, Ohio 44109.",
"authors": "Cutrona|A F|AF|;Blinkhorn|R J|RJ|;Crass|J|J|;Spagnuolo|P J|PJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1093/clinids/13.5.828",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0162-0886",
"issue": "13(5)",
"journal": "Reviews of infectious diseases",
"keywords": null,
"medline_ta": "Rev Infect Dis",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000900:Anti-Bacterial Agents; D004359:Drug Therapy, Combination; D004760:Enterocolitis; D006801:Humans; D008297:Male; D009503:Neutropenia; D012852:Sinusitis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7905878",
"other_id": null,
"pages": "828-31",
"pmc": null,
"pmid": "1962093",
"pubdate": "1991",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Probable neutropenic enterocolitis in patients with AIDS.",
"title_normalized": "probable neutropenic enterocolitis in patients with aids"
} | [
{
"companynumb": "US-PFIZER INC-2021903648",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditi... |
{
"abstract": "Facial necrotizing fasciitis (NF) is a rare fulminant infection of the soft and connective tissues that spreads along the fascial planes of the face. Its origins most commonly involve odontogenic infection and it is usually associated with a history of dentoalveolar surgery, such as tooth extraction or implant placement. We present a case of ascending facial NF with odontogenic origin in a patient taking a bisphosphonate.",
"affiliations": "Faculty, Department of Plastic and Reconstructive Surgery, The Catholic University of Korea Bucheon St. Mary's Hospital, Bucheon, Republic of Korea.;Resident, Department of Plastic and Reconstructive Surgery, The Catholic University of Korea Bucheon St. Mary's Hospital, Bucheon, Republic of Korea.;Professor, Department of Oral and Maxillofacial Surgery, The Catholic University of Korea Bucheon St. Mary's Hospital, Bucheon, Republic of Korea.;Assistant Professor, Department of Plastic and Reconstructive Surgery, The Catholic University of Korea Bucheon St. Mary's Hospital, Bucheon, Republic of Korea. Electronic address: tfm0822@catholic.ac.kr.",
"authors": "Kim|Dong Hwi|DH|;Lee|Ji Sung|JS|;Pyo|Sung Woon|SW|;Lee|Jung Ho|JH|",
"chemical_list": "D004164:Diphosphonates",
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2016.08.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "75(2)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D004164:Diphosphonates; D005145:Face; D019115:Fasciitis, Necrotizing; D006801:Humans; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "317-321",
"pmc": null,
"pmid": "27639154",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ascending Facial Necrotizing Fasciitis in a Patient Taking a Bisphosphonate.",
"title_normalized": "ascending facial necrotizing fasciitis in a patient taking a bisphosphonate"
} | [
{
"companynumb": "KR-FRESENIUS KABI-FK201704672",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,... |
{
"abstract": "Rhabdomyolysis and delayed acetaminophen hepatotoxicity may be associated with elevated serum transaminase values. Establishing the cause of elevated transaminases may be especially difficult because of limited or inaccurate histories of acetaminophen ingestion. We hypothesized that the comparative ratios of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) can differentiate acetaminophen hepatotoxicity from rhabdomyolysis.\nA retrospective chart review of patients in four hospitals from 2006 to 2011 with a discharge diagnosis of acetaminophen toxicity or rhabdomyolysis was performed. Subjects were classified into three groups: rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose with undetectable serum acetaminophen concentrations [acetaminophen(delayed)]. Ratios of AST, ALT, and CK were compared using non-parametric statistical methods.\n1,353 subjects were identified and after applying our exclusion criteria there were 160 in the rhabdomyolysis group, 68 in the acetaminophen overdose (all) group, and 29 in the acetaminophen (delayed) group. The AST/ALT ratio for the rhabdomyolysis group was 1.66 (Interquartile range: 1.18-2.22), for the acetaminophen overdose (all) group was 1.38 (1.08-1.69, statistically lower than the rhabdomyolysis group, p = 0.018), and for the acetaminophen (delayed)group was 1.30 (1.06-1.63, p = 0.037). CK/AST ratios were 21.3 (12.8-42.2), 5.49 (2.52-15.1, p < 0.001), and 3.80 (1.43-13.8, p < 0.001) respectively. CK/ALT ratios were 37.1 (16.1-80.0), 5.77 (2.79-25.2, p < 0.001), and 5.03 (2.20-17.4, p < 0.001) respectively. Increasing CK to transaminase ratio cutoffs resulted in increasing test sensitivity but lower specificity.\nAST/ALT, CK/AST and CK/ALT ratios are significantly larger in rhabdomyolysis when compared to patients with acetaminophen toxicity. This result suggests that the ratios could be used to identify patients with rhabdomyolysis who otherwise might have been diagnosed as delayed acetaminophen toxicity. Such patients may not require treatment with N-acetylcysteine, resulting in cost savings and improved resource utilization.",
"affiliations": "University of Iowa Hospitals and Clinics, Department of Emergency Medicine, Iowa City, Iowa.;Truman Medical Center, Department of Emergency Medicine, Kansas City, Missouri.;University of California, Davis, Department of Emergency Medicine, Sacramento, California.;University of California, Davis, Department of Emergency Medicine, Sacramento, California.;University of California, Davis, Department of Emergency Medicine, Sacramento, California.;University of California, Davis, Department of Internal Medicine, Sacramento, California.;University of Missouri-Kansas City, Department of Emergency Medicine, Kansas City, Missouri.",
"authors": "Radke|Joshua B|JB|;Algren|Douglas A|DA|;Chenoweth|James A|JA|;Owen|Kelly P|KP|;Ford|Jonathan B|JB|;Albertson|Timothy E|TE|;Sutter|Mark E|ME|",
"chemical_list": "D000082:Acetaminophen; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase; D003402:Creatine Kinase",
"country": "United States",
"delete": false,
"doi": "10.5811/westjem.2018.3.37076",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 10.5811/westjem.2018.3.37076wjem-19-731ToxicologyOriginal ResearchTransaminase and Creatine Kinase Ratios for Differentiating Delayed Acetaminophen Overdose from Rhabdomyolysis Radke Joshua B. MD*Algren Douglas A. MD†‡Chenoweth James A. MD§Owen Kelly P. MD§Ford Jonathan B. MD§Albertson Timothy E. MD, MPH, PhD¶||Sutter Mark E. MD‡\n* University of Iowa Hospitals and Clinics, Department of Emergency Medicine, Iowa City, Iowa\n† Truman Medical Center, Department of Emergency Medicine, Kansas City, Missouri\n‡ University of Missouri-Kansas City, Department of Emergency Medicine, Kansas City, Missouri\n§ University of California, Davis, Department of Emergency Medicine, Sacramento, California\n¶ University of California, Davis, Department of Internal Medicine, Sacramento, California\n|| Veterans Administration Northern California Health Care System, Department of Medicine, Mather, CaliforniaAddress for Correspondence: Joshua B Radke, MD, University of Iowa Hospitals and Clinics, Department of Emergency Medicine, 200 Hawkins Dr, 1008 RCP, Iowa City, IA 52242. Email: joshua-radke@uiowa.edu.7 2018 29 6 2018 19 4 731 736 17 11 2017 09 3 2018 Copyright: © 2018 Radke et al.2018This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Introduction\nRhabdomyolysis and delayed acetaminophen hepatotoxicity may be associated with elevated serum transaminase values. Establishing the cause of elevated transaminases may be especially difficult because of limited or inaccurate histories of acetaminophen ingestion. We hypothesized that the comparative ratios of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) can differentiate acetaminophen hepatotoxicity from rhabdomyolysis.\n\nMethods\nA retrospective chart review of patients in four hospitals from 2006 to 2011 with a discharge diagnosis of acetaminophen toxicity or rhabdomyolysis was performed. Subjects were classified into three groups: rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose with undetectable serum acetaminophen concentrations [acetaminophen(delayed)]. Ratios of AST, ALT, and CK were compared using non-parametric statistical methods.\n\nResults\n1,353 subjects were identified and after applying our exclusion criteria there were 160 in the rhabdomyolysis group, 68 in the acetaminophen overdose (all) group, and 29 in the acetaminophen (delayed) group. The AST/ALT ratio for the rhabdomyolysis group was 1.66 (Interquartile range: 1.18–2.22), for the acetaminophen overdose (all) group was 1.38 (1.08–1.69, statistically lower than the rhabdomyolysis group, p = 0.018), and for the acetaminophen (delayed)group was 1.30 (1.06–1.63, p = 0.037). CK/AST ratios were 21.3 (12.8–42.2), 5.49 (2.52–15.1, p < 0.001), and 3.80 (1.43–13.8, p < 0.001) respectively. CK/ALT ratios were 37.1 (16.1–80.0), 5.77 (2.79–25.2, p < 0.001), and 5.03 (2.20–17.4, p < 0.001) respectively. Increasing CK to transaminase ratio cutoffs resulted in increasing test sensitivity but lower specificity.\n\nConclusion\nAST/ALT, CK/AST and CK/ALT ratios are significantly larger in rhabdomyolysis when compared to patients with acetaminophen toxicity. This result suggests that the ratios could be used to identify patients with rhabdomyolysis who otherwise might have been diagnosed as delayed acetaminophen toxicity. Such patients may not require treatment with N-acetylcysteine, resulting in cost savings and improved resource utilization.\n==== Body\nINTRODUCTION\nDifferentiating delayed presentations of acetaminophen toxicity from rhabdomyolysis can be difficult for many reasons. First, both rhabdomyolysis and acetaminophen toxicity can be associated with increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values.1,2 Second, though patients may go on to develop hepatotoxicity from acetaminophen, their serum acetaminophen concentrations may be low or undetectable because of a delay between ingestion and hospital presentation. Lastly, patients with these conditions can be found in an unconscious state and may be able to provide little or no clinical history. Medical toxicologists and poison centers are frequently consulted with the question of whether the transaminase elevations could be due to delayed acetaminophen toxicity and if treatment with N-acetylcysteine (NAC) is required.\n\nNo common clinical tool or laboratory test can be used to help differentiate the transaminase elevation of acetaminophen toxicity from that of rhabdomyolysis. Investigators have evaluated measurement of gamma-glutamyltransferase, isoforms of ALT, and acetaminophen adducts for this purpose, but these are impractical or not routinely available in clinical practice.3–6 Many physicians rely on their clinical experience in differentiating between these two conditions, whereas others treat all patients with possible acetaminophen toxicity with NAC in order to avoid possible hepatic injury.2 Given the lack of specific findings on examination or data-driven guidance from the literature, both practices are reasonable.\n\nSince there are no objective measures to determine whether a transaminase elevation is from a delayed acetaminophen overdose or from rhabdomyolysis, we sought to determine if the relative values of ALT, AST and creatine kinase (CK) could be used for this purpose. We hypothesized that the ratios of AST/ALT, CK/AST, and CK/ALT would be higher in patients with rhabdomyolysis than in patients with acetaminophen toxicity.\n\nMETHODS\nWe performed a multi-center, retrospective chart review of admitted patients seen at four tertiary care, university hospitals, including one children’s hospital, from January 2006 to October 2011. We obtained electronic medical records (EMR) on all patients with the discharge diagnosis of rhabdomyolysis or acetaminophen overdose. Subjects were included if they had a discharge diagnosis of acetaminophen overdose or rhabdomyolysis and age ≥ 10 years. Data on those patients were extracted from the EMR, de-identified, and then evaluated for inclusion and exclusion criteria by two authors (JR and DA). The data extracted included age, sex, diagnosis, and laboratory values including AST, ALT, and CK. We excluded subjects if laboratory data were incomplete (CK, AST, or ALT values missing), or if the subject was a prisoner or pregnant. Children less than 10 years old were also excluded because the children’s hospital provided care for neuromuscular diseases, inborn errors of metabolism, and other genetic diseases that might have caused transaminase elevations for reasons other than rhabdomyolysis. The concentrations used for CK, AST, and ALT were the values on presentation, as these would likely be the results used to determine whether or not NAC is indicated for possible acetaminophen toxicity.\n\nPopulation Health Research Capsule\nWhat do we already know about this issue?\n\nAspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations can be seen in both acetaminophen overdoses and rhabdomyolysis, and differentiating between the two can often be difficult.\n\nWhat was the research question?\n\nCan commonly obtained labs be used to differentiate between rhabdomyolysis and acetaminophen toxicity?\n\nWhat was the major finding of the study?\n\nAn elevated AST/ALT, creatine kinase (CK)/ALT, or CK/ALT ratio suggests that rhabdomyolysis may be more likely than acetaminophen toxicity.\n\nHow does this improve population health?\n\nA rule similar to this may help improve resource utilization for patients with rhabdomyolysis in whom acetaminophen toxicity is unlikely.\n\nWe abstracted data from the EMRs and entered them into an Excel spreadsheet (Microsoft Corp, Redmond, Washington, USA). The data were analyzed by the use of R© (The R Foundation for Statistical Computing, version 3.1.1). We categorized the patients into three groups for analysis based on discharge diagnosis (based on ICD-9 coding by hospital coders): rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose (delayed). The acetaminophen group was broken into two separate groups because we are most interested in differentiating between cases of rhabdomyolysis and patients with a delayed presentation of acetaminophen overdose with an undetectable acetaminophen level. The acetaminophen (all) group included all patients who had a discharge diagnosis of acetaminophen overdose, regardless of initial acetaminophen concentration. The acetaminophen (delayed) group only included those who had a discharge diagnosis of acetaminophen overdose, but had an undetectable acetaminophen level on admission. The primary outcome measures were the ratios of AST to ALT, CK to AST, and CK to ALT. We tested data normality with the Shapiro-Wilk test. Because all data were non-parametric, we used the Kruskall-Wallis test to determine if there were differences between groups; when differences were present, we performed pairwise testing by use of the Mann-Whitney-Wilcox test with a Bonferroni correction for multiple-hypothesis testing. In all cases, a p-value of <0.05 was considered statistically significant. We also analyzed the sensitivity, specificity, positive likelihood, and negative likelihood ratio of various CK/AST and CK/ALT ratio cutoffs as a test to differentiate between rhabdomyolysis cases and acetaminophen overdose cases (both acute and chronic).\n\nThe study was approved by the institutional review board of each participating hospital, with approval for data to be shared and coordinated through the University of California, Davis.\n\nRESULTS\nWe identified 1,353 subjects with rhabdomyolysis or acetaminophen overdose. A majority in each group were excluded from statistical analysis due to missing laboratory data needed to calculate one or more of the ratios. Excluding those with incomplete data resulted in 160 in the rhabdomyolysis group, 68 in the acetaminophen overdose (all) group, and 29 in the acetaminophen overdose (delayed) group.\n\nPatient demographics and the ratios of AST to ALT, CK to AST, and CK to ALT along with the results of the Kruskall-Wallis comparisons are summarized in Table 1. There was a statistically significant difference in the AST/ALT ratio between the rhabdomyolysis group and the two acetaminophen overdose groups (p=0.018 for acetaminophen (all) and p=0.037 for acetaminophen (delayed). There was no difference between the two acetaminophen groups (p=1.00). Medians and interquartile ranges (IQR) are demonstrated in Figure 1.\n\nThe CK/AST ratios for the rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose (delayed) groups were 21.3 (IQR 12.8–42.2), 5.49 (IQR 2.52–15.1), and 3.80 (1.43–13.8) respectively (Figure 2, p<0.001). Pairwise comparisons revealed statistically significant differences between the rhabdomyolysis group and the acetaminophen overdose (all) group (p<0.001), as well as the rhabdomyolysis and the acetaminophen overdose (delayed) group (p<0.001). There was no statistical difference in the CK/AST ratio between the two acetaminophen-overdose groups (p=1.00).\n\nThe CK/ALT ratios for the rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose (delayed) groups were 37.1 (IQR 16.1–80.0), 5.77 (2.79–25.2), and 5.03 (2.20–17.4) respectively (Figure 3, p<0.001). Pairwise comparisons revealed statistically significant differences between the rhabdomyolysis group and the acetaminophen overdose (all) group (p<0.001), as well as the rhabdomyolysis and the acetaminophen overdose (acetaminophen negative) group (p<0.001). There was no statistical difference in the CK/ALT ratio between the two acetaminophen overdose groups (p=1.00).\n\nThe test characteristics for different CK-to-transaminase ratios are presented in Table 2 (with ratios below the cutoff designated as positive for acetaminophen overdose). Increasing the ratio cutoff resulted in improved sensitivity but markedly reduced specificity.\n\nDISCUSSION\nMeasurements of AST and ALT and their relationship with CK would seem to be useful in helping to differentiate rhabdomyolysis from delayed acetaminophen toxicity. AST and ALT are enzymes that play many vital roles, including amino acid metabolism and gluconeogenesis. 7 ALT is found predominantly in the liver, but is also present in skeletal and heart muscle. AST is found more widely throughout the body including the heart, brain, skeletal muscle, and liver.8 Despite the wide distribution of these enzymes, clinically they are used mainly as markers of hepatic injury, when they are thought to “leak out” of damaged cells into the blood.9 Since AST and ALT are present throughout the body, they may be elevated in conditions not involving the liver; and indeed both AST and ALT can be elevated in rhabdomyolysis in the absence of liver injury. 10\n\nIn the search for the cause of abnormally elevated transaminases, serum CK is often measured. The biological role of CK is that of catalyzing the phosphorylation of creatine, thus producing phosphocreatine. Phosphocreatine, in turn, rapidly produces ATP in tissues that have high energy demand. 11 CK is predominantly located in skeletal muscle, myocardium, and the brain, and serum CK values can be elevated and used as a marker of injury to these organs. 8 Although CK is present in the liver, its concentration in hepatic tissues is significantly lower than in other tissues. 8,12\n\nThe results of this study support our hypothesis that the ratios of AST/ALT, CK/AST and CK/ALT would be higher in patients with rhabdomyolysis than in patients with acetaminophen toxicity. This observation may be useful in differentiating patients with rhabdomyolysis from those who otherwise might be considered candidates for treatment with NAC for possible delayed acetaminophen poisoning. Avoiding the unnecessary treatment of patients with NAC, and possibly longer hospital length of stay, could reduce the cost of care.\n\nAdditionally, our finding of a higher ratio of CK to ALT than that of CK to AST is consistent with the tissue distribution of these enzymes; that is, higher values for AST than for ALT are more likely in rhabdomyolysis because the concentrations of AST in skeletal muscle are higher than those of ALT. 8\n\nBesides possible cost savings, it is important to minimize risk of exposure to unnecessary medications for our patients. Although NAC is generally safe, anaphylactoid reactions, sometimes resulting in death, have been reported with intravenous (IV) administration.13 Deaths have also been attributed to iatrogenic errors with IV formulations of NAC. 13,14 In patients with rhabdomyolysis, taking the risk of an iatrogenic complication from NAC may not be warranted. 15,16\n\nOur data suggest higher CK/AST or CK/ALT ratios are more likely to be seen with rhabdomyolysis than acetaminophen ingestion. This is not to say that the ratio can be used in a vacuum to differentiate patients with rhabdomyolysis from those with acetaminophen toxicity. Instead, it would ideally be used in those patients for whom there is an already-low likelihood of acetaminophen toxicity that cannot be excluded due to a limited history.\n\nLIMITATIONS\nOur study has several limitations. First, it is retrospective, with the inherent shortcomings associated with this study design. Second, patient-selection bias could be present because the majority of the patients in each group were excluded because of missing laboratory data; in the cases of acetaminophen overdose, the CK values often were absent, likely because CK is not a routinely ordered lab test on patients who have suspected overdose. Third, the discharge diagnoses may not have always been accurate, and coding errors may have existed that resulted in patient misclassification. We also did not verify each of the discharge diagnoses. Finally, the values of AST, ALT, and resulting ratios could have been different depending on when they were drawn in the course of a patient’s toxicity, as AST and ALT concentrations rise and fall at different rates.17\n\nCONCLUSION\nIn summary, we found the AST/ALT, CK/AST, and CK/ALT ratios were significantly higher in patients with rhabdomyolysis than in patients with acetaminophen toxicity. This result suggests that the ratios could be used to identify patients with rhabdomyolysis who otherwise might have been diagnosed as delayed acetaminophen toxicity. Such patients may not require hospitalization and treatment with N-acetylcysteine, resulting in considerable cost savings and decreased resource utilization. Based on the limitations of our study, however, these ratios are not ready for clinical use. Prospective validation of our findings in a diverse patient population is needed before these ratios can be applied in regular clinical practice.\n\nSection Editor: Brandon K. Wills, DO, MS\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.\n\nFigure 1 AST/ALT ratios of the three patient groups.\n\nRhabdo, rhabdomyolysis group; APAP (all), all patients with acetaminophen overdose; APAP (delayed), patients with delayed acetaminophen toxicity. Vertical bars indicate interquartile range of values; horizontal bars indicate median values.\n\nFigure 2 CK/AST ratios of the three patient groups.\n\nAST, aminotransferase; CK, creatine kinase; Rhabdo, rhabdomyolysis group; APAP (all), all patients with acetaminophen overdose; APAP (delayed), patients with delayed acetaminophen toxicity. Vertical bars indicate interquartile range of values; horizontal bars indicate median values.\n\nFigure 3 CK/ALT ratios of the three patient groups: rhabdomyolysis group; patients with acetaminophen overdose (all); and those with acetaminophen overdose (delayed).\n\nRhabdo, rhabdomyolysis group; APAP (all), all patients with acetaminophen overdose; APAP (delayed), patients with delayed acetaminophen toxicity. Vertical bars indicate interquartile range of values; horizontal bars indicate median values.\n\nTable 1 Demographics and results summary. Ratios are expressed as medians, with interquartile ranges.\n\n\tRhabdo\tAPAP all\tAPAP delayed\tP value\t\nAge\t48 (34–56)\t42 (29–52)\t46 (37–55)\tNA\t\nMale\t115 (71.9%)\t38 (55.9%)\t18 (62%)\tNA\t\nAST/ALT\t1.66 (1.18–2.22)\t1.38 (1.08–1.69)\t1.30 (1.06–1.63)\t0.003396\t\nCK/AST\t21.33 (12.75–42.21)\t5.49 (2.52–15.10)\t3.80 (1.43–13.83)\t<0.001\t\nCK/ALT\t37.06 (16.08–79.95)\t5.77 (2.79–25.18)\t5.03 (2.20–17.36)\t<0.001\t\nP values represent the results of the Kruskall-Wallis test of comparison between the rhabdomyolysis group and the acetaminophen (delayed) group.\n\nAPAP, acetaminophen; rhabdo, rhabdomyolysis; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CK, creatine kinase.\n\nTable 2 Sensitivity and specificity of different CK* to transaminase ratio cutoffs.\n\nRatio cutoff\tSensitivity (95% CI)\tSpecificity (95% CI)\tPositive likelihood ratio (95% CI)\tNegative likelihood ratio (95% CI)\t\nCK/AST\t\n 15\t75.3% (65.5–83.5%)\t68.8% (61–75.8%)\t2.41 (1.86–3.11)\t0.36 (0.25–0.52)\t\n 20\t83.5% (74.6–90.3%)\t53.2% (45.1–61.2%)\t1.78 (1.48–2.16)\t0.31 (0.19–0.5)\t\n 25\t84.5% (75.8–91.1%)\t43% (35.1–51.1%)\t1.48 (1.26–1.74)\t0.36 (0.22–0.59)\t\n 30\t89.7% (81.9–94.9%)\t35.3% (27.8–43.3%)\t1.39 (1.21–1.58)\t0.29 (0.16–0.55)\t\nCK/ALT\t\n 15\t67% (56.7–76.2%)\t76.9% (69.6–83.2%)\t2.9 (2.11–3.97)\t0.43 (0.32–0.58)\t\n 20\t73.2% (63.2–81.7%)\t71.8% (64–78.7%)\t2.6 (1.97–3.43)\t0.37 (0.26–0.53)\t\n 25\t76.3% (66.6–84.3%)\t64.1% (56–71.6%)\t2.13 (1.68–2.69)\t0.37 (0.25–0.54)\t\n 30\t83.55 (74.6–90.3%)\t59% (50.8–66.8%)\t2.04 (1.65–2.51)\t0.28 (0.18–0.45)\t\nCK, creatine kinase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CI, confidence interval.\n==== Refs\nREFERENCES\n1 Torres P Helmstetter J Kaye A Rhabdomyolysis: pathogenesis, diagnosis, and treatment Ochsner J 2015 15 1 58 69 25829882 \n2 Heard K Acetylcysteine for acetaminophen poisoning N Engl J Med 2008 359 3 285 92 18635433 \n3 Whitfield J Gamma glutamyl transferase Crit Rev Clin Lab Sci 2001 38 4 263 355 11563810 \n4 Pertusi R Dickerman R McConathy W Evaluation of aminotransferase elevations in a bodybuilder using anabolic steroids: hepatitis or rhabdomyolysis J Am Osteopath Assoc 2001 101 7 391 4 11476029 \n5 Miyazaki M Resonblum JS Kasahara Y Determination of enzymatic source of alanine aminotransferase activity in serum from dogs with liver injury J Pharmacol Toxicol Methods 2009 60 3 307 15 19748590 \n6 Bond G Acetaminophen protein adducts: a review Clin Toxicol 2009 47 1 2 7 \n7 Walker H Hall WD Hurst JW Creatine Kinase Clinical Methods: The History, Physical, and Laboratory Examinations 3rd ed Boston Butterworths 1990 \n8 Dufour D Lott JA Nolte FS Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests Clin Chem 2000 46 12 2027 49 11106349 \n9 Ramaiah SA Toxicologist guide to the diagnostic interpretation of hepatic biochemical parameters Food Chem Toxicol 2007 45 9 1551 7 17658209 \n10 Weibrecht K Dayno M Darling C Liver aminotransferases are elevated with rhabdomyolysis in the absence of significant liver injury J Med Toxicol 2010 6 3 294 300 20407858 \n11 Wallimann Y Wyss M Brdiczka D Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis Biochem J 1992 281 Pt 1 21 40 1731757 \n12 Joseph J Cardesa A Carreras J Creatine kinase activity and isoenzymes in lung, colon and liver carcinomas Br J Cancer 1997 76 5 600 5 9303358 \n13 Sandilands E Bateman D Adverse reactions associated with acetylcysteine Clin Toxicol 2009 47 2 81 8 \n14 Elms A Owen KP Albertson TE Fatal myocardial infarction associated with intravenous N-acetylcysteine error Int J Emerg Med 2011 4 1 54 21878099 \n15 Lameire N De Vriese A Vanholder R Prevention and nondialytic treatment of acute renal failure Curr Opin Crit Care 2003 9 6 481 90 14639067 \n16 Fernandez-Funez A Polo FJ Broseta L Effects of N-acetylcysteine on myoglobinuric-acute renal failure in rats Ren Fail 2002 24 6 725 33 12472195 \n17 Curtis R Sivilotti M A descriptive analysis of aspartate and alanine aminotransferase rise and fall following acetaminophen overdose Clin Toxicol 2015 53 9 849 55\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1936-900X",
"issue": "19(4)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D003402:Creatine Kinase; D003937:Diagnosis, Differential; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012206:Rhabdomyolysis; D012680:Sensitivity and Specificity; D000637:Transaminases",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "731-736",
"pmc": null,
"pmid": "30013711",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "25829882;26294195;11476029;11563810;19280424;11106349;17658209;14639067;21878099;1731757;18608255;19748590;20407858;9303358;18635433;12472195",
"title": "Transaminase and Creatine Kinase Ratios for Differentiating Delayed Acetaminophen Overdose from Rhabdomyolysis.",
"title_normalized": "transaminase and creatine kinase ratios for differentiating delayed acetaminophen overdose from rhabdomyolysis"
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"companynumb": "US-JNJFOC-20180734813",
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"abstract": "Radiation recall (RR) is a chemotherapy-induced reaction that leads to inflammation and necrosis in previously irradiated tissue. Gemcitabine is a cytidine analogue that is often used in conjunction with nab-paclitaxel in the treatment of pancreatic cancer. Herein, we present a case of a 56-year-old woman with stage III pancreatic adenocarcinoma diagnosed with gemcitabine-induced RR when she presented with lower back pain and new rim-enhancing collections within the right and left paraspinal musculature 5 months after radiation therapy to the pancreas. A PubMed search was performed for 'Radiation Recall Myositis' and a complete literature review performed. This case and review of the literature of published cases of RR myositis highlight the clinical course and presentation of RR myositis. This review highlights the importance of considering RR in the differential diagnosis when patients who are undergoing chemotherapy and radiation present with inflammatory changes in previously irradiated areas.",
"affiliations": "The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA adriel@brown.edu.;The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.;The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.;The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.",
"authors": "Barrios-Anderson|Adriel|A|http://orcid.org/0000-0002-7150-3938;Radhakrishnan|Reshmitha|R|;Yu|Esther|E|;Shimanovsky|Alexei|A|",
"chemical_list": "D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240896",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; pancreatic cancer; radiotherapy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008875:Middle Aged; D009220:Myositis; D017239:Paclitaxel; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33947675",
"pubdate": "2021-05-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Paraspinal radiation recall myositis after gemcitabine for pancreatic adenocarcinoma.",
"title_normalized": "paraspinal radiation recall myositis after gemcitabine for pancreatic adenocarcinoma"
} | [
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"abstract": "We present a case report of a 54-year-old male with metastasized nasopharyngeal carcinoma presenting to the hospital with dyspnea, anorexia and fever. Examination revealed chemotherapy-induced pancytopenia. The patient tested positive for SARSCoV-2, but respiratory complications were mild. The patient was treated with granulocyte-colony stimulating factor (G-CSF) leading to amelioration of the neutropenia. However, severe acute respiratory distress syndrome (ARDS) occurred, prompting the diagnosis of immune reconstitution inflammatory syndrome (IRIS). GCSF is currently investigated as additional therapy in ARDS, but this case report emphasizes that risks and benefits must be carefully assessed. To our knowledge, this is the first case report of IRIS-induced ARDS in a COVID-19 patient.",
"affiliations": "Department of Internal Medicine, University Hospital Antwerp, Antwerp, Belgium.;Department of Internal Medicine, University Hospital Antwerp, Antwerp, Belgium.;HIV/STI Unit, Institute of Tropical Medicine, Department of Clinical Sciences, Antwerp, Belgium.",
"authors": "Mertens|Jonathan|J|0000-0002-4822-4113;Laghrib|Yassine|Y|;Kenyon|Chris|C|0000-0001-9861-8033",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa326",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa326\nofaa326\nBrief Reports\nAcademicSubjects/MED00290\nA Case of Steroid-Responsive, COVID-19 Immune Reconstitution Inflammatory Syndrome Following the Use of Granulocyte Colony-Stimulating Factor\nhttp://orcid.org/0000-0002-4822-4113Mertens Jonathan 1 Laghrib Yassine 1 http://orcid.org/0000-0001-9861-8033Kenyon Chris 23 1 \nDepartment of Internal Medicine, University Hospital Antwerp, Antwerp, Belgium\n2 \nHIV/STI Unit, Institute of Tropical Medicine, Department of Clinical Sciences, Antwerp, Belgium\n3 \nDivision of Infectious Diseases and HIV Medicine, University of Cape Town, Observatory, South Africa\nCorrespondence: J. Mertens, MD, Universitair Ziekenhuis Antwerpen, Antwerpen, Antwerpen, Belgium (jonathan.mertens@student.uantwerpen.be; jonathan.mertens@uza.be).\n8 2020 \n17 8 2020 \n17 8 2020 \n7 8 ofaa32627 5 2020 23 7 2020 27 7 2020 22 8 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This 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\nWe present a case report of a 54-year-old male with metastasized nasopharyngeal carcinoma presenting to the hospital with dyspnea, anorexia and fever. Examination revealed chemotherapy-induced pancytopenia. The patient tested positive for SARSCoV-2, but respiratory complications were mild. The patient was treated with granulocyte-colony stimulating factor (G-CSF) leading to amelioration of the neutropenia. However, severe acute respiratory distress syndrome (ARDS) occurred, prompting the diagnosis of immune reconstitution inflammatory syndrome (IRIS). GCSF is currently investigated as additional therapy in ARDS, but this case report emphasizes that risks and benefits must be carefully assessed. To our knowledge, this is the first case report of IRIS-induced ARDS in a COVID-19 patient.\n\nARDSCOVID-19granulocyte-colony stimulating factorimmune reconstitution inflammatory syndromeIRISSARS-CoV-2\n==== Body\nCASE REPORT\nA 54-year-old male, known to have nasopharyngeal carcinoma with bone and lung metastasis, presented to the hospital with dyspnea, anorexia, and fever up to 39°C for 1 day. His last chemotherapy with cisplatinand gemcitabine was administered 4 days before presentation. As additional risk factors, he had type 2 diabetes mellitus, hypertension, and rheumatoid arthritis. His chronic medications were azathioprine, metformin, amlodipine, and pantoprazole. On presentation, he was hemodynamically stable and afebrile; respiration was stable. Arterial blood gas showed a pH within reference range with normal oxygenation levels. Blood tests revealed a profound neutropenia (0.51*109/L), a hemoglobin level of 7.1 g/dL, and thrombocytopenia of 24*109/l. His creatinine was 0.76 mg/dL (0.6–1.1 mg/dL), and his C-reactive protein (CRP) was 138.2 mg/dL (<0.10 mg/dL). Both ferritin (5452 µg/L: normal values, 22–322 µg/L) and D-dimers (3.7 µg/mL; normal values, <0.48 µg/mL) were elevated. A pulmonary computed tomography (CT) scan showed mild typical ground-glass opacities suggestive of COVID-19 (Figure 1). A positive polymerase chain reaction for SARS-CoV-2 on nasopharyngeal swab confirmed the diagnosis of COVID-19. A diagnosis of pancytopenia/neutropenic fever was made, and piperacillin/tazobactam and hydroxychloroquine were started after collection of blood and urine cultures.\n\nFigure 1. Axial computed tomography thorax image showing predominantly peripheral mild ground-glass opacities compatible with COVID-19 lung injury.\n\nOut of concern that the pancytopenia was chemotherapy-induced, granulocyte colony-stimulating factor (G-CSF) was administered on day 2 postadmission. Leukopenia and thrombopenia are described in COVID-19 [1], but anemia is not commonly present; therefore, chemotherapy-induced pancytopenia remained the preferable diagnosis. The neutropenia resolved on day 6 postadmission, but 1 day later the patient developed progressive respiratory failure with rapidly increasing oxygen demand up to 15 L/min with a nonrebreathing mask. A new pulmonary CT scan showed severe acute respiratory distress syndrome (ARDS) with worsening of the ground-glass opacities and multiple consolidations (Figure 2). His CRP levels increased to 315.6 mg/L, and his neutrophils to 21.68*109/L. The temporal association between the G-CSF, subsequent increase in neutrophil count, and concurrent worsening of respiratory failure/pulmonary infiltrates was suggestive of a paradoxical immune reconstitution inflammatory syndrome (IRIS) to the already present SARS-CoV-2 infection. To treat this presumed IRIS, high-dose corticosteroid therapy was started. The patient recovered rapidly over the subsequent 8 days. He was no longer oxygen dependent within 14 days, his CRP declined to 50.9 mg/L, and a repeat CT scan on day 19 revealed considerable resolution of pulmonary consolidation (Figure 3).\n\nFigure 2. Axial computed tomography thorax with contrast image showing acute respiratory distress syndrome with massive worsening of preexisting lesions.\n\nFigure 3. Axial computed tomography thorax image showing residual lung injury 12 days after initial acute respiratory distress syndrome. All images illustrated were taken at approximately the same level.\n\nDISCUSSION\nSevere COVID-19 is frequently characterized as a biphasic illness, with a number of patients deteriorating ~7–14 days after initial presentation. Viral replication is thought to play an important role in the pathophysiology during the first phase, whereas systemic inflammation is considered to predominate in the second phase [2]. The evolution of the clinical presentation in this patient is most suggestive of a G-CSF-induced IRIS, but we cannot exclude the possibility that he coincidentally entered the second hyperinflammatory phase of COVID-19 soon after receiving G-CSF. The temporal association between his receipt of the G-CSF, subsequent large increase in neutrophil count, and rapid increase in pulmonary infiltrates and rapid response to corticosteroid therapy are, however, most parsimoniously explained by an IRIS-type reaction. Until very recently, there was no compelling evidence advocating for the use of corticosteroids in COVID-19 [3–5]. This situation has changed with the release of the preliminary results of the RECOVERY trial. This large open-label randomized controlled trial found that the use of 6 mg of dexamethasone for 10 days was associated with a 20%/35% reduction in mortality rate in hospitalized COVID-19 patients on noninvasive oxygen therapy/on invasive mechanical ventilation [6]. Although unpublished, the results of this trial have been considered sufficiently robust to have resulted in changes to treatment guidelines in countries like the United Kingdom. These results were not available when our patient presented to us. This new evidence of the efficacy of corticosteroid therapy does, however, reinforce the notion that our patient’s deterioration and subsequent recovery may have been due to the second phase of COVID-19 and not IRIS.\n\nIRIS is a condition commonly seen in patients with severe immunosuppression in response to rapid immune reconstitution. It has been most commonly observed with HIV-infected individuals after starting antiretroviral therapy. Two forms have been described [3–5]. In unmasking IRIS, the immune reconstitution unmasks a previously undiagnosed infection. In paradoxical IRIS, the patient has recovered symptomatically from an infection such as pulmonary tuberculosis but then has a recurrence of symptoms after the commencement of antiretroviral therapy. A typical feature of this syndrome is that the pulmonary consolidations occur in the same location but as more pronounced versions of the original lesions [7]. Furthermore, rapid clinical improvement typically follows corticosteroid therapy [8]. These radiological and clinical features of paradoxical IRIS were both present in our patient’s presentation.\n\nTwo salient points to emerge from this case are the need for caution in the use of G-CSF in patients with COVID-19 and the rapid response to corticosteroids. Colony-stimulating factors are glycoproteins that promote production of white blood cells, mainly granulocytes, in response to infection. The most used types are macrophage colony-stimulating factor (M-CSF), G-CSF, and granulocyte-macrophage colony-stimulating factor (GM-CSF) [9]. They are useful to reduce time spent in neutropenia in order to decrease the risk of infections and shorten the interval between chemotherapy [10, 11]. Meta-analyses have suggested that the combination of G-CSF with chemotherapy is associated with better survival [12, 13]. A number of studies are evaluating the use of CSFs in therapy for ARDS. Local therapeutic application of GM-CSF, for example, via inhalation, has been shown to increase host defense and accelerate epithelial repair processes in preclinical models [14]. It might thus be a powerful therapy in viral pneumonia and associated ARDS [14]. Animal models have suggested a benefit of combined GM-CSF in neutropenic rats with experimentally induced lung injury [15]. A randomized controlled phase II trial of GM-CSF in 10 humans with lung injury found an improvement in oxygenation over a 5-day period [16]. Furthermore, the use of inhaled GM-CSF in a small group of patients with pneumonia-associated ARDS demonstrated improvement in oxygenation, lung compliance, and severity of illness scores [17]. On the other hand, a randomized phase II trial with 130 subjects with acute lung injury and/or ARDS given intravenous GM-CSF treatment did not find any evidence of benefit [18]. A randomized controlled trial is ongoing now at the University of Michigan to determine whether a 14-day course of G-CSF improves clinical outcomes, including ventilator-free days and mortality, in patients with ARDS from all causes (https://clinicaltrials.gov/ct2/show/NCT00201409). Another trial is ongoing evaluating the efficacy and safety of inhaled GM-CSF in 45 patients with pneumonia-associated ARDS (https://clinicaltrials.gov/ct2/show/NCT02595060).\n\nAn ongoing randomized open-label trial is investigating the effectiveness of additional inhaled sargramostim (GM-CSF) vs standard of care for blood oxygenation in patients with COVID-19 and acute hypoxic respiratory failure (https://clinicaltrials.gov/ct2/show/NCT04326920). While we await the results of this RCT, our case is a reminder to carefully weigh the risks and benefits of G-CSF therapy in patients presenting with COVID-19 and neutropenia. If patients are treated with G-CSF and then deteriorate, the diagnosis of paradoxical IRIS should be considered, as corticosteroid therapy can be highly efficacious. To our knowledge, this is the first case report of a possible IRIS-induced ARDS in COVID-19.\n\nAcknowledgments\n\nPotential\nconflicts of interest. The 3 authors declare that there is no potential conflict of interest. All authors: no reported conflicts of interest. 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\n\nPatient consent. Written consent of the patient was obtained by the authors. Since this paper discusses a case report, no approval of a local ethical committee was necessary.\n==== Refs\nReferences\n1. \nGuan W-J , Ni Z-Y , Hu Y , et al \nClinical characteristics of coronavirus disease 2019 in China\n. N Engl J Med 2020 ; 382 :1708 –20\n.32109013 \n2. \nChen J , Qi T , Liu L , et al. \nClinical progression of patients with COVID-19 in Shanghai, China\n. J Infect 2020 ; 80 :e1 –6\n.\n3. \nMeintjes G , Lawn SD , Scano F , et al ; International Network for the Study of HIV-associated IRIS \nTuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings\n. Lancet Infect Dis 2008 ; 8 :516 –23\n.18652998 \n4. \nMeintjes G , Rabie H , Wilkinson RJ , Cotton MF \nTuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy\n. Clin Chest Med 2009 ; 30 :797 –810, x\n.19925968 \n5. \nMeintjes G , Lynen L \nPrevention and treatment of the immune reconstitution inflammatory syndrome\n. Curr Opin HIV AIDS 2008 ; 3 :468 –76\n.19373007 \n6. \nHorby P , Lim WS , Emberson J , et al \nEffect of dexamethasone in hospitalized patients with COVID-19: preliminary report\n. medRxiv 20137273 [Preprint]. 22 June 2020 Available at: 10.1101/2020.06.22.20137273 . Accessed 5 July 2020\n7. \nCalligaro G , Meintjes G , Mendelson M \nPulmonary manifestations of the immune reconstitution inflammatory syndrome\n. Curr Opin Pulm Med 2011 ; 17 :180 –8\n.21346572 \n8. \nMeintjes G , Wilkinson RJ , Morroni C , et al. \nRandomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome\n. AIDS 2010 ; 24 :2381 –90\n.20808204 \n9. \nNemunaitis J \nA comparative review of colony-stimulating factors\n. Drugs 1997 ; 54 :709 –29\n.9360058 \n10. \nHeuser M , Ganser A , Bokemeyer C ; American Society of Clinical Oncology; National Comprehensive Cancer Network; European Organization for Research and Treatment of Cancer \nUse of colony-stimulating factors for chemotherapy-associated neutropenia: review of current guidelines\n. Semin Hematol 2007 ; 44 :148 –56\n.17631179 \n11. \nMhaskar R , Clark OA , Lyman G , et al \nColony-stimulating factors for chemotherapy-induced febrile neutropenia\n. Cochrane Database Syst Rev 2014 ; 2014 :CD003039 .\n12. \nLyman GH , Yau L , Nakov R , Krendyukov A \nOverall survival and risk of second malignancies with cancer chemotherapy and G-CSF support\n. Ann Oncol 2018 ; 29 :1903 –10\n.30099478 \n13. \nLyman GH , Dale DC , Culakova E , et al. \nThe impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials\n. Ann Oncol 2013 ; 24 :2475 –84\n.23788754 \n14. \nRösler B , Herold S \nLung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy?\nMol Cell Pediatr 2016 ; 3 :29 .27480877 \n15. \nLechner AJ , Lamprech KE , Potthoff LH , et al. \nRecombinant GM-CSF reduces lung injury and mortality during neutropenic Candida sepsis\n. Am J Physiol 1994 ; 266 :L561 –8\n.8203549 \n16. \nPresneill JJ , Harris T , Stewart AG , et al. \nA randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction\n. Am J Respir Crit Care Med 2002 ; 166 :138 –43\n.12119223 \n17. \nHerold S , Hoegner K , Vadász I , et al. \nInhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome\n. Am J Respir Crit Care Med 2014 ; 189 :609 –11\n.24579839 \n18. \nPaine R 3rd, Standiford TJ , Dechert RE , et al. \nA randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury\n. Crit Care Med 2012 ; 40 :90 –7\n.21926600\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(8)",
"journal": "Open forum infectious diseases",
"keywords": "ARDS; COVID-19; IRIS; SARS-CoV-2; granulocyte-colony stimulating factor; immune reconstitution inflammatory syndrome",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa326",
"pmc": null,
"pmid": "32855992",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": "32109013;30099478;12119223;32171869;25356786;18652998;19925968;24579839;23788754;20808204;21346572;27480877;9360058;21926600;8203549;19373007;17631179",
"title": "A Case of Steroid-Responsive, COVID-19 Immune Reconstitution Inflammatory Syndrome Following the Use of Granulocyte Colony-Stimulating Factor.",
"title_normalized": "a case of steroid responsive covid 19 immune reconstitution inflammatory syndrome following the use of granulocyte colony stimulating factor"
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{
"abstract": "Duodenal obstruction is an infrequent but potentially fatal complication of strongyloidiasis infection. Strongyloides stercoralis can clinically manifest in a broad variety of ways and lacks a classic clinical syndrome, which makes the diagnosis of strongyloidiasis difficult. The diagnosis is usually delayed and made by duodenal aspirate, duodenal biopsy, and/or postoperative biopsy specimen of the resection stricture segment. We present a case of partial duodenal obstruction caused by S. stercoralis. A 46-year-old man had presented with repeated bilious vomiting for 12 days. Upper gastrointestinal endoscopy showed ulceronodular mucosa with luminal compromise at the second part of the duodenum. Abdominal computed tomography scan also showed a wall thickening with luminal narrowing of the second and third part of the duodenum. Duodenal mucosal biopsy revealed larval forms of S. stercoralis.",
"affiliations": "Department of Radiodiagnosis and Imaging, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India.;Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India.;Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India.;Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India.;Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India.;Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India.;Department of Pathology, All India Institute of Medical Sciences, Bhubaneswar, India.",
"authors": "Patra|Ananya Apurba|AA|;Nath|Preetam|P|;Pati|Girish Kumar|GK|;Panigrahi|Sarat Chandra|SC|;Mallick|Bipadabhanjan|B|;Acharya|Jyotiprakash C K|JCK|;Adhya|Amit|A|",
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"country": "United States",
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"doi": "10.14309/crj.0000000000000124",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JACGCRJACGCRJAC9ACG Case Reports Journal2326-3253Wolters Kluwer Maryland, MD ACGCR-19-040610.14309/crj.000000000000012400021Case ReportSmall BowelStrongyloides Infection Presenting as Proximal Small Intestinal Obstruction Patra Ananya Apurba MBBS, MD1Nath Preetam MD, DM2Pati Girish Kumar MD, DM2Panigrahi Sarat Chandra MBBS, MD, DM2Mallick Bipadabhanjan MBBS, MD, DM2Acharya Jyotiprakash C.K. MBBS2Adhya Amit MBBS, MD31 Department of Radiodiagnosis and Imaging, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India2 Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India3 Department of Pathology, All India Institute of Medical Sciences, Bhubaneswar, IndiaCorrespondence: Preetam Nath, Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, India 751024 (preetam.nath@kims.ac.in).25 6 2019 6 2019 6 6 e0012411 1 2019 13 5 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.ABSTRACT\nDuodenal obstruction is an infrequent but potentially fatal complication of strongyloidiasis infection. Strongyloides stercoralis can clinically manifest in a broad variety of ways and lacks a classic clinical syndrome, which makes the diagnosis of strongyloidiasis difficult. The diagnosis is usually delayed and made by duodenal aspirate, duodenal biopsy, and/or postoperative biopsy specimen of the resection stricture segment. We present a case of partial duodenal obstruction caused by S. stercoralis. A 46-year-old man had presented with repeated bilious vomiting for 12 days. Upper gastrointestinal endoscopy showed ulceronodular mucosa with luminal compromise at the second part of the duodenum. Abdominal computed tomography scan also showed a wall thickening with luminal narrowing of the second and third part of the duodenum. Duodenal mucosal biopsy revealed larval forms of S. stercoralis.\n\nOPEN-ACCESSTRUESTATUSONLINE-ONLY\n==== Body\nINTRODUCTION\nStrongyloides stercoralis infection, which is commonly seen in tropical and subtropical areas of the world, is usually asymptomatic in immunocompetent individuals and can sometimes present with nonspecific gastrointestinal (GI) manifestations.1 However, in immunodeficient patients, it can lead to disseminated disease with multiple systems involvement, which is usually associated with high mortality rates.2,3 We report a case of a 46-year-old man who presented with a history of repeated bilious vomiting with duodenal obstruction.\n\nCASE REPORT\nA 46-year-old man from eastern India presented with bilious vomiting for 12 days, with a frequency of 3–4 per day without any abdominal distention, pain in the abdomen, fever, constipation, or loose stools. The patient did not have any history of similar illness. There is a history of intake of prednisolone (40 mg/d) for a period of 2 weeks before the present illness for the treatment of lichen planus. General physical examination was unremarkable, except for signs of dehydration and purple, polygon-shaped skin lesions over both legs (Figure 1). Systemic examinations did not reveal any abnormality. The patient was initially resuscitated with intravenous normal saline and lactated ringers solution along with ondansetron. The patient was advised a clear liquid diet, which he was able to tolerate suggesting that the obstruction was partial. On investigation, complete blood count, serum urea, and creatinine were within normal limits. Serum electrolytes revealed hyponatremia (128 mmol/L) and hypokalemia (3.3 mmol/L). Liver function test was normal, except for hypoalbuminemia (3 g/dL). C-reactive protein was elevated (77.6 mg/L). Upper GI endoscopy revealed ulceronodular and infiltrative lesion over the second and third part of the duodenum, with significant luminal narrowing (Figure 2). Multiple biopsies were taken, and CECT abdomen was done to rule out any malignancy. Computed tomography scan showed a circumferential wall thickening of the second and third part of the duodenum with narrowing and adjacent insignificant perilesional lymphnodes enlargement (Figure 3). Histopathology of the involved mucosa revealed mixed inflammatory infiltrate over the lamina propria and surprisingly larval forms of S. stercolaris (Figure 4). Moreover, the stool routine and microscopy examination ordered after the biopsy report also showed plenty of Strongyloides larvae.\n\nFigure 1. Purple, polygon-shaped lichen planus skin lesions over both legs.\n\nFigure 2. Upper gastrointestinal endoscopy showing ulceronodular and infiltrative lesion of the duodenum.\n\nFigure 3. Abdominal contrast-enhanced computed tomography showing duodenal wall thickening and stricture.\n\nFigure 4. Histopathology of the duodenal mucosa showing mixed inflammatory infiltrate over the lamina propria and surprisingly larval forms of S. stercolaris.\n\nThe patient was treated with a single dose of 12 mg of ivermectin tablet, with an advice to repeat the dose after 2 weeks. After 24 hours, the patient was able to tolerate liquid diet along with marked improvement in general well-being. His C-reactive protein decreased to 11.5 mg/L after 3 days of ivermectin intake. He was discharged and advised for a follow-up after 4 weeks. The patient was completely asymptomatic and gained 4 kg of body weight in 8 weeks. Repeat upper GI endoscopy to assess the mucosal healing after 8 weeks of discharge revealed minimally nodular mucosa without any ulceration (Figure 5). The gastroscope could be negotiated beyond the involved segment to D4.\n\nFigure 5. Follow-up endoscopy at 8 weeks showing minimally nodular mucosa without any ulceration.\n\nDISCUSSION\nStrongyloidiasis is often considered to be an exotic disease that occurs primarily in the tropics or under unusual predisposing host conditions. While the parasite burden remains balanced, symptoms are minimal or absent. Immunosuppression or glucocorticoid administration upsets this balance, with the result that previously asymptomatic but chronically infested patients develop fulminant, potentially fatal strongyloidiasis from massive autoinfection.3 The small intestine, particularly the duodenum and upper jejunum, is the major site of action of the parasite.4 Massive autoinfection produces disseminated fulminant strongyloidiasis, with injury to the intestinal mucosa leading to polymicrobial sepsis pneumonitis and meningitis.4–6 Intestinal strongyloides usually present with small bowel diarrhea with malabsorption.7\n\nOur patient was diagnosed quite early and responded to antihelminthic, unlike the other cases reported earlier where the diagnosis is delayed and is sometimes on the basis of postoperative biopsy.8–10 The initial disproportionately high C-reactive protein can be explained by sepsis due to bacterial translocation because of duodenal mucosal barrier dysfunction. This explains the quick improvement after empirical antibiotics. Duodenal strongyloides with only vomiting as the sole presentation is extremely rare, and there are only a few isolated case reports worldwide.8–10 In a recent review by Cruz et al, 9 cases were analyzed from 1970 to 2010, of which 3 patients were diagnosed on the basis of the histopathologic study of postoperative biopsy specimen.11 The other tests used for the confirmation were duodenal aspirate and duodenal mucosal biopsy. Hence, an early diagnosis and treatment can help in avoiding surgery.\n\nDISCLOSURES\nAuthor contributions: AA Patra and P. Nath wrote the manuscript and performed the literature review. GK Pati, SC Panigrahi, B. Mallick, JCK Acharya, and A. Adhya edited the manuscript. P. Nath is the article guarantor.\n\nFinancial disclosures: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Concha R Harrington W Rogers AI \nIntestinal strongyloidiases: Recognition, management and determinants of outcome . J Clin Gastroenterol . 2005 ;39 :203 –11 .15718861 \n2. Keiser PB Nutmann TB \nStrongyloidessterocalis in the immunocompromised population . Clin Microbiol Rev . 2004 ;17 :208 –17 .14726461 \n3. Elliott DE \nIntestinal worms ; In: Sleisenger and Fordtran's Gastrointestinal and Liver Diseases , 10th edn \nElseiver : Philadelphia, PA , 2016 , pp 1972 –3 .\n4. Marcia-Rojas RA \nPathology of protozoa and helminthic diseases . Rojas M (ed). Williams and Wilkins : Baltimore, MD , 1971 , pp 711 –53 .\n5. Mejia R Nutman TB \nScreening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis . Curr Opin Infect Dis . 2012 ;25 :458 –63 .22691685 \n6. Link K Orenstein R \nBacterial complications of strongyloidiasis: Streptococcus bovis meningitis . South Med J . 1999 ;92 :728 –31 .10414486 \n7. Berkmen YM Rabinowitz J \nGastrointestinal manifestations of the strongyloidiasis . Am J Roentgen Rad Ther . 1972 ;115 :306 –11 .\n8. Juchems MS Niess JH Leder G \nStrongyloides stercoralis: A rare cause of obstructive duodenal stenosis . Digestion . 2008 ;77 :141 –4 .18446028 \n9. Harish K Sunilkumar R Varghese T \nStrongyloidiasis presenting as duodenal obstruction . Trop Gastroenterol . 2005 ;26 :201 –2 .16737052 \n10. Hindy P Parvin R Hanna K \nStrongyloidiasis presenting as duodenal obstruction in a patient infected with human T-cell lymphotropic virus type 1 . Gastrointest Endosc . 2011 ;74 :439 –41 .21704987 \n11. Cruz RJ Vincenzi R Ketzer BM \nDuodenal obstruction-an unusual presentation of Strongyloides stercoralis enteritis: A case report . World J Emergenc Surg . 2010 ;5 :23 .\n\n",
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"title": "Strongyloides Infection Presenting as Proximal Small Intestinal Obstruction.",
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"abstract": "A primiparous woman in her late 30s at 28+1 weeks' gestation presented with a 3-day history of abdominal pain, loss of appetite, nausea and vomiting and was diagnosed with starvation ketoacidosis. A routine admission swab returned positive for COVID-19. She had been diagnosed with acrorenal syndrome from birth. Three days post admission, she deteriorated rapidly into respiratory failure requiring intubation and ventilation. She was treated with dexamethasone, prophylactic enoxaparin, a course of piperacillin/tazobactam followed by meropenem and fluconazole and 8 cycles of proning. An emergency caesarean section was performed on day 12 of hospital admission at 29+5 weeks' gestation to improve maternal oxygenation and ventilation. The baby had deformities consistent with acrorenal syndrome but no evidence of COVID-19. She spent 23 days in the intensive care unit. Our case describes an unusual presentation of COVID-19, the challenges in managing critically ill pregnant patients along with a rare background history of acrorenal syndrome.",
"affiliations": "Department of Anaesthesiology, Our Lady of Lourdes Hospital, Drogheda, Ireland aoife.brady22@gmail.com.;Department of Anaesthesiology, Our Lady of Lourdes Hospital, Drogheda, Ireland.",
"authors": "Brady|Aoife|A|;Aglan|Ahmed|A|",
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"keywords": "COVID-19; genetics; intensive care; obstetrics and gynaecology; pregnancy",
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"mesh_terms": "D000328:Adult; D000086382:COVID-19; D002585:Cesarean Section; D005260:Female; D005385:Fingers; D006228:Hand Deformities, Congenital; D006801:Humans; D007662:Ketosis; D007668:Kidney; D011247:Pregnancy",
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"title": "Critical COVID-19 in a pregnant patient who presented in starvation ketoacidosis with a background history of acrorenal syndrome.",
"title_normalized": "critical covid 19 in a pregnant patient who presented in starvation ketoacidosis with a background history of acrorenal syndrome"
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"abstract": "We herein report a 75-year-old man with non-small-cell lung cancer who developed tubulointerstitial nephritis due to pembrolizumab administration. He was successfully treated with atezolizumab following steroid administration. He was initially diagnosed with lung adenocarcinoma (T1bN3M1b, stage IV), with a programmed cell death-ligand 1 tumor proportion score of 25-49%. Although the tumor responded well to pembrolizumab, the drug was discontinued because of the diagnosis of tubulointerstitial nephritis on a renal biopsy. Tubulointerstitial nephritis was treated with 30 mg prednisolone, the dose of which was tapered to and maintained at 5 mg. Following lung cancer progression, atezolizumab was administered, and the tumor responded again. Its efficacy has been sustained for >15 months without recurrence of tubulointerstitial nephritis.",
"affiliations": "Department of Internal Medicine, Fukuyama City Hospital, Japan.;Department of Internal Medicine, Fukuyama City Hospital, Japan.;Department of Internal Medicine, Fukuyama City Hospital, Japan.;Department of Internal Medicine, Fukuyama City Hospital, Japan.;Department of Internal Medicine, Fukuyama City Hospital, Japan.;Department of Internal Medicine, Fukuyama City Hospital, Japan.;General Internal Medicine 3, Kawasaki Medical School, Japan.;General Internal Medicine 4, Kawasaki Medical School, Japan.",
"authors": "Taki|Takahiro|T|;Oda|Naohiro|N|;Fujioka|Yusuke|Y|;Mitani|Reo|R|;Tokura|Takehiko|T|;Takata|Ichiro|I|;Oshiro|Yoshiyuki|Y|;Takigawa|Nagio|N|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C000594389:atezolizumab; D011239:Prednisolone; C582435:pembrolizumab",
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"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32269191\n10.2169/internalmedicine.4260-19\nCase Report\nSuccessful Treatment of Non-small-cell Lung Cancer with Atezolizumab Following Tubulointerstitial Nephritis Due to Pembrolizumab\nTaki Takahiro 1 Oda Naohiro 1 Fujioka Yusuke 1 Mitani Reo 1 Tokura Takehiko 1 Takata Ichiro 1 Oshiro Yoshiyuki 2 Takigawa Nagio 3 \n1 Department of Internal Medicine, Fukuyama City Hospital, Japan\n\n2 General Internal Medicine 3, Kawasaki Medical School, Japan\n\n3 General Internal Medicine 4, Kawasaki Medical School, Japan\nCorrespondence to Dr. Naohiro Oda, dancingqueen121212@gmail.com\n\n\n9 4 2020 \n1 7 2020 \n59 13 1639 1642\n26 11 2019 9 2 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We herein report a 75-year-old man with non-small-cell lung cancer who developed tubulointerstitial nephritis due to pembrolizumab administration. He was successfully treated with atezolizumab following steroid administration. He was initially diagnosed with lung adenocarcinoma (T1bN3M1b, stage IV), with a programmed cell death-ligand 1 tumor proportion score of 25-49%. Although the tumor responded well to pembrolizumab, the drug was discontinued because of the diagnosis of tubulointerstitial nephritis on a renal biopsy. Tubulointerstitial nephritis was treated with 30 mg prednisolone, the dose of which was tapered to and maintained at 5 mg. Following lung cancer progression, atezolizumab was administered, and the tumor responded again. Its efficacy has been sustained for >15 months without recurrence of tubulointerstitial nephritis. \n\nimmune checkpoint inhibitorimmune-related adverse eventtubulointerstitial nephritisprogrammed death-ligand 1atezolizumab\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICIs) can lead to various immune-related adverse events (irAEs) such as interstitial lung disease, thyroid dysfunction, colitis, and type 1 diabetes mellitus. Among all irAEs, renal dysfunction is relatively rare (1). The recurrence rate of irAEs was 39-71.4% when ICIs were readministered to patients who discontinued the use of ICIs because of irAEs (2-5). There are few reports on the safety and efficacy of programmed cell death-ligand 1 antibody (anti-PD-L1) in patients who discontinued the use of programmed cell death-1 antibody (anti-PD-1) because of irAEs.\n\nWe herein report a patient with non-small-cell lung cancer (NSCLC) who developed tubulointerstitial nephritis due to anti-PD-1 (pembrolizumab), which was successfully treated with anti-PD-L1 (atezolizumab).\n\nCase Report\nThe patient was a 75-year-old man who visited our hospital with back pain. He was an ex-smoker (Brinkman index of 2,200) and had been exposed to asbestos. He was diagnosed with lung adenocarcinoma (T1bN3M1b, stage IV) with pulmonary, brain, pancreatic, and bone metastases. A molecular examination of the tumor revealed wild-type epidermal growth factor receptor gene but no rearrangement of the anaplastic lymphoma kinase fusion gene. Following stereotactic radiation therapy for brain metastasis, he received four cycles of carboplatin and pemetrexed. However, the disease progressed after three cycles of pemetrexed. Because the PD-L1 tumor proportion score according to PD-L1 IHC 22C3 pharmDx was 25-49%, pembrolizumab was administered as the second-line therapy. The tumor decreased significantly in size after four cycles of pembrolizumab (Fig. 1).\n\nFigure 1. Computed tomography before pembrolizumab administration (A, B) and after four cycles of pembrolizumab administration (C, D). The primary lesion size in the left upper lobes and pulmonary metastases was significantly reduced.\n\nAfter 4 cycles of pembrolizumab, his serum creatinine level increased from 0.75 to 1.5 mg/dL. He also received rabeprazole sodium, a proton pump inhibitor (PPI), for 11 months. Serum antinuclear and antineutrophil cytoplasmic antibodies were negative. Negative results were obtained for urinary protein and fecal occult blood; microscopically, there were 1-4 white blood cells/high-power field. Urinary protein/creatinine ratio was 0.17 g/g creatinine. The N-Acetyl-beta-D-glucosaminidase activity and beta-2 microglobulin levels were 7.1 IU/L and 1,800 μg/L, respectively. The serum creatinine level worsened to 2.09 mg/dL [grade 2 acute kidney injury (AKI), as evaluated by the Common Terminology Criteria for Adverse Events version 4] despite pembrolizumab discontinuation. Thereafter, a renal biopsy was performed. The pathological specimen contained 10 glomeruli, only 1 of which showed global sclerosis. The other glomeruli were almost normal, without mesangial cell proliferation, basement membrane change, or endocapillary proliferation (Fig. 2). Glomerular deposition of immunoglobulin (Ig) G, IgA, IgM, C3, C4, C1q, or fibrinogen was not observed upon immunofluorescence staining (data not shown). Thus, tubulointerstitial nephritis was confirmed. Following prednisolone (30 mg) administration, renal function improved, and the dose of prednisolone was tapered. However, the serum creatinine level increased after prednisolone interruption; therefore, 5 mg prednisolone was readministered and maintained (Fig. 3). Because lung cancer progressed 11 months after the last pembrolizumab administration, atezolizumab was administered as the third-line therapy. With the maintenance of the prednisolone dose (5 mg), the serum creatinine level was maintained at <1.0 mg/dL; no other irAEs were observed. Lung cancer did not progress for >15 months after atezolizumab administration (Fig. 4).\n\nFigure 2. Hematoxylin and Eosin staining (A, B) and periodic acid-Schiff staining (C) of a right kidney specimen. Infiltration of numerous lymphocytes and histiocytes into the stroma and partly into the tubule (A, B) without a glomerular lesion (C) was observed.\n\nFigure 3. Clinical course of the patient. Cre: creatinine\n\nFigure 4. Computed tomography at the time of pembrolizumab discontinuation (A), before atezolizumab administration (B), and 14 months after atezolizumab administration (C). The pulmonary lesion size in the right middle lobes was significantly reduced after atezolizumab administration.\n\nDiscussion\nWe encountered a case of NSCLC with biopsy-proven tubulointerstitial nephritis due to pembrolizumab. He was successfully treated with atezolizumab under prednisolone maintenance.\n\nIn a pooled analysis of 3,695 patients treated with ICIs, the incidence of ICI-associated AKI was 2.2% for any grade and 0.7% for or grades ≥3. AKI was more common (any grade, 4.9%; above grade 3, 1.7%) in patients receiving combination therapy with ipilimumab and nivolumab than in those receiving ICI monotherapy (6). While the spectrum of renal irAEs in patients receiving ICIs is broad, the majority of patients are diagnosed with tubulointerstitial nephritis based on a biopsy specimen. Other drugs, such as PPIs and nonsteroidal anti-inflammatory drugs, can also lead to tubulointerstitial nephritis. In the present case, PPI use may have been associated with tubulointerstitial nephritis development due to ICI, as reported previously (7). Other renal irAEs include antinuclear cytoplasmic antibody-associated diseases, lupus nephritis, and podocytopathy (8-10). In 12 patients treated with pembrolizumab that caused AKI, 4 with acute interstitial nephritis (AIN) and 5 with acute tubular necrosis (ATN) were pathologically diagnosed (11). It is important to differentiate between cases of AIN and ATN because AIN, but not ATN, often requires corticosteroid therapy. It is difficult to differentiate AIN from ATN based on clinical features alone; therefore, a renal biopsy is required to determine the exact etiology of ICI-associated AKI.\n\nA previous report noted a trend toward a higher recurrence rate following the development of a more severe initial irAE and toward more frequent recurrence in patients treated with corticosteroids following the initial irAEs (4). In the present case, because the serum creatinine level increased again after corticosteroid discontinuation, ICI was readministered with a low-dose corticosteroid, and an anticancer effect was achieved without the recurrence of any irAEs over a long period. While there are concerns that corticosteroid (particularly >10 mg prednisone) use may attenuate the effects of ICIs (12), it was recently reported that corticosteroid use for cancer-unrelated indications did not attenuate the effects of ICIs (13). In the present case, tubulointerstitial nephritis was not lethal and was well controlled with 5 mg prednisolone; therefore, we decided to readminister ICIs.\n\nSome studies have shown that treatment outcomes were similar between the readministration and discontinuation cohorts among patients with NSCLC who showed an early objective response prior to the development of a severe irAE (3,5). We switched the ICI from pembrolizumab (an anti-PD-1) to atezolizumab (an anti-PD-L1). Anti-PD-L1 inhibits the PD-1/PD-L1 and B7.1/PD-L1 pathways, promoting the binding of CD28 expressed on T cells to B7.1 expressed on antigen-presenting cells (14,15). In the priming phase, anti-PD-L1 may also promote T-cell priming and activation more strongly than anti-PD-1 (14,15). Furthermore, in previous studies, patients were rechallenged with the ICIs used in the initial treatment that had induced irAEs (3,5). Switching from anti-PD-1 to anti-PD-L1 might be suitable in terms of an improved efficacy and safety.\n\nIn conclusion, we reported a patient with NSCLC who developed tubulointerstitial nephritis due to pembrolizumab administration but was successfully treated with atezolizumab administration. Anti-PD-L1 administration to patients who respond to anti-PD-1 but whose treatment is discontinued because of irAEs might be efficacious and safe under maintenance therapy with corticosteroids.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nNagio Takigawa: Honoraria, Chugai Pharmaceutical.\n\nAcknowledgement\nWe thank Yasumasa Monobe, Department of Pathology, Kawasaki Medical School General Medical Center, for providing the pathological images.\n==== Refs\n1. Cortazar FB , Marrone KA , Troxell ML , et al \nClinicopathological features of acute kidney injury associated with immune checkpoint inhibitors\n. Kidney Int \n90 : 638 -647\n, 2016 .27282937 \n2. Pollack MH , Betof A , Dearden H , et al \nSafety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma\n. Ann Oncol \n29 : 250 -255\n, 2018 .29045547 \n3. Santini FC , Rizvi H , Plodkowski AJ , et al \nSafety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC\n. Cancer Immunol Res \n6 : 1093 -1099\n, 2018 .29991499 \n4. Simonaggio A , Michot JM , Voisin AL , et al \nEvaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer\n. JAMA Oncol \n5 : 1310 -1317\n, 2019 .\n5. Mouri A , Kaira K , Yamaguchi O , et al \nClinical difference between discontinuation and retreatment with nivolumab after immune-related adverse events in patients with lung cancer\n. Cancer Chemother Pharmacol \n84 : 873 -880\n, 2019 .31444618 \n6. Sise ME , Seethapathy H , Reynolds KL \nDiagnosis and management of immune checkpoint inhibitor-associated renal toxicity: illustrative case and review\n. Oncologist \n24 : 735 -742\n, 2019 .30902916 \n7. Shirali AC , Perazella MA , Gettinger S \nAssociation of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients\n. Am J Kidney Dis \n68 : 287 -291\n, 2016 .27113507 \n8. Fadel F , El Karoui K KB \nAnti-CTLA4 antibody-induced lupus nephritis\n. N Engl J Med \n361 : 211 -212\n, 2009 .\n9. Gao B , Lin N , Wang S , et al \nMinimal change disease associated with anti-PD1 immunotherapy: a case report\n. BMC Nephrol \n19 : 156 , 2018 .29970032 \n10. van den Brom RR , Abdulahad WH , Rutgers A , et al \nRapid granulomatosis with polyangiitis induced by immune checkpoint inhibition\n. Rheumatology (Oxford) \n55 : 1143 -1145\n, 2016 .27069016 \n11. Izzedine H , Mathian A , Champiat S , et al \nRenal toxicities associated with pembrolizumab\n. Clin Kidney J \n12 : 81 -88\n, 2019 .30746132 \n12. Arbour KC , Mezquita L , Long N , et al \nImpact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer\n. J Clin Oncol \n36 : 2872 -2878\n, 2018 .30125216 \n13. Ricciuti B , Dahlberg SE , Adeni A , Sholl LM , Nishino M , Awad MM \nImmune checkpoint inhibitor outcomes for patients with non-small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications\n. J Clin Oncol \n37 : 1927 -1934\n, 2019 .31206316 \n14. Hui E , Cheung J , Zhu J , et al \nT cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition\n. Science \n355 : 1428 -1433\n, 2017 .28280247 \n15. Butte MJ , Peña-Cruz V , Kim MJ , Freeman GJ , Sharpe AH \nInteraction of human PD-L1 and B7-1\n. Mol Immunol \n45 : 3567 -3572\n, 2008 .18585785\n\n",
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"keywords": "atezolizumab; immune checkpoint inhibitor; immune-related adverse event; programmed death-ligand 1; tubulointerstitial nephritis",
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"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009395:Nephritis, Interstitial; D011239:Prednisolone",
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"title": "Successful Treatment of Non-small-cell Lung Cancer with Atezolizumab Following Tubulointerstitial Nephritis Due to Pembrolizumab.",
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"abstract": "Retroperitoneal fibrosis (RPF) is a rare condition with an unclear etiology, presenting with the development of aberrant chronic nonspecific fibroinflammatory tissue in the retroperitoneal space, which can result in entrapment and obstruction of the retroperitoneal structures. RPF is a subtype of chronic periaortitis, and can be divided into two types: primary (or idiopathic) and secondary. RPF is usually idiopathic, but can also be secondary to malignancies, certain drugs, infections, surgery, and trauma. The systemic clinical manifestations are nonspecific and include low-grade fever, fatigue, anorexia, weight loss, and myalgia. We report five patients admitted to our hospital with clinical, laboratory, imaging, and pathologic findings compatible with RPF, and we describe their treatment and follow-up. We were suspicious that the impurities of some types of opium have an important role in the pathogenesis of RPF. Some of our patients used opium again after the follow-up period; however, they used a different type with a different origin, and we were surprised to see that RPF did not form again.",
"affiliations": "Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IR Iran.;Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IR Iran.;Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IR Iran.",
"authors": "Mohammadzadeh Rezaei|Mohammad Ali|MA|;Akhavan Rezayat|Alireza|A|;Ardalan|Shima|S|",
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"fulltext": "\n==== Front\nNephrourol MonNephrourol Mon10.5812/numonthlyKowsarNephro-urology Monthly2251-70062251-7014Kowsar 10.5812/numonthly.39788Case ReportRetroperitoneal Fibrosis Due to Opium Abuse: A Case Series and Literature Review Mohammadzadeh Rezaei Mohammad Ali 1Akhavan Rezayat Alireza 1*Ardalan Shima 11 Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IR Iran* Corresponding author: Alireza Akhavan Rezayat, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IR Iran. Tel: +98-51338022857, Fax: +98-5138022857, E-mail: alirezaakhavan30@yahoo.com21 8 2016 11 2016 8 6 e3978806 6 2016 30 7 2016 16 8 2016 Copyright © 2016, Nephrology and Urology Research Center2016This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.Retroperitoneal fibrosis (RPF) is a rare condition with an unclear etiology, presenting with the development of aberrant chronic nonspecific fibroinflammatory tissue in the retroperitoneal space, which can result in entrapment and obstruction of the retroperitoneal structures. RPF is a subtype of chronic periaortitis, and can be divided into two types: primary (or idiopathic) and secondary. RPF is usually idiopathic, but can also be secondary to malignancies, certain drugs, infections, surgery, and trauma. The systemic clinical manifestations are nonspecific and include low-grade fever, fatigue, anorexia, weight loss, and myalgia. We report five patients admitted to our hospital with clinical, laboratory, imaging, and pathologic findings compatible with RPF, and we describe their treatment and follow-up. We were suspicious that the impurities of some types of opium have an important role in the pathogenesis of RPF. Some of our patients used opium again after the follow-up period; however, they used a different type with a different origin, and we were surprised to see that RPF did not form again.\n\nRetroperitoneal FibrosisObstructionOpium Abuse\n==== Body\n1. Introduction\nRetroperitoneal fibrosis (RPF) is a rare condition with an unclear etiology. It was first described in 1905, but more cases of this disease have since been reported (1, 2). RPF presents with the development of aberrant fibroinflammatory tissue in the retroperitoneal space, which can lead to entrapment and obstruction of the retroperitoneal structures, such as the ureters, aorta, and other abdominal organs (1, 3).\n\nRPF can be primary or secondary. In primary RPF, the specific cause of disease is unknown, while in the secondary type, other factors, such as infection, neoplasm, trauma, surgery, radiotherapy, and certain drugs are the underlying factors that lead to the formation of RPF (2-4).\n\nIn this disease, systemic clinical manifestations are nonspecific, such as low-grade fever, fatigue, anorexia, weight loss, and myalgia (3, 5). It can also present with ureteral obstruction, lower extremity edema, varicocele, and renal failure (1, 2, 6).\n\nIn this case series, we present five patients with a history of opium addiction who presented with RPF, and describe their clinical manifestations, laboratory and radiologic findings, treatment, and follow-up.\n\n2. Case Presentation\n2.1. Patient 1\nA 45-year-old man with a 3-year history of opium abuse presented with a 3-month history of left lower extremity edema. He had no previous history of any specific medical condition. Physical examination was normal, with a soft abdomen and normal bowel sounds. No pain was detected in the bilateral renal area. Laboratory tests revealed an elevated erythrocyte sedimentation rate (ESR) of 90 mm/h, and the complete blood count showed anemia with a hemoglobin of 11.2. Urine analysis was normal. Blood urea nitrogen (BUN) and serum creatinine were within normal range. Tumor markers, including CEA, CA125, αFP, and LDH were within normal limits. Ultrasonography detected unilateral hydronephrosis without ureteral dilation. Abdominal and pelvic computed tomography (CT) revealed an area of retroperitoneal thickness over the sacral promontory, with maximum thickness at the level of L4 - 5. Intravenous pylography (IVP) also revealed unilateral hydronephrosis (Figure 1).\n\nThe patient underwent double-J stent insertion to improve ureteral obstruction, and then a retroperitoneal biopsy was performed. The biopsy specimen was made up of collagenous tissue with inflammatory cells, compatible with RPF. The patient began taking an NSAID (ibuprofen 400 mg q 8 h) and prednisolone 1 mg/kg/day for approximately 6 weeks, and opium abuse was discontinued for a time. However, because the patient was refractory to medical therapy and there was deterioration of his clinical, laboratory, and sonographic findings, a surgical procedure was the best alternative therapy. Ureterolysis was performed immediately to improve renal function. Via a midline abdominal incision, the ureters were transpositioned to the intraperitoneal space and wrapped with omental fat to provide an effective barrier against re-entrapment by fibrotic tissue. After 6 months of follow-up, improvements in his clinical, radiologic, and laboratory findings were seen.\n\nFigure 1. Unilateral Hydronephrosis and Double-J Stent Insertion\n2.2. Patient 2\nA 37-year-old male was admitted to the hospital with bilateral flank pain for 2 weeks. The patient had a 7-year history of opium abuse. He had no previous history of a specific medical condition. Physical examination was normal with a soft abdomen, but the exam was positive for bilateral costovertebral angle tenderness. Laboratory findings revealed elevated inflammatory markers (ESR = 70 mm/h and C-reactive protein [CRP] = 2+), mild anemia with a hemoglobin of 11.3, and elevated creatinine of 2 mg/dL. Urine analysis was normal and the results of the other biochemical screenings and electrolyte tests were all within normal limits.\n\nOn ultrasonography, bilateral severe hydroureteronephrosis was detected. Urine drainage with a percutaneous nephrostomy tube (PCN) was done to improve renal function and creatinine levels. CT of the abdomen and pelvis was obtained, showing a retroperitoneal mass measuring 5 × 6 cm with compression effect on the lower aspect of the bilateral ureters, producing bilateral hydroureteronephrosis (Figure 2A, B). The definitive diagnosis was made with a tissue biopsy, which showed a collagen-rich background with fibroblastic elements lacking signs of atypia, with diffuse perivascular inflammatory cell infiltrations, compatible with RPF.\n\nThe patient underwent therapy with an NSAID (ibuprofen 400 mg q 8 h) and prednisolone (1 mg/kg/day) for approximately 4 weeks, and the opium was discontinued. The corticosteroid and NSAID were gradually tapered off within 6 months and the PCN tube was removed. Follow-up ultrasonography at 3 and 6 months showed a gradual remission of hydroureteronephrosis and at the last follow-up visit at 6 months, the ESR level was within normal range (< 10 mm/h).\n\nFigure 2. (A, B) Retroperitoneal Mass and Abdominal Aorta Involvement\n2.3. Patient 3\nA 48-year-old male with a 15-year history of opium addiction presented with a 5-month history of low back pain. Physical examination was normal, with no back or abdominal tenderness, organ enlargement, or palpable masses. Bilateral trace pedal edema was detected. Laboratory results showed mild anemia with a hemoglobin of 11 and an elevated ESR of 50 mm/h. BUN was 75 and serum creatinine was 3 mg/dL. Urine analysis was normal and the results of the other biochemical screenings and electrolyte tests were all within normal limits. Tumor markers, including CEA, CA125, αFP, and LDH, were also within normal limits.\n\nAbdominal ultrasonography showed bilateral pyelocaliceal system dilation, and abdominal and pelvic CT revealed bilateral hydronephrosis and fibrotic tissue surrounding the abdominal aorta and common iliac arteries at the level of the sacral promontory. A double-J stent was inserted and retroperitoneal biopsy was performed. The biopsy specimen was made up of fibrotic tissue with inflammatory cells, compatible with retroperitoneal fibrosis. Medical treatment with an NSAID (ibuprofen 400 mg/dL) and prednisolone (1 mg/kg/day) was administered for 4 weeks. After clinical and radiologic improvement, the drugs were tapered off in 6 months and the PCN tube was removed. At the same time, the opium abuse was stopped. After 9 months of follow-up, the patient’s laboratory and radiologic findings were all within normal limits.\n\n2.4. Patient 4\nA 36-year-old man with a 10-year history of opium addiction presented with bilateral pedal edema and a 5-kg weight loss over the previous 9 months. He had no previous history of any specific medical condition. Physical examination was normal, with no back or abdominal tenderness. No costovertebral angle tenderness, organ enlargement, or palpable masses were identified. Laboratory tests revealed microscopic hematuria on urine analysis. BUN and serum creatinine were within normal range, and ESR was elevated (60 mm/h). The results of the other biochemical screenings and electrolyte tests were all within normal limits. Abdominal ultrasonography revealed unilateral pyelectasia, and abdominal and pelvic CT revealed a retroperitoneal mass (Figure 3). Post-void urine residue volume was normal.\n\nAfter double-J stent insertion to correct ureteral obstruction, a retroperitoneal biopsy was performed. The result showed that the biopsy specimen was made up of fiber and fat tissue with infiltration of inflammatory cells, compatible with RPF.\n\nThe patient began taking an NSAID (ibuprofen 400 mg q 8 h) and prednisolone (1 mg/kg/day) for approximately one month, and was recommended to stop using opium. The NSAID and prednisolone were then tapered off at 8 months. On radiologic, laboratory, and clinical follow-up, full recovery was observed.\n\nFigure 3. Unilateral Hydronephrosis and Retroperitoneal Mass\n2.5. Patient 5\nA 40-year-old female with a 5-year history of opium abuse presented with 6-month history of fatigue, low back pain, and menometrorrhagia. She had no previous history of any specific medical condition. Physical examination was normal and no abdominal tenderness, organ enlargement, or palpable masses were identified.\n\nLaboratory tests revealed an elevated ESR (70 mm/h) and anemia with hemoglobin of 10.2. Urine analysis was normal. Serum creatinine was elevated (2.5). The tumor markers (CEA, CA125, LDH, αFP, and βHCG) were within normal limits. The results of the other biochemical screenings and electrolyte tests were all within normal range.\n\nUltrasonography revealed bilateral moderate hydronephrosis without ureteral dilation. On abdominal and pelvic CT, fibrotic tissue was observed surrounding the abdominal aorta and common iliac arteries at the level of the sacral promontory. A double-J stent was inserted and the patient began taking an NSAID (ibuprofen 400 mg q 8 h) and prednisolone (1 mg/kg/day) for approximately 6 weeks. She was also advised to stop using opium. After 9 months, the NSAID and prednisolone were tapered off, and improvements in the patient’s clinical manifestation and radiologic and laboratory findings were observed.\n\n3. Discussion\nRPF is a rare condition with a prevalence of 11.4/100,000 individuals and an incidence of 0.1/100,000 per year (2). RPF has an unclear etiology, and was first described by Albarron in 1905 (1, 2). However, more cases of this disease have since been reported (1, 7, 8). RPF is also known as Ormond’s disease (9).\n\nThe peritoneum is a membranous tissue that lines the abdominal cavity and covers the abdominal organs. Abdominal structures located outside of the peritoneum, known as retroperitoneal structures, include blood vessels, such as the aorta, and ureters. RPF presents with the development of aberrant chronic nonspecific fibroinflammatory tissue in the retroperitoneal space. It usually presents around the infrarenal portions of the abdominal aorta and the iliac vessels. This formation of fibrotic tissue in the majority of patients results in the entrapment and obstruction of retroperitoneal structures, such as the aorta, ureters, inferior vena cava, or other abdominal organs (2, 3).\n\nRPF can be divided in two types: primary (or idiopathic) and secondary to other conditions. More than two thirds of cases are idiopathic, which means that the specific cause of disease is unknown. The remaining third of cases are secondary, resulting from other factors, such as infections, neoplasms, trauma, surgery, radiotherapy, and the use of certain drugs (4, 10).\n\nInfections such as tuberculosis, histoplasmosis, actinomycosis, and syphilis can result in secondary RPF (2, 3). Various drugs, including methysergide, pergolide, bromocriptine, ergotamine, methyldopa, hydralazine, and beta blockers, as well as illegal drugs such as cocaine, can also lead to the development of RPF (9, 10). Opium abuse may be suspected as a strong risk factor for secondary RPF, as we reported in our five cases.\n\nRecent abdominal or pelvic trauma, hemorrhage, or surgery, such as aortic bypass or anterior spinal fusion, can lead to RPF (2, 3). Idiopathic RPF can affect anyone at any age; the average age at onset of signs and symptoms is approximately 50 years. Individuals at the highest risk are men aged 40 - 60 years, with a 2 - 3: 1 male: female predominance (2). In cases associated with malignancy, the sex distribution is equal (6, 11, 12).\n\nThe systemic clinical manifestations of RPF are nonspecific constitutional symptoms, including low-grade fever, fatigue, anorexia, weight loss, and myalgia.(3, 5) Signs and symptoms of RPF may be seen as a result of entrapment and compression of retroperitoneal organs, such as the ureters, the inferior vena cava, the aorta and its branches, and the gonadal vessels (6).\n\nCompression and obstruction of the ureters may be indicated by a dull and non-colicky pain, costovertebral angle tenderness (ureteral colic), hematuria, oliguria, anurea, and renal failure. Bilateral ureteral obstruction can present with uremic symptoms. Entrapment of the inferior vena cava can present as lower extremity edema, scrotal edema, or deep vein thrombophlebitis of the leg (1, 6, 13).\n\nLaboratory findings in RPF are nonspecific, although anemia with a hematocrit of < 33% is common. Blood tests to check renal function, autoantibodies, and tumor markers are advised (1). Inflammatory markers (acute-phase reactants), such as ESR and CRP, are elevated in more than half of RPF patients (2, 14).\n\nDue to bilateral ureteral compression and obstruction, renal failure can be present in 43% - 95% of cases. RPF is difficult to detect and it is important for clinicians to have sufficient awareness of this disease (1, 3). In some cases, an accurate diagnosis is made secondary to urological obstruction or renal failure (1). The diagnosis also relies strongly on radiologic findings. Radiologic imaging modalities such as X-ray, CT, magnetic resonance imaging (MRI), and positron emission tomography (PET) play an important role in making a definitive distinction between idiopathic or secondary RPF. Ultrasonography is performed as the first-line study in RPF and is useful for detecting hydronephrosis and aneurysm. Abdominal CT and MRI are the most reliable modalities for diagnosing idiopathic RPF (2, 3).\n\nMRI can also differentiate between idiopathic RPF and malignant RPF. PET scans can be performed to evaluate disease activity, are useful for the diagnosis and for monitoring the response to treatment, and can be helpful during follow-up (3, 6). Performing a tissue biopsy remains the only way to make a definitive diagnosis, and this is required for patients with resistance to empirical corticosteroid therapy (1, 3).\n\nThe best way to treat RPF is unknown. Treatment of RPF depends on whether the underlying cause is idiopathic or secondary. There are two therapeutic strategies: medical and surgical. The treatment goal is to induce regression of the inflammatory reaction and its systemic manifestations, to stop the formation of fibrotic tissue, to improve ureteral obstruction, to relieve other retroperitoneal organs, and to prevent disease deterioration (2).\n\nThe treatment of idiopathic RPF is empirical and based on the use of corticosteroids (2, 6, 13). Induction therapy with high-dose prednisolone (1 mg/kg/day), at a maximum dose of 80 mg/kg, is recommended for 4 - 6 weeks with tapering in approximately 1 - 2 years. A reassessment of disease activity by monitoring disease features, ESR, CRP, and mass size is recommended after one month of corticosteroid therapy. After disease remission, prednisolone may be tapered to 5 - 10 mg/day in 3 - 4 months and maintained for 6 - 9 months (2, 13).\n\nIn some RPF cases in which resistance to corticosteroid treatment is seen or ureteral obstruction recurs after stopping the corticosteroid therapy, immunosuppressive agents such as azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, and cyclosporine are advisable as adjunct medical treatments in combination with corticosteroids (2, 6, 13).\n\nIn the presence of any contraindications to corticosteroid therapy, tamoxifen (0.5 mg/kg/day) is a good alternative drug as first-line therapy. When idiopathic RPF is refractory to other treatments, biological agents can be used, including rituximab, infliximab, and tocilizumab (3, 13).\n\nIn drug-related RPF, such as in our five cases, stopping the specific causative medication is the treatment goal. In the presence of severe systemic manifestations or in cases with deterioration of disease manifestations despite discontinuation of the drug, corticosteroid therapy is recommended (2, 6). In bilateral or severe unilateral ureteral obstructions with normal renal function or refraction to medical therapy, such as in our first patient, the surgical approach is a good therapeutic choice to prevent renal damage (2, 13).\n\nThe surgical approach has no effect on disease regression and its systemic manifestations. Conservational approaches, including temporary placement of ureteral stents or nephrostomy tubes, as we used in our cases, are good therapeutic choices to correct underlying ureteral obstructions. These surgical procedures are advisable in cases with idiopathic RPF or for benign disease in patients who are poor surgical risks (2). In advanced ureteral stenosis, for which these two modalities may be ineffective, an open surgical approach, such as ureterolysis (intraperitoneal transposition and wrapping of the ureter with omental fat to provide an effective barrier against ureteral re-entrapment by fibrotic tissue, as we did in our first patient), may be necessary as an alternative procedure. Ureterolysis is an acceptable therapeutic procedure for the treatment of idiopathic RPF with or without corticosteroid therapy (2, 6).\n\nOpium abuse may be a strong risk factor for secondary RPF. All five of our reported patients had a history of opium addiction. All of our patients used the same opium, prepared from the same region in Iran (Sistan). We suspect that impurities in certain types of opium play an important role in the pathogenesis of RPF. Some of our patients used opium again after the follow-up period; however, they used a different type of opium with a different origin, and we were surprised to see that RPF did not form again. More research needs to be carried out to prove the role of opium abuse as an etiology of secondary RPF.\n\n3.1. Conclusion\nThe clinical and laboratory findings in RPF are nonspecific, and it is important to be aware of the predisposing factors for this condition, including drug abuse. We suggest that in cases with drug-induced RPF, the discontinuation of opium or changing to medical therapies may be useful and can be recommended.\n\nWe are thankful to the research council at Mashhad University of Medical Science for financial support.\n\nAuthors’ Contribution:Mohammad Ali Mohammadzadeh Rezaei: study concept and design, acquisition of data, analysis and interpretation of data, and drafting of the manuscript. Alireza Akhavan Rezayat: drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, administrative, technical, and material support, and study supervision. Shima Ardalan: drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, and administrative, technical, and material support.\n\nFunding/Support:We were supported financially by the research council of Mashad University of Medical Sciences.\n==== Refs\nReferences\n1 Liang B Yin Z Guo Q Wei Y Liu L Yang J Diagnosis and treatment of retroperitoneal fibrosis: A case report. Exp Ther Med. 2013 5 4 1236 8 10.3892/etm.2013.943 23599742 \n2 Ezimora A Faulkner ML Adebiyi O Ogungbemile A Marianna SV Nzerue C Retroperitoneal fibrosis: a rare cause of acute renal failure. Case Rep Nephrol. 2012 2012 645407 10.1155/2012/645407 24533204 \n3 Urban ML Palmisano A Nicastro M Corradi D Buzio C Vaglio A Idiopathic and secondary forms of retroperitoneal fibrosis: a diagnostic approach. Rev Med Interne. 2015 36 1 15 21 10.1016/j.revmed.2014.10.008 25455951 \n4 Koep L Zuidema GD The clinical significance of retroperitoneal fibrosis. Surgery. 1977 81 3 250 7 841463 \n5 Vaglio A Salvarani C Buzio C Retroperitoneal fibrosis. Lancet. 2006 367 9506 241 51 10.1016/S0140-6736(06)68035-5 16427494 \n6 Amis ES Retroperitoneal fibrosis. AJR Am J Roentgenol. 1991 157 2 321 9 10.2214/ajr.157.2.1853816 1853816 \n7 Yokoyama R Tazaki R Morita H Nishitani H Ariumi S Osuga S et al. Retroperitoneal fibrosis in a patient with gastric cancer manifested by lower extremity edema and hydrocele. Intern Med. 2012 51 16 2157 60 22892495 \n8 Ghanaati H Mohammadifar M Ghajarzadeh M Firouznia K Motevalli M Jalali AH The Role of Multidetector CT in the Diagnosis of Retroperitoneal Fibrosis: Report of a Case. Iran J Radiol. 2012 9 1 28 31 10.5812/iranjradiol.6343 23329957 \n9 Alberti C Drug-induced retroperitoneal fibrosis: short aetiopathogenetic note, from the past times of ergot-derivatives large use to currently applied bio-pharmacology. Il Giornale Di Chirurgia. 2014 36 4 187 91 \n10 Linder JD Monkemuller KE Raijman I Johnson L Lazenby AJ Wilcox CM Cocaine-associated ischemic colitis. South Med J. 2000 93 9 909 13 11005354 \n11 Sherman C Winchester P Brill PW Mininberg D Childhood retroperitoneal fibrosis. Pediatr Radiol. 1988 18 3 245 7 3368253 \n12 Birnberg FA Vinstein AL Gorlick G Lee FA Hales MS Retroperitoneal fibrosis in children. Radiology. 1982 145 1 59 61 10.1148/radiology.145.1.7122898 7122898 \n13 Shiber S Eliakim-Raz N Yair M Retroperitoneal fibrosis: case series of five patients and review of the literature. Rev Bras Reumatol Engl Ed. 2016 56 2 101 4 10.1016/j.rbre.2014.09.006 27267521 \n14 Kisiel B Kruszewski R Jurek-Urbanowska A Kidzinski R Frankowska E Sulek M et al. Idiopathic retroperitoneal fibrosis: case report. Pol Arch Med Wewn. 2009 119 10 677 9 19847146\n\n",
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"keywords": "Obstruction; Opium Abuse; Retroperitoneal Fibrosis",
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"title": "Retroperitoneal Fibrosis Due to Opium Abuse: A Case Series and Literature Review.",
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"affiliations": "Department of Pharmacology, NDMC Medical College, Hindu Rao Hospital, Delhi, India.;Department of Psychiatry, NDMC Medical College, Hindu Rao Hospital, Delhi, India.",
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"doi": "10.4103/0976-500X.155490",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-6-10310.4103/0976-500X.155490Case ReportDexamethasone-induced withdrawal seizure Mahar Santwana Malhotra Mahima 1Department of Pharmacology, NDMC Medical College, Hindu Rao Hospital, Delhi, India1 Department of Psychiatry, NDMC Medical College, Hindu Rao Hospital, Delhi, IndiaAddress for correspondence: Sanwana Mahar, Swastik Kunj, HN-131, Rohini, Sector - 13, Delhi – 110 085, India. E-mail: sanu2011mohanty@gmail.comApr-Jun 2015 6 2 103 104 15 3 2014 21 3 2014 15 9 2014 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Dexamethasone-induced withdrawal seizure, which is a very rare and uncommon event, occurred after discontinuation of steroid therapy that was taken to increase weight by the patient. The pathogenesis is not well understood. In this submission, we have highlighted the fact that withdrawal of steroid has a propensity to cause seizure as a rare withdrawal phenomenon.\n\nDexamethasoneseizurewithdrawal phenomenon\n==== Body\nINTRODUCTION\nDexamethasone is a very potent, long-acting highly selective glucocorticoid exhibiting both anti-inflammatory and immunosuppressant properties. Glucocorticoids are important mediators of the stress response, regulating both glucose homeostasis and the immune system and have wide clinical use as anti-inflammatory agents because of their profound effects on immune and inflammatory processes.[1] It binds to specific receptor proteins in the target tissues to regulate the expression of corticosteroid responsive genes, changing the levels and arrays of proteins synthesized by the various target tissues.[2] Dexamethasone is a commonly used drug used in the treatment of allergic states, dermatological diseases, endocrine diseases, hematological disorders, neoplastic diseases, nervous disorders, ophthalmic, respiratory, renal disease and rheumatic disorders. It is relatively well tolerated but has some adverse effects, particularly in high doses. Two categories of adverse effects result from the therapeutic use of corticosteroids: Those resulting from withdrawal of steroid therapy and those due to continued use at supraphysiological doses. The adverse effects from both categories are potentially life threatening. However, discontinuation of steroid therapy can present a significant clinical challenge. Treatment with supraphysiological doses of corticosteroid at levels commonly used for the treatment of inflammatory and autoimmune disorders will suppress the hypothalamic–pituitary–adrenal (HPA) axis. The most severe complication of steroid cessation is acute adrenal insufficiency characterized by lethargy, malaise, anorexia, myalgia, headache and fever.[3] It has been frequently associated with hyperglycemia, peptic ulceration, delayed healing, osteoporosis, posterior sub-capsular cataract, psychiatric disturbances and suppression of the HPA axis after prolonged use. No case of steroid-induced withdrawal generalized tonic clonic seizure (GTCS) has been reported earlier, which is very unusual and rare. We hereby report a case of dexamethasone–induced GTCS in a young boy after prolonged use.\n\nCASE REPORT\nA 19-year-old male, educated till class 8, currently working as a tailor in a factory presented to the psychiatry outpatient department. The patient gave a history that 3 months back he had joined the gym where a friend told him that if he takes dexamethasone he would have better muscles and hence better looks. Therefore, he took 0.5 mg of dexamethasone tablet twice a day to increase his weight, although we do not have any written proof that he had taken the medications that he claims. He started taking these tablets as he thought he would look good on gaining weight. Although there was no preoccupation with weight or body image, he was not even spending excessive time thinking about his looks. There was no interference with his social life or his work. He took dexamethasone tablets for 2 months and had a weight gain of around 3 kg and also suffered mild gastritis, although not documented. Subsequently, he could not take the tablets for 2 days and on the second day he experienced GTCS characterized by tonic, clonic movements with up-rolling of eyes and tongue bite with loss of consciousness. There was also postictal drowsiness for 30 min. After the first seizure, he had gone to the emergency department of a nearby hospital, then dilantinzed exact details of which are not available, and he did not follow-up there and he did not even inform them about his steroid intake. Thereafter, assuming that the episode was due to missing medications, he again started taking the dexamethasone tablets, but at a dose of 0.5 mg once a day. After taking these tablets for 1 month, he again missed doses for 2 days and on the second day had a GTCS. Subsequently, he reported to the hospital outpatient department. There was no family history of seizures. There was no history of smoking, alcohol consumption or any other illicit substances abuse; there was no history of head injury or high-grade fever. The 19-year-old male patient was investigated regarding the seizure and to evaluate any adverse effect on any organ due to chronic steroid intake. Hemogram, electrolytes, blood sugar, liver function test and lipid profile were within normal limits. Contrast-enhanced computed tomography of the head and electroencephalography were normal. The patient was advised to stop the drug and was given lorazepam for 2 weeks and gradually tapered over 2 weeks; he did not develop any further seizure.\n\nDISCUSSION\nCorticosteroids exert a number of indirect effects on the central nervous system through maintenance of blood pressure, plasma glucose concentrations and electrolyte concentration. Steroid receptors are expressed in different areas of the brain, and their role is related to the regulation of various neurotransmission, including serotonin and dopamine.[3] Increasingly direct effect of corticosteroids has been recognized, including effects on mood, behavior and brain excitability. The mechanisms whereby corticosteroids affect neuronal activity are unknown, but it has been proposed that steroids produced locally in the brain (neurosteroids) may regulate neuronal excitability.[4] The discontinuation of steroid therapy can present a significant challenge. A further literature search revealed that glucocorticoid courses of less than 3 weeks duration will not lead to HPA axis suppression, no matter what the steroid dose.[5] Therefore, in patients who have received more than physiological doses of systemic corticosteroid (approximately 1 mg dexamethasone) for greater than 3 weeks, withdrawal should not be abrupt. Steroid withdrawal syndrome is understood poorly.\n\nThe case presented here is an extremely rare glucocorticoid- induced withdrawal phenomenon and has not been reported in any literature till date. We tried to rule out other causes of seizure in a 19-year-old male, e.g. substance abuse, infections, tumor, head injury, electrolyte imbalance or any other medication use. In this case, the patient had seizures on both occasions within 2 days of stopping dexamethasone, which clearly indicated that this is due to the drug withdrawal. Mostly, withdrawal symptoms are due to acute adrenal insufficiency but here the mechanism of seizure after withdrawal is unclear and still needs to be elucidated. The incidence and the onset of such symptoms are quite variable depending on several factors; in any case, all healthcare professionals should be aware of such a possibility. Furthermore, such an event should be recognized early and treated accordingly. This case report should alert physicians prescribing steroids about the potentially life-threatening withdrawal phenomenon.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Armstrong EJ Dluhg RG Golan DE Pharmacology of the adrenal cortex Principles of Pharmacology 2008 2nd ed New Delhi Wolters Kluwer 498 502 \n2 Stahn C Buttgereit F Genomic and nongenomic effects of glucocorticoid Nat Clin Pract Rheumatology 2008 4 525 33 \n3 Sahacke H Docke WD Asadullah K Ganda JC Mechanisms of disease 1723 Mechanisms involved in the side effects of glucocorticoids Pharmacol Ther 2002 96 23 43 12441176 \n4 Schimmer BP Funder JW Laurence L Brunton Adrenal Steroids and Pharmacology of the Adrenal Cortex The Pharmacological Basis of therapeutics 2011 12th ed China McGraw-Hill 1221 7 \n5 Orth DN kovacs WJ Wilson JD The adrenal cortex Williams's textbook of endocrinology 1998 9th ed Philadelphia WB Saunders Company 605 10\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-500X",
"issue": "6(2)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Dexamethasone; seizure; withdrawal phenomenon",
"medline_ta": "J Pharmacol Pharmacother",
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"other_id": null,
"pages": "103-4",
"pmc": null,
"pmid": "25969660",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "12441176;18762788",
"title": "Dexamethasone-induced withdrawal seizure.",
"title_normalized": "dexamethasone induced withdrawal seizure"
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"abstract": "The number of Hansen's disease cases in Latin America and the Caribbean has decreased in the last decade; nevertheless, the region is still struggling with infections caused by Mycobacterium leprae. This is a case report that portrays the diagnostic and management challenges associated with atypical uveitic glaucoma that is due to Hansen's disease.\nA 62-year-old female was referred with a 2-year history of anterior uveitis of unknown etiology and ocular hypertension. Past medical history and general physical examination were unremarkable. Upon ocular examination, her best-corrected visual acuity (BCVA) was 20/25 in the OD and 20/60 in the OS. Tonometry showed intraocular pressures (IOPs) of 29 mmHg and 22 mmHg in her right and left eyes, respectively. The slit-lamp examination showed clinical signs of bilateral granulomatous anterior uveitis and cataracts; gonioscopy revealed open angles with some peripheral anterior synechiae for both eyes. Fundus examination and glaucoma tests revealed mild glaucomatous damage in the right eye. Given the presentation of uveitis, the respective questionnaire was completed by internal medicine and rheumatology. Four months later, after bilateral cataract surgery, the patient developed skin plaques on the face, neck, upper back, and extremities, which were biopsied and identified as positive for tuberculoid leprosy.\nThis is the first case report in Ecuador of atypical glaucoma triggered by infectious uveitis produced by Mycobacterium leprae. We describe a female patient's clinical presentation with several ocular signs of leprosy and other nonspecific and rarely seen symptoms. Uveitis is a condition that often requires a multidisciplinary team of ophthalmologists and clinicians because of the possible manifestation of an underlying systemic disease, creating a challenge for all the medical personnel involved in the management of the case.",
"affiliations": "Massachusetts Eye and Ear, Boston, USA.;Universidad San Francisco de Quito, School of Medicine, Quito, Ecuador.;Instituto de Oftalmología y Glaucoma Vásquez, Hospital Metropolitano, Quito, Ecuador.",
"authors": "Roldan-Vasquez|Ana|A|;Roldan-Vasquez|Estefania|E|;Vasquez|Ana M|AM|",
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"country": "United States",
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"doi": "10.1016/j.ajoc.2021.101096",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00105-5\n10.1016/j.ajoc.2021.101096\n101096\nCase Report\nUveitic Glaucoma and Hansen's disease, A case report\nRoldan-Vasquez Ana ana_roldanvasquez@meei.harvard.edu\nac∗\nRoldan-Vasquez Estefania bc\nVasquez Ana M. c\na Massachusetts Eye and Ear, Boston, USA\nb Universidad San Francisco de Quito, School of Medicine, Quito, Ecuador\nc Instituto de Oftalmología y Glaucoma Vásquez, Hospital Metropolitano, Quito, Ecuador\n∗ Corresponding author. Massachusetts Eye and Ear, 243 Charles St, Boston, MA, 02114, USA. ana_roldanvasquez@meei.harvard.edu\n22 4 2021\n6 2021\n22 4 2021\n22 10109625 8 2020\n23 3 2021\n12 4 2021\n© 2021 Published by Elsevier Inc.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nThe number of Hansen's disease cases in Latin America and the Caribbean has decreased in the last decade; nevertheless, the region is still struggling with infections caused by Mycobacterium leprae. This is a case report that portrays the diagnostic and management challenges associated with atypical uveitic glaucoma that is due to Hansen's disease.\n\nCase presentation\n\nA 62-year-old female was referred with a 2-year history of anterior uveitis of unknown etiology and ocular hypertension. Past medical history and general physical examination were unremarkable. Upon ocular examination, her best-corrected visual acuity (BCVA) was 20/25 in the OD and 20/60 in the OS. Tonometry showed intraocular pressures (IOPs) of 29 mmHg and 22 mmHg in her right and left eyes, respectively. The slit-lamp examination showed clinical signs of bilateral granulomatous anterior uveitis and cataracts; gonioscopy revealed open angles with some peripheral anterior synechiae for both eyes. Fundus examination and glaucoma tests revealed mild glaucomatous damage in the right eye. Given the presentation of uveitis, the respective questionnaire was completed by internal medicine and rheumatology. Four months later, after bilateral cataract surgery, the patient developed skin plaques on the face, neck, upper back, and extremities, which were biopsied and identified as positive for tuberculoid leprosy.\n\nConclusion\n\nThis is the first case report in Ecuador of atypical glaucoma triggered by infectious uveitis produced by Mycobacterium leprae. We describe a female patient's clinical presentation with several ocular signs of leprosy and other nonspecific and rarely seen symptoms. Uveitis is a condition that often requires a multidisciplinary team of ophthalmologists and clinicians because of the possible manifestation of an underlying systemic disease, creating a challenge for all the medical personnel involved in the management of the case.\n\nKeywords\n\nOcular leprosy\nTuberculoid leprosy\nHansen's disease\nGlaucoma\nAnterior uveitis\n==== Body\n1 Background\n\nLeprosy, one of the most common diseases documented throughout human history, is still present among patients with ocular morbidities.1 As Hansen stated, “there is no disease which so frequently gives rise to disorders of the eye as leprosy does\".2 The microorganism responsible for causing leprosy is Mycobacterium leprae, an acid-fast-stained bacilli, discovered by Gerhard Henrik Armauer Hansen in 1874.3 This disease, previously attributed to witchcraft, was responsible for millions of deaths before the arrival of antibiotics. The main features of this disease are skin ulcers, lack of skin sensitivity, muscle weakness, destruction of the nasal appendix, absence of hair on the eyebrows and eyelashes, changes in pigmentation, and diffuse involvement of the facial skin causing leonine facies, peripheral nervous system alterations and upper respiratory tract mucosa and eyes affections.4,5\n\nThis infection is transmitted via airborne droplets of infected individuals; however, there have been reports of trauma-related transmission and zoonotic cases, which were the result of contact with armadillos and environmental reservoirs such as water sources.6,7 Mycobacterium leprae replicates at temperatures of approximately 30 °C; therefore, it has a preference for low-temperature body areas, such as the peripheral nervous system, musculoskeletal system, upper respiratory tract, skin, mucosa, testicles, and anterior chamber of the eye.3,6,8 Because of the deformities and disabilities associated with the infection, patients throughout history have suffered from discrimination and stigmatization.3 In fact, the name leprosy derives from the Latin word lepros, which means defilement.3\n\nLeprosy is a disease that has been forgotten because of its low prevalence. In 2015, World Health Organization (WHO) reported 176,176 cases, calculating a prevalence of 0.2 cases per 10,000 people.9 In Ecuador, which is located in South America, the incidence reported in 2019 was less than 1 case per 100,000 persons, and was mainly concentrated in the Amazonian region of the country.10 In 2015, there were 178 new cases in the United States, predominantly in the states of Arkansas, California, Florida, Hawaii, Louisiana, New York, and Texas.11 Centers for Disease Control and Prevention (CDC) estimates that 5000 people in the United States have been cured but suffer from long-term sequelae such as blindness.12\n\nThe Ridley and Jopling classification takes into account clinical, pathological, bacilloscopic, and immunological criteria to classify leprosy into six forms: tuberculoid (TT), borderline tuberculoid (BT), mid-borderline (BB), borderline lepromatous (BL), lepromatous (LL), and indeterminate (I).7,13,14 Lepromatous leprosy patients tend to have more ocular complications and vision impairment (p = .037) than patients with tuberculoid leprosy, borderline tuberculoid, and indeterminate leprosy.15\n\nThe WHO has proposed a more straightforward classification for treatment purposes, based on cutaneous manifestations and skin smears, which categorizes leprosy into 1) paucibacillary (PB): ≤5 skin plaques and negative smears and 2) multibacillary (MB): ≥6 skin plaques or positive smears.13\n\nUp to 75% of individuals with leprosy have ocular manifestations, and 39.40% have a visual disability.8,16 There are a wide variety of ocular manifestations, such as lagophthalmos, madarosis, corneal ulcers, cataracts, uveitis, and iridocyclitis.6 It has been proposed that Mycobacterium leprae has a preference for the iris, which is due to its safety from the immune system and systemic treatment.17 The diagnosis of ocular leprosy is challenging in the absence of characteristic skin lesions because of its diverse ocular manifestations and extensive time for development.18 We describe the first case of a patient with bilateral cataracts and uveitic glaucoma secondary to tuberculoid leprosy confirmed by histopathological studies in Quito, Ecuador.\n\n2 Case presentation\n\nA 62-year-old female was referred to our clinic by an ophthalmologist, as she was diagnosed with anterior uveitis of unknown etiology and ocular hypertension. During the past two years, the patient had suffered from elevated intraocular pressure (IOP) in both eyes (OU) refractory to topical therapy and bilateral anterior uveitis refractory to corticosteroid therapy. For her IOP, the patient was on a fixed combination of timolol-dorzolamide bid in her left eye (OS) and only timolol bid in her right eye (OD). The previous corticosteroid treatment that the patient followed whenever a crisis reappeared was topical prednisolone acetate every 3 h. This medical regimen was maintained for a year. She was not on systemic medications.\n\nThe patient presented to our clinic complaining of conjunctival injection in OU, persistent headache, eyelid irritation, and a decrease in visual acuity in the OS. The physical exam revealed mild ptosis in OU and no other findings. Upon ocular examination, her best-corrected visual acuity was 20/25 in the OD and 20/60 in the OS. IOP was 29 mmHg and 22 mmHg in her OD and OS, respectively.\n\nThe slit-lamp examination in OU showed the following findings: erythema and scales at eyelid margins, decreased tear break-up time, cornea with diffuse punctate epitheliopathy, mutton-fat keratic precipitates, symmetric, round and reactive pupils, sparse patches of iris atrophy, anterior chamber cells 1+, posterior subcapsular opacities in both eyes denser in the OS, and clear vitreous. Gonioscopy showed open angles in OU and peripheral anterior synechiae (PAS) in the inferior quadrant in the OD and in the superior quadrant in the OS (Fig. 1).Fig. 1 Gonioscopy exam reveals peripheral anterior synechiae (PAS) in OS.\n\nFig. 1\n\nThe fundus examination revealed a cup disc ratio of 0.55 × 0.45 in the OD with thinning of the inferior neuroretinal rim and localized loss of the retinal nerve fiber layer (RNFL) in the inferior quadrant; the cup disc ratio in the OS was 0.4 × 0.3. The macula, blood vessels, and peripheral retina were unremarkable as well as fluorescein angiography of the retina in OU. The visual field showed a mild superior arcuate defect and a glaucoma hemifield test (GHT) “outside normal limits” in the OD. The GHT in the OS showed “general depression of sensitivity.” The RNFL deviation map in the optical coherence tomography (OCT) showed a loss of nerve fibers in the inferior quadrant in the OD and no abnormal OS results. The average RNFL thickness was within normal parameters OU; however, RNFL symmetry was 71%. The deviation map in the macular ganglion cell analysis revealed mild thinning in the temporal quadrant in the OD and no abnormal findings in the OS. The average ganglion cell layer (GCL) plus inner plexiform layer (IPL) thickness was in the normal range in OU. The macular thickness OCT showed a central thickness of 241 μm in the OD and 247 μm in the OS. Specular microscopy indicated a cell density of 2387 cells/mm3 in the OD and 2625 cells/mm3 in the OS.\n\nThe patient was diagnosed with anterior uveitis and cataracts in OU, uveitic glaucoma in the OD, and ocular hypertension in the OS. Given the presenting chronic granulomatous uveitis of unknown etiology, the respective questionnaire and evaluation were performed by internal medicine and rheumatology. This multidisciplinary team ordered laboratory tests to assess immunological and infectious profiles (Table 1). The serological antibodies for toxoplasmosis, rubella, syphilis, tuberculosis, and cytomegalovirus (CMV) showed no active infection. Aqueous tap was also performed to study different infectious etiologies with DNA-PCR. CMV, HSV-1, HSV-2, and Toxoplasma gondii had undetectable levels, meaning a negative result. A smear and culture of the aqueous humor were not done due to insufficient sample quantity; therefore, the DNA-PCR tests were prioritized. The immunological tests were negative for rheumatoid factor (RF) and antinuclear antibodies (ANAs). Anti-neutrophil cytoplasmic antibodies (c-ANCA and p-ANCA) were positive. Because of these results, the patient underwent a complete evaluation and imaging workup that did not reveal a conclusive diagnosis.Table 1 Laboratory results for plausible immunological and infectious etiologies.\n\nTable 1\tResult\tReference values\t\nVDRL\t\n\tNot reactive\t\t\nToxoplasma gondii\t\n IgG (U/mL)\t17.70\tReactive: ≥ 6.5\nNot reactive: < 6.5\t\n IgM (U/mL)\t<0.9\tReactive: > 1.1\nNot reactive: < 0.9\nUndetermined: 0.9–1.1\t\nRubella\t\n IgG (U/mL)\t15.20\tReactive: > 10\nUndetermined: 5–9\nNot reactive: < 5\t\n IgM (U/mL)\t<0.9\tReactive: > 1.1\nUndetermined: 0.9–1.1\nNot reactive: < 0.9\t\nMycobacterium tuberculosis\t\n PPD (mm)\t<5\tPositive: ≥ 10\nNegative: < 10\t\nCytomegalovirus\t\n IgG (U/mL)\t8.82\tReactive: > 1.1\nUndetermined: 0.9–1.1\nNot reactive: < 0.9\t\n IgM (U/mL)\t0.185\tReactive: > 1.0\nUndetermined: 0.7–1.0\nNot reactive: < 0.7\t\nANA\t\n\t0.7\tPositive: > 1.2\nUndetermined: 1.0–1.2\nNot reactive: < 1.0\t\nANCA\t\n\t6.1\tPositive: >1.0\nNegative: < 1.0\t\nRheumatoid factor\t\n (U/mL)\t32.6\tPositive: > 60\nNegative: < 60\t\nAqueous Humor PCR-DNA\t\n Cytomegalovirus\tNot detectable\t\t\n HSV-1 and HSV-2\tNot detectable\t\t\n Toxoplasma gondii\tNot detectable\t\t\nVDRL: Venereal Disease Research Laboratory; PPD: Purified Protein Derivative.\n\nPCR: polymerase chain reaction.\n\nTo manage the ocular conditions, her treatment was changed to a fixed combination of timolol-dorzolamide-brimonidine bid in OU, lowering the IOP to the low teens in OU. For her anterior uveitis, loteprednol was indicated qid in OU for one month, obtaining optimal control. The patient underwent femtosecond laser-assisted cataract surgery (FLACS) in OU, with an interval of one month between each eye. There were no complications. The postoperative IOP was 15 mmHg in the OD and 14 mmHg in the OS with the same topical medication. The BCVA was 20/25 in the OD and 20/20 in the OS. There were no postoperative changes in structural and functional glaucoma tests.\n\nFour months after her last cataract surgery, the patient started to present systemic and ocular symptoms, such as headache, skin lesions, arthralgias in fingers and wrists, ocular pain, blepharitis conjunctival injection, blurry vision, and photophobia. The physical exam revealed erythematous skin plaques with irregular and poorly defined borders with clear centers over the face, neck, upper back, forearms, legs, and dorsum of hands (Fig. 2). Some of the skin plaques were anesthesic. At the ocular examination, the BCVA was 20/30 in the OD and 20/40 in the OS; the IOP was 32 mmHg in OU, despite maximal topical treatment. There were severe signs of inflammation on the anterior chamber in OU (Fig. 3) and opacification of the posterior capsule in the OS.Fig. 2 Disseminated erythematous skin plaques with irregular borders and clear centers in arms and upper-back.\n\nFig. 2\n\nFig. 3 A. Conjunctival injection and keratic precipitates in OD. B. Slit lamp exam reveals keratic precipitates in OS.\n\nFig. 3\n\nThe patient was referred to dermatology for skin incisional biopsies, which revealed dense dermal lymphohistiocytic infiltrates along the superficial and deep vessels that compromised the nerve fascicles (Fig. 4A). Fite Faraco staining revealed scarce acid-fast bacilli within nerve fascicles (Fig. 4B). The findings were consistent with tuberculoid leprosy, which can explain both the skin and ocular symptoms. The diagnosis of ocular tuberculoid leprosy was made based on discard and skin incisional biopsies.Fig. 4 A. Lymphohistiocytic perivascular infiltration (arrows) seen with Hematoxylin & Eosin stain. B. Bacilli in the middle of nerve (arrow) seen with Fite Faraco stain.\n\nFig. 4\n\nWith the diagnosis, comprehensive treatment with a multidrug regimen of rifampicin, clofazimine, and dapsone was initiated. With this treatment, the patient's systemic symptoms, such as skin lesions and arthralgia, as well as uveitis, went under control. However, her IOPs in OU were in the high teen mmHg despite being on maximal topical therapy, which was due to the damage in the TM and the increased amount of synechiae in the angles. The structural and functional tests showed progression of glaucomatous damage in OU (Fig. 5). To ensure further control of the IOPs, the patient underwent trabeculectomy with mitomycin-C in OU without complications.Fig. 5 A. Hemorrhage in the right optic disc with a loss of the RNFL in the inferior quadrant (arrows). B. Structure-Function Guided Progression Analysis (GPA) shows in the RNFL thickness profile (NSTIN) a progression of the thinning in the inferior quadrant, consistent with the progression of the superior arcuate defect in the visual field in OD. C. Structure-Function GPA shows in the RNFL thickness profile (NSTIN) a progression of the thinning in the inferior quadrant in OS.\n\nFig. 5\n\n3 Discussion and conclusions\n\nLeprosy is a chronic granulomatous disease with a decreasing incidence, which is mainly due to efforts and campaigns coordinated by the WHO. Since 1981, multidrug treatment (MDT), consisting of dapsone, rifampicin, and clofazimine, has been the standard therapy, and since 1995, the WHO has distributed this MDT free of cost.6 The rarity of cases has caused medical providers to be unfamiliar with it, leading to a misdiagnosis or a late one.18 With the increasing number of people living in unsanitary conditions and with limited healthcare access that is due to global immigration, refugee crises, and homeless situations, the incidence and prevalence patterns of leprosy might change.19 Because the ocular manifestations can be as severe as blindness, it is relevant to address this forgotten disease.18\n\nEven though the majority of patients are asymptomatic, those with symptoms can develop two possible spectra of the disease.6,7 The tuberculoid leprosy spectrum is associated with a strong cellular immune response, while the lepromatous leprosy spectrum is associated with a humoral immune response.6 In histologic cuts with Fite Faraco and Ziehl Neelsen stains, tuberculoid leprosy presents with inflammatory infiltrate in the dermis and epidermis, epithelioid histiocytes surrounding small cutaneous nerves, and scarce bacilli, as was seen in our patient.6,18,20 Regarding immunological tests, there are reported cases of positive ANA, ANCA, and RF, with c-ANCA being the most common antibody.21\n\nThe ocular signs and symptoms of leprosy arise from different mechanisms, such as direct bacterial infection and trigeminal or facial nerve involvement.8 Direct invasion of hair follicles is responsible for madarosis and trichiasis, invasion of the eyelids and CN III invasion is responsible for ptosis, and invasion of CN VII is responsible for ectropion, punctate keratitis and lagophthalmos.8,15 All these consequences could cause neurotrophic keratitis, which is responsible for corneal ulcers and scarring and can lead to blindness.8 The direct infiltration of unmyelinated nerves may also cause corneal hypoesthesia, similar to the glove-and-stocking anesthesia seen in the extremities.6 On the ocular surface, conjunctivitis, conjunctival scarring, and pterygium can develop.6,8 Other adnexal effects of Mycobacterium leprae are entropion, blink reflex alteration, dacryocystitis, and blockage of the nasolacrimal duct.6,8\n\nUveitis is a common presentation in these patients because of the preference of Mycobacterium leprae invasion to the iris and ciliary body. There are three possible mechanisms of iridocyclitis: direct invasion, sympathetic denervation, and autoimmune response. Direct invasion is associated with photophobia, pain, reduced visual acuity, and keratic precipitates.8 The sympathetic denervation of the iris, secondary to a chronic inflammatory process, is associated with iris atrophy, synechiae, punctiform pupils, and the presence of iris pearls. Iris atrophy is present in more than 25% of patients, making it the most common ocular lesion.8 The iris pearls, present in 4.8% of patients, are spherical white-yellow lesions considered pathognomonic of Hansen's disease.6 Last, the autoimmune response is associated with the appearance of granulomas in the iris.8\n\nChronic inflammation triples the risk of cataracts, especially posterior subcapsular inflammation, with an incidence of 33.2%.6,8,22 In leprosy eyes with iris atrophy, cataract surgery is technically challenging, and studies have shown uncertain results.23 In this case, FLACS was the technique used based on the patient's uveitis history. FLACS uses less time for ultrasound and fewer levels of phacoemulsification energy.24 These factors generate lower levels of anterior segment inflammation, making FLACS beneficial for uveitic patients.\n\nLeprosy patients tend to have lower IOP because atrophic areas of the iris are more permeable to aqueous humor, while atrophy of the ciliary body decreases its production.8,25 However, glaucoma was recognized in 10% of leprosy patients, mostly secondary to uveitis.26 In these cases, glaucoma requires close and frequent surveillance because of the risk of recurrent hypertensive peaks and progression of glaucomatous damage, as in the case of our patient.\n\nAnterior uveitis has a wide variety of etiologies from infectious to autoimmune. The first step is to perform a complete history and physical examination; for this case, it helped make some etiologies, such as juvenile rheumatoid arthritis and Posner-Scholssman syndrome, more unlikely. Then, a detailed slit lamp and ophthalmoscopic eye examination was crucial for observing different signs, such as trabecular meshwork nodules, vitreous opacities displaying snowballs and optic disc nodules, which are pathognomonic of sarcoidosis. None of these were found in our patient, making sarcoidosis more unlikely. For infectious etiologies, aqueous tap DNA-PCR and serological antibodies were crucial, discarding CMV, HSV-1, HSV-2, toxoplasmosis, rubella, tuberculosis, and syphilis. Finally, the excisional skin biopsy smear with staining was the key for making the diagnosis of Mycobacterium leprae.27\n\nIn terms of treatment, an essential consideration is the side effect of cumulative clofazimine dose, which may cause crystalline keratopathy.8 Despite the completion of MDT, 24% of patients have a relapse of ocular manifestations, even with negative smears.8,28 This is due to the ability of M. leprae to persist inside iris macrophages.8 Therefore, regular ocular examinations are warranted even after completion of treatment.\n\nAs ophthalmologists, we should not forget that in a high percentage of cases, uveitis is an ocular manifestation of a systemic process. Hence, a multidisciplinary approach is needed to investigate all possible etiologies. This case illustrates how challenging the diagnosis, treatment, and follow-up can be.\n\nDeclaration of competing interest\n\nThe authors declare that they have no conflicts of interest.\n\nAbbreviations\n\nANA Antinuclear Antibodies\n\nANCA Antineutrophil Cytoplasmic Antibodies\n\nBCVA Best-Corrected Visual Acuity\n\nBT Borderline Tuberculoid\n\nBB Mid-borderline\n\nBL Borderline Lepromatous\n\nCDC Centers for Disease Control and Prevention\n\nCMV Cytomegalovirus\n\nCN Cranial Nerve\n\nFLACS Femtosecond Laser-Assisted Cataract Surgery\n\nIOP Intraocular Pressure\n\nIPL Inner Plexiform Layer\n\nGCL Ganglion Cell Layer\n\nGHT Glaucoma Hemifield Test\n\nHVS Herpes Virus Simplex\n\nI Indeterminate\n\nLL Lepromatous\n\nMDT Multidrug Treatment\n\nOCT Optical Coherence Tomography\n\nOS Left Eye\n\nOD Right Eye\n\nPAS Peripheral Anterior Synechiae\n\nRF Rheumatoid factor\n\nRNGL Retinal nerve fiber layer\n\nTT Tuberculoid\n\nTM Trabecular Mesh\n\nWHO World Health Organization\n\nFunding\n\nNo funding was received for this work.\n\nPatient consent\n\nThe patient consented in writing to the publication of this case and associated images.\n\nContributorship statement\n\nARV, ERV, and AMV all contributed to the first draft and revision and approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n==== Refs\nReferences\n\n1 Lasrindy V.V. Menaldi S.L. Yusharyahya S.N. Validation of assessment tools for the early detection of ocular involvement in Leprosy J Nat Sci Biol Med 10 2019 62\n2 Bull O.B. Hansen G.A. The leprous diseases of the eye Albert Cammermeyer 1873\n3 Sasaki S. Takeshita F. Okuda K. Mycobacterium leprae and Leprosy: a compendium Microbiol Immunol 45 2001 729 736 10.1111/j.1348-0421.2001.tb01308.x 11791665\n4 Vinitha G. Asha T. Tp T. Hansen's disease–clinically atypical presentation with atypical histopathology Indian J Lepr 91 2019 159 164\n5 Brown D.N. Wieser I. Wang C. Leonine facies (LF) and mycosis fungoides (MF): a single-center study and systematic review of the literature J Am Acad Dermatol 73 2015 976 986 26476898\n6 Duran C.E. Úsuga M.C.O. Jaramillo M.J. Chronic unilateral uveitis as a manifestation of leprosy: a case report and literature review Ocul Immunol Inflamm 2020 1 5 10.1080/09273948.2020.1720256 0\n7 Fonseca AB. de L. Simon M. do V. Cazzaniga R.A. The influence of innate and adaptative immune responses on the differential clinical outcomes of Leprosy Infect Dis Poverty 6 2017 5 10.1186/s40249-016-0229-3 28162092\n8 Grzybowski A. Nita M. Virmond M. Ocular leprosy Clin Dermatol 33 2015 79 89 10.1016/j.clindermatol.2014.07.003 25432813\n9 World Health Organization WHO | Epidemiology 2016 WHO http://www.who.int/lep/epidemiology/en/\n10 Coello C. Lepra: Ecuador tiene menos de un caso por cien mil habitantes. edición médica https://www.edicionmedica.ec/secciones/salud-publica/lepra-ecuador-tiene-menos-de-un-caso-por-cien-mil-habitantes--93566 2019\n11 Health Resources and Services Administration National Hansen's disease (leprosy) program caring and curing since 1894 | official web site of the US Health resources & services administration Health Resour Serv Adm 2020 https://www.hrsa.gov/hansens-disease/index.html\n12 Centers for Disease Control and Prevention World Leprosy Day 2018 Retrieved. Cent. Dis. Control Prev https://www.cdc.gov/features/world-leprosy-day/index.html\n13 Health Resources and Services Administration Classification for treatment purposes Off Web site US Health resour Serv Adm 2017 https://www.hrsa.gov/hansens-disease/diagnosis/classification.html\n14 Ridley D.S. Jopling W.H. Classification of Leprosy according to immunity. A five-group system Int J Lepr Mycobact Dis Off Organ Int Lepr Assoc 34 1966 255 273\n15 Daniel E. Koshy S. Joseph G.A. Ocular complications in incident relapsed borderline lepromatous and lepromatous leprosy patients in south India Indian J Ophthalmol 51 2003 155 159 12831146\n16 Singh L. Malhotra R. Bundela R.K. Ocular disability--WHO grade 2 in persons affected with Leprosy Indian J Lepr 86 2014 1 6 25163254\n17 Cardozo A.V. Antunes J. Belone A. Mycobacterium leprae in Ocular Tissues: Histopathological Findings in Experimental Leprosy. - Abstract - Europe PMC 2011 Eur. PMC https://europepmc.org/article/med/21393973\n18 Wroblewski K.J. Hidayat A. Neafie R. The AFIP history of ocular Leprosy Saudi J Ophthalmol Off J Saudi Ophthalmol Soc 33 2019 255 259 10.1016/j.sjopt.2019.09.003\n19 Ward A. Leprosy outbreak in United States only a \"matter of time,\" one physician argues. ContagionLive https://www.contagionlive.com/news/leprosy-outbreak-in-united-states-only-a-matter-of-time-one-physician-argues 2019\n20 Hamodat M. Leprosy. PathologyOutlines.com http://www.pathologyoutlines.com/topic/skinnontumorleprosy.html 2019\n21 Edington F.L.B. Bacellar M.O.A.R. Machado P.R. Anti-neutrophil cytoplasmic antibodies in Leprosy Clin Rheumatol 26 2007 208 210 10.1007/s10067-006-0281-7 16572282\n22 Mvogo C.E. Bella‐Hiag A.L. Ellong A. Ocular complications of leprosy in Cameroon Acta Ophthalmol Scand 79 2001 31 33 10.1034/j.1600-0420.2001.079001031.x 11167283\n23 Hogeweg M. Keunen J.E.E. Prevention of blindness in leprosy and the role of the vision 2020 programme Eye 19 2005 1099 1105 10.1038/sj.eye.6701984 16304590\n24 Abell R.G. Allen P.L. Vote B.J. Anterior chamber flare after femtosecond laser–assisted cataract surgery J Cataract Refract Surg 39 2013 1321 1326 10.1016/j.jcrs.2013.06.009 23850229\n25 Alio J.L. Hosny M. Ocular Inflammation. Basic and Clinical Concepts 1999 David BenEzra London\n26 Walton R.C. Ball S.F. Joffrion V.C. Glaucoma in Hansen's disease Br J Ophthalmol 75 1991 270 272 2036342\n27 Gueudry J. Muraine M. Anterior uveitis J Fr Ophtalmol 2017 10.1016/j.jfo.2017.11.003\n28 Ffytche T.J. Residual sight-threatening lesions in leprosy patients completing multidrug therapy and sulphone monotherapy Lepr Rev 62 1991 35 43 10.5935/0305-7518.19910005 2034023\n\n",
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"issue": "22()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Anterior uveitis; Glaucoma; Hansen's disease; Ocular leprosy; Tuberculoid leprosy",
"medline_ta": "Am J Ophthalmol Case Rep",
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"title": "Uveitic Glaucoma and Hansen's disease, A case report.",
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"abstract": "Dissociation is a disconnection between a person's thoughts, memories, feelings, actions, or sense of who he or she is. Dissociative disorders can be described and understood using the combination of five core symptoms: amnesia, depersonalisation, derealisation, identity confusion, or identity alteration. They are frequently associated with previous experience of trauma. The challenge in diagnosis and the lifetime prevalence of approximately 10% in the general population and clinical psychiatric setting ensures the relevance of this case. We write about a 21-year-old gentleman with history of autism and obsessive compulsive disorder, but no significant medical history was presented to the emergency department with increased anxiety, subsequently progressing to agitation, pacing, and becoming nonverbal. No significant findings were uncovered on laboratory blood testing (other than prolactin 737 mu/L and phosphate 0.35 mmol/L), lumbar puncture, or brain imaging. Consequently, he was admitted to a psychiatric unit for assessment. The patient continued to present with severe disorientation, limited speech, and altered state of consciousness with occasional spastic-like movements. Antipsychotic and benzodiazepine medication was initiated, with no significant change in presentation. The patient continued to be witnessed wandering and having incoherent speech. First signs of improvement came 21 days postadmission with brief conversation and lucidity. This continued to improve over the next 7 days where he was reported to be at his baseline mental state. Environmental stressors including university examinations, the COVID-19 pandemic, and recent contact with his estranged father were possible precipitants to the episode. The patient reported almost complete unawareness of the psychiatric admission. A diagnosis of dissociative disorder, unspecified, was given. This case shows the management and diagnostic challenges of patients presenting with the aforementioned symptoms. There are no formal guidelines for the management of treating dissociative episodes, and this case report suggests the possible benefits of a drug-free period of watchful waiting upon admission.",
"affiliations": "Holt Ward, The Elgar Unit, Newtown Hospital, Worcestershire Health and Care Trust, Newtown Road, Worcester, Worcestershire WR5 1JG, UK.;Holt Ward, The Elgar Unit, Newtown Hospital, Worcestershire Health and Care Trust, Newtown Road, Worcester, Worcestershire WR5 1JG, UK.;Holt Ward, The Elgar Unit, Newtown Hospital, Worcestershire Health and Care Trust, Newtown Road, Worcester, Worcestershire WR5 1JG, UK.;Holt Ward, The Elgar Unit, Newtown Hospital, Worcestershire Health and Care Trust, Newtown Road, Worcester, Worcestershire WR5 1JG, UK.",
"authors": "Tong|Godwin|G|https://orcid.org/0000-0001-5061-9838;Groom|Kieran|K|;Ward|Louisa|L|;Naeem|Muhammad|M|",
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"doi": "10.1155/2021/6619579",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X\n2090-6838\nHindawi\n\n10.1155/2021/6619579\nCase Report\n“This Is Not the Original Timeline”: A Case Report of an Extended Dissociative Episode in a Healthy Young Male Accompanied with Severe Decline in Mental State\nhttps://orcid.org/0000-0001-5061-9838\nTong Godwin godwin.tong@nhs.net\n\nGroom Kieran\nWard Louisa\nNaeem Muhammad\nHolt Ward, The Elgar Unit, Newtown Hospital, Worcestershire Health and Care Trust, Newtown Road, Worcester, Worcestershire WR5 1JG, UK\nAcademic Editor: Michael Kluge\n\n2021\n3 5 2021\n2021 661957910 12 2020\n28 4 2021\n29 4 2021\nCopyright © 2021 Godwin Tong et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nDissociation is a disconnection between a person's thoughts, memories, feelings, actions, or sense of who he or she is. Dissociative disorders can be described and understood using the combination of five core symptoms: amnesia, depersonalisation, derealisation, identity confusion, or identity alteration. They are frequently associated with previous experience of trauma. The challenge in diagnosis and the lifetime prevalence of approximately 10% in the general population and clinical psychiatric setting ensures the relevance of this case. We write about a 21-year-old gentleman with history of autism and obsessive compulsive disorder, but no significant medical history was presented to the emergency department with increased anxiety, subsequently progressing to agitation, pacing, and becoming nonverbal. No significant findings were uncovered on laboratory blood testing (other than prolactin 737 mu/L and phosphate 0.35 mmol/L), lumbar puncture, or brain imaging. Consequently, he was admitted to a psychiatric unit for assessment. The patient continued to present with severe disorientation, limited speech, and altered state of consciousness with occasional spastic-like movements. Antipsychotic and benzodiazepine medication was initiated, with no significant change in presentation. The patient continued to be witnessed wandering and having incoherent speech. First signs of improvement came 21 days postadmission with brief conversation and lucidity. This continued to improve over the next 7 days where he was reported to be at his baseline mental state. Environmental stressors including university examinations, the COVID-19 pandemic, and recent contact with his estranged father were possible precipitants to the episode. The patient reported almost complete unawareness of the psychiatric admission. A diagnosis of dissociative disorder, unspecified, was given. This case shows the management and diagnostic challenges of patients presenting with the aforementioned symptoms. There are no formal guidelines for the management of treating dissociative episodes, and this case report suggests the possible benefits of a drug-free period of watchful waiting upon admission.\n\nPsychiatry Foundation Fellowship Programme\n==== Body\n1. Introduction\n\nDissociative (conversion) disorder (F44, ICD-10) is an umbrella term overarching various subtypes of dissociative disorders like but shares the common themes of partial or complete impairment of memories, awareness of identity, sensations, or control of body movements. From a medical perspective, patients with dissociative disorders have no physical or neurological problems. Episodes are often associated with traumatic life events or psychological stress. Dissociative disorders are underrecognised in general, and dissociative (conversion) disorder, unspecified (F44.9), is even less prevalent; hence, it is no surprise that limited literature exists around the subject. Available studies have shown that dissociative disorders have a lifetime prevalence of about 10% in the general population and clinical psychiatric setting [1]. Dissociative Identity Disorder (DID) (F44.8) is the most pervasive and most common out of the group of dissociative disorders, forming up to 5%, leaving the remaining 5% split between the lesser reported subtypes [2]. The onset of dissociative episodes is usually sudden and usually follows traumatic or stressful events [2]. Duration of dissociative episodes can range from hours to days but typically not more than 2 weeks [3–7]. Here, we present a case of a young male who experienced a dissociative episode over a prolonged period of time—4 weeks, with a unique mix of psychiatric and behavioural symptoms including formal thought disorder accompanied with severe thought block and word salad, purposeless wandering, chaotic behaviour, and bizarre delusions. Whilst we had various initial differential diagnoses, we explain later in the discussion section why the other differentials are unlikely and how this mix of symptoms has prompted us to give him a diagnosis of dissociative (conversion) disorder, unspecified (F44.9).\n\n2. Case Report\n\nA 21-year-old male initially presented to the Accident and Emergency (A&E) department of a district general hospital with increased anxiety reporting that they felt like he was dying. He had a background of high functioning autism, obsessive-compulsive disorder (OCD), and no significant physical health problems. In terms of family history, he was the only child and had no significant family history of medical nor psychiatric illnesses. He admitted to using cocaine that day but subsequent collateral history from his aunt, whom he was staying with at the time denied this. A&E doctors diagnosed him as having a panic attack and discharged him shortly after back to his aunt's farm. Within hours, he presented to A&E again with increased signs of agitation, pacing around, and being nonverbal. As such, no further history could be obtained from him. Initial bloodwork from A&E looking at full blood count, liver function, renal profile, and inflammatory markers were normal. Urine toxic substance screen was negative. The only positive findings were low phosphate 0.35 mmol/L and raised prolactin 737 mu/L despite no previous antipsychotic use. X-ray of the skull revealed no fractures. At this time, differential diagnoses included meningitis, encephalitis, psychosis, and delirium. MRI head subsequently revealed a normal-sized pituitary gland, and no specific abnormalities were seen intracranially. A&E then started treatment for IV acyclovir for prophylaxis against potential encephalitis. He was moved to the acute medical unit where his hypophosphataemia was treated with oral phosphate replacement and levels returned to normal shortly after. A week later, lumbar puncture analysis returned negative for bacteria and viruses. Due to this unusual presentation, he was referred to the mental health liaison of the acute psychiatric unit for mental health assessment and was formally admitted to our acute psychiatric unit for treatment 9 days after initial presentation.\n\nBy the time of admission, he was displaying severe disorientation to time, place, and person. Thought block was evident and major, accompanied by markedly limited speech. He appeared to be in an altered state of consciousness and had a dazed confused look, accompanied with an almost catatonic-like physical presentation whereby there was increased muscle tone in upper and lower limbs bilaterally but was able to withdraw sharply to needles when doctors attempted phlebotomy. Movements were few and spastic. There were no features associated with an ictal episode. To quote some of his word salad—“this is not the original,” “this is not the right timeline,” “two people fighting,” “two people joined in the middle, different timelines.” He did on occasion seem able to answer a yes/no question but with great effort and could never remember what he said. He was still able to withdraw from the pain from an attempted venepuncture. Mental state examination demonstrated a relatively well-kempt young man who had poor eye contact but when eye contact was made, displayed an intense stare. His speech was of normal tone and volume but very stilted. Contents of speech were disjointed and bizarre. Mood was subjectively and objectively euthymic. Thoughts were considered to be very disordered and chaotic. From what we could make out of his jumbled and limited speech, it seemed like he was occasionally describing two people arguing, possibly suggesting auditory hallucinations. He was disorientated to time, person, and place, and he lacked insight and capacity with regard to his mental state.\n\nWe then prescribed him lorazepam 1 mg four times daily and quetiapine 50 mg daily with a plan of increasing it to 300 mg in five days in the hope of ruling out psychosis. Five days later, there was no change in presentation in this patient as he continued to display symptoms of thought block and jumbled speech. From what we could discern from his speech, it seemed like he had delusions about him not living in the correct timeline; his DNA is not being his own, and his mother was not his original birth mother. He did however start to mobilise and walked around the ward albeit with a slightly spastic gait. Behaviour remained bizarre as he was often found removing his clothes and walking around aimlessly on the ward. As quetiapine did not appear to be working, we decided to replace quetiapine with haloperidol 5 mg once daily and to replace lorazepam with diazepam 10 mg three times daily. We then added sertraline 50 mg once every morning. Unfortunately, he shortly developed some extrapyramidal side effects (EPSEs)—leg stiffness from haloperidol, and we replaced it with aripiprazole 10 mg once daily after three days. Procyclidine 5 mg three times daily was found to be helpful in treating the EPSEs.\n\nOne week later, we repeated blood tests which revealed a continued rise of prolactin and reduced parathyroid hormone as the only positive findings. Upon discussion with the endocrinology department, the rising trend of prolactin was believed to be secondary to antipsychotic use. Furthermore, since the recent MRI was unremarkable, we felt it did not warrant further investigation. Blood was also negative for NMDA receptor antibodies, Treponema pallidum antibodies, hepatitis B and C antibodies, and HIV 1&2 antigen/antibodies. By the 19th day postadmission, presentation remained unchanged except with the addition of increased frequency of agitation episodes which include but not limited to using excessive strength to hold onto staff, throwing of ward furniture, not complying with staff instructions, and trying to access staff areas with force. In view of this, we increased aripiprazole dose to 20 mg once a day. He continued to be wandering aimlessly on the ward, speech remained mainly incoherent, but word range had expanded slightly to being able to speak half sentences. For example, “Jesus, these are genuinely not one of the original sounds or thoughts or sound tracks,” “These are both our original thoughts. I think it was all of them, there was no, this is wait, there was no original timeline,” “I am not the soft science in the Jurassic thoughts.” Despite no improvement in this thought block after prescribing aripiprazole, we did notice a reduction in agitation episode frequency and severity; hence, we decided to persist with the medication.\n\nFirst signs of improvement only came about 21 days after admission where nurses observed a moment of lucidity where the patient was able to speak full sentences and engage in a brief conversation but returned to his confused state shortly after. On the 22nd day, the patient suddenly appeared calm and regained some cognitive orientation to person and place. He was able to hold conversations, but as the day progressed, his ability to retain information and overall mental state declined and was observed to be asking the same questions repetitively such as when he was going to be seen by doctors. On the 23rd day, the patient did not display any of the previous symptoms and his mental state appeared to almost match that of baseline with the exception of reduced concentration levels. He was able to engage with staff for most of the day and was even observed to be using his personal laptop computer at one point in time. On the 28th day, the patient was reviewed and it was decided that the patient was not displaying any acute signs of mental illness and was able to perform all activities of daily living independently. It was thus decided that he was fit for discharge. In conversation, the clinicians asked him if he had any awareness of the past few weeks and he displayed localised episodic amnesia by not being able to recall anything in the past few weeks. COVID-19 antibodies and nasal swab results were negative.\n\n3. Discussion\n\nHere, we present a case of a young male who suffered from a dissociative episode for an extended period of about 28 days. The case piqued our interest in its duration and severity of the associated symptoms. The patient suffered from severe functional impairment and decline of mental state as seen from the purposeless wandering, thought block, and delusional word salad, yet still retaining the ability to perform certain activities of daily living like eating his meals independently. It is also important to consider several aspects of this patient's background and social history and discuss the thoughts leading to this diagnosis. He was born in England but moved to Gibraltar early on and spent his formative years there. His parents separated when he was nine years old, and he has a family history of Asperger's syndrome. Socially, the patient is highly intelligent from birth; it was reported by his mother that he had a reading age of four at 18 months and he recently graduated from a top British university. However, he did have an extensive recreational drug history involving cocaine, amphetamines, cannabis, and Ritalin. Our differential diagnoses included the following: encephalitis, meningitis, drug-induced psychosis, delirium, dissociative amnesia (F44.0), and dissociative (conversion) disorder, unspecified (F44.9).\n\nBoth meningitis and encephalitis were easily ruled out with lumbar puncture showing normal protein and glucose levels. Autoimmune encephalitis was also ruled out with a negative array of antibodies against GABA/AMPA/NMDA/CASPR. Whilst it might be tempting to suggest his presentation to be simply drug induced, urine drug screen on the first day of admission to A&E was positive for benzodiazepines but negative for THC, amphetamines, cocaine, antidepressants, and antipsychotics. The presence of benzodiazepines in his urine was not surprising as he was given a stat dose of lorazepam at A&E when he first presented. We note that the initial hypophosphataemia could lead to electrolyte imbalance-induced delirium and indeed delirium was one of the initial differentials in A&E, but within two days, his phosphate levels were replaced orally and remained normal for the entirety of admission, along with his other bone profile parameters. As such, delirium secondary to hypophosphataemia would be an unlikely diagnosis considering his presentation persisted despite electrolyte levels being at normal levels. With regard to his raised prolactin on presentation, one could systematically rule out each potential cause, i.e., physiological, pharmacological, and pathological. A normal MRI scan showing no gross abnormalities would rule out any pathological cause. From a pharmacological perspective, considering this patient was previously antipsychotic naïve, the hyperprolactinaemia could be explained by his historical recreational opiate drug use, coupled with evidence of acute benzodiazepine use as seen from his initial urine drug screen. It has been reported that both opiate and benzodiazepine use can lead to hyperprolactinaemia via dopaminergic receptor inhibition and GABAergic modulation, respectively [8, 9]. From a physiological perspective, stress would be a potential factor for raising prolactin. Collateral history from his mother reported that the patient was under a lot of stress from preparing for examinations, his usual routine being disrupted due to the nationwide lockdown due to COVID-19, and his estranged father recently coming into contact with him. As such, his hyperprolactinaemia could be due to a mixture of physiological and pharmacological causes. Even so, there have not been any reports that hyperprolactinaemia can directly manifest as delirium thus further convincing us that delirium was not a likely differential. Towards the end of his admission, we reviewed his blood biochemistry again and all parameters returned to baseline with the exception of his prolactin which was 1359 mu/L. However, as he was presenting clinically well, we accepted this as a result of the various antipsychotic medication during this admission.\n\nWe interviewed the patient after his dissociative episode, and he described his experience like a never-ending nightmare. Memory loss was episodic as he did not remember majority of the past few weeks and his last memory was entering the A&E department. He was completely unaware of what happened on the acute psychiatry unit ward. Whilst we did not attempt any formal memory assessments, his gross long-term memory appeared intact. When we reminded him some of the phrases he used to say, for example, phrases involving how we belonged to a different timeline or how he seemingly described two people fighting, he was puzzled and did not understand why he would say those things as he was not a fan of science fiction. Dissociative identity disorder was briefly considered due to a certain phrase regarding two people fighting which the patient initially mentioned on his first day of admission. However, we excluded this differential quickly as the patient did not verbalise this statement on subsequent observations. Furthermore, there were no distinct personalities displayed by the patient nor any differing patterns in the way the patient experienced his body or the environment. His symptoms mainly revolve around the blocking of thoughts and impairment of general functioning which we feel did not fulfil the criteria for diagnosing dissociative identity disorder. One might also suggest dissociative amnesia to be a possible differential as whilst the patient did experience memory loss of about four weeks, we felt our patient's symptoms were not best described by the ICD10's criteria of memory loss being the main feature. We feel his unique blend of symptoms of being severely thought blocked as though in a trance-like state, purposeless roaming around the ward, postevent amnesia, feelings of depersonalisation, and alterations in sense of self would support our diagnosis of dissociative disorder, unspecified.\n\nWhen exploring possible triggers, the patient later admitted to feeling overwhelmed by academic pressures from his postgraduate course applications and a disruption of normal routine by having to be confined indoors during the nationwide lockdown prior to admission. He also added that the falling out with his partner coupled with an unsolicited contact attempt by his father contributed to his anxiety. He usually relies heavily on his mother who lives abroad for anxiety management, but in this episode, it was believed that the compounding of multiple stressful events proved too much for him to handle. This element of stress preceding this patient's presentation might well be a major trigger to this dissociative episode.\n\nEventually, the recovery of this patient was as quick as its onset. With regard to his management, antipsychotic medication did not appear to have any positive effect on his mental state. Sedation was beneficial in managing agitated episodes, and the patient was even observed to expand his speech range after. As he no longer displayed signs of mental illness, he was discharged to the community psychiatric team. He was discharged with aripiprazole 20 mg OD and lorazepam 1 mg TDS with the plan of weaning it off. We would have liked to arrange for psychotherapy to be delivered as a form of long-term treatment in the community, but unfortunately, the patient moved to a different city and would be under the care of a different trust.\n\nOn reflection, whilst the old adage “common things are common” still rings true in general medical practice, we would like to remind clinicians to consider alternative diagnoses, especially when the presentation does not fully meet the diagnosing criteria. In this case, drug-induced psychosis would be a tempting easy diagnosis based on the patient's history of drug use, but on further analysis, his behaviour did not fulfil the criteria of psychosis, and even after cessation of drug use, his symptoms persisted. Thus, we feel that when querying a diagnosis of dissociative disorder, management should ideally involve an element of watchful waiting whilst ruling out other differentials before trialling antipsychotics. Perhaps, antipsychotics can be trialled if more definitive symptoms of psychosis are evident. Whilst benzodiazepine was helpful in treating symptomatic agitation, antipsychotic had little effect on his presentation. We did discharge the patient on aripiprazole, but this was mainly for its mood stabilising effect and for relapse prevention. We understand that watchful waiting might unfortunately be difficult to implement on most acute psychiatric units where there are pressures on the clinical team to “medicate and evacuate” so new patients can be admitted. Since there are no formal medical guidelines other than symptom management in treating dissociative episodes, we would like to report our experience and encourage the use of a drug-free period of watchful waiting.\n\nAcknowledgments\n\nThe authors would like to thank the patient for kindly consenting to use his clinical details for academic purposes. We would also like to thank our nursing team for their unrelenting care towards their patients—past, present, and future. This work was supported by the Psychiatry Foundation Fellowship Programme which GT is part of.\n\nConflicts of Interest\n\nThe authors report no conflicts of interest in this work.\n==== Refs\n1 Wenzel A. The SAGE Encyclopedia of Abnormal and Clinical Psychology 2017 Sage Press 10.4135/9781483365817\n2 Sar V. Epidemiology of dissociative disorders: an overview Epidemiology Research International 2011 2011 8 10.1155/2011/404538\n3 American Psychiatric Association Diagnostic And Statistical Manual Of Mental Disorders 2017 Arlington, VA American Psychiatric Association\n4 Igwe M. N. Dissociative fugue symptoms in a 28-year-old male Nigerian medical student: a case report Journal of Medical Case Reports 2013 7 1 10.1186/1752-1947-7-143 2-s2.0-84878352948\n5 Clouden T. A. Dissociative amnesia and dissociative fugue in a 20-year-old woman with schizoaffective disorder and post-traumatic stress disorder Cureus 2020 12 5 10.7759/cureus.8289\n6 Spiegel D. “Dissociative Amnesia-Psychiatric Disorders.” MSD Manual Professional Edition 2019 https://www.msdmanuals.com/en-gb/professional/psychiatric-disorders/dissociative-disorders/dissociative-amnesia\n7 Arzy S. Collette S. Wissmeyer M. Lazeyras F. Kaplan P. W. Blanke O. Psychogenic amnesia and self-identity: a multimodal functional investigation European Journal of Neurology 2011 18 12 1422 1425 10.1111/j.1468-1331.2011.03423.x 2-s2.0-81855182123 21554495\n8 López M. Á. C. Rodríguez J. L. R. García M. R. Prolactin Nagy G. M. Bela E. Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice? Toth, IntechOpen 2013 https://www.intechopen.com/books/prolactin/physiological-and-pathological-hyperprolactinemia-can-we-minimize-errors-in-the-clinical-practice-9 10.5772/54758\n9 te Beek E. T. Chen X. Jacobs G. E. The effects of the nonselective benzodiazepine lorazepam and the α2/α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280 on plasma prolactin levels Clinical Pharmacology in Drug Development 2015 4 2 149 154 10.1002/cpdd.134 2-s2.0-85027938618 27128218\n\n",
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"title": "\"This Is Not the Original Timeline\": A Case Report of an Extended Dissociative Episode in a Healthy Young Male Accompanied with Severe Decline in Mental State.",
"title_normalized": "this is not the original timeline a case report of an extended dissociative episode in a healthy young male accompanied with severe decline in mental state"
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"abstract": "BACKGROUND\nKeratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.\n\n\nMETHODS\nWe describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.\n\n\nCONCLUSIONS\nMolecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.",
"affiliations": "Department of Morphology, Surgery and Experimental Medicine, Infectious Diseases Unit, University 'S. Anna' Hospital of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy. ctr@unife.it.;Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.;Department of Biomedical and Surgical Sciences, Ophthalmology Unit, 'S. Anna' University Hospital of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.;Department of Morphology, Surgery and Experimental Medicine, Infectious Diseases Unit, University 'S. Anna' Hospital of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.;Department of Biomedical and Surgical Sciences, Ophthalmology Unit, 'S. Anna' University Hospital of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.;Clinical Microbiology, 'S. Anna' University Hospital of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.;Department of Biomedical and Surgical Sciences, Ophthalmology Unit, 'S. Anna' University Hospital of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.;Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.",
"authors": "Cultrera|Rosario|R|http://orcid.org/0000-0002-7440-6447;Torelli|Riccardo|R|https://orcid.org/0000-0001-7927-4343;Sarnicola|Caterina|C|https://orcid.org/0000-0003-0219-8009;Segala|Daniela|D|https://orcid.org/0000-0001-6133-0386;Mengoli|Andrea|A|;Chiaretto|Giuseppina|G|;Perri|Paolo|P|https://orcid.org/0000-0003-4652-9842;Sanguinetti|Maurizio|M|https://orcid.org/0000-0002-9780-7059",
"chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D009883:Ophthalmic Solutions; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole",
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"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5768\n10.1186/s12879-021-05768-7\nCase Report\nIdentification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report\nhttp://orcid.org/0000-0002-7440-6447Cultrera Rosario ctr@unife.it 1 https://orcid.org/0000-0001-7927-4343Torelli Riccardo riccardo.torelli@policlinicogemelli.it 2 https://orcid.org/0000-0003-0219-8009Sarnicola Caterina c.sarnicola@hotmail.it 3 https://orcid.org/0000-0001-6133-0386Segala Daniela sgldnl@unife.it 1 Mengoli Andrea a.mengoli@ospfe.it 3 Chiaretto Giuseppina g.chiaretto@ospfe.it 4 https://orcid.org/0000-0003-4652-9842Perri Paolo paolo.perri@unife.it 3 https://orcid.org/0000-0002-9780-7059Sanguinetti Maurizio Maurizio.Sanguinetti@unicatt.it 25 1 Department of Morphology, Surgery and Experimental Medicine, Infectious Diseases Unit, University ‘S. Anna’ Hospital of Ferrara, Via Aldo Moro 8, 44124 Ferrara, Italy \n2 grid.414603.4Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy \n3 grid.416315.4Department of Biomedical and Surgical Sciences, Ophthalmology Unit, ‘S. Anna’ University Hospital of Ferrara, Via Aldo Moro 8, 44124 Ferrara, Italy \n4 grid.416315.4Clinical Microbiology, ‘S. Anna’ University Hospital of Ferrara, Via Aldo Moro 8, 44124 Ferrara, Italy \n5 grid.8142.f0000 0001 0941 3192Dipartimento di Scienze Biotecnologiche di base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy \n18 1 2021 \n18 1 2021 \n2021 \n21 8230 7 2020 5 1 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nKeratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.\n\nCase presentation\nWe describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud’s dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.\n\nConclusions\nMolecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.\n\nKeywords\nFungal keratitisSubramaniula asteroidesMolecular identificationβ-Tubulin geneIsavuconazoleCase reportissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nFungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].\n\nFKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].\n\nMolecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.\n\nFKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.\n\nWe report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.\n\nCase presentation\nA 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.\n\nOn admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.\nFig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)\n\n\n\nSince the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.\n\nForty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).\nFig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal\n\n\n\nCultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].\n\nMolecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).\n\nAntifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).\nTable 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested\n\nAntifungal drugs\tMIC\t\nAmphotericin B\t0.25\t\nAnidulafungin\t0.125\t\nCaspofungin\t0.5\t\nMicafungin\t0.125\t\nVoriconazole\t0.06\t\nPosaconazole\t0.06\t\nItraconazole\t0.06\t\nIsavuconazole\t0.06\t\n\n\nAntifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.\n\nDue to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.\n\nThe fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.\nFig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50\n\n\n\nDiscussion and conclusion\nFilamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.\n\nAspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.\n\nIn our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].\n\nOnly molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].\n\nThis is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.\n\nAbbreviations\ntidTer in die\n\nqidQuarter in die\n\nS. asteroidesSubramaniula asteroides\n\nMICMinimal inhibitory concentration\n\nBtubβ-tubulin gene\n\nCLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors would like to thank the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.\n\nAuthors’ contributions\nAll authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.\n\nFunding\nAll authors state, that for this work, there was no funding.\n\nAvailability of data and materials\nThe datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable. This type of study does not require approval by our Ethics Committee.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Thomas PA Kaliamurthy J Mycotic keratitis: epidemiology, diagnosis and management Clin Microbiol Infect 2013 19 210 220 10.1111/1469-0691.12126 23398543 \n2. Oliveira Dos Santos C Kolwijck E van Rooij J Stoutenbeek R Visser N Cheng YY Epidemiology and Clinical Management of Fusarium keratitis in the Netherlands, 2005–2016 Front Cell Infect Microbiol 2020 10 133 10.3389/fcimb.2020.00133 32318355 \n3. Kredics L Narendran V Shobana CS Vágvölgyi C Manikandan P Indo-Hungarian fungal keratitis working group. Filamentous fungal infections of the cornea: a global overview of epidemiology and drug sensitivity Mycoses. 2015 58 4 243 260 10.1111/myc.12306 25728367 \n4. Peggy Chang HY Chodosh J Diagnostic and therapeutic considerations in fungal keratitis Int Ophthalmol Clin 2011 51 4 33 42 10.1097/IIO.0b013e31822d64dc \n5. Yildiz EH Haresh A Hammersmith KM Eagle RC Rapuano CJ Cohen EJ Alternaria and paecilomyces keratitis associated with soft contact lens wear Cornea 2010 29 564 10.1097/ICO.0b013e3181ba0cde 20335812 \n6. Hung N Yeh LK Ma DH Lin HC Tan HY Chen HC Filamentous fungal keratitis in Taiwan: based on molecular diagnosis Transl Vis Sci Technol 2020 9 8 32 10.1167/tvst.9.8.32 \n7. Sun S Lui Q Han L Ma Q He S Li X Identification and characterization of Fusarium proliferatum , a new species of Fungi that cause fungal keratitis Sci Rep 2018 8 4859 4867 10.1038/s41598-018-23255-z 29559666 \n8. Chidambaram JD Prajna NV Larke N Macleod D Srikanthi P Lanjewar S In vivo confocal microscopy appearance of Fusarium and Aspergillus species in fungal keratitis Br J Ophthalmol 2017 101 1119 1123 10.1136/bjophthalmol-2016-309656 28043985 \n9. Takezawa Y Shiraishi A Noda E Hara Y Yamaguchi M Uno T Ohashi Y Effectiveness of in vivo confocal microscopy in detecting filamentous fungi during clinical course of fungal keratitis Cornea 2010 29 1346 10.1097/ICO.0b013e3181cd3c84 20847667 \n10. Embong Z Hitam WHW Yean CY Rashid NHA Kamarudin B Abidin SKZ Specific detection of fungal pathogens by 18S rRNA gene PCR in microbial keratitis BMC Ophthalmol 2008 8 1 7 10.1186/1471-2415-8-7 18445283 \n11. Kuo MT Chang HC Cheng CK Chien CC Fang PC Chang TC A highly sensitive method for molecular diagnosis of fungal keratitis: a dot hybridization assay Ophthalmology 2012 119 2434 2442 10.1016/j.ophtha.2012.06.049 22968143 \n12. Sabatino F Sarnicola E Sarnicola C Tosi GM Perri P Sarnicola V Early deep anterior lamellar keratoplasty for fungal keratitis poorly responsive to medical treatment Eye 2017 31 1639 1646 10.1038/eye.2017.228 29192684 \n13. Wang XW Houbraken J Groenewald JZ Meijer M Andersen B Nielsen KF Diversity and taxonomy of Chaetomium and chaetomium-like fungi from indoor environments Stud Mycol 2016 84 145 224 10.1016/j.simyco.2016.11.005 28082757 \n14. Sun CQ Lalitha P Prajna NV Karpagam R Geetha M O'Brien KS Mycotic ulcer treatment trial group. Association between in vitro susceptibility to natamycin and voriconazole and clinical outcomes in fungal keratitis Ophthalmology 2014 121 1495 1500 10.1016/j.ophtha.2014.03.004 24746358 \n15. Sanguinetti M Posteraro B Identification of molds by matrix-assisted laser desorption ionization-time of flight mass spectrometry J Clin Microbiol 2017 55 369 379 10.1128/JCM.01640-16 27807151 \n16. Zhao G Zhai H Yuan Q Sun S Liu T Xie L Rapid and sensitive diagnosis of fungal keratitis with direct PCR without template DNA extraction Clin Microbiol Infect 2014 20 O776 O782 10.1111/1469-0691.12571 24471925 \n17. Zhao Z Liu H Luo Y Zhou S An L Wang C Molecular evolution and functional divergence of tubulin superfamily in the fungal tree of life Sci Rep 2014 4 6746 10.1038/srep06746 25339375 \n18. Ahmed SA Khan Z Wang X Moussa TAA Al-Zahrani HS Almaghrabi OA Chaetomium-like fungi causing opportunistic infections in humans: a possible role for extremotolerance Fungal Divers 2016 76 11 26 10.1007/s13225-015-0338-5 \n19. Clinical and Laboratory Standards Institute (CLSI) Reference method for broth dilution antifungal susceptibility testing of filamentous fungi 2017 Wayne, PA CLSI Document M38, Clinical and Laboratory Standards Institute \n20. Mello E Posteraro B Vella A De Carolis E Torelli R D’Inzeo T Verweij PE Sanguinetti M Susceptibility testing of common and uncommon Aspergillus species against posaconazole and other mold-active antifungal azoles using the Sensititre method Antimicrob Agents Chemother 2017 61 6 e00168 e00117 10.1128/AAC.00168-17 28416538 \n21. Li Y Wang H Hou X Huang JJ Wang PC Xu YC Identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry and antifungal susceptibility testing of non-Aspergillus molds Front Microbiol 2020 11 922 10.3389/fmicb.2020.00922 32582045 \n22. Clinical and Laboratory Standards Institute (CLSI) Epidemiological Cutoff Values for antifungal susceptibility testing of yeasts 2018 Wayne, PA CLSI Document M59 \n23. Vinod Mootha V Shahinpoor P Sutton DA Xin L Najafzadeh MJ de Hoog GS Identification problems with sterile fungi, illustrated by a keratitis due to a non-sporulating chaetomium-like species Med Mycol 2012 50 361 367 10.3109/13693786.2011.611179 21954952 \n24. Agarwal M, Gayatri S, Kumar SK, Rajagopal R. Voriconazole Induced Ocular Surface Dysplasia - Report of Two Cases. Ocul Immunol Inflamm. 2020;1-5. 10.1080/09273948.2020.1781903.\n25. Prajna NV Krishnan T Mascarenhas J Rajaraman R Prajna L Srinivasan M The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole JAMA Ophthalmol 2013 131 422 429 10.1001/jamaophthalmol.2013.1497 23710492 \n26. Schmitt-Hoffmann AH Kato K Townsend R Potchoiba MJ Hope WW Andes D Spickermann J Schneidkraut MJ Tissue distribution and elimination of isavuconazole following single and repeat oral-dose administration of isavuconazonium sulfate to rats Antimicrob Agents Chemother 2017 61 e01292 e01217 10.1128/AAC.01292-17 28971866\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "Case report; Fungal keratitis; Isavuconazole; Molecular identification; Subramaniula asteroides; β-Tubulin gene",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D003320:Corneal Ulcer; D003937:Diagnosis, Differential; D015821:Eye Infections, Fungal; D006801:Humans; D008297:Male; D009570:Nitriles; D009883:Ophthalmic Solutions; D011725:Pyridines; D020037:Sordariales; D014230:Triazoles",
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"title": "Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.",
"title_normalized": "identification and molecular characterization of subramaniula asteroides causing human fungal keratitis a case report"
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"abstract": "Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). In clinical practice, tyrosine kinase inhibitor (TKI) dose reductions can be considered a means of preventing adverse effects and improving quality of life. We hypothesized that administration of low-dose TKIs before treatment discontinuation does not impair TFR in patients with CML who have a deep molecular response (DMR, ≥MR4 ).\n\n\n\nWe conducted a retrospective analysis of 77 patients with CML who discontinued treatment with TKIs. Twenty-six patients had been managed with low-dose TKIs before stopping treatment. Patients were to be exposed to TKIs for ≥5 years and to low-dose TKIs for ≥1 year and in DMR for ≥2 years. The loss of major molecular response (MMR) was considered a trigger for restarting therapy.\n\n\n\nIn the low-dose group, 61.5% of patients received second-generation TKIs, and dose reduction was ≥50% for 65.4% of patients. With a median follow-up of 61.5 months, TFR at 12 months was 56.8% in the full-dose TKI group and 80.8% in the low-dose group, and TFR at 60 months was 47.5% and 58.8%, respectively. The median time to molecular recurrence (≥MMR) from TKI discontinuation in the entire cohort was 6.2 months. All patients quickly achieved MMR after resuming TKI therapy. Results appear independent of both dose reduction and potential pretreatment with interferon-α.\n\n\n\nThis retrospective study shows that TFR was not impaired by low-dose TKI regimens before TKI cessation in Patients with CML. Nevertheless, prospective randomized clinical trials must be undertaken to analyze the probability of successful TFR in patients managed with TKI dose de-escalation strategies before TKI discontinuation.",
"affiliations": "Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;INSERM CIC 1402, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique, CH La Rochelle, La Rochelle, France.;Service d'Oncologie Hématologique, CH La Rochelle, La Rochelle, France.;Service d'Hématologie, CH Niort, Niort, France.;Service d'Hématologie, CH Rochefort, Rochefort, France.;INSERM 1082, Poitiers, France.;INSERM 1082, Poitiers, France.;Service Clinique d'Hématologie, Hôpital Henri-Mondor, Creteil, France.;INSERM CIC 1402, CHU Poitiers, Poitiers, France.;Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU Poitiers, Poitiers, France.;INSERM CIC 1402, CHU Poitiers, Poitiers, France.;Service de Cancérologie Biologique, CHU Poitiers, Poitiers, France.",
"authors": "Cayssials|Emilie|E|0000-0003-1654-5948;Torregrosa-Diaz|Jose|J|;Gallego-Hernanz|Pilar|P|;Tartarin|Florence|F|;Systchenko|Thomas|T|;Maillard|Natacha|N|;Desmier|Déborah|D|;Machet|Antoine|A|0000-0003-4958-3908;Fleck|Emmanuel|E|;Corby|Anne|A|;Motard|Carine|C|;Denis|Guillaume|G|;Herbelin|André|A|;Gombert|Jean-Marc|JM|;Roy|Lydia|L|;Ragot|Stéphanie|S|;Leleu|Xavier|X|;Guilhot|François|F|;Chomel|Jean-Claude|JC|0000-0001-9227-1104",
"chemical_list": "D047428:Protein Kinase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.32940",
"fulltext": null,
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"issn_linking": "0008-543X",
"issue": "126(15)",
"journal": "Cancer",
"keywords": "TKI de-escalation; chronic myeloid leukemia; treatment discontinuation; treatment-free remission; tyrosine kinase inhibitors",
"medline_ta": "Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3438-3447",
"pmc": null,
"pmid": "32459375",
"pubdate": "2020-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Low-dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment-free remission in chronic myeloid leukemia patients: Results of a retrospective study.",
"title_normalized": "low dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment free remission in chronic myeloid leukemia patients results of a retrospective study"
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"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-285808",
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"abstract": "The cure rate of multidrug-resistant tuberculosis (MDR-TB) is relatively low in China. The reasons for the treatment failure and within-host evolution during treatment have not been sufficiently studied. All MDR-TB patients receiving standard treatment from January 2014 to September 2016 at a designated TB Hospital in Zhejiang Province were retrospectively included and grouped according to their known treatment outcome. Clinical information was collected. Baseline strains of all patients and serial strains of treatment-failure patients were revived. Drug susceptibility tests (DSTs) of 14 drugs and single nucleotide polymorphism (SNP) analysis based on whole-genome sequencing (WGS) were performed. The genetic distance and within-host evolution were investigated based on SNPs. In total, 20 treatment failure patients and 74 patients who succeeded in treatment were included. The number of effective drugs for patients who failed treatment was no more than three. Eighteen (90.0%) treatment-failure patients were characterized by a continuous infection of the primary strain, of which 14 patients (77.8%) developed phenotypic or genotypic acquired drug resistance under ineffective treatment. Acquired resistance to amikacin and moxifloxacin (2.0 mg/ml) was detected most frequently, in 5 and 4 patients, respectively. The insufficient number of effective drugs in the combined treatment regimen was the main reason for MDR-TB treatment failure. The study emphasizes the importance of DST for second-line drugs when implementing the second-line drug regimen in MDR-TB patients. For patients with risk factors for MDR-TB, DST of second-line antituberculosis drugs should be performed at initiation of treatment. Second-line drugs should be selected based on the results of DST to avoid acquired resistance. WGS detects low-frequency resistance mutations and heterogeneous resistance with high sensitivity, which is of great significance for guiding clinical treatment and preventing acquired resistance.IMPORTANCE Few studies have focused on the reasons for the low cure rate of multidrug-resistant tuberculosis in China and within-host evolution during treatment, which is of great significance for improving clinical treatment regimens. Acquired resistance events were common during the ineffective treatment, among which resistance to amikacin and high-level moxifloxacin were the most common. The main reason for the treatment failure of MDR-TB patients was insufficient effective drugs, which may lead to higher levels of drug resistance in MDR-TB strains. Therefore, the study emphasizes the importance of DST in the development of second-line treatment regimen when there is a risk of MDR. By performing whole-genome sequencing of serial strains from patients with treatment failure, we found that WGS can detect low-frequency resistance mutations and heterogeneous resistance with high sensitivity. It is thus recommended to conduct drug susceptibility tests at the beginning of treatment and repeat the DST when the sputum bacteria remain positive.",
"affiliations": "Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.;Department of Infectious Diseases, Wenzhou Central Hospital, Affiliated Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, China.;Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.;Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.;Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.;Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China jiazhen_chen@163.com zhangwenhong@fudan.edu.cn.;Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China jiazhen_chen@163.com zhangwenhong@fudan.edu.cn.",
"authors": "Chen|Xinchang|X|;He|Guiqing|G|;Lin|Siran|S|;Wang|Shiyong|S|;Sun|Feng|F|;Chen|Jiazhen|J|;Zhang|Wenhong|W|0000-0002-9165-3212",
"chemical_list": "D000995:Antitubercular Agents; D000583:Amikacin; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.1128/mSphere.00884-20",
"fulltext": "\n==== Front\nmSphere\nmSphere\nmsph\nmsph\nmSphere\nmSphere\n2379-5042 American Society for Microbiology 1752 N St., N.W., Washington, DC \n\nmSphere00884-20\n10.1128/mSphere.00884-20\nResearch Article\nMolecular Biology and Physiology\nAnalysis of Serial Multidrug-Resistant Tuberculosis Strains Causing Treatment Failure and Within-Host Evolution by Whole-Genome Sequencing\nChen Xinchang a He Guiqing b Lin Siran a Wang Shiyong a Sun Feng a Chen Jiazhen a https://orcid.org/0000-0002-9165-3212Zhang Wenhong acde a Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China\nb Department of Infectious Diseases, Wenzhou Central Hospital, Affiliated Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, China\nc State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China\nd National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China\ne Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China\nFey Paul D. EditorUniversity of Nebraska Medical Center\n Address correspondence to Jiazhen Chen, jiazhen_chen@163.com, or Wenhong Zhang, zhangwenhong@fudan.edu.cn.Xinchang Chen and Guiqing He contributed equally to this work. Author order was determined both alphabetically and in order of increasing seniority. Jiazhen Chen and Wenhong Zhang contributed equally to this work. Author order was determined both alphabetically and in order of increasing seniority.\n\nCitation Chen X, He G, Lin S, Wang S, Sun F, Chen J, Zhang W. 2020. Analysis of serial multidrug-resistant tuberculosis strains causing treatment failure and within-host evolution by whole-genome sequencing. mSphere 5:e00884-20. https://doi.org/10.1128/mSphere.00884-20.\n\n\n23 12 2020 \nNov-Dec 2020 \n5 6 e00884-2031 8 2020 20 11 2020 Copyright © 2020 Chen et al.2020Chen et al.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.Few studies have focused on the reasons for the low cure rate of multidrug-resistant tuberculosis in China and within-host evolution during treatment, which is of great significance for improving clinical treatment regimens. Acquired resistance events were common during the ineffective treatment, among which resistance to amikacin and high-level moxifloxacin were the most common.\n\nABSTRACT\nThe cure rate of multidrug-resistant tuberculosis (MDR-TB) is relatively low in China. The reasons for the treatment failure and within-host evolution during treatment have not been sufficiently studied. All MDR-TB patients receiving standard treatment from January 2014 to September 2016 at a designated TB Hospital in Zhejiang Province were retrospectively included and grouped according to their known treatment outcome. Clinical information was collected. Baseline strains of all patients and serial strains of treatment-failure patients were revived. Drug susceptibility tests (DSTs) of 14 drugs and single nucleotide polymorphism (SNP) analysis based on whole-genome sequencing (WGS) were performed. The genetic distance and within-host evolution were investigated based on SNPs. In total, 20 treatment failure patients and 74 patients who succeeded in treatment were included. The number of effective drugs for patients who failed treatment was no more than three. Eighteen (90.0%) treatment-failure patients were characterized by a continuous infection of the primary strain, of which 14 patients (77.8%) developed phenotypic or genotypic acquired drug resistance under ineffective treatment. Acquired resistance to amikacin and moxifloxacin (2.0 mg/ml) was detected most frequently, in 5 and 4 patients, respectively. The insufficient number of effective drugs in the combined treatment regimen was the main reason for MDR-TB treatment failure. The study emphasizes the importance of DST for second-line drugs when implementing the second-line drug regimen in MDR-TB patients. For patients with risk factors for MDR-TB, DST of second-line antituberculosis drugs should be performed at initiation of treatment. Second-line drugs should be selected based on the results of DST to avoid acquired resistance. WGS detects low-frequency resistance mutations and heterogeneous resistance with high sensitivity, which is of great significance for guiding clinical treatment and preventing acquired resistance.\n\nIMPORTANCE Few studies have focused on the reasons for the low cure rate of multidrug-resistant tuberculosis in China and within-host evolution during treatment, which is of great significance for improving clinical treatment regimens. Acquired resistance events were common during the ineffective treatment, among which resistance to amikacin and high-level moxifloxacin were the most common. The main reason for the treatment failure of MDR-TB patients was insufficient effective drugs, which may lead to higher levels of drug resistance in MDR-TB strains. Therefore, the study emphasizes the importance of DST in the development of second-line treatment regimen when there is a risk of MDR. By performing whole-genome sequencing of serial strains from patients with treatment failure, we found that WGS can detect low-frequency resistance mutations and heterogeneous resistance with high sensitivity. It is thus recommended to conduct drug susceptibility tests at the beginning of treatment and repeat the DST when the sputum bacteria remain positive.\n\nKEYWORDS\ndrug resistancewhole-genome sequencingmultidrug-resistant tuberculosiswithin-host evolutiontreatment outcomeDNA sequencingMycobacterium tuberculosisadaptive resistancedrug resistance evolutiongenome analysisheteroresistancemultidrug resistanceNational Science and Technology Major Project of China2017ZX10302301-001Chen Jiazhen National Natural Science Foundation of China (NSFC)https://doi.org/10.13039/50110000180981761148027Chen Jiazhen Zhejiang Provincial Department of Science and Technology | Basic Public Welfare Research Program of Zhejiang Province (Zhejiang Basic Public Welfare Research Project)https://doi.org/10.13039/501100017577LGF20H010003He Guiqing cover-dateNovember/December 2020\n==== Body\nINTRODUCTION\nDrug-resistant tuberculosis (DR-TB) constitutes one of the main threats to the End-TB by 2035 strategy of the World Health Organization (WHO) (1–3). China accounts for 13% of the worldwide cases of multidrug resistant (MDR)/resistant to rifampin (RR)-TB. However, the cure rate of MDR-TB in China is as low as 41% (3). Risk factors for treatment failure include health and socioeconomic characteristics of patients, such as homelessness and anemia, as well as bacterial factors, such as infection by lineage 2 and higher resistance strains (4–11). The success rate of treatment is positively correlated with the number of effective drugs administered to patients (12, 13).\n\nAll MDR-TB patients who failed standardized treatment in accordance with the 2011 version of the WHO guidelines (14) were retrospectively analyzed in a designated TB Hospital in Zhejiang Province, China from January 2014 to September 2016 to investigate the current status and reasons for MDR-TB treatment failure. Due to the high occurrence and transmission rate of MDR-TB in China (15), it was speculated that treatment failure is likely caused by two factors: (i) a reinfection with a more resistant exogenous strain during treatment and (ii) resistance evolution of the primary strain (16–19). To distinguish between reinfection and resistance evolution, SNPs obtained by whole-genome sequencing (WGS) of strains were used to provide detailed information regarding drug resistance and its evolutionary events (20, 21). MTB infection is more genetically heterogeneous than traditionally thought (22). However, the microevolution and genetic resistance profiles acquired during treatment failure and identified on the molecular level by WGS have been even less studied.\n\nWe elucidated the current reality and the factors influencing treatment failure of MDR-TB in China and used WGS to further investigate the molecular evolution of strains during treatment failure, which has been less explored (19). These findings might reveal the current status of DR-TB treatment, which is crucial for improving future treatment strategies.\n\nRESULTS\nBasic information and DST profiles of baseline strains.\nIn total, 123 MDR-TB patients were diagnosed between January 2014 and September 2016. Among these, 94 patients had treatment outcomes by December 2018, of which 20 were treatment failure and 74 cured. We successfully revived 94 baseline strains from the 94 patients and 40 serial strains from the 20 treatment-failure patients (Fig. 1).\n\nFIG 1 Flowchart of included and excluded patients and isolates in this study.\n\nThe characteristics of patients, such as history of TB treatment with or without second-line anti-TB drugs and previous treatment duration of over 1 year, were associated with poor treatment outcomes (Table S1 in the supplemental material).The higher resistance level of baseline strains (especially extensively drug resistant [XDR], which means resistant to both SLID [second-line injectable drug] and FQ [fluoroquinolone], or pre-XDR, which means resistant to either SLID or FQ, resistance to FQ or to pyrazinamide [PZA]) was also associated with poor treatment outcomes (Table 1).\n\nTABLE 1 Treatment outcomes in relation to resistance patterns of baseline strains and administration of effective drugs\n\nParametera\tSuccessful outcomes (no. [%])\tPoor outcomes (no. [%])\tP valueb\tRisk ratio (95% CI) for treatment successb\t\nResistance Pattern of baseline strains\t\t\t<0.001\t0.13 (0.04–0.45)\t\n MDR\t40 (54.1)\t2 (10.0)\t\t\t\n pre-XDR R to SLID\t32 (43.2)\t1 (5.0)\t\t\t\n pre-XDR R to FQ\t1 (1.4)\t15 (75.0)\t\t\t\n XDR\t1 (1.4)\t2 (10.0)\t\t\t\nResistance to individual drugs\t\n EMB\t41 (55.4)\t15 (75.0)\t0.113\t0.84 (0.69–1.03)\t\n PZA\t34 (45.9)\t17 (85.0)\t0.002\t0.72 (0.58–0.89)\t\n LFX\t33 (44.6)\t17 (85.0)\t0.001\t0.71 (0.57–0.88)\t\n MFX\t11 (14.9)\t10 (50.0)\t0.002\t0.61 (0.40–0.92)\t\n SLID\t2 (2.7)\t3 (15.0)\t0.107\t0.49 (0.17–1.45)\t\n SM\t49 (66.2)\t14 (70.0)\t0.749\t0.96 (0.78–1.20)\t\n PTO\t10 (13.5)\t8 (40.0)\t0.019\t0.66 (0.43–1.01)\t\n PAS\t6 (8.1)\t2 (10.0)\t0.792\t0.95 (0.63–1.44)\t\n CS\t3 (4.1)\t6 (30.0)\t0.002\t0.40 (0.16–1.01)\t\nNo. of effective drugs in patient's treatment\t\t\t<0.001\t0.04 (0.01–0.18)\t\n 0–1\t0 (0.0)\t1 (5.0)\t\t\t\n 2\t2 (2.7)\t6 (30.0)\t\t\t\n 3\t14 (18.9)\t13 (65.0)\t\t\t\n ≥4\t58 (78.4)\t0 (0.0)\t\t\t\nEffectiveness of specific drugs\t\n EMB\t12 (16.2)\t1 (5.0)\t0.452\t1.17 (0.97–1.41)\t\n PZA\t41 (55.4)\t3 (15.0)\t<0.001\t1.41 (1.14–1.75)\t\n FQ\t25 (33.8)\t5 (25.0)\t<0.001\t1.68 (1.22–2.32)\t\n SLID\t71 (96.0)\t17 (85.0)\t0.207\t1.61 (0.72–3.62)\t\n SM\t0 (0)\t0 (0.0)\t/\t/\t\n PTO\t62 (83.8)\t9 (45.0)\t0.001\t1.67 (1.12–2.50)\t\n PAS\t10 (13.5)\t4 (20.0)\t0.712\t0.89 (0.63–1.27)\t\n CS\t49 (66.2)\t10 (50.0)\t0.183\t1.16 (0.92–1.48)\t\n CFZ\t4 (5.4)\t5 (25.0)\t0.027\t0.54 (0.26–1.13)\t\na MDR, multidrug resistant; XDR, extensively drug resistant; SLID, second-line injectable drug; FQ, fluoroquinolone; EMB, ethambutol; PZA, pyrazinamide; LFX, levofloxacin; MFX, moxifloxacin; SM, streptomycin; PTO, prothionamide; PAS, para-aminosalicylic acid; CS, cycloserine; CFZ, clofazimine; /, not applicable.\n\nb P value and risk ratio (95% CI) values given in boldface indicate statistical significance.\n\nImportantly, insufficient administration of effective drugs was associated with poor clinical outcomes. In contrast, treatment regimens using specific effective drugs, such as PZA, levofloxacin (LFX), moxifloxacin (MFX), and prothionamide (PTO), were associated with successful outcomes (Table 1). We calculated the number of effective drugs by comparing the baseline DST and the initial treatment regimen. As the number of effective drugs decreased from ≥4, to 3, to ≤2 in the regimen of patients, treatment failure was observed to increase stepwise from 0% (0/58), to 48.1% (13/27), and to 77.8% (7/9), respectively (P < 0.001; relative risk [RR], 0.04, 95% confidence interval [CI] 0.01 to 0.18). Further analysis revealed no significant differences in the drug resistance profile or effective use of specific drugs in 27 patients treated with three effective drugs; however, any history of TB treatment with or without second-line anti-TB drugs was associated with treatment failure.\n\nPrimary infection strain or reinfection distinguished by WGS.\nAs reinfection by another higher-resistance MDR strain was considered a plausible reason for treatment failure, we used WGS to distinguish between primary infection and reinfection of 20 patients with poor treatment outcome. The number of different SNPs between the serial strains was in the range of 0 to 1,143. Eighteen (90.0%) cases were identified as the same strains, of which the number of SNP differences varied from 0 to 8 in this study. Only two cases (10%) were identified as reinfection by another, more resistant strain (no. 6 and no. 16), which had 1,134 and 313 SNPs in genetic distance, respectively (Fig. 2, Fig. S1 in the supplemental material).\n\nFIG 2 Evolution of drug resistance and treatment regimen for each patient. Different colors represent corresponding drugs. Solid circles represent resistance; hollow circle represents sensitivity. Gray lines under each patient show the treatment regimen and any changes to it. Letters in gray indicate ineffective use of this drug. Letters in bold with an asterisk indicate acquired resistance to this drug. E, ethambutol; Z, pyrazinamide; L, levofloxacin; M, moxifloxacin; A, amikacin; C, capreomycin; T, prothionamide; P, para-aminosalicylic acid; S, cycloserine; and F, clofazimine.\n\nAmong the 18 cases infected with the same strain during the whole period of treatment, a total of 14 patients (77.8%) were observed to develop phenotypic or genotypic acquired drug resistance (ADR) (Table 2). The ADR events of FQ (both MFX 2.0 mg/ml and LFX) and second-line injectable drugs (SLID) were the most frequent, and were found in six (33.3%) and five (27.8%) out of 18 patients, respectively. The evolution from being drug susceptible to resistant was consistent in both the phenotype and genotype in most patients, except for the PTO phenotypic resistance of patient no. 4 and the cycloserine (CS) phenotypic resistance of patient no. 14, in which cases no mutations responsible for the acquired resistance were detected.\n\nTABLE 2 Phenotypic or genotypic acquired resistance in patients of poor outcomes\n\nPatient no.\tAcquired phenotypic drug resistancea\tAcquired genotypic drug resistancea\tGenetic drug resistance consistent with phenotypeb\tOther mutations in drug resistance related genesb\t\n1\t/\t/\t/\t/\t\n2\tPZA\tPZA\tpncA_L85R*, pncA_166c_in*\t/\t\n3\tMFX2.0, SLID\tFQ, SLID\tgyrA A90V→D94N, rrs_a1401g\t/\t\n4\tPTO\t/\t/\t/\t\n5\tSLID\tSLID\trrs_a1401g\tethA S57P*, ethA Y461stop*\t\n7\t/\t/\t/\tethA S183R*, ethA Q254P*, ethA Y286stop*\t\n8\tEMB, PTO, CS\tEMB, PTO, CS\tembB M306V; ethA_W116C*; alr_c-13g,L113R,Y388D*\tgyrB T500A; pncA D8A*, pncA T142S*\t\n9\tMFX2.0\tFQ\tgyrB_E501D*\t\t\n10\tMFX2.0\tFQ\tgyrA_A90V→D94G\t/\t\n11\tSLID\tSLID\trrs_a1401g*\t/\t\n12\t/\t/\t/\t/\t\n13\tFQ, PZA\tFQ, PZA\tgyrA_D94Y, pncA_T153P\t/\t\n14\tSLID, CS\tSLID\trrs_a1401g\t/\t\n15\t/\t/\t/\t/\t\n17\tFQ, PTO\tFQ, PTO\tgyrA_D94N; ethA_F48V*, ethA_694tc_in*\t/\t\n18\tSLID\tSLID\trrs_a1401g\t/\t\n19\tMFX2.0\tFQ\tgyrB_A504V*\t/\t\n20\t/\tEMB, FQ\t/\tembB_Q497H, gyrB_D461N\t\na Boldface type indicates the genetic mutation responsible for resistance was not found. SLID, second-line injectable drug; FQ, fluoroquinolone; EMB, ethambutol; PZA, pyrazinamide; LFX, levofloxacin; MFX, moxifloxacin; PTO, prothionamide; CS, cycloserine; /, not applicable.\n\nb *, hetero-resistance.\n\nAs no resistance-related mutation was discovered in the PTO-resistant isolate from patient no. 4 and the CS phenotypic resistance of patient no. 14, we further analyzed all differential SNPs identified between the serial isolates of these two patients. After excluding synonymous mutations, three mutations were identified to distinguish the resistant from the susceptible isolates of patient no. 14. These were Rv0565c Y306C (probable monooxygenase), Rne N649D (RNase E), and Rv2611c I102M (probable acyltransferase). Only two mutations were detected in the intergenic region of the isolate of patient no. 4, located in the promoter of mprA (mycobacterial persistence regulator protein) and amount genes (ammonium-transport integral membrane protein). These results provided a new insight into the acquired resistance of TB strains to drugs.\n\nMicroevolution of resistance genes revealed by whole-genome sequencing.\nHere, the evolution of resistance-related genes included the identification of the pncA mutation related to PZA (patients no. 2 and no. 13), the gyrA and gyrB mutations related to FQ (patients no. 3, no. 9, no. 10, no. 13, no. 17, and no. 19), the rrs mutation related to SLID (patients no. 3, no. 5, no. 11, no. 14, and no. 18), the embB mutation related to EMB (patients no. 8 and no. 20), the alr mutation related to CS (patients no. 8 and no. 14), and the ethA mutation related to PTO (patients no. 4, no. 8, and no. 17) (Table 2). Moreover, heterogeneous resistance, indicating the coexistence of either both drug-resistant and sensitive subpopulations or several drug-resistant subpopulations with different gene mutations, was found in 8 out of 14 patients. An ongoing change in the frequency of resistance mutations was detected by WGS in a series of isolates from nine patients (patients no. 2, 3, 5, 7, 8, 9, 11, 17, and 19), indicating the process of emergence or substitution of resistant subpopulations (Fig. 2, Table 3).\n\nIn patients no. 8, no. 11, and no. 19, the emergence, selection, and fixation process of a drug resistance-related mutation were entirely recorded by WGS. In detail, the frequency of ethA W116C of patient no. 8, rrs a1401g of patient no. 11, and gyrB A504V of patient no. 19 increased from 0% at the initiation of treatment to nearly 100% in the last cultured isolates.\n\nInterestingly, we found a mutation shift from a low-level resistance mutation to a different high-level resistance mutation. In patient no. 3, the gyrA D94N mutation, usually characterized by high level of resistance to FQ, gradually replaced the existing A90V mutation, resulting in low level of resistance to FQ. This phenomenon was also observed in isolates from patient no. 10, in which the gyrA D94G mutation was demonstrated to have replaced the previous A90V mutation during treatment containing MFX (Table 2, Table 3).\n\nTABLE 3 Mutation frequencies changing gradually for resistance-related mutations as detected by WGS\n\nPatient no.\tAcquired phenotypic drug resistancea\tAcquired genetic drug resistance\tResistant mutations\tFrequency of resistant mutations\t\n2\tPZA\tpncA\tL85R\t0 ↗ 15.5 ↘ 0\t\n166c in\t0 ↗ 35.7 ↘ 0\t\n3\tMFX2.0\tgyrA\tA90V\t98.2 ↘ 83.5 ↘ 0\t\nD94N\t0 ↗ 81.7 ↗ 84.6\t\n5\t/\tethA\tS57P\t54.9 ↘ 0 ↗ 99.6\t\nY461stop\t34.9 ↗ 99.2 ↘ 0\t\n7\t/\tethA\tS183R\t42.1 ↘ 15.1 ↘ 0 → 0\t\nQ254P\t0 ↗ 59.9 ↘ 0 → 0\t\nY286stop\t34.3 ↘ 23.6 ↗ 99.8 → 99.8\t\n8\tCS\talr\tc-13g\t0 → 0 → 0 ↗ 83.6\t\nL1134\t0 → 0 → 0 ↗ 15.0\t\nY388D\t0 → 0 → 0 ↗ 44.4\t\n\tPTO\tethA\tW116C\t0 ↗ 29.6 ↗ 98.2 → 98.2\t\n9\tMFX2.0\tgyrA\tD94H\t0 → 0 → 22.8 ↘ 0 → 0\t\ngyrB\tE501V\t0 → 0 ↗ 24.3 ↗ 47.1 ↘ 29.6\t\nE501D\t0 → 0 → 0 ↗ 48.7 ↗ 51.3\t\n11\tSLID\trrs\ta1401g\t0 ↗ 79.5 ↗ 99.7\t\n17\tPTO\tethA\tF48V\t0 ↗ 88.7 ↘ 62.2 ↘ 20.9\t\n694tc_in\t0 ↗ 10.9 ↗ 28.2 ↗ 82.4\t\n19\tMFX2.0\tgyrB\tA504V\t0 ↗ 24.8 ↗ 86.0\t\na SLID, second-line injectable drug; PZA, pyrazinamide; MFX, moxifloxacin; PTO, prothionamide; CS, cycloserine; /, not applicable.\n\nIn patients no. 5, 7, 9, and 17, several different drug-resistant subpopulations were coexisting. In patient no. 5, two mutations in the ethA gene were found at the start of treatment, ethA S57P and ethA Y461*, with frequencies of 54.9% and 34.9%, respectively. In the second (6 months later) and third (23 months later) specimens, only the ethA S57P or ethA Y461* mutations were present (Table 3). Similarly, in patient 7, three different subpopulations with drug resistance mutations of ethA were gradually fixed to carry ethA Y286* as the only mutation during ineffective treatment with PTO. The strain of patient no. 17 was initially sensitive to PTO, exhibiting a wild-type ethA. After 6 months of ineffective treatment, ethA F48V and ethA 694t-insertion mutations were both detected with frequencies of 88.7% and 10.9%, respectively. After another 16 months of continued treatment, the subpopulation carrying the ethA 694t-insertion became the majority, with its proportion rising to 82.4%, whereas the proportion of the subpopulation carrying the ethA F48V mutation decreased to 20.9%.\n\nDISCUSSION\nThe WGS method is widely used in distinguishing relapse from exogenous reinfection in cases of recurrence after treatment completion, revealing that about 60% are relapse and 40% are reinfection (10, 20, 23–25). However, few studies have investigated this issue in MDR-TB treatment failure patients, who were hard to treat and remained a source of infection during unsuccessful treatment. The majority of paired strains (18/20, 90.0%) persisted genetically unchanged (SNPs ≤8), consistent with previous studies by WGS (21, 26), but higher than previous studies in which the genotype was defined by mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) (18, 27, 28). The reason for the lower frequency of reinfection could be that small changes in MIRU-VNTR can make closely related strains appear very different, but the higher resolution WGS method can distinguish that these strains are actually very similar. Since the study was conducted in Wenzhou City, Zhejiang Province, there could be fewer transmission incidents in this city than in the communities sampled in other studies (21, 29).\n\nDeep analysis of the failure cases might lead to a road of better treatment options for MDR-TB. Here, administration of an insufficient number of effective drugs was strongly associated with treatment failure and acquired drug resistance events, strengthening the previous results defining the genotype by MIRU-VNTR (13). We performed a comprehensive and standardized DST for all second-line antituberculosis drugs available at that time, remedying the limitation that previous studies did not include DST results for PZA, MFX, and PTO. Another strength of this study was that WGS-based mutations were also analyzed to confirm the acquired phenotypic resistance, highlighting the importance of DST in the treatment of DR-TB (17, 30).\n\nIn total, among patients persistently infected with the same strain, 77.8% patients (14/18) were noted to develop acquired drug resistance, which was higher than that reported previously. A previous study only performed DST of FQ and SLID at the initiation and checkpoint of treatment to determine the resistance pattern, which might have underestimated the prevalence of acquired resistance to other drugs (13, 28). The acquired resistance to FQ is the most common evolutionary event in the duration of MDR-TB treatment (13). However, in this study, as 83.8% (15/18) patients were initially resistant to FQ (resistance to either LFX or MFX), we did not focus much on the evolution event of the resistance to FQ. Acquired resistance to SLID and higher resistance level to MFX (from 0.5 mg/ml to 2.0 mg/ml) was the most frequent event and detected in five and four patients, respectively, followed by the acquired resistance to LFX (from sensitivity to resistance), PZA, PTO, CS, and ethambutol (EMB) found in two patients.\n\nOur study reemphasized the importance of the usage of FQ in treatment (31), as the success rate of treatment was significantly higher in FQ-S patients effectively treated with FQ, in accordance with previously reported conclusions (32, 33). The usage of MFX to treat LFX-resistant MDR-TB patients, regardless of the effectiveness of the treatment combination, resulted in the evolution of a higher level of resistance to FQ (34), a finding that merits serious attention. In patients no. 3 and no. 10, the originally identified gyrA A90V resistance mutation (low level) was replaced by mutations with higher levels of resistance, gyrA D94N and D94G (35). Accordingly, in patients no. 9 and no. 19, carrying the gyrA A90V low-level resistance mutation, the emergence of gyrB mutations resulted in higher level of resistance to MFX.\n\nHeterogeneous drug resistance is a common reason for discordant results in phenotypic and genotypic DSTs. The coexistence of subpopulations with different drug resistance profiles in the same patient might result in unfavorable responses to treatment, and might lead to treatment failure (36–39). Accordingly, we noted the simultaneous coexistence of multiple subpopulations containing different drug-resistant mutations in the early isolates of patients no. 3, 5, 7, and 17. After a period of drug pressure screening, a single subpopulation began to dominate, and in some cases became the sole population, with the mutation reaching 100% frequency, suggesting that the selection of TB resistance is common under long-term infection and drug pressure (39–42). Hence, these highly resistant and relatively fit TB bacteria might be involved in the spread from the early steps of infection (43). These findings underscore the importance of early detection of resistance, especially the detection of the resistant subpopulations before and during the treatment of DR-TB. As a highly sensitive molecular detection method, WGS could be used to diagnose these drug-resistant subgroups early, thereby reducing the possibility of being screened as fully drug-resistant infections in the future.\n\nMost cases of phenotypic drug resistance can be explained by mutations in drug resistance-related genes. However, no corresponding molecular resistance mutations were found in two of these strains, resistance to PTO in patient no. 4 and resistance to CS in patient no. 14. We targeted a few SNPs during the microevolution of these resistance cases, which requires subsequent in vitro validation and screening in a larger population.\n\nThis study had the following limitations. First, the treatment regimen was based on the 2011 version of the WHO guidelines, what was available and used at that time. The order of recommendation for the administration of some of the drugs has since changed. As a retrospective study, DSTs could not be provided to the clinic in a timely manner. Second, any compliance issues of patients and loss of follow-up were ignored. Third, due to the procedure of revival of sputum specimens and the decontamination operations involved in this process, some subpopulations might have been lost and become undetected in WGS analysis. Third, as this was a single-center study, it included an insufficient number of MDR-TB patients. Finally, other factors that might influence treatment outcome, such as host-pathogen interaction or socioeconomic status, were not investigated in this study.\n\nIn this study, the main reason for the treatment failure of MDR-TB patients was insufficient effective drugs, which may lead to higher levels of drug resistance in MDR-TB strains. Therefore, the study emphasizes the importance of DST of second-line drugs when implementing the second-line drug regimen in MDR-TB patients. WGS detects low-frequency resistance mutations and emerging heterogeneous resistance with high sensitivity, which is of great significance for guiding clinical treatment and preventing acquired resistance.\n\nMATERIALS AND METHODS\nClinical MDR-TB cases.\nWe retrospectively included all MDR-TB patients from January 2014 to September 2016 in the Wenzhou Central Hospital (Zhejiang Province, China) with a known outcome according to the standard outcome definitions by WHO (3). DST of first-line antituberculosis agents (isoniazid [INH] and rifampin [RIF]) was conducted routinely on positive cultures by MGIT 960 to determine whether it was MDR. Patients were divided into two groups according to the treatment outcome: treatment success and treatment failure. The treatment-success group included patients who had been either cured or had completed treatment. The treatment-failure group included patients exhibiting lack of conversion by the end of the intensive phase or bacteriological reversion in the continuation phase after conversion to negative. As these patients received treatment from 2014 to 2016, the WHO guidelines for the programmatic management of the drug-resistant tuberculosis 2011 update (14) was the only one available and used at that time. This standardized treatment combination included the administration of pyrazinamide (PZA), a second-line injectable drug (SLID) (amikacin [AM], kanamycin [KM], or capreomycin [CM]), a fluoroquinolone (levofloxacin [LFX], or moxifloxacin [MFX]), and two of cycloserine (CS), prothionamide (PTO), p-aminosalicylic acid (PAS), clofazimine (CFZ), or ethambutol (EMB) for the period of 6 to 8 months during the intense phase, continued with administration of a combination of 3 to 4 drugs without a SLID for another 18 months.\n\nClinical information, including age, gender, comorbid conditions, treatment history, and treatment regimen was extracted from the medical records of patients to analyze the risk factors related to treatment outcomes. Baseline strains, the first sputum culture positive strain, of all enrolled patients were collected and revived from refrigeration. For all treatment failure patients, sputum specimens were collected every month for the first 6 months, and then every 1 to 2 months according to WHO guidelines. In order to observe evolution events and heterogeneity, we selected at least two more serial strains at intervals of more than 6 months. Strains that failed to revive or were contaminated were excluded. All colonies on the plate were scraped off and resuspended in 30% glycerol before freezing.\n\nThe study was approved by the Ethics Committee of Wenzhou Central Hospital, Zhejiang Province, China. All patients provided written informed consent before the study.\n\nPhenotypic drug susceptibility tests.\nDrug susceptibility tests (DSTs) were conducted on all included strains to compare the resistance profiles between the two groups. Following the revival of strains on Löwenstein–Jensen medium, we performed DSTs for 14 drugs (44–50) on the baseline strains of all patients and the series strains of treatment failure patients, namely, INH (0.2 μg ml−1), RIF (40.0 μg ml−1), EMB (2.0 μg ml−1), LFX (2.0 μg ml−1), MFX (2.0 μg ml−1), AM (30.0 μg ml−1), KM (30.0 μg ml−1), CM (40.0 μg ml−1), streptomycin (SM) (4.0 μg ml−1), PAS (1.0 μg ml−1), CFZ (1.0 μg ml−1), and CS (30.0 μg ml−1) using the proportion method on Löwenstein–Jensen medium (Baso, Zhuhai, Guangzhou Province, China). Exceptions were for PZA (100.0 μg ml−1) and PTO (2.5 μg ml−1), the DSTs of which were performed using an automated MGIT 960 (Becton, Dickinson Diagnostic Systems, Franklin Lakes, NJ, USA) according to the manufacturer's guidelines. We conducted the DSTs of EMB, PZA, and PTO at least twice due to their unsatisfactory reproducibility. Where the results were inconsistent, a third test was performed and the interpretation was based on the two most consistent results out of the total three.\n\nWhole-genome sequencing.\nWhole-genome sequencing (WGS) was performed on all selected strains to provide genotypic resistance, distinguish between a continuous infection with the primary strain or reinfection, and elucidate the microevolution of serial strains. Growth was scraped from Löwenstein–Jensen medium. Genomic DNA was extracted using the Qiagen DNeasy blood and tissue kit (Cat. no. 69506) and sequencing libraries were constructed using the Nextera XT sample prep kit (Illumina, San Diego, CA, USA) following the manufacturer's protocol. All strains were sequenced on an Illumina Miseq or X 10 with at least 100-fold coverage.\n\nWGS data were analyzed (51) according to previous studies. After filtering the low-quality reads, the reads were aligned to the MTB H37Rv (GenBank NC_000962.3) reference sequence using Bowtie2 (version 2.3.3.1) with default parameters. Single nucleotide polymorphisms (SNPs) were detected using SAMtools (version 1.6) with a minimum sequencing depth of 10 reads without strand bias and a frequency of no less than 10%. All SNPs with a mutation frequency exceeding 10% were retained in the step of calling SNPs to detect microevolution and minor subpopulations. If the mutation ratio of a certain site was above 80%, it was considered a fixed mutation.\n\nSNPs in highly repetitive regions such as PE and PPE, GC-enriched sequences, and drug resistance-related genes were removed from the analysis. The phylogenetic tree was constructed using the maximum likelihood method using MEGA (version 7.0) software based on the fixed SNPs, with H37Rv as the root. The strains with a genetic distance of no more than 12 SNPs were considered persistent infection with the same strain.\n\nEthical approval.\nThe study was approved by the Ethics Committee of Wenzhou Central Hospital, Zhejiang Province, China. All patients provided written informed consent before the study.\n\nStatistical analysis.\nWe used the chi-square test or Fisher's exact test to calculate significant differences between characteristics of patients, drug resistance, and treatment regimen and outcome. We performed univariable logistic regression analysis and calculated the relative risk (RR) followed by its 95% confidence intervals. Variables with a P < 0.05 were considered significant. We performed all analyses using the SPSS version 21 software.\n\nData availability.\nThe raw data of WGS are submitted to the SRA database and can be accessed by the public via BioProject accession number PRJNA613359. The SRA accession numbers for these isolates are SAMN14402132 to SAMN14402172. The WGS data for a portion of these strains were previously made available to the public under BioProject number PRJNA522942 (51).\n\n10.1128/mSphere.00884-20.1TABLE S1 Treatment outcomes of MDR-TB patients according to patient characteristics; P value and risk ratio (95% CI) values given in boldface indicate statistical significance. Download Table S1, DOCX file, 0.01 MB.\n\nCopyright © 2020 Chen et al.2020Chen et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. 10.1128/mSphere.00884-20.2TABLE S2 Diagnostic criteria of genetic sequencing for genotypic resistance. Download Table S2, DOCX file, 0.02 MB.\n\nCopyright © 2020 Chen et al.2020Chen et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. 10.1128/mSphere.00884-20.3FIG S1 Phylogenetic tree of 60 serial strains in 20 patients with treatment failure; branch in red means reinfection by different strains during treatment. Download FIG S1, DOCX file, 0.1 MB.\n\nCopyright © 2020 Chen et al.2020Chen et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. ACKNOWLEDGMENTS\nAll persons meeting authorship criteria are listed as authors, and all authors certify that they have sufficiently participated in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.\n\nConception and design of study, critically revising the manuscript for important intellectual content: J.C. and W.Z.; acquisition of data, analysis, and interpretation of data: X.C., G.H., S.W., S.L., and F.S.; drafting the manuscript: X.C. and J.C.\n\nAll authors declare they have no competing interests regarding the manuscript.\n\nThe work was supported in part by the National Science and Technology Major Project of China (2017ZX10302301-001), the National Natural Science Foundation of China (81761148027), and the Basic Public Welfare Research Project of Zhejiang Province (LGF20H010003). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.\n\nWe are grateful for the support of the Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response (20dz2260100).\n==== Refs\nREFERENCES\n1. Pankhurst LJ , del Ojo Elias C , Votintseva AA , Walker TM , Cole K , Davies J , Fermont JM , Gascoyne-Binzi DM , Kohl TA , Kong C , Lemaitre N , Niemann S , Paul J , Rogers TR , Roycroft E , Smith EG , Supply P , Tang P , Wilcox MH , Wordsworth S , Wyllie D , Xu L , Crook DW , COMPASS-TB Study Group \n2016 \nRapid, comprehensive, and affordable mycobacterial diagnosis with whole-genome sequencing: a prospective study\n. Lancet Respir Med \n4 :49 –58\n. doi:10.1016/S2213-2600(15)00466-X .26669893 \n2. 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"fulltext_license": "CC BY",
"issn_linking": "2379-5042",
"issue": "5(6)",
"journal": "mSphere",
"keywords": "DNA sequencing; Mycobacterium tuberculosis; adaptive resistance; drug resistance; drug resistance evolution; genome analysis; heteroresistance; multidrug resistance; multidrug-resistant tuberculosis; treatment outcome; whole-genome sequencing; within-host evolution",
"medline_ta": "mSphere",
"mesh_terms": "D000583:Amikacin; D000995:Antitubercular Agents; D002681:China; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D009169:Mycobacterium tuberculosis; D012189:Retrospective Studies; D017211:Treatment Failure; D018088:Tuberculosis, Multidrug-Resistant; D000073336:Whole Genome Sequencing",
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"pages": null,
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"pubdate": "2020-12-23",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29203478;22942206;27903602;25732036;29017248;24590481;28424085;22952439;28351427;30306102;24366731;27973588;26045528;21345102;25057101;21356062;26669893;25421465;27919643;30918049;29510687;27978594;21682802;31420303;28814276;22294518;30578402;21698208;25336729;25732626;31417530;28237039;26508515;20064071;25988954;26620446;22984115;23995135;21828024;20686077;24461758;27587552;28173763;29460735;12087520;22005918;30154770",
"title": "Analysis of Serial Multidrug-Resistant Tuberculosis Strains Causing Treatment Failure and Within-Host Evolution by Whole-Genome Sequencing.",
"title_normalized": "analysis of serial multidrug resistant tuberculosis strains causing treatment failure and within host evolution by whole genome sequencing"
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"abstract": "Percutaneous left atrial appendage closure (LAAC) is an effective and safe operation strategy for stroke prevention in patients who are diagnosed with atrial fibrillation (AF) but cannot tolerate long term anticoagulation medication. We presented four rare cases of thrombosis formation on the occluder device. After the LAAC operation was successfully performed on patients, they followed a course of anticoagulation with dabigatran (110 mg b.i.d.), and device-related thrombosis (DRT) occurred as indicated by a transesophageal echocardiogram (TEE) during the follow-up period. Regressions were achieved after replacing dabigatran with rivaroxaban or warfarin for more than 1 month. No thrombosis or bleeding-related complications occurred in subsequent follow-ups.",
"affiliations": "Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.;Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.;Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.",
"authors": "Li|Xiaoye|X|;Jin|Qinchun|Q|;Zhang|Xiaochun|X|",
"chemical_list": null,
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"doi": "10.3389/fphar.2020.563920",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812 Frontiers Media S.A. \n\n10.3389/fphar.2020.563920\nPharmacology\nCase Report\nClosure Device-Related Thrombosis After Anticoagulation With Dabigatran in Patients Undergoing Percutaneous Left Atrial Appendage Closure: Case Reports and Literature Review\nLi Xiaoye \n1\n Jin Qinchun \n2\n Zhang Xiaochun \n2\n\n*\n \n1\nDepartment of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China\n\n\n2\nDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China\n\nEdited by: Suren Soghomonyan, The Ohio State University, United States\n\nReviewed by: Renuka Shenoy, Ohio State University Hospital, United States; Wiebke Ackermann, The Ohio State University, United States\n\n*Correspondence: Xiaochun Zhang, zhang.xiaochun@zs-hospital.sh.cn\nThis article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology\n\n\n08 9 2020 \n2020 \n11 56392020 5 2020 21 8 2020 Copyright © 2020 Li, Jin and Zhang2020Li, Jin and ZhangThis 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.Percutaneous left atrial appendage closure (LAAC) is an effective and safe operation strategy for stroke prevention in patients who are diagnosed with atrial fibrillation (AF) but cannot tolerate long term anticoagulation medication. We presented four rare cases of thrombosis formation on the occluder device. After the LAAC operation was successfully performed on patients, they followed a course of anticoagulation with dabigatran (110 mg b.i.d.), and device-related thrombosis (DRT) occurred as indicated by a transesophageal echocardiogram (TEE) during the follow-up period. Regressions were achieved after replacing dabigatran with rivaroxaban or warfarin for more than 1 month. No thrombosis or bleeding-related complications occurred in subsequent follow-ups.\n\natrial fibrillationleft atrial appendage closuredabigatrandevice-related thrombosisnovel oral anticoagulation\n==== Body\nIntroduction\nRecently, percutaneous left atrial appendage closure (LAAC) has been developed as an effective and safe operation strategy for stroke prevention in patients who are diagnosed with atrial fibrillation (AF) but cannot tolerate long term anticoagulation (Glikson et al., 2019; Holmes et al., 2019; Skurk and Landmesser, 2020). The left atrium plays an important role in the formation of thrombosis for patients with AF, and about 90% of identified cases of left atrium thrombosis are located in the left atrial appendage (LAA) (Kirchhof et al., 2016; Saw et al., 2019). LAAC raises an intriguing concept mainly due to the combination of the reduction in thromboembolism and bleeding risks based on its technical success without the need for long-term pharmacological treatment (Hobohm et al., 2019; Masjuan et al., 2019; Wintgens et al., 2019).\n\nSimilar to other implanted devices in the human body, there is a requisite time for full endothelialization on occluders that are exposed to circulating blood (Cornelissen and Vogt, 2019). However, there was significant interindividual variability on anticoagulation before complete endothelialization on devices, which might add to uncertainty on the duration of antithrombotic therapy during this vulnerable time for device-related thrombosis (DRT) (Massarenti and Yilmaz, 2012; Tang et al., 2017). Previous research reported that the incidence of DRT with oral anticoagulants (OAC) was lower than that with antiplatelet therapy (3.1 vs. 1.4%; p = 0.018) (Bergmann et al., 2017). However, the optimal anticoagulation regimen is uncertain owing to the lack of comparative clinical studies on different antithrombotic agents (mainly dabigatran and rivaroxaban). Previous studies have provided definitive evidence on the safety and efficacy of rivaroxaban for post anticoagulation of LAAC (Panikker et al., 2016), but little is known about the anticoagulation effects of dabigatran on LAAC. Current evidence shows that medication with dabigatran fails to prevent thromboembolic complications for patients after stents were implanted and mechanical heart valves replaced (Jaffer et al., 2015).\n\nGiven the recent increase in the prescription of novel oral anticoagulants (NOAC), such as dabigatran, for post-implantation anticoagulation after LAAC operations, it seems important to obtain a better understanding of the pharmacology and adverse effects during anticoagulation. Here, we report on four cases of occluder-related thrombosis anticoagulated with dabigatran in patients undergoing LAAC operations.\n\nCase Studies\n\n\nFigure 1\n presents progression of clinical picture in our patients.\n\nFigure 1 Flow chart of the care process for the presented cases. LAAO, left atrial appendage occlusion; TEE, transesophageal echocardiogram; DRT, device-related thrombosis; dual antiplatelet, 100 mg of aspirin combined with 75 mg of clopidogrel; mono antiplatelet, 100 mg of aspirin only.\n\nCase 1\nA 78-year-old woman (weight, 73 kg; height, 158 cm; BMI, 29.2 kg/m2) developed paroxysmal AF with clinical presentation as palpitations after exercise accompanied by chest discomfort. The electrocardiogram (ECG) showed the typical pattern of AF: irregular RR intervals and no discernible, distinct P waves. She presented a history of hypertension for 10 years mediated with valsartan and amlodipine to control blood pressure. As her CHA2DS2-VASc score was 4 (female, elderly, and hypertensive), she now had a clear reason for anticoagulation and was temporarily treated with a vitamin K antagonist (VKA) within the therapeutic range [international normalized ratio (INR), 2.0–3.0). One year after warfarin initiation, she was referred to a tertiary cardiology center for further analysis of AF and was considered for the LAAC operation due to her unsuitability for continuous long-term OAC. A 33-mm Watchman occluder device (Boston Scientific, MA, USA) was successfully deployed under general anesthesia in the LAA with a good seal and no leaks. A transesophageal echocardiogram (TEE) detected no mural thrombus. She was discharged with an 8-week course of dabigatran (110 mg b.i.d.) and a follow-up TEE to assess cardiac function and LAAC device positioning, which might affect further anticoagulation strategies. A proton pump inhibitor (PPI; rabeprazole, 10 mg b.i.d.) was prescribed to reduce the risk of gastrointestinal bleeding. A follow-up TEE, performed 6 weeks later, indicated that thrombus had formed on the occluder surface (\nFigure 2\n, a1). The physicians decided to switch from dabigatran to warfarin (INR, 2.0–3.0) for anticoagulation. Six weeks later, a TEE revealed the gradual reduction of thrombosis formation on the occluder (\nFigure 2\n, a2), and physicians made an informed decision to continue on warfarin.\n\nFigure 2 Left atrial appendage occlusion-related thrombus anticoagulated with dabigatran. (a) TEE 2-dimensional view displayed thrombosis (2.59 cm × 1.67 cm) on the surface of the occluder (a1). After six weeks of warfarin treatment, a regression of the thrombosis was shown (1.27 cm × 0.605 cm), which confirmed the diagnosis of device-related thrombosis (a2). (b) TEE revealed a thrombus (0.713 cm × 0.621 cm) on the anterolateral surface of the occluder (b1) and the total disappearance of the thrombus after initiation of anticoagulation therapy with rivaroxaban (b2). (c) TEE check-up revealed abnormal hemodynamics in the LAA, identified as thrombosis (0.713 cm × 0.621 cm) (c1), and total elimination of DRT after 3 months following anticoagulation treatment with warfarin (c2). (d) TEE revealed a thrombus (0.661 cm×0.227 cm) on the surface of the occluder (d1) and the total disappearance of the thrombus after the initiation of anticoagulation therapy with warfarin (d2). Red arrows indicate the thrombosis.\n\nCase 2\nA 66−year−old female patient (weight, 65 kg; height, 156 cm; BMI, 26.7 kg/m2) visited our clinic for further evaluation after having an ischemic stroke. She reported recurrent palpitations and chest pain for 2 years. The ECG demonstrated typical AF patterns with irregular RR intervals and no discernible, distinct P waves. She had a history of hypertension with currently uncontrolled high blood pressure. Paroxysmal AF was diagnosed, and OAC treatment with warfarin was initiated (the CHA2DS2-VASc score is 5). After medication with OAC, she suffered upper gastrointestinal bleeding in the following year. She was then transferred to a tertiary cardiology center for a LAAC operation, which provides stroke prevention in patients with nonvalvular AF who are eligible for OAC therapy. As the LAA and left atrium were free of thrombosis, the LAAC operation was performed, and a 30-mm Watchman occluder device (Boston Scientific, MA, USA) was successfully deployed under general anesthesia in the LAA with a good seal and no leaks. She was discharged with an 8-week course of dabigatran (110 mg b.i.d.) for anticoagulation and a follow-up TEE for the assessment of DRT. In consideration of the gastrointestinal bleeding, she was medicated with PPI (rabeprazole, 10 mg b.i.d.). Six weeks after implantation, a TEE revealed thrombosis in the anterolateral surface of the occluder (\nFigure 2\n, b1). In consideration of warfarin-induced upper gastrointestinal bleeding, the anticoagulation strategy switched from dabigatran to rivaroxaban (15 mg q.d.) due to the appearance of thrombosis, and another TEE was scheduled for 12 weeks later. Under the effective anticoagulation, the new TEE showed a total elimination of thrombosis (\nFigure 2\n, b2). She suffered no bleeding event after the anticoagulation strategy change in the following 2 years.\n\nCase 3\nA 66-year-old man (weight, 87 kg; height, 170 cm; BMI, 30.1 kg/m2) was referred to our cardiovascular center for the management of a recent ischemic stroke complicated by permanent AF despite receiving antiplatelet therapy with gastrointestinal hemorrhage transformation. A 24-h Holter monitor displayed a dominant rhythm as AF. His medical history included hypertension and coronary heart disease treated with nifedipine controlled-release tablets (30 mg q.d.) and clopidogrel (75 mg q.d.). His CHA2DS2-VASc score was 5, in the high-risk category of thrombosis and his HAS-BLED score was 5, in the category of high bleeding risk. Although there was no strong case against OAC use, neurologists indicated a high risk of cerebral bleeding under anticoagulant therapy. Upon confirming no thrombosis in the LAA and left atrium, a LAAC operation was successfully performed on the patient using a 33-mm Watchman occluder device (Boston Scientific, MA, USA) that was placed accurately on the LAA with no immediate complications. The patient was discharged, and anticoagulated with dabigatran (110 mg b.i.d.) for 8 weeks was combined with PPI (rabeprazole, 10 mg b.i.d.). Two months later, a TEE check-up revealed abnormal hemodynamics in the LAA, suspected as thrombosis (\nFigure 2\n, c1). The antithrombotic regimen was switched from dabigatran to warfarin (3.75 mg q.d.) within the therapeutic range (INR, 2.0–3.0), combined with clopidogrel (75 mg q.d.). A further TEE was performed to confirm the resolution of DRT after 3 months following anticoagulation treatment (\nFigure 2\n, c2). Warfarin was stopped, and the patient resumed dual antiplatelet therapy for six more months followed by life-long aspirin. No transient ischemic attacks (TIA) or bleeding related complications occurred in the follow-up examinations.\n\nCase 4\nA 78-year-old man (weight, 78 kg; height, 173 cm; BMI, 26.0 kg/m2) suffered a transient ischemic attack (TIA) with clinical presentation as hemiplegia and slurred speech for 5 months. The 24-h Holter monitor displayed paroxysmal AF. The patient had an extensive medical history, including coronary artery disease (CAD), arteriosclerosis obliterans, hypertension, and chronic kidney disease (CKD III). The estimated glomerular filtration rate (eGFR) was calculated as 45 by the modified MDRD equation and was diagnosed as stage III renal dysfunction. He received dabigatran (110 mg b.i.d.) for stroke prevention, and routine urine tests revealed hematuria after anticoagulation initiation. His CHA2DS2-VASc score was 6 (hypertensive, aged 75 years, and suffering from transient ischemic attacks and vascular disease), and his HAS-BLED score was 6 (hypertension, abnormal renal function, stroke, bleeding, elderly, and drugs). Due to his unsuitability for long term anticoagulation and the high risk of stroke, he was transferred to the cardiology center for further analysis of AF and consideration of LAAC. A 30-mm Watchman occluder device (Boston Scientific, MA, USA) was successfully deployed under general anesthesia in the LAA with a good seal and no leaks. It was confirmed by a TEE that there was no thrombosis in the LAA. He was discharged with an eight-week course of dabigatran (110 mg b.i.d.) for post-implantation anticoagulation treatment, followed by dual antiplatelet therapy (aspirin, 100 mg q.d.; clopidogrel, 75 mg q.d.) for 6 months and aspirin (100 mg q.d.) for life. The routine follow-up TEE for the LAAC device position after 2 months revealed thrombus on the surface of the occluder (\nFigure 2\n, d1). He was switched from dabigatran to warfarin with a target INR of 2.0–3.0 for prolonged anticoagulation, followed by a repeat TEE scheduled for 8 weeks later. TEE check-ups later revealed the total disappearance of the abnormal thrombosis with the final diagnosis refined as DRT (\nFigure 2\n, d2). No TIA and bleeding-related complications occurred. Warfarin was stopped and dual antiplatelet therapy (100 mg of aspirin and 75 mg clopidogrel) was initiated instead.\n\nDiscussion\nTo the best of our knowledge, this is the first report to investigate thrombosis formed on LAA devices associated with dabigatran exposure in patients undergoing percutaneous LAAC. There was a total disappearance of the abnormal thrombosis under anticoagulation conversion from dabigatran to rivaroxaban and warfarin. Our findings indicate that dabigatran is less effective than warfarin and rivaroxaban in reducing thrombosis after LAAC procedures. Our report indicates that postoperative DRT may still take place despite the use of dabigatran.\n\nAntithrombotic Therapy for Postoperative Care\nPrevious animal test results showed that device endothelialization might occur over the LAA surface and extend over the adjacent endothelium following occluder implantation (Bass, 2010; Schwartz et al., 2010). In our review, the occurrence of thrombosis on the novel Watchman device is thought to be more frequent in the first few weeks after implantation and to decline with complete endothelialization of the device surface. According to current guidelines, it is recommended that an intensive course of anticoagulation with NOAC is given to patients ineligible for warfarin to facilitate device endothelialization, followed by dual antiplatelet therapy for six months and then lifelong aspirin (Glikson et al., 2019).\n\nRisk Factors of Thrombosis Formation After LAAC Operation\nIn our study of the four patients with DRT, routine follow-up TEE identified post-procedure thrombosis formation. Given the common use of LAAC operations in patients with intolerant bleeding risk under OAC, DRT leaves both patients and physicians with a dilemma: it provides an iatrogenic indication for therapeutic anticoagulant therapy and additional TEE check-ups. Many risk factors might contribute to DRT including procoagulant patient-specific factors with a high risk of thrombosis, device implantation specific factors, and inappropriate anticoagulation (Kaneko et al., 2017). Notably, incomplete closures with peri-device leakage were associated with thromboembolic events (Kanderian et al., 2008). It was likely that residual flow around the device into a stagnant LAA pouch might contribute to turbulent blood flow and enhance platelet adhesion and clot formation (Saw et al., 2017). In our four cases, TEE imaging displayed a good seal and no leaks for occluders inserted on the LAA which ruled out device implantation specific factors. The mechanism of thrombosis formation after LAAC operations was more likely involved with high-risk procoagulant features and inappropriate anticoagulation. Also, the deployed device size may be another probable contributor to DRT. A previous study reported that the device size was larger in patients with development of thrombus (29.3 ± 3.8 mm vs. 25.7 ± 3.2 mm, respectively) after the Watchman device implantation (Kubo et al., 2017). The increased risk of thrombus formation may be explained by the larger area of the fabric on the larger device. In our cases, the patients were implanted with a device size of 33 mm, which could add up to the risk of postoperative DRT. However, we think that anticoagulation with dabigatran played a principal role, since complete thrombus resolution was observed after switching to alternative anticoagulation therapy.\n\nPost-LAAC Anticoagulation With NOAC for DRT Prevention\nAfter successful Watchman implantation, a post-thrombotic regimen with NOAC is considered as a substitute for patients who are unable to tolerate a short duration of warfarin until complete endothelialization of LAA devices (Reddy et al., 2017). Effective and safe therapy with warfarin requires continuous monitoring of prothrombin time (PT) and INR levels to adjust the dose of warfarin (Numao et al., 2017). Warfarin has a narrow therapeutic window with an INR in the range of 2.0–3.0, and many factors can influence the warfarin dosing algorithm including patient characteristics such as body mass index (BMI), age, comorbidities, concomitant drugs, and diet, as well as genetic variants for warfarin metabolism via cytochrome P450 (CYP) 2C9 and genetic differences in recycling vitamin K through vitamin K epoxide reductase (VKORC1) (Verhoef et al., 2014; Gage et al., 2017; Drozda et al., 2018). Many randomized clinical trials (RCT) demonstrated that NOAC was superior to warfarin in efficacy and safety and NOACs seemed to be more effective and safer for short period anticoagulation compared with warfarin for patients post LAAC operation (Connolly et al., 2009; Reddy et al., 2017). However, there are currently no comparisons of clinical efficacy and safety with NOACs for patients undergoing LAAC operations.\n\nThrombosis on Closure Devices Anticoagulated With Dabigatran\nDabigatran, a direct inhibitor of thrombin, has been shown to be an alternative anticoagulant for patients intolerant of warfarin in the prevention and treatment of thromboembolic disease (Connolly et al., 2009). In these four cases, the follow-up TEE imaging displayed thrombosis with DRT; therefore, anticoagulant adjustment was needed to treat the thrombus. At present, there is no relevant literature about the mechanism for dabigatran medication increasing thrombosis risks post LAAC operation. One clinical study demonstrated that dabigatran medication could increase platelet reactivity by enhancing thrombin receptor density on thrombocytes, contributing to increased risk of myocardial infarction (Franchi et al., 2016). Dabigatran-enhanced platelet reactivity induced by the thrombin receptor activating peptide is specific to thrombin-induced platelet activation (Reilly et al., 2014; Yau et al., 2014). This might be one reason for the occurrence of DRT after a LAAC operation.\n\nLike other blood-contacting medical devices, the occluder components trigger thrombosis formation via activation of the intrinsic pathway. It is possible that after LAAC higher than the conventionally used doses of dabigatran (i.e., 100 mg b.i.d.) may be required to prevent DRT. Also, some studies indicate that standard dosing regimens may be associated with lower dabigatran plasma concentrations in obese patients because of higher volumes of distribution (Yau et al., 2014). BMI of >25 was the cut-off point according to the World Health Organization for obesity (Haschke et al., 2016). This might lead to a reduction in the anti-thrombosis effect of dabigatran and an increase in the incidence of DRT (Lucijanic et al., 2020). One probable explanation for our four cases with closure device-related thrombosis anticoagulated with dabigatran was the suboptimal drug dosage levels which potentially increased the risk of thrombosis.\n\nAnother probable mechanism for attenuated anticoagulation might be a dabigatran/PPI interaction leading to decreased dabigatran plasma concentration. The bioavailability of dabigatran etexilate is pH-dependent, and co-administration with PPI could increase gastric pH levels, which might decrease the dissolution of dabigatran etexilate (Schnierer et al., 2020). Three cases in our study were in concomitant medication with PPI after the LAAC operation.\n\nThe common genetic variants of CES1 and ABCB1 have been identified to potentially account for the interindividual variations in dabigatran plasma levels which could lead to varied anticoagulation therapeutic responses (Sychev et al., 2020). It has been proven that the single nucleotide polymorphism (SNP) in the CES1 gene (rs2244613) could alter dabigatran metabolism, leading to lower trough concentrations and increasing thrombosis risks (Sychev et al., 2020). However, we did not investigate the two associated genetic variants in these four cases.\n\nThrombus Reversal After Transferring to Rivaroxaban and Warfarin\nAfter the confirmation of thrombus, we switched to rivaroxaban and warfarin for anticoagulation, leading to a gradual reduction of thrombosis. In contrast to the anticoagulation mechanism of dabigatran, rivaroxaban is a factor X inhibitor and selectively inhibits FXa with a rapid onset of action, which was beneficial to the prevention of thrombosis and platelet aggregation (Enomoto et al., 2017). Many clinical trials demonstrated that oral rivaroxaban co-administration with antiplatelet therapy could decrease the incidence of thromboembolism with thromboembolic events and deaths due to cardiovascular events, myocardial infarction and stroke (Rubboli et al., 2015).\n\nConclusion\nDRT after LAAO has been acknowledged to have a strong correlation with the risks of postoperative stroke and systematic embolic events. Hence, in these cases, the patients are still confronted with neurologic morbidity and mortality. Moreover, the incidence of re-hospitalization and outpatient follow-up visits for adjusting anticoagulation medication might also lead to a waste of medical resources and the added burden of medical expenses. Besides procedural factors including larger device size and deep implantation, which were related to the risk of thrombus formation, novel oral anticoagulant usage such as dabigatran at discharge was also associated with a risk of thrombus formation. The patient BMI and co-administration with PPI should be taken into account during the medication process. The management of such a complication is not standardized, and transferring to rivaroxaban and warfarin might be an alternative anticoagulation strategy. The limitation was the absence of dabigatran related genetic testing for these patients.\n\nData Availability Statement\nAll datasets presented in this study are included in the article/supplementary material.\n\nEthics Statement\nWritten informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nXL wrote manuscript and performed literature search and review. XZ provided case and corrected manuscript. 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Incidence and Clinical Impact of Device-Associated Thrombus and Peri-Device Leak Following Left Atrial Appendage Closure With the Amplatzer Cardiac Plug\n. JACC Cardiovasc. Interv. \n10 (4 ), 391 –399\n. 10.1016/j.jcin.2016.11.029 \n28231907 \n\nSaw J. Nielsen-Kudsk J. E. Bergmann M. Daniels M. J. Tzikas A. Reisman M. (2019 ). Antithrombotic Therapy and Device-Related Thrombosis Following Endovascular Left Atrial Appendage Closure\n. JACC Cardiovasc. Interv. \n12 (11 ), 1067 –1076\n. 10.1016/j.jcin.2018.11.001 \n31103535 \n\nSchnierer M. Samoš M. Bolek T. Škorňová I. Nosáková L. Bánovčin P. (2020 ). The Effect of Proton Pump Inhibitor Withdrawal on Dabigatran Etexilate Plasma Levels in Patients With Atrial Fibrillation: A Washout Study\n. J. Cardiovasc. Pharmacol. \n75 (4 ), 333 –335\n. 10.1097/fjc.0000000000000791 \n31895873 \n\nSchwartz R. S. Holmes D. R. Van Tassel R. A. Hauser R. Henry T. D. Mooney M. (2010 ). Left atrial appendage obliteration: mechanisms of healing and intracardiac integration\n. JACC Cardiovasc. Interv. \n3 (8 ), 870 –877\n. 10.1016/j.jcin.2010.04.017 \n20723861 \n\nSkurk C. Landmesser U. (2020 ). Left atrial appendage occlusion for stroke prevention - state of the art as provided in an updated EHRA/EAPCI consensus statement and future perspectives\n. EuroIntervention \n15 (13 ), 1117 –1119\n. 10.4244/eijv15i13a207 \n31951209 \n\nSychev D. Skripka A. Ryzhikova K. Bochkov P. Shevchenko R. Krupenin P. (2020 ). Effect of CES1 and ABCB1 genotypes on the pharmacokinetics and clinical outcomes of dabigatran etexilate in patients with atrial fibrillation and chronic kidney disease\n. Drug Metab. Pers. Ther. \n35 (1 ). 10.1515/dmpt-2019-0029 \n\n\nTang X. Zhang Z. Wang F. Bai Y. Xu X. Huang X. (2017 ). Percutaneous Left Atrial Appendage Closure With LACBES(®) Occluder - A Preclinical Feasibility Study\n. Circ. J. \n82 (1 ), 87 –92\n. 10.1253/circj.CJ-17-0412 \n28781331 \n\nVerhoef T. I. Redekop W. K. Daly A. K. van Schie R. M. de Boer A. Maitland-van der Zee A. H. (2014 ). Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon\n. Br. J. Clin. Pharmacol. \n77 (4 ), 626 –641\n. 10.1111/bcp.12220 \n23919835 \n\nWintgens L. I. S. Vorselaars V. M. M. Klaver M. N. Swaans M. J. Alipour A. Rensing B. (2019 ). Left atrial appendage closure in atrial fibrillation patients with prior major bleeding or ineligible for oral anticoagulation\n. Neth Heart J. \n27 (12 ), 613 –620\n. 10.1007/s12471-019-1295-5 \n31187455 \n\nYau J. W. Liao P. Fredenburgh J. C. Roberts R. S. Weitz J. I. (2014 ). Only high levels of dabigatran attenuate catheter thrombosis in vitro and in rabbits\n. Thromb. Haemost. \n112 (1 ), 79 –86\n. 10.1160/th13-12-1047 \n24573541\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "11()",
"journal": "Frontiers in pharmacology",
"keywords": "atrial fibrillation; dabigatran; device-related thrombosis; left atrial appendage closure; novel oral anticoagulation",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "563920",
"pmc": null,
"pmid": "33013399",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "28231907;24573541;24076487;30962008;29759668;28638002;30175278;26935273;20665856;28606886;28973620;26304938;27771552;22612654;29103847;27088337;30353645;30586229;20723861;31951209;31895873;27567408;31504441;31748190;31171280;23919835;32134727;28781331;31103535;18772063;31187455;19717844;26633836;28477098;26093527",
"title": "Closure Device-Related Thrombosis After Anticoagulation With Dabigatran in Patients Undergoing Percutaneous Left Atrial Appendage Closure: Case Reports and Literature Review.",
"title_normalized": "closure device related thrombosis after anticoagulation with dabigatran in patients undergoing percutaneous left atrial appendage closure case reports and literature review"
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"companynumb": "CN-AYTU BIOSCIENCES, INC.-2020AYT000278",
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"activesubstancename": "RABEPRAZOLE SODIUM"
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"abstract": "To evaluate the incidence of newly diagnosed intracardiac thrombi (ICT) in respect to the mode of OAC in patients undergoing cardioversion (CV).\n\n\n\nWe prospectively assessed transesophageal echocardiography (TEE) and OAC therapy prior to CV in AF patients with ≥48-hour duration scheduled for CV. A total of 60 first-time ICT (4.7%) were diagnosed in 1,286 TEE, with highest rate in patients without OAC (9.6% vs. OAC 4.1%, P = 0.009) and an apparently lower rate in nonvitamin K antagonist anticoagulants (NOAC) therapy compared to vitamin K antagonist (VKA) (2.5% vs. 5.3%, P = 0.02). VKA therapy control 4 weeks prior to CV was overall average (time in therapeutic range 60%) and patients showed more frequently clinical characteristics and TEE parameters associated with risk for ICT. Even among patients with effective OAC therapy (uninterrupted NOAC and VKA therapy with international normalized ratio (INR) ≥2.0 for 3 weeks), ICT occurred in 2.7%, but with no difference between both groups (P = 0.22). There was no difference between different types of NOAC. Independent predictors for ICT were history of embolism, hypertension, BMI, absence of OAC, renal function, reduced atrial appendage flow, and presence of spontaneous echo contrast.\n\n\n\nNOAC therapy seems favorable in the overall prevention of ICT, although this is likely to be caused by suboptimal VKA therapy control and differences in the overall health status between VKA and NOAC patients. ICT occurred even with effective OAC therapy suggesting individual TEE-guided cardioversion in patients at risk.",
"affiliations": "Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Medical Biometry and Epidemiology, University Hospital Hamburg, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Cologne, Cologne, Germany.;Department of Cardiology - Electrophysiology, University Hospital Cologne, Cologne, Germany.;Department of Cardiology - Electrophysiology, University Hospital Cologne, Cologne, Germany.;Department of Cardiology - Electrophysiology, University Hospital Hamburg, University Heart Center, Hamburg, Germany.;Department of Cardiology - Electrophysiology, University Hospital Mainz, Mainz, Germany.",
"authors": "Schaeffer|Benjamin|B|0000-0002-8044-8408;Rüden|Lea|L|;Salzbrunn|Tim|T|;Pinnschmidt|Hans O|HO|;Akbulak|Ruken Özge|RÖ|;Moser|Julia Magdalena|JM|;Jularic|Mario|M|;Meyer|Christian|C|;Eickholt|Christian|C|0000-0002-5458-9688;Sultan|Arian|A|;Lüker|Jakob|J|;Steven|Daniel|D|;Willems|Stephan|S|;Hoffmann|Boris Alexander|BA|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1111/jce.13447",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1045-3873",
"issue": "29(4)",
"journal": "Journal of cardiovascular electrophysiology",
"keywords": "NOAC; atrial fibrillation; cardioversion; oral anticoagulation; thrombus",
"medline_ta": "J Cardiovasc Electrophysiol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D018619:Echocardiography, Doppler, Pulsed; D017548:Echocardiography, Transesophageal; D004554:Electric Countershock; D004562:Electrocardiography; D005260:Female; D006304:Health Status; D006801:Humans; D015994:Incidence; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D013927:Thrombosis; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9010756",
"other_id": null,
"pages": "537-547",
"pmc": null,
"pmid": "29377448",
"pubdate": "2018-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Incidence of intracardiac thrombus formation prior to electrical cardioversion in respect to the mode of oral anticoagulation.",
"title_normalized": "incidence of intracardiac thrombus formation prior to electrical cardioversion in respect to the mode of oral anticoagulation"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-47140GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nCurrent data on incidence of interstitial lung diseases (ILDs) are sparse and concerns about an increasing trend have been raised. We examined incidence rates (IRs) of ILDs and changes in IRs between 1995 and 2005.\n\n\nMETHODS\nAll persons with a first-time hospital discharge or outpatient diagnosis of ILD were identified through the Danish National Registry of Patients, which covers all Danish hospitals. Crude and age-standardised IRs were computed for ILD overall, as well as stratified by ILD subcategories.\n\n\nRESULTS\nA total of 21,765 patients with ILD were identified. Between 1995 and 1998 the overall standardised IR of ILD decreased from 27.14 (95% CI 25.82-28.46) per 100,000 person-years to 19.36 (95% CI 18.26-20.46) per 100,000 person-years. After 1998 the IR increased considerably, peaking at 34.34 (95% CI 32.84-35.85) per 100,000 person-years in 2002. Subsequently there was a slight decrease. The highest IR was observed in the non-specific category \"Respiratory disorders in diseases classified elsewhere\". By ILD subcategory, the greatest average increase during the study period was observed in \"Respiratory disorders in diseases classified elsewhere\".\n\n\nCONCLUSIONS\nThe incidence rate of ILD in Denmark increased during the study period, most pronounced for ILDs associated with systemic diseases.",
"affiliations": "Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Aalborg, Denmark. j.kornum@rn.dk",
"authors": "Kornum|Jette B|JB|;Christensen|Steffen|S|;Grijota|Miriam|M|;Pedersen|Lars|L|;Wogelius|Pia|P|;Beiderbeck|Annette|A|;Sørensen|Henrik Toft|HT|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1471-2466-8-24",
"fulltext": "\n==== Front\nBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central 1471-2466-8-241898365310.1186/1471-2466-8-24Research ArticleThe incidence of interstitial lung disease 1995–2005: a Danish nationwide population-based study Kornum Jette B 1j.kornum@rn.dkChristensen Steffen 1sc@dce.au.dkGrijota Miriam 1miriam.grijota@dce.au.dkPedersen Lars 1lap@dce.au.dkWogelius Pia 1wog-fb@aalborg.dkBeiderbeck Annette 2abeiderbeck@tgrd.comSørensen Henrik Toft 1hts@dce.au.dk1 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Aalborg, Denmark2 Worldwide Epidemiology, GlaxoSmithKline, Greenford, UK2008 4 11 2008 8 24 24 24 6 2008 4 11 2008 Copyright © 2008 Kornum et al; licensee BioMed Central Ltd.2008Kornum et al; licensee BioMed Central Ltd.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.\n\nBackground\nCurrent data on incidence of interstitial lung diseases (ILDs) are sparse and concerns about an increasing trend have been raised. We examined incidence rates (IRs) of ILDs and changes in IRs between 1995 and 2005.\n\nMethods\nAll persons with a first-time hospital discharge or outpatient diagnosis of ILD were identified through the Danish National Registry of Patients, which covers all Danish hospitals. Crude and age-standardised IRs were computed for ILD overall, as well as stratified by ILD subcategories.\n\nResults\nA total of 21,765 patients with ILD were identified. Between 1995 and 1998 the overall standardised IR of ILD decreased from 27.14 (95% CI 25.82–28.46) per 100,000 person-years to 19.36 (95% CI 18.26–20.46) per 100,000 person-years. After 1998 the IR increased considerably, peaking at 34.34 (95% CI 32.84–35.85) per 100,000 person-years in 2002. Subsequently there was a slight decrease. The highest IR was observed in the non-specific category \"Respiratory disorders in diseases classified elsewhere\". By ILD subcategory, the greatest average increase during the study period was observed in \"Respiratory disorders in diseases classified elsewhere\".\n\nConclusion\nThe incidence rate of ILD in Denmark increased during the study period, most pronounced for ILDs associated with systemic diseases.\n==== Body\nBackground\nInterstitial lung diseases (ILDs) are a heterogeneous group of more than 200 different serious disease entities with common functional characteristics such as restrictive physiology and impaired gas exchange, and with variable degrees of pulmonary inflammation and fibrosis [1,2]. Approximately two-thirds of ILD cases have no reported aetiology [3]. The remaining one-third is associated with or defined by various environmental or occupational factors including cigarette smoking, aspiration, certain drugs, radiation therapy, cancer, and systemic diseases with lung involvement [2-4].\n\nData on the incidence of ILDs are sparse [2,4]. The few previous studies have reported an eightfold variation in ILD incidence, from 3.62 per 100,000 person-years in southern Spain [5] to 31.5 per 100,000 person-years in males and 26.1 per 100,000 person-years in females in New Mexico, USA [6]. The inconsistency of estimated incidence rates internationally may stem from differences in sampling procedures and diagnostic criteria and measurement bias arising from variation in coding practices and case ascertainment. Previous European studies of ILD occurrence, based on questionnaires sent to chest physicians, may underestimate the true incidence [5,7-10]. The only truly population-based study, conducted over 15 years ago, encompassed a relatively small US population of 480,577 and was restricted to a 2-year study period [6].\n\nWhile some reports suggest that the prevalence and incidence of ILDs have increased during recent decades [3], no population-based longitudinal studies have documented recent temporal trends in ILD subgroups.\n\nUpdated incidence data are essential for predicting health care demand, for evaluating continuing needs for prevention programs such as asbestosis abatement, and to foster our understanding of possible changes in presumed risk factors over time.\n\nWe conducted this population-based study to examine the current incidence rate of ILDs and temporal changes in incidence rate between 1995 and 2005.\n\nMethods\nSetting and study population\nThe entire Danish population of 5.4 million people was setting for this population-based study [11]. The Danish National Health Service provides tax-supported health care for all residents, including free access to primary care and hospitals. Care of all patients with complicated respiratory diseases, including ILDs, is provided by specialised centres within public hospitals operating under the auspices of the Danish National Health Service. Since 1968, the Danish Civil Registration System has kept electronic records, updated daily, on date of birth, gender, change of address, date of emigration, and changes in vital status for all Danish residents. Use of civil registration numbers, assigned to every Danish resident, allows accurate linkage among Danish registries [11].\n\nIdentification of patients with interstitial lung disease\nThe Danish National Registry of Patients (NRP) contains information on all discharges from non-psychiatric hospitals since 1977. Information on outpatient and emergency room visits was added in 1995. The NRP includes civil registration number, dates of hospital admission and discharge, and up to 20 discharge diagnoses, classified by physicians according to the International Classification of Diseases, 8th revision (ICD-8) until the end of 1993 and according to the 10th revision (ICD-10) thereafter. We included all patients with a first-time hospital discharge or hospital outpatient visit diagnosis of ILD between 1 January, 1995 and 31 December, 2005. We included ILD diagnoses registered as either primary or secondary diagnosis in the hospital discharge list. The following ICD-10 codes were used: J60.X–J70.X (except J66, J68.2, J70.8, and J70.9), J82.X, J84.X, J99.X, D76.0, D86.0 and D86.2. (See additional file 1 for further information on ICD codes). Since we were interested in the incidence of ILD, we excluded patients diagnosed with ILD in 1994.\n\nStatistical analysis\nWe computed annual crude and age-standardised incidence rates (IRs) for ILD overall and stratified by gender. IRs were defined as the number of patients with a first-time diagnosis of ILD in a given year divided by the number of citizens alive in Denmark in the middle of that year (obtained from Statistics Denmark). Age-standardised IRs were computed based on the 2000 world population (age groups: 0–14 years, 15–39 years, 40–64 years, 65–79 years, and 80+ years).\n\nWe divided the 10-year study into two periods (1 January, 1995 – 31 December, 2000 and 1 January, 2001 – 31 December, 2005) and defined IRs as the number of patients with a first time diagnosis of ILD in each time period divided by the total number of citizens alive in Denmark in the middle of each calendar year band. This approach was used overall and within subcategories of ICD-10 codes, as well as for gender- and age-specific strata. We then computed age-standardised rates for overall ILDs, gender, and subcategories of ILDs, standardised to the 2000 world population.\n\nStatistical analyses were performed with SAS software (version 9.1.3; SAS Institute, Cary, NC). The study was approved by the Danish Data Protection Agency (Record no. 2005-41-5511). No ethics approval was required because no primary data collection was done.\n\nResults\nOverall incidence\nBetween 1995 and 2005, 21,765 patients were registered with a first-time discharge or outpatient diagnosis of ILD. The median age of the 12,639 (58%) men was 63 years (interquartile range 44–75 years) and that of the 9,126 (42%) women was 64 years (interquartile range 45–76 years).\n\nFigure 1 shows the annual standardised IRs of ILD. Between 1995 and 1998 the overall standardised IR of ILD decreased from 27.14 (95% CI 25.82–28.46) per 100,000 person-years to 19.36 (95% CI 18.26–20.46) per 100,000 person-years. After 1998 the IR increased considerably, peaking at 34.34 (95% CI 32.84–35.85) per 100,000 person-years in 2002. Subsequently there was a slight decrease.\n\nFigure 1 Standardised incidence rates of ILD overall and by gender. Denmark 1995–2005. Age-standardised to the 2000 world population.\n\nThe age-standardised IR increased from 23.54 (95% CI 23.04–24.04) per 100,000 person-years in 1995–2000 to 31.28 (95% CI 30.64–31.92) per 100,000 person-years in 2001–2005 (Table 1). The IR of ILDs increased with increasing age, from 18.90 (95% CI 18.00–19.80) per 100,000 person-years in those aged 15–39 years to 165.41 (95% CI 157.73–173.08) per 100,000 person-years in those aged ≥80 years. Age-standardised incidence rates of ILDs were approximately 50% higher in males than in females throughout the study period.\n\nTable 1 The incidence (per 100,000 person-years) of ILD in Denmark overall and within age- and gender-specific strata\n\n1995–2000\tCases\n(N)\tIncidence rates\nCrude\n(95% CI)*\tIncidence rates\nAge-standardised\n(95% CI)*\t\nOverall\t10,318\t32.57 (31.94–33.20)\t23.54 (23.04–24.04)\t\n\t\t\t\t\nAge\t\t\t\t\n 0–14\t609\t10.76 (9.91–11.62)\t\t\n 15–39\t1,449\t13.01 (12.34–13.68)\t\t\n 40–64\t3,312\t32.72 (31.61–33.84)\t\t\n 65–79\t3,584\t101.81 (98.48–105.15)\t\t\n 80+\t1,364\t110.06 (104.21–115.90)\t\t\nGender\t\t\t\t\n Male\t6,063\t38.75 (37.78–39.73)\t29.12 (28.33–29.90)\t\n Female\t4,255\t26.54 (25.74–27.33)\t18.69 (18.05–19.33)\t\n\t\n2001–2005\t\t\t\t\n\t\t\t\t\nOverall\t11,447\t42.66 (41.88–43.44)\t31.28 (30.64–31.92)\t\n\t\t\t\t\nAge\t\t\t\t\n 0–14\t815\t16.23 (15.12–17.35)\t\t\n 15–39\t1,693\t18.90 (18.00–19.80)\t\t\n 40–64\t3,737\t42.08 (40.74–43.43)\t\t\n 65–79\t3,418\t118.02 (114.07–121.98)\t\t\n 80+\t1,784\t165.41 (157.73–173.08)\t\t\nGender\t\t\t\t\n Male\t6,576\t49.56 (48.36–50.76)\t37.79 (36.81–38.78)\t\n Female\t4,871\t35.90 (34.90–36.91)\t25.43 (24.61–26.25)\t\n*CI: confidence interval\n\nIncidence of specific ILD diagnoses\nIn the 2001–2005 period, ILD subcategories with the highest IRs were \"Respiratory disorders in diseases classified elsewhere\" (standardised IR 7.73; 95% CI 7.39–8.07), \"Other interstitial pulmonary diseases except idiopathic pulmonary fibrosis\" (standardised IR 6.26; 95% CI 6.00–6.52), \"Pneumonitis due to solids and liquids\" (standardised IR 5.20; 95% CI 4.92–5.47) and \"Sarcoidosis with lung involvement\" (standardised IR 4.11; 95% CI 3.87–4.34) (Table 2). The highest average increase in incidence between 1995–2000 and 2001–2005 was in the subcategory J99 \"Respiratory disorders in diseases classified elsewhere\" (Table 2 and 3). The IR for each subcategory of J99 (\"J99.0 Rheumatoid lung disease\", \"J99.1 Respiratory disorders in other diffuse connective tissue disorders\" and \"J99.8 Respiratory disorders in other diseases classified elsewhere\") is also shown in table 2 and 3. Of the 3,152 patients with a J99 diagnosis, 862 were coded with a subcategory of J99. A decrease in incidence between the two periods was found only in the following subcategories: \"pneumoconiosis due to asbestos and other mineral fibres, dust containing silica, and other inorganic dust\", \"unspecified pneumoconiosis\", \"pulmonary eosinophilia\", \"idiopathic pulmonary fibrosis\".\n\nTable 2 Crude and age-standardized incidence (per 100,000 persons-years) within subcategories of ILD in Denmark 2001–2005\n\nSubcategories and diseases\tICD code\tCases (N)\tIncidence rates\nCrude\n(95% CI)*\tIncidence rates\nAge-standardised\n(95% CI)*\t\nCoalworkers' pneumoconiosis\tJ60\t17\t0.06 (0.03–0.09)\t0.05 (0.03–0.08)\t\nPneumoconiosis due to asbestos and other mineral fibres\tJ61\t332\t1.24 (1.10–1.37)\t0.70 (0.62–0.78)\t\nPneumoconiosis due to dust containing silica\tJ62\t53\t0.20 (0.14–0.25)\t0.14 (0.10–0.18)\t\nPneumoconiosis due to other inorganic dusts\tJ63\t29\t0.11 (0.07–0.15)\t0.07 (0.04–0.10)\t\nUnspecified pneumoconiosis\tJ64\t173\t0.64 (0.55–0.74)\t0.36 (0.30–0.42)\t\nPneumoconiosis associated with tuberculosis\tJ65\t18\t0.07 (0.04–0.10)\t0.08 (0.04–0.12)\t\nHypersensitivity pneumonitis due to organic dust\tJ67\t213\t0.79 (0.69–0.90)\t0.70 (0.60–0.80)\t\nRespiratory conditions due to inhalation of chemicals, gases, fumes and vapours\tJ68 (except J68.2)\t519\t1.93 (1.77–2.10)\t1.80 (1.64–1.97)\t\nPneumonitis due to solids and liquids\tJ69\t1,915\t7.14 (6.82–7.46)\t5.20 (4.92–5.47)\t\nRespiratory conditions due to other external agents\tJ70 (except J70.8, J70.9)\t191\t0.71 (0.61–0.81)\t0.43 (0.37–0.50)\t\nPulmonary eosinophilia, not elsewhere classified\tJ82\t161\t0.60 (0.51–0.69)\t0.39 (0.32–0.45)\t\nIdiopathic pulmonary fibrosis\tJ84.1\t1,417\t5.28 (5.01–5.56)\t2.91 (2.75–3.08)\t\nOther interstitial pulmonary diseases except idiopathic pulmonary fibrosis\tJ84 (except J84.1)\t2,619\t9.76 (9.39–10.13)\t6.26 (6.00–6.52)\t\nRespiratory disorders in diseases classified elsewhere\tJ99\t2,461\t9.17 (8.81–9.53)\t7.73 (7.39–8.07)\t\nRheumatoid lung disease\tJ99.0\t21\t0.08 (0.04–0.11)\t0.06 (0.03–0.09)\t\nRespiratory disorders in other diffuse connective tissue disorders\tJ99.1\t46\t0.17 (0.12–0.22)\t0.12 (0.08–0.16)\t\nRespiratory disorders in other diseases classified elsewhere\tJ99.8\t705\t2.63 (2.43–2.82)\t2.27 (2.09–2.46)\t\nLangerhans'cell histiocytosis\tD76.0\t72\t0.27 (0.21–0.33)\t0.35 (0.27–0.44)\t\nSarcoidosis with lung involvement\tD86.0 orD86.2\t1,257\t4.68 (4.43–4.94)\t4.11 (3.87–4.34)\t\n*CI: confidence interval\n\nTable 3 Crude and age-standardized incidence (per 100,000 persons-years) within subcategories of ILD in Denmark 1995–2000\n\nSubcategories\nand diseases\tICD code\tCases\n(N)\tIncidence \nrates Crude\n(95% CI)*\tIncidence rates\nAge-standardised\n(95% CI)*\t\nCoalworkers' pneumoconiosis\tJ60\t7\t0.02 (0.01–0.04)\t0.02 (0.00–0.03)\t\nPneumoconiosis due to asbestos and other mineral fibres\tJ61\t540\t1.70 (1.56–1.85)\t1.01 (0.92–1.09)\t\nPneumoconiosis due to dust containing silica\tJ62\t116\t0.37 (0.30–0.43)\t0.24 (0.19–0.29)\t\nPneumoconiosis due to other inorganic dusts\tJ63\t45\t0.14 (0.10–0.18)\t0.10 (0.07–0.13)\t\nUnspecified pneumoconiosis\tJ64\t229\t0.72 (0.63–0.82)\t0.41 (0.35–0.47)\t\nPneumoconiosis associated with tuberculosis\tJ65\t13\t0.04 (0.02–0.06)\t0.05 (0.02–0.08)\t\nHypersensitivity pneumonitis due to organic dust\tJ67\t255\t0.80 (0.71–0.90)\t0.68 (0.59–0.77)\t\nRespiratory conditions due to inhalation of chemicals, gases, fumes and vapours\tJ68 (except J68.2)\t549\t1.73 (1.59–1.88)\t1.62 (1.48–1.77)\t\nPneumonitis due to solids and liquids\tJ69\t1,449\t4.57 (4.34–4.81)\t3.86 (3.63–4.10)\t\nRespiratory conditions due to other external agents\tJ70 (except J70.8, J70.9)\t174\t0.55 (0.47–0.63)\t0.38 (0.32–0.45)\t\nPulmonary eosinophilia, not elsewhere classified\tJ82\t299\t0.94 (0.84–1.05)\t0.63 (0.56–0.71)\t\nIdiopathic pulmonary fibrosis\tJ84.1\t2,303\t7.27 (6.97–7.57)\t4.17 (3.99–4.36)\t\nOther interstitial pulmonary diseases except idiopathic pulmonary fibrosis\tJ84\n(except J84.1)\t2,374\t7.49 (7.19–7.80)\t4.89 (4.68–5.10)\t\nRespiratory disorders in diseases classified elsewhere\tJ99\t691\t2.18 (2.02–2.34)\t1.83 (1.68–1.99)\t\nRheumatoid lung disease\tJ99.0\t4\t0.01 (0.00–0.02)\t0.01 (0.00–0.02)\t\nRespiratory disorders in other diffuse connective tissue disorders\tJ99.1\t20\t0.06 (0.04–0.09)\t0.05 (0.03–0.08)\t\nRespiratory disorders in other diseases classified elsewhere\tJ99.8\t66\t0.21 (0.16–0.26)\t0.19 (0.14–0.24)\t\nLangerhans'cell histiocytosis\tD76.0\t85\t0.27 (0.21–0.33)\t0.37 (0.29–0.45)\t\nSarcoidosis with lung involvement\tD86.0 or D86.2\t1,189\t3.75 (3.54–3.97)\t3.27 (3.08–3.46)\t\n*CI: confidence interval\n\nDiscussion\nIn this large population-based study conducted within a well-defined Northern European population, the overall IR of ILDs was around 31 per 100,000 person-years in 2001–2005 and increased with 33% between 1995–2000 and 2001–2005. The increased incidence was observed in all age groups and in both genders. The increase was most noticeable in ILDs associated with other systemic diseases.\n\nThe study's longitudinal population-based design, based on data from the free tax-supported Danish health care system, enabled us to identify all hospital discharge and outpatient diagnoses of ILDs during a 10-year period, and limited the risk of referral and diagnostic bias. The validity of our findings depends ultimately on the accuracy of ILD coding, including levels of diagnostic work-up, and completeness of reporting in the Danish National Registry of Patients. A previous examination of the validity of diagnoses of interstitial lung diseases caused by external agents in the Danish National Registry of Patients yielded high positive predictive values of 92% (95% CI: 73%–98%) for drug induced ILDs and 87% (95% CI: 59%–98%) for radiation induced ILDs, compared with other discharge diagnoses [12,13]. The ICD-10 codes used to identify cases in this study do not correspond completely to the new classification recently developed for ILDs [14]. We thus were not able to apply the new classification to data in the Danish National Registry of Patients.\n\nWe may have missed patients with ILD seen only by primary care physicians, causing an underestimation of the true incidence. However, to explain the increasing incidence of ILDs, the number of ILD patients treated by primary care physicians should have changed substantially during the 10 year study period. This is an unlikely scenario, particularly since the Danish National Board of Health recommends that diagnosis and treatment of patients with ILDs occur only at highly specialised national centres [15]. While younger patients with ILD may be more likely to be referred to a hospital for treatment, controlling for age in the analysis limited the potential effect of this bias on our results.\n\nWe excluded patients registered with a diagnosis of ILD in 1994, to avoid including prevalent ILD cases. Still, we cannot entirely exclude the possibility that a combination of prevalent and incident cases might have been captured in the beginning of the study period. This potentially could lead to overestimation of ILD incidence in the beginning of the study period and to underestimation of the increase in incidence during the entire period and thus attenuate the time trend changes.\n\nThe IR found in our study is almost ninefold higher than that reported for previous European studies [5], perhaps because the earlier studies may have been limited by incomplete reporting restricted to chest physicians' diagnoses [5,8]. Contrary, our results accord with those from the 1994 population-based two-year cross sectional study conducted by Coultas et al. in New Mexico [6] despite the use of different case ascertainment methods and patients' exposure to different environmental factors. In the New Mexico study, patients with ILDs were identified from a number of sources: hospital diagnoses, physician referrals, histopathology reports, and death certificates.\n\nOur study is the first to report recent 10-year time trends for ILD subgroups in a defined population. Our findings of a slightly decreased incidence rate of idiopathic pulmonary fibrosis is in contrast to two recent US studies reporting an increased incidence and mortality from idiopathic pulmonary fibrosis [16,17]. This discrepancy could in part be due to geographic variations but also to differences in data collection methods. Based on death certificates diagnoses, classified according to ICD-9 until the end of 1998 and according to ICD-10 thereafter, Olson et al. found increasing mortality rates from pulmonary fibrosis between 1992 and 2003 [16]. They were, however not able to determine, whether this increase at least in part could be explained by differences in coding during the study period. Using a national health care claims database Raghu et al. found that idiopathic pulmonary fibrosis is more common than previous reported but no time trends were presented [17]. In our study, although using the same coding system throughout the study period, we can not entirely exclude the possibility that there may have been changes in coding of diagnoses with a shift from idiopathic pulmonary fibrosis (J84.1) to more disease specific codes.\"\n\nThe rising overall incidence of ILDs could reflect a causal rise, but the use of new and more sensitive diagnostic methods, such as high-resolution CT-scans may have contributed to the rise [3]. In Denmark the number of CT-scans increased during the study period, which may have increased the likelihood of diagnosing mild ILD cases and thus could explain some of the observed rising incidence rate of ILD. Still, the increased use of CT-scans would most likely primarily have influenced diseases classification. However, the large group of unclassified patients with ILDs both in earlier and later years of the study period argues against major diagnostic improvements over time. Finally, the coding practice may have become more meticulous during the last decade due to more focus on ILD.\n\nSome of the observed changes in subgroups are of interests. The observed predominance of ILD among male patients has previously been described [5,6,9]. It could stem from higher occupational exposure to risk factors [9] or to higher smoking frequency among men. Among ILD subcategories, the highest average increase in incidence was observed in the non-specific category \"Respiratory disorders in diseases classified elsewhere\". This category includes, however, not only rheumatoid lung disease and ILD associated with diffuse connective tissue disorders but also respiratory disorders in infections and other illnesses. Decreased ILD incidence for most subcategories of pneumoconiosis may reflect reduced use of asbestosis products and safer working environments.\n\nConclusion\nIn conclusion, we found a higher incidence of ILD than reported in previous European studies [5]. The overall IR of ILD showed a clear increase between 1995–2000 and 2001–2005, in particular for ILDs associated with other systemic diseases. These findings underscore the need for improved primary prevention efforts to reduce risk factors associated with ILD.\n\nCompeting interests\nDr Annette Beiderbeck was full-time employee of Glaxo Smith Kline at time of the study. All authors declare they have no conflicts of interest.\n\nAuthors' contributions\nJBK coordinated the study, contributed to the analysis of the data and preparation of the paper. SC and PW contributed to the design of the study and the analysis of the data and preparation of the paper. MCG and LP analysed the data and contributed to the design of the study and preparation of the paper. AB and HTS originated the study, contributed to the design of the study and preparation of the paper.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\n\n\nSupplementary Material\nAdditional file 1\nAppendix. This appendix shows the ICD-10 codes used to identify patients with ILD.\n\nClick here for file\n\n Acknowledgements\nThe study was partly funded by a grant from Glaxo Smith Kline, UK given to and administered by Aarhus University. Glaxo Smith Kline had no influence on design; collection, analysis, and interpretation of data or reporting of this study.\n==== Refs\nBehr J Ryu JH Pulmonary hypertension in interstitial lung disease Eur Respir J 2008 31 1357 67 18515559 10.1183/09031936.00171307 \nAmerican Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS) Am J Respir Crit Care Med 2000 161 646 664 10673212 \nRaghu G Nyberg F Morgan G The epidemiology of interstitial lung disease and its association with lung cancer Br J Cancer 2004 91 S3 10 15340372 10.1038/sj.bjc.6602061 \nBRITISH THORACIC SOCIETY and STANDARDS OF CARE COMMMITTEE The Diagnosis, Assessment and Treatment of Diffuse Parenchymal Lung Disease in Adults Thorax 1999 54 Suppl 1 S1 14 11006787 \nLopez-Campos JL Rodriguez-Becerra E Neumosur Task Group; Registry of Interstitial Lung Diseases Incidence of interstitial lung diseases in the south of Spain 1998–2000: the RENIA study Eur J Epidemiol 2004 19 155 161 15074571 10.1023/B:EJEP.0000017660.18541.83 \nCoultas DB Zumwalt RE Black WC Sobonya RE The epidemiology of interstitial lung diseases Am J Respir Crit Care Med 1994 150 967 972 7921471 \nRoelandt M Demedts M Callebaut W Coolen D Slabbynck H Bockaert J Kips J Brie J Ulburghs M De Boeck K epidemiology of interstitial lung disease (ILD) in flanders: registration by pneumologists in 1992–1994. Working group on ILD, VRGT. Vereniging voor Respiratoire Gezondheidszorg en Tuberculosebestrijding Acta Clin Belg 1995 50 260 268 8533525 \nSchweisfurth H [Report by the Scientific Working Group for Therapy of Lung Diseases: German Fibrosis Register with initial results] Pneumologie 1996 50 899 901 9091884 \nThomeer MJ Costabe U Rizzato G Poletti V Demedts M Comparison of registries of interstitial lung diseases in three European countries Eur Respir J Suppl 2001 32 114s 118s 11816817 \nXaubet A Ancochea J Blanquer R Montero C Morell F Rodríguez Becerra E Sueiro A Villena V Grupo de Investigación en Enfermedades Pulmonares Intersticiales Difusas. Area de Técnicas y Transplante. SEPAR Report on the incidence of interstitial lung diseases in Spain Sarcoidosis Vasc Diffuse Lung Dis 2004 21 64 70 15127977 \nFrank L Epidemiology When an entire country is a cohort Science 2000 287 2398 2399 10766613 10.1126/science.287.5462.2398 \nChristensen S Pedersen L Grijota M Kornum JB Beiderbeck A Sørensen HT Incidence of interstitial pneumonitis among breast cancer patients: a 10-year Danish population-based cohort study Br J Cancer 2008 98 1870 1875 18506191 10.1038/sj.bjc.6604393 \nSørensen HT Regional administrative health registers as a resource in clinical epidemiology A study of options, strengths, limitations and data quality provided with examples of use Int J Risk Safety Med 1997 10 1 22 \nAmerican Thoracic Society, European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001 Am J Respir Crit Care Med 2002 165 277 304 11790668 \nDirksen A Larsson A Mortensen J Milman N Faurschou P Tønnesen P Lange P Vestbo J Mosbech H Iversen M Arendrup H Harving H Clementsen P Viskum K Rasmussen FV Lungesygdomme Hansen EH, Haunsø S, Schaffalitzky de Muckadell OB Medicinsk Kompendium 2004 16 Copenhagen: Nyt Nordisk Forlag Arnold Busck 1286 1432 \nOlson AL Swigris JJ Lezotte DC Norris JM Wilson CG Brown KK Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003 Am J Respir Crit Care Med 2007 176 277 284 17478620 10.1164/rccm.200701-044OC \nRaghu G Weycker D Edelsberg J Bradford WZ Oster G Incidence and prevalence of idiopathic pulmonary fibrosis Am J Respir Crit Care Med 2006 174 810 816 16809633 10.1164/rccm.200602-163OC\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "8()",
"journal": "BMC pulmonary medicine",
"keywords": null,
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003718:Denmark; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D012042:Registries; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "100968563",
"other_id": null,
"pages": "24",
"pmc": null,
"pmid": "18983653",
"pubdate": "2008-11-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18515559;16809633;17478620;10673212;15074571;23511270;18506191;7921471;8533525;11816817;15127977;15340372;11006787;10766613;9091884;11790668",
"title": "The incidence of interstitial lung disease 1995-2005: a Danish nationwide population-based study.",
"title_normalized": "the incidence of interstitial lung disease 1995 2005 a danish nationwide population based study"
} | [
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"companynumb": "DK-MYLANLABS-2020M1019929",
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"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
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"abstract": "Bing-Neel syndrome is known as Waldenström's macroglobulinemia with central nervous system infiltration by neoplastic lymphoplasmacytoid and plasma cells. A 74-year-old man was admitted because of progressive cognitive impairment. Serum immunoelectrophoresis showed a monoclonal IgM-kappa component. Bone marrow aspiration revealed 59% small lymphocytes showing plasmacytoid differentiation. Bone marrow flow cytometry disclosed a population of kappa light-chain positive lymphoid cells expressing CD19, CD20, CD38, and CD138. Magnetic resonance imaging of the brain demonstrated gadolinium-enhancement in the right temporo-parieto-occipital meninges with sulcal enhancement. Cerebrospinal fluid cytology showed a population of lymphoplasmacytoid cells, positive for CD19, CD20, CD25, and kappa light-chain. Based on these findings, Bing-Neel syndrome was diagnosed. Although combination chemotherapy consisting of intrathecal methotrexate and oral cyclophosphamide was started, his symptoms continued to worsen. Then, we initiated treatment with a regimen consisting of fludarabine/rituximab (FR). After 6 courses of this FR regimen, a complete remission was achieved. Our case suggests the FR regimen to potentially be an effective treatment option for Bing-Neel syndrome of the scattered type.",
"affiliations": "Department of Hematology and Oncology, Mie University Graduate School of Medicine.",
"authors": "Nagaharu|Keiki|K|;Miyazami|Kana|K|;Imai|Hiroshi|H|;Tamura|Asako|A|;Umino|Akira|A|;Fujieda|Atsushi|A|;Sugimoto|Yuka|Y|;Yamaguchi|Motoko|M|;Masuya|Masahiro|M|;Katayama|Naoyuki|N|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D004338:Drug Combinations; D000069283:Rituximab; D014740:Vidarabine; C024352:fludarabine",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.55.2423",
"fulltext": null,
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"issn_linking": "0485-1439",
"issue": "55(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D001853:Bone Marrow; D004338:Drug Combinations; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D000069283:Rituximab; D014740:Vidarabine; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "2423-8",
"pmc": null,
"pmid": "25744044",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Successful treatment of Bing-Neel syndrome using combination therapy with fludarabine and rituximab.",
"title_normalized": "successful treatment of bing neel syndrome using combination therapy with fludarabine and rituximab"
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"companynumb": "JP-SA-2015SA105456",
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"abstract": "Despite the clinical efficacy of anthracycline agents such as doxorubicin, dose-limiting cardiac toxicities significantly limit their long-term use. Here, we present the case of a 33-year-old female patient with extensive metastatic ER+/PR+/HER2- mucinous adenocarcinoma of the breast, who was started on doxorubicin/cyclophosphamide therapy after progressing on paclitaxel and ovarian suppressor goserelin with aromatase inhibitor exemestane. The patient was comanaged by cardiology, who carefully monitored measures of cardiac function, including EKGs, serial echocardiograms, and profiling of lipids, troponin, and pro-BNP every 2 months. The patient was treated with the cardioprotective agent dexrazoxane, and changes in cardiac markers [e.g. decreases in ejection fraction (EF)] were immediately addressed by therapeutic intervention with the ACE inhibitor lisinopril and beta-blocker metoprolol. The patient had a complete response to doxorubicin therapy, with a cumulative dose of 1,350 mg/m2, which is significantly above the recommended limits, and to our knowledge, the highest dose reported in literature. Two and a half years after the last doxorubicin cycle, the patient is asymptomatic with no cardiotoxicity and an excellent quality of life. This case highlights the importance of careful monitoring and management of doxorubicin-mediated cardiotoxicity, and that higher cumulative doses of anthracyclines can be considered in patients with ongoing clinical benefit.",
"affiliations": "Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.;Department of Cardiovascular Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.;Department of Cardiovascular Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.;Department of Radiology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.;Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.;Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.;Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA; Department of Hematology/Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.",
"authors": "Shee|Kevin|K|;Kono|Alan T|AT|;D'Anna|Susan P|SP|;Seltzer|Mark A|MA|;Lu|Xiaoying|X|;Miller|Todd W|TW|;Chamberlin|Mary D|MD|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000453608",
"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 10.1159/000453608cro-0009-0840Case ReportMaximizing the Benefit-Cost Ratio of Anthracyclines in Metastatic Breast Cancer: Case Report of a Patient with a Complete Response to High-Dose Doxorubicin Shee Kevin a*Kono Alan T. cD'Anna Susan P. cSeltzer Mark A. dLu Xiaoying eMiller Todd W. aChamberlin Mary D. abaNorris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USAbDepartment of Hematology/Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USAcDepartment of Cardiovascular Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USAdDepartment of Radiology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USAeDepartment of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA*Kevin Shee, Geisel School of Medicine at Dartmouth, 61 Drake Ln, West Lebanon, NH 03784 (USA), E-Mail Kevin.Shee.MED@dartmouth.eduSep-Dec 2016 8 12 2016 8 12 2016 9 3 840 846 17 11 2016 18 11 2016 Copyright © 2016 the Author(s)2016This 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.Despite the clinical efficacy of anthracycline agents such as doxorubicin, dose-limiting cardiac toxicities significantly limit their long-term use. Here, we present the case of a 33-year-old female patient with extensive metastatic ER+/PR+/HER2– mucinous adenocarcinoma of the breast, who was started on doxorubicin/cyclophosphamide therapy after progressing on paclitaxel and ovarian suppressor goserelin with aromatase inhibitor exemestane. The patient was comanaged by cardiology, who carefully monitored measures of cardiac function, including EKGs, serial echocardiograms, and profiling of lipids, troponin, and pro-BNP every 2 months. The patient was treated with the cardioprotective agent dexrazoxane, and changes in cardiac markers [e.g. decreases in ejection fraction (EF)] were immediately addressed by therapeutic intervention with the ACE inhibitor lisinopril and beta-blocker metoprolol. The patient had a complete response to doxorubicin therapy, with a cumulative dose of 1,350 mg/m2, which is significantly above the recommended limits, and to our knowledge, the highest dose reported in literature. Two and a half years after the last doxorubicin cycle, the patient is asymptomatic with no cardiotoxicity and an excellent quality of life. This case highlights the importance of careful monitoring and management of doxorubicin-mediated cardiotoxicity, and that higher cumulative doses of anthracyclines can be considered in patients with ongoing clinical benefit.\n\nKeywords\nAnthracyclineDoxorubicinCardiotoxicityCardio-oncologyMetastatic breast cancerComplete response\n==== Body\nIntroduction\nAnthracyclines, such as doxorubicin (adriamycin), are a class of drugs that have been used in cancer chemotherapy regimens in a large number of tumor types since their discovery in the 1970s [1]. These agents exert anticancer effects by binding topoisomerase-II (topo2) and intercalating with DNA to inhibit macromolecular biosynthesis [2]. In breast cancer, anthracyclines are a mainstay of adjuvant breast cancer treatment either alone or in combination with other cytotoxic therapy [3]. However, these drugs are commonly associated with cardiac toxicity which significantly limits their long-term use, even in the case of ongoing response [4].\n\nCurrent guidelines are limited in that they fail to address high-risk patient populations, where the benefit of higher cumulative doses of anthracyclines has the potential to outweigh the risks. In this case report, we describe a patient with extensive metastatic estrogen receptor-positive (ER+) breast cancer, who achieved a complete response on well-managed prolonged doxorubicin treatment with a total cumulative dose of 1,350 mg/m2. Here, we demonstrate that higher cumulative doses of anthracyclines can be considered in patients with ongoing clinical benefit, and that a multidisciplinary approach to early detection and treatment of asymptomatic cardiac dysfunction can maximize the risk-benefit ratio for anthracycline-based therapy.\n\nCase Report\nIn December 2010, a 33-year-old woman presented with a 2-week history of moderate left hip pain and a lump in her stomach. On exam, a mildly tender palpable mass was noted in her epigastrium, with pain upon flexion, abduction and rotation of her left hip without atrophy or weakness. An abdominal CT was performed showing a large heterogeneous mass replacing the majority of the left lobe of the liver. CT of the chest and pelvis showed 4 indeterminate pulmonary nodules, all smaller than 5 mm, and an osseous metastasis in the anterior left acetabulum. The patient was 4 months postpartum and still lactating but a possibly 4-cm mass was noted in the left breast with bilateral lobular irregularities consistent with lactation. PET scan confirmed hypermetabolic breast, liver, and acetabular lesions, with additional detection of small hypermetabolic masses in the sacrum, inferior pubic ramus, and bilateral ovaries. Biopsy of left breast mass and metastatic liver lesion revealed histologically similar ER+/PR+/HER2– mucinous adenocarcinoma (Fig 1).\n\nIn January 2011, the patient was started on chemotherapy with weekly paclitaxel (80 mg/m2) and monthly zoledronic acid (4 mg), which led to initial stable disease with clinical improvement. After 4 cycles (July 2011), restaging CT demonstrated progressive disease, leading to the substitution of paclitaxel with ovarian suppression by goserelin and the aromatase inhibitor exemestane plus the bone-targeted agent denosumab. After 3 months on hormone therapy, the patient progressed further. In November 2011, the decision was made to pursue doublet therapy consisting of 60 mg/m2 doxorubicin and 600 mg/m2 cyclophosphamide with continuation of denosumab (120 mg monthly). At baseline, PET scan revealed extensive hypermetabolic regions in the liver and right acetabulum (Fig 2a). After 8 cycles (May 2012), with a cumulative doxorubicin dose of 444 mg/m2 (20% dose reduction for cycles 6–8), PET scan revealed no residual disease in the left breast, 75% reduction of activity in the liver, minimal residual activity in the acetabulum, and no new areas of disease (Fig 2b). In a PET scan taken on cycle 22 (June 2013; cumulative doxorubicin dose of 1,116 mg/m2), the patient achieved nearly complete resolution of disease by PET (Fig 2c). Complete response was achieved on cycle 24 (August 2013; cumulative dose of 1,200 mg/m2) and maintained through cycle 30 (May 2014; a cumulative dose of 1,350 mg/m2) (Fig 2d), after which a multidisciplinary tumor board recommended the patient be switched to second-line anti-estrogen fulvestrant with continuation of denosumab monthly.\n\nAs cardiotoxicity is the primary concern for doxorubicin-based therapy, the patient was closely comanaged by cardiology over the course of treatment. Cardioprotective iron chelator dexrazoxane was initiated with cycle 6 (March 2012; cumulative anthracycline dose of 300 mg/m2). Baseline EKG, lipid profile, cardiac biomarkers troponin and pro-BNP, and serial echocardiograms every 2–3 months were also recommended. Two decreases in ejection fraction (EF) to below normal limits (55% on August 2012 and 52% on April 2013), were managed by addition of lisinopril (2.5 mg daily) and metoprolol (12.5 mg daily), respectively, which reversed the drop in EF (Fig 3).\n\nIn 2016, 6 years after diagnosis, nearly 5 years after initial AC treatment, and 2.5 years after termination of AC therapy, the patient remains minimally symptomatic on capecitabine, working full time with no cardiotoxicity and an excellent quality of life with her husband and 6-year old daughter.\n\nDiscussion\nHere, we describe a patient who achieved a complete response after cumulative doses of anthracyclines of 1,350 mg/m2, with well-managed normal cardiac function (as measured by echocardiogram) through the entire duration of treatment and for >2.5 years of follow-up. While we cannot rule out future late-onset cardiotoxicity (>2 years after treatment), most cardiotoxicity after anthracycline-containing therapy occurs within the first year [5]. Here, we will discuss what is currently known about anthracycline-induced cardiotoxicity, including risk factors, molecular mechanisms, genetics, management, and limitations of current guidelines.\n\nThe strongest predictor of anthracycline-induced cardiotoxicity is cumulative dose. In the most recent analysis of 630 patients from 3 prospective studies, the estimated cumulative percentage of patients with doxorubicin-related cardiotoxicity (congestive heart failure) was 5% at a cumulative dose of 400 mg/m2, 26% at 550 mg, 48% at 700 mg/m2, and 100% above 800 mg/m2 [6]. In light of this analysis, the well-managed cardiotoxicity in our patient is remarkable. Additional well-characterized risk factors of anthracycline-induced cardiotoxicity include coadministration of other cardiotoxic chemotherapeutic agents (e.g. trastuzumab), prior radiation to the mediastinum, older age, and pre-existing cardiovascular disease (e.g. hypertension, vascular disease, diabetes) [7, 8].\n\nMultiple hypotheses exist for the mechanism of anthracycline-mediated toxicity. The predominant hypothesis is treatment-induced increased production of toxic oxygen free radicals and oxidative stress, which leads to irreversible damage to myocytes and fibrosis of tissues [9]. Alternative hypotheses include myocyte damage due to (1) anthracycline inhibition of the beta isoform of topoisomerase-II (Top2), (2) calcium overload, (3) disruption of adrenergic function, (4) release of anthracycline metabolites, (5) release of vasoactive amines, and/or (6) release of proinflammatory cytokines [9, 10]. The lack of clear consensus despite a wealth of evidence suggests that the mechanism of anthracycline-induced cardiotoxicity is likely multifactorial, and may differ on a case-by-case basis.\n\nSignificant interindividual variability in the development of anthracycline-mediated cardiotoxicity has recently been attributed to genetics. Early data describes significant associations between the incidence of cardiotoxicity and inherited polymorphisms in genes involved in anthracycline metabolism (e.g. carbonyl reductase CBR1, CBR3), drug efflux (e.g. MRP1, MRP2), and reactive oxygen species generation (e.g. NAPD[H] oxidase), which have been further confirmed in functional animal studies [11, 12]. Genes involving cell survival (Hsp27, TLR2/4), DNA damage and repair (p53, Rac1), as well as transcriptional regulation (GATA4, STAT3, and AMPK) have also been implicated [13]. In this patient, molecular analyses (DNA sequencing of custom 196-gene panel, chromosomal microarray) were performed on tumor and plasma DNA, which revealed no known genetic alteration that could account for cardioprotection. However, we cannot rule out the possible contribution of an uncharacterized or undetected genetic mechanism.\n\nThe management of anthracycline-mediated cardiotoxicity consists of constant monitoring and treatment with cardioprotective agents. Several cardiac tests used successfully to detect or predict early changes in cardiac function or health include echocardiogram, radionuclear cardiac imaging, cardiac MRI, electrocardiogram, and serum biomarkers such as troponin-T and NT pro-BNP [7]. Dexrazoxane has been clinically proven to significantly reduce the incidence of clinical and subclinical cardiotoxicity, and is currently recommended in metastatic patients who have received a cumulative dose of doxorubicin ≥300 mg/m2 [14]. Additional cardioprotective therapeutics used in preventative treatment include beta-blocker (e.g. carvedilol) and ACE inhibitor (e.g. elanapril), which have also been used in combination to decrease the incidence of death, heart failure, or a final LVEF <45% in patients treated with anthracyclines [15]. Additional strategies to combat cardiotoxicity include the use of less toxic structural analogs of doxorubicin, such as epirubicin and mitoxantrone, or incorporation of anthracyclines into liposomes [7].\n\nSeveral guidelines are available regarding the monitoring and management of anthracycline-related cardiotoxicity [5]. These guidelines generally provide an upper limit for cumulative dosages of anthracyclines based on cardiotoxicity data from retrospective analyses, generally recommending cumulative doses of less than 450–500 mg/m2 [7]. However, these guidelines are limited in that they fail to address high-risk patient populations where the benefit of higher cumulative doses of anthracyclines has the potential to outweigh the costs. This case thus highlights the need to establish evidence-based clinical guidelines for the monitoring and management of cardiotoxicity in these high-risk patient populations who respond to doxorubicin therapy.\n\nConclusion\nAnthracyclines are an extremely effective chemotherapeutic agent, but concerns of cardiotoxicity at higher doses prevents maximal therapeutic benefit of anthracycline treatment. Our case demonstrates that higher cumulative doses of anthracycline can be considered in high-risk patients with ongoing clinical benefit, and that maximum benefit-cost ratio from anthracyclines can be achieved through vigilant monitoring and managing of small changes in cardiac function.\n\nStatement of Ethics\nThe authors received informed consent from the patient prior to writing of the case report.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nFig. 1 a Biopsy of the left breast reveals an extracellular mucin pool containing nests of neoplastic epithelial cells, classic features of mucinous (colloid) carcinoma (HE. ×20). b–d The tumor cells in the CT-guided biopsy of the metastatic liver lesion shows similar morphology to the left breast lesion (b; HE. ×20). A total of 80–90% of tumor cells are strongly positive for ER (c; HE ×20) and ∼5% are positive for PR with low intensity (d; HE ×20). HER2 fluorescence in situ hybridization (FISH) study performed on liver biopsy shows negative HER2/NEU amplification (not shown).\n\nFig. 2 a Initial PET scan prior to treatment with doxorubicin shows multiple FDG-avid metastases throughout the liver (red arrow) and a large FDG-avid metastasis in the right acetabulum (blue arrow). b–d PET scans during therapy show decreasing metabolic tumor burden in the liver and in the right acetabulum, achieving a complete metabolic response at both sites by the end of X cycles of doxorubicin. e The maximum standardized uptake value (SUV) of liver metastases decreases from the baseline pretreatment value of 5.6 to an end of treatment maximum SUV of 2.9 which is not significantly different than normal liver SUV.\n\nFig. 3 Image showing EF (%) over time as measured by echocardiogram. Two points at the lower limit of normal or below the normal EF limit (arrows) were treated immediately with therapeutic intervention by cardiology, each of which was able to restore the EF to normal limits. The EF remained stable over the course of doxorubicin treatment and afterwards. Each point represents the date at which the patient had an echocardiogram. EF, ejection fraction.\n==== Refs\nReferences\n1 Arcamone F Cassinelli G Fantini G Grein A Orezzi P Pol C Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S peucetius var. caesius. Biotechnol Bioeng 1969 11 1101 1110 5365804 \n2 Momparler RL Karon M Siegel SE Avila F Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells Cancer Res 1976 36 2891 2895 1277199 \n3 Early Breast Cancer Trialists’ Collaborative Group Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials Lancet 2005 365 1687 1717 15894097 \n4 Chatterjee K Zhang J Honbo N Karliner JS Doxorubicin cardiomyopathy Cardiology 2010 115 155 162 20016174 \n5 Cardinale D Colombo A Bacchiani G Tedeschi I Meroni CA Veglia F Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy Circulation 2015 131 1981 1988 25948538 \n6 Swain SM Whaley FS Ewer MS Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials Cancer 2003 97 2869 2879 12767102 \n7 Floyd JMJ Berg S Drews REPD Gottlieb SS Cardiotoxicity of anthracycline-like chemotherapy agents UpToDate. Waltham, MA UpToDate (accessed September 7, 2016). \n8 Von Hoff DD Layard MW Basa P Davis HL Jr Von Hoff AL Rozencweig M Risk factors for doxorubicin-induced congestive heart failure Ann Intern Med 1979 91 710 717 496103 \n9 Shan K Lincoff AM Young JB Anthracycline-induced cardiotoxicity Ann Intern Med 1996 125 47 58 8644988 \n10 Zhang S Liu X Bawa-Khalfe T Lu LS Lyu YL Liu LF Identification of the molecular basis of doxorubicin-induced cardiotoxicity Nat Med 2012 18 1639 1642 23104132 \n11 Blanco JG Sun CL Landier W Chen L Esparza-Duran D Leisenring W Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes – a report from the Children's Oncology Group J Clin Oncol 2012 30 1415 1421 22124095 \n12 Wojnowski L Kulle B Schirmer M Schluter G Schmidt A Rosenberger A NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity Circulation 2005 112 3754 3762 16330681 \n13 Jensen BC McLeod HL Pharmacogenomics as a risk mitigation strategy for chemotherapeutic cardiotoxicity Pharmacogenomics 2013 14 205 213 23327580 \n14 Hensley ML Hagerty KL Kewalramani T Green DM Meropol NJ Wasserman TH American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants J Clin Oncol 2009 27 127 145 19018081 \n15 Bosch X Rovira M Sitges M Domenech A Ortiz-Perez JT de Caralt TM Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (Prevention of left Ventricular dysfunction with Enalapril and Carvedilol in patients submitted to intensive Chemotherapy for the treatment of Malignant Hemopathies) J Am Coll Cardiol 2013 61 2355 2362 23583763\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "9(3)",
"journal": "Case reports in oncology",
"keywords": "Anthracycline; Cardio-oncology; Cardiotoxicity; Complete response; Doxorubicin; Metastatic breast cancer",
"medline_ta": "Case Rep Oncol",
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"title": "Maximizing the Benefit-Cost Ratio of Anthracyclines in Metastatic Breast Cancer: Case Report of a Patient with a Complete Response to High-Dose Doxorubicin.",
"title_normalized": "maximizing the benefit cost ratio of anthracyclines in metastatic breast cancer case report of a patient with a complete response to high dose doxorubicin"
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"abstract": "Radiation-induced optic neuropathy (RION) is still a devastating complication of brain and skull base radiation that has no effective treatment up until today, thus uttermost caution must be taken in treating patients that brain radiotherapy is needed. We present two cases of RION that happened in seemingly safe radiation doses.\nA 48-year-old female with a history of pleomorphic pituitary adenoma developed bilateral and painless loss of vision 10 months after radiation to the brain; the total radiation dose was 45 Gy in 25 fractions and no other risk factors of RION were found. Magnetic resonance imaging of the brain depicted bilateral prechiasmatic optic nerve enhancement with involvement of the optic chiasm. Treatment with high doses of corticosteroids was unsuccessful. A 62-year-old female with a history of lung adenocarcinoma and brain metastases presented with a 1-month history of decreased vision in both eyes. He had undergone whole-brain radiotherapy with a total dose of 30 Gy over 10 fractions and concurrent chemotherapy with cisplatin and pemetrexed. Brain magnetic resonance imaging (MRI) with contrast showed bilateral intracranial optic nerve enhancement.\nThis is the second case report of RION in a patient with a history of brain radiotherapy and concurrent chemotherapy with pemetrexed. History of chiasmal compression, concurrent use of chemotherapeutic agents, and high fraction size (despite the safety of total radiation dose) were possible contributing risk factors to develop RION in our cases. Hence, adjusting the radiation dose according to the presence of these risk factors is recommended.",
"affiliations": "Department of Ophthalmology, Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.;Department of Ophthalmology, Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.;Department of Ophthalmology, Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.;Department of Neurology, Hazrat Rasool Hospital, Iran University of Medical Sciences, Tehran, Iran.;Department of Ophthalmology, Eye Research Center, The Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Abri Aghdam|Kaveh|K|https://orcid.org/0000-0001-7568-6455;Soltan Sanjari|Mostafa|M|;Khosravi Farsani|Mohsen|M|;Moghadasi|Mehdi|M|https://orcid.org/0000-0002-3164-180X;Aghajani|Ali|A|https://orcid.org/0000-0002-7790-6033",
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"journal": "European journal of ophthalmology",
"keywords": "Chemotherapy; pemetrexed; radiation-induced optic neuropathy; whole-brain radiotherapy",
"medline_ta": "Eur J Ophthalmol",
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"title": "Necrosis of the optic nerve and chiasm with safe radiation doses: Report of two rare cases.",
"title_normalized": "necrosis of the optic nerve and chiasm with safe radiation doses report of two rare cases"
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"abstract": "Anatomic interventions for pulmonary vein stenosis (PVS) in infants and children have been met with limited success. Sirolimus, a mammalian target of rapamycin inhibitor, has demonstrated promise as a primary medical therapy for PVS, but the impact on patient survival is unknown.\n\n\n\nThe authors sought to investigate whether mTOR inhibition with sirolimus as a primary medical therapy would improve outcomes in high-risk infants and children with PVS.\n\n\n\nIn this single-center study, patients with severe PVS were considered for systemic sirolimus therapy (SST) following a strict protocol while receiving standardized surveillance and anatomic therapies. The SST cohort was compared with a contemporary control group. The primary endpoint for this study was survival. The primary safety endpoint was adverse events (AEs) related to SST.\n\n\n\nBetween 2015 and 2020, our PVS program diagnosed and treated 67 patients with ≥moderate PVS. Of these, 15 patients were treated with sirolimus, whereas the remaining patients represent the control group. There was 100% survival in the SST group compared with 45% survival in the control group (log-rank p = 0.004). A sensitivity analysis was completed to address survival bias using median time from diagnosis of PVS to SST. A survival advantage persisted (log-rank p = 0.027). Two patients on sirolimus developed treatable AEs. Patients in the SST group underwent frequent transcatheter interventions with 3.7 catheterizations per person-year (25th to 75th percentile: 2.7 to 4.4 person-years). Median follow up time was 2.2 years (25th to 75th percentile: 1.2 to 2.9 years) in the SST group versus 0.9 years (25th to 75th percentile: 0.5 to 2.7 years) in the control group.\n\n\n\nThe authors found a survival benefit associated with SST in infants and children with moderate-to-severe PVS. This survival benefit persisted after adjusting the analysis for survival bias. There were 2 mild AEs associated with SST during the study period; both patients were able to resume therapy without recurrence.",
"affiliations": "Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Pediatrics, Division of Cardiology, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Electronic address: cjp2196@cumc.columbia.edu.",
"authors": "Patel|Jay D|JD|;Briones|Michael|M|;Mandhani|Mansi|M|;Jones|Shannon|S|;Suthar|Divya|D|;Gray|Rosemary|R|;Pettus|Joelle|J|;McCracken|Courtney|C|;Thomas|Amanda|A|;Petit|Christopher J|CJ|",
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"mesh_terms": "D000903:Antibiotics, Antineoplastic; D002675:Child, Preschool; D005260:Female; D005845:Georgia; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D020123:Sirolimus; D000071078:Stenosis, Pulmonary Vein",
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"title": "Systemic Sirolimus Therapy for Infants and Children With Pulmonary Vein Stenosis.",
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"abstract": "Drug error is a significant hazard to patient health. Poor, incorrect, and inconsistent labeling of injectable medicines and fluids, and the devices used to deliver these, has been identified as a patient safety issue. We report 5 cases of medication error as a consequence of incorrect or inappropriate labeling and analyze their cause. Recommendations for safe and practical labeling practices in anesthesia based on a review of the literature are presented. Implementation of the recommended labeling practices can reduce the risk of medication error and contribute to the safe administration of drugs.",
"affiliations": "From the Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;From the Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.;Department of Anaesthesia and Critical Care, Deen Dayal Upadhyay Hospital, New Delhi, India.;From the Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.",
"authors": "Prakash|Smita|S|;Mullick|Parul|P|;Kumar|Ajay|A|;Pawar|Mridula|M|",
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"title": "Safe Labeling Practices to Minimize Medication Errors in Anesthesia: 5 Case Reports and Review of the Literature.",
"title_normalized": "safe labeling practices to minimize medication errors in anesthesia 5 case reports and review of the literature"
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{
"abstract": "Progressive multifocal leukoencephalopathy (PML), caused by JC polyomavirus, is a demyelinating disease of the central nervous system that primarily affects oligodendrocytes. It can cause significant morbidity and mortality. An early diagnosis is of high relevance as timely immune reconstitution is essential. However, diagnosis can be challenging if virus detection via cerebrospinal fluid (CSF) PCR remains negative. Hence, identifying CSF biomarkers for this disease is of crucial importance. We applied a targeted metabolomic screen to CSF from 23 PML patients and eight normal pressure hydrocephalus (NPH) patients as controls. Out of 188 potentially detectable metabolites, 48 (13 amino acids, 4 biogenic amines, 1 acylcarnitine, 21 phosphatidylcholines, 8 sphingolipids, and the sum of hexoses) passed the quality screen and were included in the analyses. Even though there was a tendency towards lower concentrations in PML (mostly of phosphatidylcholines and sphingomyelins), none of the differences between PML and controls in individual metabolite concentrations reached statistical significance (lowest p = 0.104) and there were no potential diagnostic biomarkers (highest area under the ROC curve 0.68). Thus, CSF metabolite changes in PML are likely subtle and possibly larger group sizes and broader metabolite screens are needed to identify potential CSF metabolite biomarkers for PML.",
"affiliations": "Department of Neurology, Hannover Medical School, Hannover, Germany.;Department of Neurology, Hannover Medical School, Hannover, Germany.;Helmholtz Centre for Infection Research, Braunschweig, Germany.;Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.;Department of Neurology, Hannover Medical School, Hannover, Germany.;Department of Neurology, Hannover Medical School, Hannover, Germany.;Helmholtz Centre for Infection Research, Braunschweig, Germany.;Department of Neurology, Hannover Medical School, Hannover, Germany.",
"authors": "Luo|Yi|Y|;Möhn|Nora|N|;Al-Mekhlafi|Amani|A|;Schuchardt|Sven|S|;Skripuletz|Thomas|T|;Sühs|Wolfram|W|;Pessler|Frank|F|;Stangel|Martin|M|",
"chemical_list": "D010713:Phosphatidylcholines; D013109:Sphingomyelins",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0242321",
"fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nplosone\nPLoS ONE\n1932-6203 Public Library of Science San Francisco, CA USA \n\n10.1371/journal.pone.0242321\nPONE-D-20-26573\nResearch Article\nBiology and Life Sciences\nAnatomy\nBody Fluids\nCerebrospinal Fluid\nMedicine and Health Sciences\nAnatomy\nBody Fluids\nCerebrospinal Fluid\nBiology and Life Sciences\nPhysiology\nBody Fluids\nCerebrospinal Fluid\nBiology and Life Sciences\nAnatomy\nNervous System\nCerebrospinal Fluid\nMedicine and Health Sciences\nAnatomy\nNervous System\nCerebrospinal Fluid\nBiology and Life Sciences\nBiochemistry\nMetabolism\nMetabolites\nBiology and Life Sciences\nBiochemistry\nBiomarkers\nBiology and Life Sciences\nMolecular Biology\nMolecular Biology Techniques\nArtificial Gene Amplification and Extension\nPolymerase Chain Reaction\nResearch and Analysis Methods\nMolecular Biology Techniques\nArtificial Gene Amplification and Extension\nPolymerase Chain Reaction\nBiology and Life Sciences\nBiochemistry\nMetabolism\nMetabolomics\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nImmunodeficiency Viruses\nHIV\nBiology and life sciences\nOrganisms\nViruses\nRNA viruses\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nAnatomy\nNervous System\nCentral Nervous System\nMedicine and Health Sciences\nAnatomy\nNervous System\nCentral Nervous System\nBiology and Life Sciences\nMolecular Biology\nMolecular Biology Techniques\nMolecular Biology Assays and Analysis Techniques\nAmino Acid Analysis\nResearch and Analysis Methods\nMolecular Biology Techniques\nMolecular Biology Assays and Analysis Techniques\nAmino Acid Analysis\nTargeted metabolomic profiling of cerebrospinal fluid from patients with progressive multifocal leukoencephalopathy\nMetabolomic profiling in PML patientsLuo Yi Formal analysisWriting – original draft1 Möhn Nora ConceptualizationWriting – original draft1 Al-Mekhlafi Amani Formal analysisInvestigationWriting – review & editing2 Schuchardt Sven SupervisionWriting – review & editing3 Skripuletz Thomas SupervisionWriting – review & editing1 Sühs Wolfram Project administrationSupervisionWriting – review & editing1 Pessler Frank ConceptualizationProject administrationSupervisionWriting – review & editing24‡ Stangel Martin ConceptualizationProject administrationSupervisionWriting – review & editing1‡* 1 \nDepartment of Neurology, Hannover Medical School, Hannover, Germany\n2 \nHelmholtz Centre for Infection Research, Braunschweig, Germany\n3 \nFraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany\n4 \nTWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany\nAktas Orhan Editor Heinrich-Heine-Universitat Dusseldorf, GERMANY\nCompeting Interests: The authors have declared that no competing interests exist.\n\n‡ These authors also contributed equally to this work.\n\n* E-mail: Stangel.Martin@mh-hannover.de\n24 11 2020 \n2020 \n15 11 e024232124 8 2020 1 11 2020 © 2020 Luo et al2020Luo et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Progressive multifocal leukoencephalopathy (PML), caused by JC polyomavirus, is a demyelinating disease of the central nervous system that primarily affects oligodendrocytes. It can cause significant morbidity and mortality. An early diagnosis is of high relevance as timely immune reconstitution is essential. However, diagnosis can be challenging if virus detection via cerebrospinal fluid (CSF) PCR remains negative. Hence, identifying CSF biomarkers for this disease is of crucial importance. We applied a targeted metabolomic screen to CSF from 23 PML patients and eight normal pressure hydrocephalus (NPH) patients as controls. Out of 188 potentially detectable metabolites, 48 (13 amino acids, 4 biogenic amines, 1 acylcarnitine, 21 phosphatidylcholines, 8 sphingolipids, and the sum of hexoses) passed the quality screen and were included in the analyses. Even though there was a tendency towards lower concentrations in PML (mostly of phosphatidylcholines and sphingomyelins), none of the differences between PML and controls in individual metabolite concentrations reached statistical significance (lowest p = 0.104) and there were no potential diagnostic biomarkers (highest area under the ROC curve 0.68). Thus, CSF metabolite changes in PML are likely subtle and possibly larger group sizes and broader metabolite screens are needed to identify potential CSF metabolite biomarkers for PML.\n\nhttp://dx.doi.org/10.13039/501100001659Deutsche ForschungsgemeinschaftEXC 2155Stangel Martin This study was partly funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – Projektnummer 390874280 (to MS). There was no additional external funding received for this study. Data AvailabilityOur study data is available on a public repository, which is accessible via the following link: http://81.14.181.117:8080/share.cgi?ssid=0ZWzo98.Data Availability\nOur study data is available on a public repository, which is accessible via the following link: http://81.14.181.117:8080/share.cgi?ssid=0ZWzo98.\n==== Body\nIntroduction\nProgressive multifocal leukoencephalopathy (PML) is a rare, opportunistic, demyelinating disease of the central nervous system (CNS) caused by the human JC polyomavirus (HPyV-2). HPyV-2 is a small ubiquitous DNA polyomavirus with a 5.13 Kb circular enclosed double-stranded DNA. Antibodies against this virus are detectable in about half of all people worldwide [1, 2]. In healthy conditions the infection usually does not cause disease. Especially in immune-compromised patients, for example patients suffering from acquired immune deficiency syndrome, or hematologic malignancies, in organ transplant recipients, and patients treated with immunosuppressive drugs the infection with HPyV-2 can cause a progressive demyelination of the CNS. Unfortunately, there is no effective anti-HPYV-2 treatment yet, but immunosuppressants should be discontinued when possible [3–6]. As PML usually occurs as part of the underlying disease, the clinical presentation varies. Besides a clinical neurological examination, brain MRI and cerebrospinal fluid (CSF) analysis are standard procedures in the diagnostic work-up. The detection of HPyV-2 DNA in CSF via quantitative polymerase chain reaction (qPCR) proves the diagnosis of PML. As qPCR results may be negative in early stages of the disease, a negative CSF HPyV-2 PCR does not rule out PML. In cases where ascertaining the diagnosis of PML remains elusive, a brain biopsy with detection of HPyV-2 protein by immunohistochemistry and/or HPyV-2 DNA by in situ hybridization or PCR assay is considered the gold standard for diagnosis and needs to be conducted. However, brain biopsy has several disadvantages such as invasive protocol, risks of complication, and poor patient compliance, which limits its usefulness for dynamic surveillance and follow-up [7–10]. Therefore, novel biomarkers for the diagnosis of PML especially in PCR-negative patients are needed.\n\nAs demonstrated in studies on neurodegenerative disorders (for example Alzheimer’s disease or amyotrophic lateral sclerosis) and also in the context of neuroinflammation, metabolomic profiling of CSF has a considerable potential for identifying biomarker candidates and elucidating disease-associated metabolic networks [11–15]. Furthermore, our previous studies have shown that metabolomic analysis of CSF can identify biomarkers that are able to discriminate CNS infections with varicella zoster virus (VZV) infection from non-infectious diseases [16], identify enterovirus infection in patients with normal CSF cell count [17], distinguish between viral and autoimmune neuroinflammation [18], and identify bacterial CNS infections with high sensitivity [19].\n\nIn the present study, we applied the AbsoluteIDQ®-p180 kit (Biocrates Life Science AG, Innsbruck, Austria) for CSF analysis as a targeted metabolomics approach based on liquid chromatography tandem mass spectrometry (LC-MS/MS) to investigate differences in CSF metabolic profiles between patients with PML and controls with normal pressure hydrocephalus (NPH). The aim was to identify and validate potential biomarkers for the diagnosis of PML, especially in HPYV-2-PCR negative patients.\n\nMaterials and methods\nPatients and sample preparation\nThe study subjects comprised 23 patients with PML and 8 patients with normal pressure hydrocephalus (NPH) as controls. All patients were treated at the Department of Neurology at Hannover Medical School during the years 2007 and 2019. CSF samples were obtained via lumbar puncture. The following routine CSF parameters were determined within 2 hours: cell count, lactate concentration, protein concentrations (via Bradford dye-binding assay). HPYV-2 DNA concentrations were measured with a real-time PCR assay. Determination of HPYV-2 DNA concentrations by PCR and HPYV-2 antibody specificity index in CSF were performed as routine tests at the Institute of Virology, Hannover Medical School, Germany, and at the Institute of Virology, University of Düsseldorf, Germany, as described before [20]. qPCR for the detection of HPYV-2-DNA was performed amplifying a 78 bp product in the large T antigen region. For the HPYV-2 antibody specificity index serum and CSF were tested in an enzyme-linked immunosorbent assay using a HPYV-2-VP1 protein fused to GST as antigen, and the HPYV-2 antibody specificity index was calculated. The calculation required the additional determination of albumin and total IgG from serum and CSF. The remaining CSF was immediately centrifuged and the cell-free supernatant frozen in aliquots and stored at −80°C until metabolomic analysis. The PML patients were further divided into two subgroups according to the PCR results: PCR positive PML (PML-P, n = 18) and PCR negative PML (PML-N, n = 5) patients.\n\nThe study was approved by the institutional review board of Hannover Medical School (file no. 2413–2014). All patients gave written informed consent to the use of their data.\n\nMetabolite profiling\nLC-MS/MS and FIA-MS/MS conditions\nAll CSF samples were shipped on dry ice and analyzed in duplicate using a targeted metabolomics kit (AbsoluteIDQ®p180 Kit: BIOCRATES Life Sciences AG, Innsbruck, Austria). This approach allows for the simultaneous quantification of 188 metabolites from different compound classes (21 amino acids, 21 biogenic amines, 40 acylcarnitines, 38 acyl/alkyl phosphatidylcholines, 38 acyl/alkyl phosphatidylcholines, 14 lysophosphatidyl-cholines, 15 sphingomyelins, and the sum of hexoses) using a combination of liquid chromatography (Agilent 1290 Infinity II LC, Santa Clara, CA, USA) and mass spectrometry (AB SCIEX 5500 QTrap™ mass spectrometer; AB SCIEX, Darmstadt, Germany). The lipids, acylcarnitines, and the hexoses were determined via flow injection analysis-tandem mass spectrometry (FIA-MS/MS), while the amino acids and biogenic amines were measured by LC-MS/MS. Sample preparation and measurements were performed according to the manufacturers’ instructions. It has to be noted that some of the CSF samples had been stored for more than ten years. Knowledge about possible effects on long-term storage of CSF samples on metabolite profiling is rare. Regarding serum and plasma, metabolomic profiles are affected by repeated freeze/thaw cycles [21], but not by storage time. Additionally, different studies could prove that the levels of CSF biomarkers or the stability of small-molecule metabolites did not significantly change during long-term storage at -80°C [22–24].\n\nData processing\nAfter normalization and pre‐processing of the data, MetIDQ™ software (Biocrates) was used for peak integration and calculation of metabolite concentrations. All analytes that were above the limit of detection (LOD) in ≥50% of patients were selected for further investigation. Values below the LOD were replaced by the reference value provided by the manufacturer (LOD/2), and all values between LOD and LLOQ were replaced by the value LLOQ/2. Nine analytes (citrulline, dopamine, glycine, leucine, methionine, proline, spermidine, t4OH-proline, tryptophan) passed the initial screen based on LOD but were subsequently excluded because most of the values >LOD were <LLOQ. The concentration data were entered into the Metaboanalyst 3.0 software for multivariate analyses, including partial least squares discriminant analysis (PLS-DA), classical univariate receiver operating characteristic (ROC) curve analysis and multivariate ROC curve based exploratory analysis.\n\nStatistical analysis\nThe clinical characteristics of all patients and the relative concentrations of the CSF metabolites are presented as mean ± standard deviation (SD). For demographic and clinical characteristics, outcome comparison in PML and control groups was achieved using the independent sample t test for continuous variables and chi-square test for categorical variables. The Wilcoxon Mann-Whitney U test, as an alternative for not normally distributed variables, was applied to determine whether there was a significant difference between the two groups regarding the concentration of each metabolite. P values are 2-tailed and P < 0.05 was considered statistically significant. All analyses were performed using SPSS version 24.0 (IBM, New York, USA).\n\nResults\nPatients’ characteristics and standard CSF parameters\nThe demographics and clinical characteristics of the PML subjects are shown in Table 1. Underlying diseases of the PML group included human immunodeficiency virus infection (n = 7), relapsing remitting multiple sclerosis treated with natalizumab (n = 4), lymphoproliferative disorders (n = 6), vasculitis (n = 2), liver transplant (n = 1), kidney transplant (n = 1), bronchial carcinoma (n = 1), and one case with unknown cause of PML (n = 1). There was no significant difference in age or sex between the two groups. Regarding the standard CSF parameters, patients with PML showed a significantly higher level of CSF leukocytes (8 vs 1 per/μL) and CSF protein (624 vs 419 mg/L) compared with NPH patients. This effect was largely due to the HIV patients. Within the PML group, the PCR negative subgroup demonstrated a significantly lower number of CSF leukocytes compared with the PCR positive subgroup (mean 1/μL and 10/μL, respectively). There also was a tendency toward lower CSF lactate (p = 0.239) concentrations in the PCR negative subgroup than the PCR-positive subgroup (Table 2).\n\n10.1371/journal.pone.0242321.t001Table 1 Demographics and clinical characteristics of PML patients.\nPatient\tAge (years)\tSex (M = male, F = female)\tUnderlying immune defect\tHPYV-2 DNA (copies/mL)\t\nP1\t36\tM\tHIV\tNeg\t\nP2\t73\tF\tNHL\tNeg\t\nP3\t52\tM\tVA\tNeg\t\nP4\t72\tM\tLT\tNeg\t\nP5\t42\tF\tRRMS\tNeg\t\nP6\t73\tM\tHIV\tPos\t\nP7\t62\tF\tHIV\t3000\t\nP8\t77\tF\tB-CLL\t250\t\nP9\t36\tF\tRRMS/NTZ\t800\t\nP10\t32\tF\tRRMS/NTZ\t260\t\nP11\t47\tM\tHIV\t400\t\nP12\t65\tM\tT-CLL\t203\t\nP13\t65\tF\tKT\t500\t\nP14\t68\tM\tUnknow\t1000\t\nP15\t52\tM\tVA\t30\t\nP16\t76\tM\tNHL\t200000\t\nP17\t43\tM\tRRMS/NTZ\t500\t\nP18\t54\tM\tMM\t179\t\nP19\t77\tM\tBC\t100000\t\nP20\t55\tM\tCLL\t500\t\nP21\t31\tM\tHIV,HL\t1080\t\nP22\t54\tM\tHIV\t249\t\nP23\t57\tM\tHIV\t800\t\nBC: bronchial carcinoma, B-CLL: B-cell leukaemia, CLL: chronic lymphocytic leukemia, HIV: human immunodeficiency virus, HL: Hodgkin lymphoma, KT: kidney transplant, LT: liver transplant, MM: multiple myeloma, NHL: non-Hodgkin lymphoma, RRMS/NTZ: relapsing remitting multiple sclerosis treated with natalizumab, T-CLL: T-cell leukaemia, VA: vasculitis. P1 and P4: PML verified by brain biopsy; P2: first HPYV-2 PCR positive, follow up CSF HPYV-2 DNA negative; P3: HPYV-2 PCR positive in follow-up CSF analysis three weeks later; P5: elevated HPYV-2 antibody specificity index. Sample P15 was thawed and re-frozen twice.\n\n10.1371/journal.pone.0242321.t002Table 2 Demographic and CSF characteristics of PML patients compared with NPH patients.\n\tControl\t\tPML\t\t\n\t\tALL\tPCR-positive\tPCR-negative\t\n\t(NPH = 8)\t(n = 23)\t(n = 18)\t(n = 5)\t\nAge (years)\t62.8±15.9\t56.5±15.0\t56.9±14.9\t55.0±17.0\t\nSex (M/F)\t4/4\t16/7\t13/5\t3/2\t\nCSF_leukocytes (per/μL)\t1±1\t8±13a*\t10±14b*\t1±1\t\nCSF_protein (mg/L)\t419±141\t624±271a*\t638±281\t573±252\t\nCSF_lactate (mmol/L)\t1.6±0.2\t1.8±0.3\t1.8±0.3\t1.6±0.2\t\nData presented as means ± SD, M: male, F: female, CSF: cerebrospinal fluid, NPH: normal pressure hydrocephalus, PML: Progressive multifocal leukoencephalopathy,\n\na: PML vs Control;\n\nb: PCR-positive vs PCR-negative,\n\n* p < 0.05.\n\nEfficiency of CSF metabolite detection via mass spectrometry\nOf the 188 potentially detectable metabolites, 48 passed the 2-step quality assessment mentioned above. These metabolites comprised 13 amino acids, 4 biogenic amines, 1 acylcarnitine, 21 phosphatidylcholines, 8 sphingolipids, and the sum of hexoses.\n\nMetabolomic difference between PML and NPH patients\nAll 48 detected metabolites were analyzed by multivariate statistical analysis, using PLS-DA to identify differentially abundant metabolites. The PLS-DA score plot suggested that there were some differences between PML and NPH metabolite abundance patterns (Fig 1A). Metabolites that could potentially contribute to the separation between PML and NPH patients were, therefore, identified based on a threshold of variable importance in projection (VIP) values (VIP>1.0) taken from the PLS-DA model. Firstly, the 19 metabolites with VIP>1.0 were selected as they seem to be the most influential variables that could separate the two groups (Fig 1C and 1D). These 19 metabolites comprised 13 phosphatidylcholines (PCaaC386, PCaeC321, PCaaC321, PCaaC381, PCaeC386, PCaeC361, PCaaC342, PCaeC364, PCaeC365, PCaaC320, PCaaC341, PCaeC341, and PCaaC362), 4 sphingolipids (SMOHC161, SMOHC222, SMC181, and SMC161), 1 amino acid (alanine), and the sum of hexoses (H1). In the PML group, concentrations of 10/13 phosphatidylcholines, all 4 sphingolipids, alanine, and the generic hexose appeared to be lower than in the control group (Fig 1C). However, subsequent Wilcoxon Mann-Whitney U testing did not reveal statistical significance in any of these metabolites (range of p values: 0.104–0.964). ROC analysis was used to evaluate their discriminatory potential in the binary comparison. As shown in Fig 1B, these metabolites did not exhibit biomarker potential, as AUCs of individual metabolites ranged between 0.5 and 0.679, AUCs of various combined classifiers ranged between 0.411 and 0.607, and all CI crossed the chance line of 0.5.\n\n10.1371/journal.pone.0242321.g001Fig 1 Analysis of metabolomic alterations of the PML and control samples.\n(A) Partial least squares discriminant analysis (PLS-DA) scores plot showing some separation between the PML (n = 23) and NPH (n = 8) subjects based on their metabolic profile of selected metabolites. (B) Concentrations of the 19 most promising metabolites (VIP>1). (C) Areas under the receiver-operating characteristic curves (AUROCs) of combinations of metabolites. (D) Variable influence on projection (VIP) plot showing the metabolites that are most important in driving the separation of the two groups.\n\nA similar analysis was performed with the PML group being divided into HPYV-2 PCR positive (PML-P) and HPYV-2 PCR negative (PML-N) patients. Using PLS-DA, compared to the control group, we found 18 metabolites with VIP scores ≥1.0 in PML-P patients and 20 in PML-N patients. In the subsequent non-parametric test and ROC curve analysis all of them failed to meet the criteria for significance or biomarker potential (Fig 2).\n\n10.1371/journal.pone.0242321.g002Fig 2 Analysis of metabolomic alterations of the PMLP or PMLN vs. control samples.\n(A) Variable influence on projection (VIP) plot showing the metabolites that are most important in driving the separation of the PML PCR-positive (PMLP) vs. the NPH group. (B) Concentrations of the 18 most promising metabolites (VIP>1 for PMLP vs. NPH)(C) Variable influence on projection (VIP) plot showing the metabolites that are most important in driving the separation of the PML PCR-negative (PMLN) and the NPH group. (D) Concentrations of the 20 most promising metabolites (VIP>1 for PMLN vs. NPH).\n\nDiscussion\nIn this study, we employed a targeted LC-MS/MS approach to investigate the metabolic profile of CSF samples from PML patients in comparison to a control group. CSF is an important source of biomarkers for neurodegenerative and neuroinflammatory diseases because it has close contact to the damaged tissue. Therefore, metabolic changes within the brain are likely to be reflected in the CSF composition [25, 26].\n\nAlthough the CSF routine examination revealed that the CSF cell count and the CSF protein concentrations in PML patients were significantly higher than those in control patients, this was mostly driven by patients with HIV as the underlying cause for immunodeficiency. This only reflects that an elevated cell count or protein concentration in the CSF does not exclude PML and that the routine CSF parameters are normal in the majority of PML cases. Thus, there is a need for new biomarker for PML, in particular in patients with negative HPYV-2 PCR.\n\nAs the CNS contains a high concentration of lipids, it is assumed that metabolites belonging to lipid/fatty acids, glutathione, and energy metabolism have a strong association with autoimmune or degenerative neurological diseases, such as multiple sclerosis or Parkinson’s disease [27–29]. To our knowledge, no metabolomics study in PML using LC-MS/MS has been reported as of yet. Using the PLS-DA analysis (VIP>1.0), we found 19 metabolites that contributed to differences between PML and NPH, which was used as a non-inflammatory/non-infected control group. Even though we did not identify any single significantly differentially abundant metabolite, we did observe a tendency toward lower concentrations (mostly in phosphatidylcholines and sphingomyelins) in the PML group which was accompanied by a tendency toward higher lactate levels. The tendency towards downregulation may be due to a loss of metabolites caused by dysfunction of neurons and/or oligodendrocytes. It has been previously reported that phosphatidylcholine constitutes the backbone of the neural membrane. Sphingolipids are cell membrane-derived lipids which act as signaling molecules and play a critical role in cell death and survival, proliferation, recognition, and migration. The decrease of them is closely related to neuronal pathways involved in neurodegenerative diseases [30, 31]. Those findings are consistent with our current results. However, the metabolites were not statistically significant in further non-parametric and ROC curve analysis and consequently could not serve as diagnostic biomarkers. Also, by combining several metabolites no reliable set of biomarkers could be found to differentiate between PML and controls (see public repository). Taken together, these results suggest that metabolic changes in the CNS of PML patients are relatively subtle. They may be driven by an attenuation of neuronal function due to loss of oligodendrocyte function that is typical of PML [32, 33], which would be consistent with the insidious onset and slow progression of this disease and the lack of overt tissue destruction. In contrast, we have observed pronounced increases in membrane phospholipids in CSF from patients with both viral and bacterial CNS infections that feature an acute clinical course and pronounced neuroinflammation [16–19].\n\nThis study has some limitations. Firstly, it captured only a fraction of the more than 430 metabolites that have been reported for CSF [34], and we have no explanation why we detected substantially fewer metabolites >LOD than in our previous studies [16, 17]. It has not yet been shown that long-term storage has a negative influence on the stability of small-molecule metabolites. Secondly, the sample size was relatively small; due to the low degree (or absence) of neuroinflammation a higher sample size may be needed to reach statistical significance than in our previous studies of acute viral CNS infections, where we identified highly accurate biomarkers with even smaller sample sizes [16, 17]. We performed a power calculation to estimate the size of a future cohort study that would be required to expect significance of the two metabolites with the highest AUCs. Assuming equal prevalence of cases (PML) and controls, and correcting for multiple testing of 48 hypotheses, the number of participants (samples) in each group would be 44 to 45 to validate H1 (the sum of hexoses, which is mostly glucose in CSF, AUC 0.70) and 49 to validate PC.aa.C32.2 (AUC 0.69). However, metabolites with AUCs in this range will unlikely prove to be clinically useful biomarkers, and recruitment of larger cohorts is difficult in a rare disease like PML. This analysis therefore suggests that a more promising strategy would be to perform new screens featuring additional classes of molecules in order to obtain more accurate biomarker candidates. Thirdly, it is possible that (even though none of the samples featured pleocytosis) the control samples from NPH patients do not entirely reflect findings in CSF from healthy individuals.\n\nConclusion\nMass spectrometry is a key technique in CSF biomarker research, involved in discovery, verification, validation and the establishment of reference methods, and it should not be abandoned as a tool for biomarker discovery for PML. Our results suggest that any changes in CSF metabolites in PML may be subtle and that larger sample sizes and broader metabolite screens are needed to identify clinically useful CSF metabolite biomarkers for this rare and insidious disorder.\n\nThe authors thank Karin Fricke, Sabine Lang, Kathrin Scheiwe, and Ilona Cierpka-Leja for excellent technical support, and Eilert Woebker for IT-support.\n==== Refs\nReferences\n1 Tan CS , Koralnik IJ . Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis\n. Lancet Neurol . 2010 ;9 : 425 –437\n. 10.1016/S1474-4422(10)70040-5 \n20298966 \n2 Weber T . Progressive multifocal leukoencephalopathy\n. Neurol Clin . 2008 ;26 : 833 –854\n. 10.1016/j.ncl.2008.03.007 \n18657729 \n3 Touma M , Rasmussen LD , Martin-Iguacel R , Engsig FN , Stærke NB , Stærkind M , et al\nIncidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study\n. J Infect Dis . 2009 ;199 : 77 –83\n. 10.1086/595299 \n19007313 \n4 Molloy ES , Calabrese L.H . Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases\n. Arthritis Rheum . 2009 ;60 : 3761 –3765\n. 10.1002/art.24966 \n19950261 \n5 Pavlovic D , Patera AC , Nyberg F , Gerber M , Liu M , et al\nProgressive multifocal leukoencephalopathy: current treatment options and future perspectives\n. Ther Adv Neurol Disord . 2015 ;8 : 255 –273\n. 10.1177/1756285615602832 \n26600871 \n6 Kartau M , Sipila JO , Auvinen E , Palomaki M , Verkkoniemi-Ahola A . Progressive Multifocal Leukoencephalopathy: Current Insights\n. Degener Neurol Neuromuscul Dis . 2019 ;9 : 109 –121\n. 10.2147/DNND.S203405 \n31819703 \n7 Berenguer J , Miralles P , Arrizabalaga J , Ribera E , Dronda F , Baraia-Etxaburu J , et al\nClinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy\n. Clin Infect Dis . 2003 ;36 : 1047 –1052\n. 10.1086/374048 \n12684918 \n8 Major EO . Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies\n. Annu Rev Med . 2010 ;61 : 35 –47\n. 10.1146/annurev.med.080708.082655 \n19719397 \n9 Berger JR , Aksamit AJ , Clifford DB , Davis L , Koralnik IJ , Sejvar JJ , et al\nPML diagnostic criteria: consensus statement from the AAN. Neuroinfectious disease section\n. Neurology . 2013 ;80 : 1430 –1438\n. 10.1212/WNL.0b013e31828c2fa1 \n23568998 \n10 Fong IW , Britton CB , Luinstra KE , Toma E , Mahony JB . Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy\n. J Clin Microbiol . 1995 ;33 : 484 –486\n. 10.1128/JCM.33.2.484-486.1995 \n7714213 \n11 Johnson CH , Ivanisevic J , Siuzdak G . Metabolomics: beyond biomarkers and towards mechanisms\n. Nat Rev Mol Cell Biol . 2016 ;17 : 451 –459\n. 10.1038/nrm.2016.25 \n26979502 \n12 Zhang A , Sun H , Yan G , Wang P , Wang X . Mass spectrometry-based metabolomics: applications to biomarker and metabolic pathway research\n. Biomed Chromatogr . 2016 ;30 : 7 –12\n. 10.1002/bmc.3453 \n25739660 \n13 Cui L , Lu H , Lee YH . Challenges and emergent solutions for LC-MS/MS based untargeted metabolomics in diseases\n. Mass Spectrom Rev . 2018 ;37 : 772 –792\n. 10.1002/mas.21562 \n29486047 \n14 Dehelean L , Sarbu M , Petrut A , Zamfir AD . Trends in Glycolipid Biomarker Discovery in Neurodegenerative Disorders by Mass Spectrometry\n. Adv Exp Med Biol . 2019 ; 1140 : 703 –729\n\n10.1007/978-3-030-15950-4_42 \n31347080 \n15 Zhong F , Xu M , Bruno RS , Ballard KD , Zhu J . Targeted High Performance Liquid Chromatography Tandem Mass Spectrometry-based Metabolomics differentiates metabolic syndrome from obesity\n. Exp Biol Med . 2017 ;242 : 773 –780\n. 10.1177/1535370217694098 \n28299975 \n16 Kuhn M , Sühs KW , Akmatov MK , et al\nMass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation\n. J Neuroinflammation . 2018 ;15 : 20 \n10.1186/s12974-017-1041-0 \n29343258 \n17 Ratuszny D , Sühs KW , Novoselova N , Kuhn M , Kaever V , Skripuletz T , et al\nIdentification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis\n. Int J Mol Sci . 2019 ;15 : 20 \n10.3390/ijms20020337 \n30650575 \n18 Sühs KW , Novoselova N , Kuhn M , Seegers L , Kaever V , Müller-Vahl K , et al\nKynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections\n. J Infect Dis . 2019 ;220 : 127 –138\n. 10.1093/infdis/jiz048 \n30721966 \n19 de Araujo LS , Pessler K , Sühs KW , Novoselova N , Klawonn F , Kuhn M , et al\nPhosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis\n. J Transl Med . 2020 ;18 : 9 \n10.1186/s12967-019-02179-w \n31910875 \n20 Warnke C , Pawlita M , Dehmel T , et al\nAn assay to quantify species-specific anti-JC virus antibody levels in MS patients\n. Multiple sclerosis . 2013 ;19 :1137 –1144\n. 10.1177/1352458513475489 \n23388163 \n21 Stevens VL , Hoover E , Wang Y , Zanetti KA . Pre-Analytical Factors that Affect Metabolite Stability in Human Urine, Plasma, and Serum: A Review\n. Metabolites . 2019 ;9 :156 .\n22 Schipke CG , Jessen F , Teipel S , Luckhaus C , Wiltfang J , Esselmann H , et al\nLong-term stability of Alzheimer's disease biomarker proteins in cerebrospinal fluid\n. J Alzheimers Dis . 2011 ;26 :255 –62\n. 10.3233/JAD-2011-110329 \n21606567 \n23 Willemse EAJ , van Uffelen KWJ , van der Flier WM , Teunissen CE . Effect of long-term storage in biobanks on cerebrospinal fluid biomarker Aβ1–42, T-tau, and P-tau values\n. Alzheimers Dement (Amst) . 2017 ;8 :45 –50\n.28462389 \n24 Haijes HA , Willemse EAJ , Gerrits J , van der Flier WM , Teunissen CE , Verhoeven-Duif NM , et al\nAssessing the Pre-Analytical Stability of Small-Molecule Metabolites in Cerebrospinal Fluid Using Direct-Infusion Metabolomics\n. Metabolites . 2019 ;9 :236 \n10.3390/metabo9100236 \n31635433 \n25 Blennow K , Hampel H , Weiner M , Zetterberg H . Cerebrospinal fluid and plasma biomarkers in Alzheimer disease\n. Nat Rev Neurol . 2010 ;6 : 131 –144\n. 10.1038/nrneurol.2010.4 \n20157306 \n26 Michalke B , Berthele A . Contribution to selenium speciation in cerebrospinal fluid samples\n. J Anal At Spectrom . 2011 ;26 : 165 –170\n.\n27 Ayala A , Munoz MF , Arguelles S . Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal\n. Oxid Med Cell Longev . 2014 .\n28 Lee HJ , Bazinet RP , Rapoport SI , Bhattacharjee AK . Brain arachidonic acid cascade enzymes are upregulated in a rat model of unilateral Parkinson disease\n. Neurochem Res . 2010 ;35 : 613 –619\n. 10.1007/s11064-009-0106-6 \n19997776 \n29 Sinclair AJ , Viant MR , Ball AK , Burdon MA , Walker EA , Stewart PM , et al\nNMR-based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases—A diagnostic tool?\n\nNMR Biomed . 2010 ;23 : 123 –132\n. 10.1002/nbm.1428 \n19691132 \n30 Frisardi V , Panza F , Seripa D , Farooqui T , Farooqui AA . Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer’s disease pathology\n. Prog Lipid Res . 2011 ;50 : 313 –330\n. 10.1016/j.plipres.2011.06.001 \n21703303 \n31 Michell AW , Mosedale D , Grainger DJ , Barker RA . Metabolomic analysis of urine and serum in Parkinson’s disease\n. Metabolomics . 2008 ;4 : 191 –201\n.\n32 Simons M , Nave KA . Oligodendrocytes: Myelination and Axonal Support\n. Cold Spring Harb Perspect Biol . 2015 ;8 : a020479 \n10.1101/cshperspect.a020479 \n26101081 \n33 White MK , Sariyer IK , Gordon J , Delbue S , Pietropaolo V , Berger JR , et al\nDiagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy\n. Rev Med Virol . 2016 ;26 : 102 –114\n. 10.1002/rmv.1866 \n26663440 \n34 Kennedy AD , Pappan KL , Donti TR , Evans AM , Wulff JE , Miller LAD , et al\nElucidation of the complex metabolic profile of cerebrospinal fluid using an untargeted biochemical profiling assay\n. Mol Genet Metab . 2017 ;121 : 83 –90\n. 10.1016/j.ymgme.2017.04.005 \n28412083\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "15(11)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016022:Case-Control Studies; D002555:Cerebrospinal Fluid; D002851:Chromatography, High Pressure Liquid; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D010713:Phosphatidylcholines; D012372:ROC Curve; D013109:Sphingomyelins; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0242321",
"pmc": null,
"pmid": "33232337",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12684918;21703303;20157306;19007313;29343258;28299975;20298966;23388163;31349624;31910875;29486047;23568998;31635433;19691132;7714213;28462389;26101081;31819703;26979502;31347080;30650575;26600871;21606567;26663440;28412083;30721966;25739660;19950261;19719397;18657729;24999379;19997776",
"title": "Targeted metabolomic profiling of cerebrospinal fluid from patients with progressive multifocal leukoencephalopathy.",
"title_normalized": "targeted metabolomic profiling of cerebrospinal fluid from patients with progressive multifocal leukoencephalopathy"
} | [
{
"companynumb": "DE-BIOGEN-2013BI043494",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthor... |
{
"abstract": "High-dose methotrexate (HD-MTX) is used to treat a variety of cancers. In all patients receiving HD-MTX, plasma MTX levels are monitored mainly to anticipate rescue therapy to prevent adverse events. We present 2 children treated with HD-MTX and afterward treated with glucarpidase at different time-points after their HD-MTX infusions. After the administration of glucarpidase, a nontoxic metabolite of MTX cross-reacts with MTX in the standard immunoassay (Abbott Diagnostics, Hoofddorp, the Netherlands) resulting in an artificially elevated MTX level. An artificially elevated MTX level results in unnecessarily long folinic acid administration, which decreases the effectivity of MTX. This grand round highlights the importance of measuring plasma MTX levels after the administration of glucarpidase with an ultra high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method instead of with an immunoassay.",
"affiliations": "Department of Pharmacy, Erasmus University Medical Center.;Department of Pharmacy, Erasmus University Medical Center.;Department of Pharmacy, Sophia Children's Hospital, Erasmus University Medical Center.;Department of Pediatric Haemato-Oncology, Sophia Children's Hospital Rotterdam, Erasmus University Medical Center, the Netherlands.;Department of Pharmacy, Erasmus University Medical Center.",
"authors": "Mulder|Midas B|MB|;Huisman|Ruud|R|;Engels|Frederike K|FK|;van der Sluis|Inge M|IM|;Koch|Birgit C P|BCP|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; C000629556:glucarpidase; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/FTD.0000000000000515",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4356",
"issue": "40(4)",
"journal": "Therapeutic drug monitoring",
"keywords": null,
"medline_ta": "Ther Drug Monit",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D002648:Child; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate; D011994:Recombinant Proteins; D053719:Tandem Mass Spectrometry; D011623:gamma-Glutamyl Hydrolase",
"nlm_unique_id": "7909660",
"other_id": null,
"pages": "383-385",
"pmc": null,
"pmid": "29994985",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapeutic Drug Monitoring of Methotrexate in Plasma Using Ultra High-Performance Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry: Necessary After Administration of Glucarpidase in Methotrexate Intoxications.",
"title_normalized": "therapeutic drug monitoring of methotrexate in plasma using ultra high performance liquid chromatography electrospray ionization tandem mass spectrometry necessary after administration of glucarpidase in methotrexate intoxications"
} | [
{
"companynumb": "NL-MYLANLABS-2018M1092175",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "A 95-year-old man with chronic obstructive pulmonary disease and chronic hepatitis C virus infection was treated for acute lung injury caused by Chlamydophila pneumoniae with antibiotics and high-dose corticosteroids. In total, 7,500 mg methylprednisolone and 680 mg prednisolone were administered over 21 days. However, respiratory failure progressed, and chest computed tomography (CT) scan showed bilateral ground-glass opacity and cavity-forming consolidation in the right upper lobe. Despite intensive therapy, the patient died of multiple organ failure on day 7. CT-guided necropsy was performed, and pathological examination revealed invasive pulmonary aspergillosis and Pneumocystis jirovecii pneumonia. Invasive pulmonary aspergillosis and P. jirovecii pneumonia are both life-threatening opportunistic fungal infections. Co-infection of these organisms is rare but possible if the patient is in an extremely immunocompromised state. Short-term but high-dose systemic corticosteroid therapy was considered to be the risk factor in this case. We should pay more attention to immunocompromised hosts who might be suffering from co-infection of opportunistic infections. Moreover, we need to consider preventive measures in such high-risk cases.",
"affiliations": "Emergency Unit and Critical Care Center, Tsuyama Central Hospital, 1756 Kawasaki, Tsuyama, Okayama, Japan, e_dai_for_all@hotmail.com",
"authors": "Hagiya|Hideharu|H|;Miyake|Takayoshi|T|;Kokumai|Yusuke|Y|;Murase|Tomoko|T|;Kuroe|Yasutoshi|Y|;Nojima|Hiroyoshi|H|;Sugiyama|Junichi|J|;Naito|Hiromichi|H|;Hagioka|Shingo|S|;Morimoto|Naoki|N|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone; D008775:Methylprednisolone",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10156-012-0473-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "19(2)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": null,
"medline_ta": "J Infect Chemother",
"mesh_terms": "D055371:Acute Lung Injury; D000369:Aged, 80 and over; D017809:Fatal Outcome; D005938:Glucocorticoids; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D008775:Methylprednisolone; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D011239:Prednisolone",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "342-7",
"pmc": null,
"pmid": "22965844",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Co-infection with invasive pulmonary aspergillosis and Pneumocystis jirovecii pneumonia after corticosteroid therapy.",
"title_normalized": "co infection with invasive pulmonary aspergillosis and pneumocystis jirovecii pneumonia after corticosteroid therapy"
} | [
{
"companynumb": "PHHY2013JP090967",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Pseudo-subarachnoid hemorrhage (PSAH) is a false-positive finding on cranial computed tomography (CT) in patients with cerebral edema. Its appearance on CT resembles subarachnoid hemorrhage despite the absence of subarachnoid blood. We report the finding of PSAH in a case of massive valproic acid overdose.",
"affiliations": "Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea.",
"authors": "Min|Young-Gi|YG|;Tse|Man Li|ML|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2011.602082",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "49(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000927:Anticonvulsants; D001929:Brain Edema; D062787:Drug Overdose; D005189:False Positive Reactions; D006801:Humans; D008297:Male; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D013345:Subarachnoid Hemorrhage; D013346:Subarachnoid Space; D014057:Tomography, X-Ray Computed; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "699-700",
"pmc": null,
"pmid": "21819343",
"pubdate": "2011-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Image in toxicology: Pseudo-subarachnoid hemorrhage in a case of severe valproic acid poisoning.",
"title_normalized": "image in toxicology pseudo subarachnoid hemorrhage in a case of severe valproic acid poisoning"
} | [
{
"companynumb": "CN-VISTAPHARM, INC.-VER201712-001436",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional"... |
{
"abstract": "Lithium continues to be the treatment of choice for bipolar disorder. Acute lithium poisoning is a potentially serious event. We present a retrospective observational significative study of episodes of acute lithium poisoning during a 52- month period. Poisoning was defined by a blood lithium concentration of 1.5 mEq/L or higher. We analyzed treatment and epidemiologic and clinical characteristics of 70 episodes were identified (incidence density among treated patients, 1.76 per 100 patient-years). The most frequent cause of lithium poisoning was a concurrent medical condition (46%). Most poisonings were mild (74.2%), but neurologic involvement was identified in 40.3%. Electrocardiographic abnormalities were found in 8 cases. Acute renal failure, found in 23 patients (37.1%), was mild in most cases, although 11 patients required hemodialysis. We concluded that acute lithium poisoning is an uncommon complication, but risk needs to be lowered. Patients should be warned to avoid dosage errors and to take special care during concurrent illnesses and while taking other medications.",
"affiliations": "Servicio de Nefrología, Hospital Universitario Ramón y Cajal, IRYCIS, UAH, REDinREN Madrid, España.;Servicio de Psiquiatría, Hospital Universitario Ramón y Cajal, UAH, CIBERSAM, IRYCIS, Madrid, España.;Servicio de Bioquímica Clínica, Hospital Universitario Ramón y Cajal, Madrid, España.;Servicio de Nefrología, Hospital Universitario Ramón y Cajal, IRYCIS, UAH, REDinREN Madrid, España.;Servicio de Psiquiatría, Hospital Universitario Ramón y Cajal, UAH, CIBERSAM, IRYCIS, Madrid, España.;Servicio de Nefrología, Hospital Universitario Ramón y Cajal, IRYCIS, UAH, REDinREN Madrid, España.;Servicio de Psiquiatría, Hospital Universitario Ramón y Cajal, UAH, CIBERSAM, IRYCIS, Madrid, España.;Servicio de Nefrología, Hospital Universitario Ramón y Cajal, IRYCIS, UAH, REDinREN Madrid, España.",
"authors": "Burguera Vion|Víctor|V|;Montes|José Manuel|JM|;Del Rey|José Manuel|JM|;Rivera-Gorrín|Maite|M|;Rodao|José María|JM|;Tenorio|Maite|M|;Saiz-Ruiz|Jerónimo|J|;Liaño|Fernando|F|",
"chemical_list": "D000928:Antidepressive Agents; D018021:Lithium Chloride",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1137-6821",
"issue": "29(1)",
"journal": "Emergencias : revista de la Sociedad Espanola de Medicina de Emergencias",
"keywords": "Acute poisoning; Bipolar disorder; Fracaso renal; Intoxicación; Lithium; Litio; Renal failure; Trastorno bipolar",
"medline_ta": "Emergencias",
"mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D000368:Aged; D000928:Antidepressive Agents; D001714:Bipolar Disorder; D015897:Comorbidity; D005260:Female; D006801:Humans; D018021:Lithium Chloride; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D011041:Poisoning; D006435:Renal Dialysis; D012189:Retrospective Studies",
"nlm_unique_id": "9805751",
"other_id": null,
"pages": "46-48",
"pmc": null,
"pmid": "28825269",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Acute lithium poisoning: epidemiology, clinical characteristics, and treatment.",
"title_normalized": "acute lithium poisoning epidemiology clinical characteristics and treatment"
} | [
{
"companynumb": "ES-ALEMBIC PHARMACUETICALS LIMITED-2017SCAL000223",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
... |
{
"abstract": "The clinical scenario of a pulmonary nodule following lung transplantation is one with limited experience and no supporting guidelines for the approach to diagnosis and management. Given the broad differential diagnosis for pulmonary nodules in this setting, most of which are life-threatening without appropriate treatment, aggressive evaluation is required. Here we present a case of a 70-year-old female with the development of a large pulmonary nodule in the native lung four years following a single lung transplant. She underwent bronchoscopy with endobronchial ultrasound to achieve a tissue diagnosis which showed small cell lung carcinoma. The patient was started on chemotherapy and has shown clinical and radiographic improvement at most recent follow up seven months after the initial diagnosis. In this report we discuss the differential diagnosis and corresponding imaging findings for the pulmonary nodule following lung transplantation to aid in guiding clinicians navigate this challenging clinical situation.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, United States of America.;Department of Medicine, Weiss Memorial Hospital, Chicago, IL, United States of America.;Department of Radiology, Henry Ford Hospital, Detroit, MI, United States of America.;Department of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, United States of America; Department of Medicine, Wayne State University, Detroit, MI, United States of America. Electronic address: Jdiaz1@hfhs.org.",
"authors": "Reaume|Michael|M|;Duong|Thomas|T|;Song|Thomas|T|;Diaz-Mendoza|Javier|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinimag.2020.11.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "72()",
"journal": "Clinical imaging",
"keywords": "Complications; Diagnostic radiology; Lung transplantation; Pulmonary nodule; Thoracic imaging",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000368:Aged; D001999:Bronchoscopy; D005260:Female; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms; D016040:Lung Transplantation; D055613:Multiple Pulmonary Nodules; D003074:Solitary Pulmonary Nodule",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "37-41",
"pmc": null,
"pmid": "33202293",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The pulmonary nodule following lung transplantation.",
"title_normalized": "the pulmonary nodule following lung transplantation"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-01051",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"d... |
{
"abstract": "Letter to the editor.",
"affiliations": "Servicio de Psiquiatría y Psicología. Hospital Clínic. Barcelona. fortea@clinic.ub.es.",
"authors": "Fortea González|Adriana|A|;Oriolo|Giovanni|G|;Balcells Oliveró|Mercedes|M|;Sánchez Del Valle|Raquel|R|;Castellvi|Magda|M|",
"chemical_list": "D001569:Benzodiazepines",
"country": "Spain",
"delete": false,
"doi": "10.20882/adicciones.767",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0214-4840",
"issue": "29(1)",
"journal": "Adicciones",
"keywords": null,
"medline_ta": "Adicciones",
"mesh_terms": "D001569:Benzodiazepines; D060825:Cognitive Dysfunction; D005260:Female; D006801:Humans; D008875:Middle Aged; D019966:Substance-Related Disorders",
"nlm_unique_id": "9605506",
"other_id": null,
"pages": "61-63",
"pmc": null,
"pmid": "27749978",
"pubdate": "2016-09-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cognitive impairment induced by benzodiazepine use disorder and its reversibility: a case report.",
"title_normalized": "cognitive impairment induced by benzodiazepine use disorder and its reversibility a case report"
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"companynumb": "ES-BAUSCH-BL-2019-000515",
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"abstract": "Extramedullary plasmacytomas occurs in about 20% of multiple myeloma (MM) recurrences. Extramedullary disease seems to respond poorly to thalidomide and has adverse prognostic implication. When disease recurs in the oral cavity with soft tissue infiltration, some authors defend upfront surgical excision prior to radiotherapy with the aim of achieving better local control. We describe herein such an atypical case of recurrence from MM, with complete local response after 2 cycles of chemotherapy. Unfortunately, disease progressed later on, and the patient died after 9 months post-recurrence. This emphasizes the prognostic impact of extramedullary disease manifestation in MM.",
"affiliations": "Former Medical Resident in Clinical Oncology, A.C.Camargo Cancer Center, São Paulo, Brazil.;Hematologist, A.C.Camargo Cancer Center, São Paulo, Brazil.;Hematologist, A.C.Camargo Cancer Center, São Paulo, Brazil.;Chief of Dental Surgery Department, A.C.Camargo Cancer Center, São Paulo, Brazil.;Former Medical Resident in Pathology, A.C.Camargo Cancer Center, São Paulo, Brazil.;Pathologist, A.C.Camargo Cancer Center, São Paulo, Brazil.",
"authors": "de Assis Pereira Hansen|Cristiano|C|;Filho|Jayr Schmidt|JS|;de Mattos Nascimento|Marina|M|;Alves|Fábio Abreu|FA|;Neotti|Tatiane|T|;D Almeida Costa|Felipe|F|",
"chemical_list": "D013792:Thalidomide",
"country": "Iran",
"delete": false,
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"issn_linking": "1029-2977",
"issue": "21(12)",
"journal": "Archives of Iranian medicine",
"keywords": "Multiple myeloma; Oral cavity; Recurrences",
"medline_ta": "Arch Iran Med",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D009055:Mouth; D009062:Mouth Neoplasms; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D010954:Plasmacytoma; D011878:Radiotherapy; D013792:Thalidomide",
"nlm_unique_id": "100889644",
"other_id": null,
"pages": "611-612",
"pmc": null,
"pmid": "30634861",
"pubdate": "2018-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extramedullary Manifestation of Multiple Myeloma in the Oral Cavity.",
"title_normalized": "extramedullary manifestation of multiple myeloma in the oral cavity"
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"abstract": "Sialadenitis is a rare adverse effect of captopril. We report a case of captopril-induced sialadenitis in a patient with end-stage renal disease (ESRD). A 20-year-old man with ESRD encountered parotid and submandibular swelling after receiving two doses of captopril, administered sublingually. Despite of prescribing dexamethasone, resuming hemodialysis, and discontinuing other drugs that also can cause parotitis, he improved later than what was reported in patients with normal renal function. In conclusion recovery from captopril-induced sialadenitis in patients with ESRD may be more prolonged than that of patients with normal renal function; moreover, early hemodialysis which helps in drug removal may be the most effective treatment.",
"affiliations": "Department of Internal Medicine, Kerman University of Medical Sciences, Kerman, Iran.;Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.",
"authors": "Mahdiabadi|Fatemeh Musavi|FM|;Nikvarz|Naemeh|N|",
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"country": "India",
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"doi": "10.4103/2279-042X.179585",
"fulltext": "\n==== Front\nJ Res Pharm PractJ Res Pharm PractJRPPJournal of Research in Pharmacy Practice2319-96442279-042XMedknow Publications & Media Pvt Ltd India JRPP-5-14610.4103/2279-042X.179585Case ReportCaptopril-induced sialadenitis in a patient with end-stage renal disease\n Mahdiabadi Fatemeh Musavi 1Nikvarz Naemeh 21 Department of Internal Medicine, Kerman University of Medical Sciences, Kerman, Iran2 Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, IranCorresponding author: Dr. Naemeh Nikvarz, E-mail: nnikvarz@kmu.ac.irApr-Jun 2016 5 2 146 148 11 2015 1 2016 Copyright: © Journal of Research in Pharmacy Practice2016This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms.Sialadenitis is a rare adverse effect of captopril. We report a case of captopril-induced sialadenitis in a patient with end-stage renal disease (ESRD). A 20-year-old man with ESRD encountered parotid and submandibular swelling after receiving two doses of captopril, administered sublingually. Despite of prescribing dexamethasone, resuming hemodialysis, and discontinuing other drugs that also can cause parotitis, he improved later than what was reported in patients with normal renal function. In conclusion recovery from captopril-induced sialadenitis in patients with ESRD may be more prolonged than that of patients with normal renal function; moreover, early hemodialysis which helps in drug removal may be the most effective treatment.\n\nCaptoprilend-stage renal diseasesialadenitis\n==== Body\nINTRODUCTION\nInflammation and swelling of salivary glands is called sialadenitis which can be unilateral or bilateral. Many conditions such as bacterial and viral infections, sjogren syndrome, ductal obstruction by stones, tumors or duct stricture, and drugs can cause sialadenitis.[1] Although there are numerous reports of drug-induced parotitis, this is not a common phenomenon.[2] Angiotensin-converting enzyme inhibitors (ACEIs) are among drugs that have been reported in the literature as causes of sialadenitis which include two cases of captopril-induced parotid and submandibular swelling,[3] one case of enalaprilat[4] and one case of ramipril induced parotitis.[5] It should be noted that all cases were patients with normal renal function.\n\nIn this article, we describe the first report of captopril-induced parotid and submandibular swelling in a patient with end-stage renal disease (ESRD) whose sialadenitis duration was longer than that of other cases of parotitis induced by this drug or other ACEIs.[345]\n\nCASE REPORT\nA 20-year-old man with ESRD was admitted to our hospital because of a double lumen catheter infection. Prescribed drugs during the admission course were teicoplanin, meropenem, amikacin, sevelamer hydrochloride, furosemide, losartan, prazosin, amlodipine, and recombinant human erythropoietin. In the early morning of the 15th day of the admission, he experienced a blood pressure (BP) crisis which was controlled by 25 mg of captopril administered sublingually. Nine hours later, BP rose again and captopril was prescribed at 25 mg again. Three hours after that, patient experienced a bilateral parotid and submandibular enlargement without any pain, purulent salivary discharge, skin rash, pruritus, wheezing, tachypnea, and dyspnea. His lungs were bilateral clear to auscultation, and the arterial saturation of oxygen was 94%. Ultrasound imaging showed severe bilateral parotid and submandibular edema without any mass, collection, abscess, or intravascular thrombosis. We may rule out mumps because we did not have facilities to measure mumps virus-specific antibodies and only relied on the patient positive history of the infection in childhood which causes lifelong immunity.[6] Moreover, other viral infections were ruled out because the patient had no pain and no prodromal systemic symptoms such as myalgia, arthralgia, headache, and anorexia. Being under treatment of broad spectrum antibiotics and having no purulent salivary discharge made bacterial infection as a very unlikely cause. As a result, captopril was recognized as the most likely cause of the sialadenitis and was withdrawn. Despite discontinuation of captopril, enlargement of the glands was progressive, and the patient was intubated at night, and transferred to the Intensive Care Unit (ICU). Dexamethasone 8 mg 3 times per day, propofol, midazolam, morphine, and haloperidol were added to his drug regimen in the ICU. Fortunately, increase in the size of the glands stopped in the 1st day in the ICU, but the size of the glands did not reduce. We related the delay in improvement to two causes which were the administration of morphine and midazolam and resuming hemodialysis 48 h after the occurrence of parotitis. Since there are case reports of midazolam[7] and morphine[8] induced parotitis, it was suggested that stopping administration of these drugs may be helpful. However, because the patient struggled to extubate himself in the conscious state, only morphine was discontinued. Delayed hemodialysis may cause prolongation of effects of captopril, which is primarily eliminated via kidneys, and 35-40% of the blood concentration of captopril are removed in each hemodialysis session.[910] Eventually, 5 days after the discontinuation of captopril, the size of the glands reduced, and the patient was extubated. Calculated score of the Naranjo Adverse Drug Reaction Probability Scale[11] in this case was 7 which represents a probable casualty relationship between captopril and sialadenitis.\n\nDISCUSSION\nBased on our knowledge, it is the first report of parotid and submandibular swelling due to captopril in an ESRD patient who had no previous history of consuming any ACEI; moreover, this case is unique because of the long duration of recovery from this adverse drug reaction.\n\nIn all of the previously reported cases parotitis disappeared several hours after discontinuation of culprit drug without any further intervention, except for prescription of hydrocortisone in the case of enalaprilat induced parotitis, but in the present case the size of the salivary glands decreased nearly 5 days after the administration of captopril, and dexamethasone was also administered. We attributed this prolonged time of recovery to the renal failure which increases elimination half-life of captopril, delayed hemodialysis, and administration of other drugs that may cause parotitis such as morphine and midazolam.[278]\n\nUnderlying mechanism of this adverse drug reaction is not clearly known. Moss et al. suggested that parotitis may be a sign of the ACEIs induced angioedema.[5] In contrast, da saliva related captopril-induced sialadenitis to a type B idiosyncratic reaction. Since renal impairment and a postponed hemodialysis session, likely prolonged recovery time of sialadenitis in the present case, we suggest that this adverse drug reaction may be a concentration dependent phenomenon.\n\nClinicians should be aware that recovery from captopril-induced sialadenitis in patients with renal failure may need several days. Furthermore, early hemodialysis is the most effective treatment option, and more than one hemodialysis session may be required to accelerate the improvement of sialadenitis.\n\nAUTHORS’ CONTRIBUTION\nFatemeh Musavi Mahdiabadi: Case presentation, interpretation of data, critical revision of the manuscript for important intellectual content and final approval of the version to be published. Naemeh Nikvarz: Case presentation, interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and final approval of the version to be published.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Krishnamurthy S Vasudeva SB Vijayasarathy S Salivary gland disorders: A comprehensive review World J Stomatol 2015 4 56 71 \n2 Brooks KG Thompson DF A review and assessment of drug-induced parotitis Ann Pharmacother 2012 46 1688 99 23249870 \n3 Gislon Da Silva RM Captopril-induced bilateral parotid and submandibular sialadenitis Eur J Clin Pharmacol 2004 60 449 53 15241572 \n4 Chauhan V Negi RC Sharma A Gupta S Mokta J Verma B Enalaprilat induced acute parotitis J Assoc Physicians India 2008 56 128 9 18472517 \n5 Moss JR Zanation AM Shores CG ACE inhibitor associated recurrent intermittent parotid gland swelling Otolaryngol Head Neck Surg 2005 133 992 4 16360530 \n6 Atkinson W Wolfe S Hamborsky J Centers for Disease Control and Prevention Epidemiology and Prevention of Vaccine-Preventable Diseases, “Pink Book,” 2011 Washington, DC Public Health Foundation \n7 Gültuna S Usküdar O Yüksel I Basar O Köklü S Transient parotitis after conscious sedation for endoscopy Endoscopy 2009 41 Suppl 2 E53 19319777 \n8 Kenningham J An unusual case of postoperative facial swelling Anaesthesia 2000 55 601 2 10866742 \n9 Suki WN Massry SG Therapy of Renal Diseases and Related Disorders 1991 Boston Kluwer Academic Publishers \n10 Drummer OH Workman BS Miach PJ Jarrott B Louis WJ The pharmacokinetics of captopril and captopril disulfide conjugates in uraemic patients on maintenance dialysis: Comparison with patients with normal renal function Eur J Clin Pharmacol 1987 32 267 71 3297733 \n11 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n\n",
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"issue": "5(2)",
"journal": "Journal of research in pharmacy practice",
"keywords": "Captopril; end-stage renal disease; sialadenitis",
"medline_ta": "J Res Pharm Pract",
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"nlm_unique_id": "101614023",
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"pages": "146-8",
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"pmid": "27162811",
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"references": "3297733;23249870;19319777;16360530;7249508;10866742;18472517;15241572",
"title": "Captopril-induced sialadenitis in a patient with end-stage renal disease.",
"title_normalized": "captopril induced sialadenitis in a patient with end stage renal disease"
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"abstract": "Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular syndrome characterized by multi-segmental constrictions of the cerebral arteries that resolves spontaneously within 3 months. Although RCVS is considered to be due to transient dysregulation of vascular tone, the exact pathomechanism remains unclear. We describe the case of a 15-year-old girl with RCVS induced by tacrolimus, who developed generalized seizure during the postoperative course of orthotropic heart transplantation. Magnetic resonance imaging at symptom onset showed a few vasoconstrictions accompanying brain edema and convexity subarachnoid hemorrhage. Although her neurological conditions rapidly improved after discontinuing tacrolimus, a repeat magnetic resonance angiogram demonstrated delayed progression of the multi-segmental vasoconstrictions followed by subsequent resolution. Our case demonstrates that cautious observation of the cerebral arteries using magnetic resonance angiography and careful management of vasoconstrictions with vasodilators are necessary for delayed vasoconstrictions even when the clinical symptoms improve.",
"affiliations": "Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: tatsuomano@gmail.com.;Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.",
"authors": "Kodama|Satoshi|S|;Mano|Tatsuo|T|;Masuzawa|Akihiro|A|;Hirata|Yasutaka|Y|;Nagasako|Yuki|Y|;Koshi Mano|Kagari|K|;Hamada|Masashi|M|;Terao|Yasuo|Y|;Hayashi|Toshihiro|T|;Ono|Minoru|M|;Tsuji|Shoji|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D016559:Tacrolimus",
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"doi": "10.1016/j.jstrokecerebrovasdis.2017.03.006",
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"issue": "26(5)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Vasoconstriction; angiography; calcineurin inhibitor; magnetic resonance imaging; stroke; subarachnoid hemorrhage",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000293:Adolescent; D001929:Brain Edema; D002533:Cerebral Angiography; D002536:Cerebral Arteries; D018450:Disease Progression; D004569:Electroencephalography; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D018810:Magnetic Resonance Angiography; D064847:Multimodal Imaging; D012640:Seizures; D013345:Subarachnoid Hemorrhage; D013577:Syndrome; D016559:Tacrolimus; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014661:Vasoconstriction; D014665:Vasodilator Agents; D020301:Vasospasm, Intracranial",
"nlm_unique_id": "9111633",
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"pages": "e75-e77",
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"pmid": "28342655",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tacrolimus-Induced Reversible Cerebral Vasoconstriction Syndrome with Delayed Multi-Segmental Vasoconstriction.",
"title_normalized": "tacrolimus induced reversible cerebral vasoconstriction syndrome with delayed multi segmental vasoconstriction"
} | [
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"abstract": "Careful morphology and immunohistochemistry study can make an accurate differential diagnosis of primary adenocarcinoma of urinary bladder from metastatic lesions involving bladder, especially cancer arising in colon, but there is yet no consensus regarding the standard chemotherapy for advanced adenocarcinoma of urinary bladder among medical oncologists. Sustained response to modified FOLFOX6 (fluorouracil, oxaliplatin plus leucovorin) regimen and oral capecitabine for multiple metastases in a patient with primary nonurachal adenocarcinoma of urinary bladder is presented here as a strong support that the frontline chemotherapy for this infrequent malignant disease is just like what could be chosen for colorectal cancer.",
"affiliations": "Section of Haematology and Oncology, Department of Medicine, Ministry of Health and Welfare Changhua Hospital, Chang-Hua County, Taiwan, ROC.;Department of Pathology, Ministry of Health and Welfare Changhua Hospital, Chang-Hua County, Taiwan, ROC.",
"authors": "Fan|Frank S|FS|0000-0002-8123-6941;Yang|Chung-Fan|CF|",
"chemical_list": null,
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"doi": "10.1093/omcr/omy050",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omy050omy050Case ReportAdvanced primary nonurachal adenocarcinoma of urinary bladder responding to modified FOLFOX6 and capecitabine: a case report http://orcid.org/0000-0002-8123-6941Fan Frank S 1Yang Chung-Fan 21 Section of Haematology and Oncology, Department of Medicine, Ministry of Health and Welfare Changhua Hospital, Chang-Hua County, Taiwan, ROC2 Department of Pathology, Ministry of Health and Welfare Changhua Hospital, Chang-Hua County, Taiwan, ROCCorrespondence address. 80, Sec. 2, Chung-Jeng Rd, Pu-Shin Township, Department of Administration, Ministry of Health and Welfare Changhua Hospital, Chang-Hua County, Taiwan, ROC. Tel: 886-4-829-8686x8802; Fax: 886-4-829-9962; E-mail: fantast.fan@msa.hinet.net8 2018 11 8 2018 11 8 2018 2018 8 omy05031 1 2018 26 5 2018 © The Author(s) 2018. Published by Oxford University Press.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\nCareful morphology and immunohistochemistry study can make an accurate differential diagnosis of primary adenocarcinoma of urinary bladder from metastatic lesions involving bladder, especially cancer arising in colon, but there is yet no consensus regarding the standard chemotherapy for advanced adenocarcinoma of urinary bladder among medical oncologists. Sustained response to modified FOLFOX6 (fluorouracil, oxaliplatin plus leucovorin) regimen and oral capecitabine for multiple metastases in a patient with primary nonurachal adenocarcinoma of urinary bladder is presented here as a strong support that the frontline chemotherapy for this infrequent malignant disease is just like what could be chosen for colorectal cancer.\n==== Body\nINTRODUCTION\nPrimary adenocarcinoma of urinary bladder is an uncommon tumour which can be further classified into urachal and nonurachal ones. Histologically, they can be subclassified into five common pathologic patterns, including enteric (colonic or intestinal), mucinous, signet-ring cell, not otherwise specified, and mixed types [1]. Distinction from secondary adenocarcinoma involving bladder is difficult but important in diagnosis and management, especially for nonurachal adenocarcinoma which tends to arise from trigone and posterior bladder wall, in contrast to the rather specific location of urachal carcinoma on the dome and anterior wall. The prognosis and survival are poorer in nonurachal than urachal adenocarinoma [2]. Choosing an adequate chemotherapy regimen for metastatic adenocarcinoma of urinary bladder has long been a dilemma due to its rarity and lack of clinical trial evidence. We like to present our successful experience of treating multiple metastases from a primary nonurachal adenocarcinoma of urinary bladder with modified FOLFOX6 protocol (fluorouracil, oxaliplatin plus leucovorin) and oral capecitabine, the regimens frequently adopted in frontline chemotherapy for colorectal cancer.\n\nCASE REPORT\nA 72-year-old man visited our urology clinic with the chief complaints of urinary hesitancy for 4 months and gross haematuria for 4 days in March 2017. There were also mild pain and tenderness over his back. He was scheduled to receive a transurethral surgical procedure aiming at relieving symptoms of the presumed benign prostate hyperplasia. Surprisingly, a papillary tumour growing over right half of trigone and left bladder neck base with prostate invasion was detected. The tumour was then excised as much as possible for pathologic study.\n\nSpecimens from both bladder and prostate turned out to be adenocarcinoma morphologically very similar to that arising from colon (Figs 1 and 2). Immunohistochemical staining revealed that the tumour was positive for cytokeratin 20 (CK20) and Caudal Type Homeobox 2 (CDX2), negative for cytokeratin 7 (CK7) and prostate specific antigen (PSA) (Figs 3 and 4). In addition, β-catenin was strongly reactive over membranous and cytoplasmic portions of the carcinoma cells (Fig. 5). Accordingly, the diagnosis was consistent with a primary nonurachal adenocarcinoma of urinary bladder with invasion into prostate based on previously published pathologic studies [3]. A colonoscopy failed to detect suspicious malignant lesions except for a harmatomatous polyp in the sigmoid colon.\n\nFigure 1: Enteric-type adenocarcinoma arising from urinary bladder (haematoxylin and eosin stain). (A) Cribriform and fused glandular pattern (×100). (B) Tumour cells similar to colon cancer with coagulative necrosis in the right upper field (×400).\n\nFigure 2: Enteric-type adenocarcinoma invading into prostate gland (haematoxylin and eosin stain). (A) Enteric-type adenocarcinoma with dirty coagulative necrosis (×200). (B) Enteric-type adenocarcinoma similar to that seen in bladder specimen (×400).\n\nFigure 3: Enteric-type adenocarcinoma arising from urinary bladder. Immunohistochemical staining: Positive for CK20 (A) and CDX2 (B). Negative for CK7 (C) and PSA (D).\n\nFigure 4: Enteric-type adenocarcinoma invading into prostate gland. Immunohistochemical staining: Positive for CK20 (A) and CDX2 (B). Negative for CK7 (C) and PSA (D).\n\nFigure 5: Enteric-type adenocarcinoma arising from urinary bladder. Immunohistochemical staining: Positive for β-catenin over cell membrane and cytoplasm (×400).\n\nBone scan and positron emission tomography (PET)/computerized tomography (CT) scan afterwards showed multiple metastases involving the third and fourth thoracic vertebral bodies, lung, liver and right side adrenal gland besides lymph adenopathy over bilateral neck, left axilla and paraoesophageal regions.\n\nLocal radiotherapy with a total dose of 3600 cGy divided in 12 fractions was given over his spinal metastatic sites as the first step of therapy for smoothening back pain in April 2017. During the same period, the patient took one course of oral capecitabine plus intravenous oxaliplatin (CapOX) for his systemic disease. In the subsequent three months, the chemotherapy regimen was shifted to a modified FOLOFX6 (mFOLFOX6): a 2-h intravenous injection of oxaliplatin (85 mg/m2) on Day 1, a 2-h intravenous injection of leucovorin (400 mg/m2) on Day 1, an intravenous injection of fluorouracil (400 mg/m2), and then a 46-h continuous infusion (2400 mg/m2) on Day 1, repeated every 2 weeks [4]. Unfortunately, extravasation of the chemotherapeutic agent happened during the seventh cycle of mFOLFOX6. Consequently, intravenous chemotherapy was replaced by oral capecitabine, 2 weeks on/1 week off, after recovery of the severe skin reaction in August 2017. The daily dose of capecitabine was initially 1500 mg, later increased to 2000 mg in December 2017.\n\nThe patient’s back pain responded to chemotherapy quickly with accompanying downhill change of the serum tumour markers. His CEA and CA19-9 levels decreased from 71.9 ng/ml to 942.5 U/ml, respectively, before mFOLFOX6 infusion in April to 9.85 ng/ml and 69.7 U/ml, respectively, upon taking oral capecitabine in November 2017 (Fig. 6). Much improvement of the metastatic lesions in lymph nodes, lung, liver, and right side adrenal gland could also be demonstrated in the follow-up CT scan (Figs 7 and 8).\n\nFigure 6: Change of serum tumour marker CA19-9 along the clinical course. Vertical axis: CA19-9 (U/ml). Horizontal axis: date in 2017. Dashed arrow boxes: periods of therapy with mFOLFOX6 and capecitabine, respectively.\n\nFigure 7: CT scan, lung and liver windows. (A) and (B) 29 March 2017. (C) and (D) 22 November 2017. Much improvement of pulmonary and hepatic metastasis is demonstrated.\n\nFigure 8: CT scan. (A) 15 March 2017. (B) 22 November 2017. Much improvement of right side adrenal metastasis is demonstrated.\n\nDISCUSSION\nDifferential diagnosis of primary from secondary adenocarcinoma involving urinary bladder is sometimes a puzzling issue because of the similarity between primary bladder adenocarcinoma and colorectal cancer in their tumour marker expression, morphology and immunohistochemistry characteristics. Staining of CK20, CK7 and CDX2 is not able to distinguish one from the other. Nevertheless, β-catenin usually shows nuclear reactivity in colon cancer but membranous and cytoplasmic staining in primary bladder adenocarcinoma, thus becomes a very helpful tool in this respect.\n\nThe chemotherapeutic options for advanced urachal adenocarcinoma have confused clinicians in the past decade. Cisplatin-based regimens, probably deriving from what used for urothelial carcinoma, were adopted in early years. Fluorouracil and S1 joined the protocol list later. It was only until recently that oxaliplatin or irinotican combined with either fluorouracil, bevacizumab or cetuximab were recognized in a few reports to have high efficacy for this rare cancer [5]. Among them, the FOLFOX regimen (fluorouracil, oxaliplatin plus leucovorin), commonly used for metastatic colorectal cancer, appeared as a reasonable frontline choice after the similarity of morphology and pathogenesis between urachal adenocarcinoma and colon cancer were recognized, supported further by sporadic successful therapy experience [6, 7].\n\nAs for the nonurachal adenocarcinoma, so far to our knowledge, satisfactory treatment results with FOLOFX had been disclosed only in three case reports in the English literature. The tumour cell types of these three aforementioned patients were enteric-type [8], mucinous [9] and signet-ring cell [10], respectively. We are glad to present here the astonishing effect of mFOLFOX6 and capecitabine for another enteric-type nonurachal adenocarinoma of urinary bladder. Although it is difficult to do therapeutic clinical trials for cancer of relatively low incidence, this case presentation surely can provide more evidence for making FOLFOX a preferred first choice chemotherapy regimen for advanced primary adenocarcinoma of urinary bladder, especially the nonurachal ones.\n\nACKNOWLEDGEMENTS\nThere is no financial support for this report.\n\nCONFLICT OF INTEREST STATEMENT\nNo conflicts of interest.\n\nFUNDING\nThere was no funding for this report.\n\nEthical approval\nNo ethical approval required.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nGuarantor\nDr Frank S. Fan.\n==== Refs\nReferences\n1 \nDadhania V , Czerniak B , Guo CC \nAdenocarcinoma of the urinary bladder . Am J Clin Exp Urol 2015 ;3 :51 –63 .26309895 \n2 \nWright JL , Porter MP , Li CI , Lange PH , Lin DW \nDifferences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder . Cancer 2006 ;107 :721 –8 .16826584 \n3 \nRoy S , Smith MA , Cieply KM , Acquafondata MB , Parwani AV \nPrimary bladder adenocarcinoma versus metastatic colorectal adenocarcinoma: a persisting diagnostic challenge . Diagn Pathol 2012 ;7 :151 .23121893 \n4 \nAllegra CJ , Yothers G , O’Connell MJ , Sharif S , Colangelo LH , Lopa SH , et al \nInitial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer . J Clin Oncol 2009 ;27 :3385 –90 .19414665 \n5 \nSiefker-Radtke A \nUrachal adenocarcinoma: a clinician’s guide for treatment . Semin Oncol 2012 ;39 :619 –24 .23040259 \n6 \nTran B , McKendrick J \nMetastatic urachal cancer responding to FOLFOX chemotherapy . Can J Urol 2010 ;17 :5120 –3 .20398453 \n7 \nYanagihara Y , Tanji N , Miura N , Shirato A , Nishimura K , Fukumoto T , et al \nModified FOLFOX6 chemotherapy in patients with metastatic urachal cancer . Chemotherapy 2013 ;59 :402 –6 .24969043 \n8 \nTeo M , Swan NC , McDermott RS \nSustained response of adenocarcinoma of the urinary bladder to FOLFOX plus bevacizumab . Nat Rev Urol 2011 ;8 :282 –5 .21487385 \n9 \nTatli AM , Uysal M , Goksu SS , Arslan D , Gunduz S , Ozdogan M , et al \nPrimary mucinous adenocarcinoma of the bladder: complete response with FOLFOX-4 regimen . Med Oncol 2012 ;29 :1935 –7 .22042507 \n10 \nTatli AM , Uysal M , Goksu SS , Gunduz S , Arslan D , Ozdogan M \nComplete response of primary bladder adenocarcinoma with the FOLFOX4 regimen . Urol Int 2015 ;94 :363 –5 .24281125\n\n",
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"title": "Advanced primary nonurachal adenocarcinoma of urinary bladder responding to modified FOLFOX6 and capecitabine: a case report.",
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"abstract": "Auto-SCT is a common approach for metastatic neuroblastoma with the intention to rescue hematopoiesis after megadose chemotherapy. PBSC or BM is the usual stem cell source for auto-SCT. Auto-CBT for neuroblastoma has very rarely been performed. Currently, case reports are available for two patients only. We performed 13 auto-SCTs for high-risk neuroblastoma from 2007 to 2013, including four cases of metastatic neuroblastoma aged 11-64 months treated with auto-CBT. All four patients had partial or CR to upfront treatments before auto-CBT. Nucleated cell dose and CD34+ cell dose infused were 2.8-8.7 × 10(7) /kg and 0.36-3.9 × 10(5) /kg, respectively. Post-thawed viability was 57-76%. Neutrophil engraftment (>0.5 × 10(9) /L) occurred at 15-33 days, while platelet engraftment occurred at 31-43 days (>20 × 10(9) /L) and 33-65 days (>50 × 10(9) /L) post-transplant, respectively. There was no severe acute or chronic complication. Three patients survived for 1.9-7.7 yr without evidence of recurrence. One patient relapsed at 16 months post-transplant and died of progressive disease. Cord blood may be a feasible alternative stem cell source for auto-SCT in patients with stage 4 neuroblastoma, and outcomes may be improved compared to autologous PBSC or BM transplants.",
"affiliations": "Department of Pediatric Intensive Care Unit, Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Paediatrics & Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.;Department of Paediatrics & Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.;Department of Paediatrics & Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.;Department of Paediatrics & Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.;Department of Paediatrics & Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.",
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"abstract": "We present a 86-year-old patient who suffered from progressive weakness in his right leg. Due to a hypercholesterinemia he had received Simvastatin for a few years. Because of higher cholesterine levels the dosis had been increased from 40 to 80 mg 6 months ago.\n\n\n\nWe saw elevated levels of creatinine kinase and creatinine. In the EMG, a neuromuscular impairment was detected. In context with the medical history we could make the diagnosis of a statin-induced myopathy with rhabdomyolysis.\n\n\n\nAfter stopping the medication with statin and under liquid substitution, creatinine kinase and creatinine levels dropped. After therapy the weakness of the leg was totally recurrent.\n\n\n\nIn case of unclear neurological symptoms and under therapy with statins, a myopathy should be considered.",
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"authors": "Kandzia|Imke|I|;Kowar|Michael|M|;Frackowiak|Monika|M|;Jacobs|Andreas H|AH|",
"chemical_list": "D000924:Anticholesteremic Agents; D019821:Simvastatin",
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"abstract": "We present a case of Kluyveromyces marxianus keratitis nine months after Descement's membrane endothelial keratoplasty (DMEK) in a patient with Fuchs endothelial disease. Endothelial scraping revealed this rare yeast infection at the interface between graft and host cornea. Immediate antifungal treatment with intracameral and corneal intrastromal injections of voriconazole and amphotericin B remained unsuccessful, requiring penetrating keratoplasty. This case highlights the challenging management of keratomycosis in patients with endothelial grafts.",
"affiliations": "Julius-Maximilians-University, Institute for Hygiene and Microbiology, Josef-Schneider- Str.2, 97080, Würzburg, Germany.;University Hospital of Würzburg, Department of Ophthalmology, Josef- Schneider-Str. 11, 97080, Würzburg, Germany.;Julius-Maximilians-University, Institute of Pathology, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.;University Hospital of Würzburg, Department of Ophthalmology, Josef- Schneider-Str. 11, 97080, Würzburg, Germany.;National Reference Center for Invasive Fungal Infections NRZMyk, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), Adolf-Reichwein-Str. 23, 07745, Jena, Germany.;Julius-Maximilians-University, Institute for Hygiene and Microbiology, Josef-Schneider- Str.2, 97080, Würzburg, Germany.;University Hospital of Würzburg, Department of Ophthalmology, Josef- Schneider-Str. 11, 97080, Würzburg, Germany.;University Hospital of Würzburg, Department of Ophthalmology, Josef- Schneider-Str. 11, 97080, Würzburg, Germany.",
"authors": "Aldejohann|Alexander M|AM|;Theuersbacher|Johanna|J|;Haug|Lukas|L|;Lamm|Olga S|OS|;Walther|Grit|G|;Kurzai|Oliver|O|;Hillenkamp|Jost|J|;Kampik|Daniel|D|",
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"fulltext": "\n==== Front\nMed Mycol Case Rep\nMed Mycol Case Rep\nMedical Mycology Case Reports\n2211-7539 Elsevier \n\nS2211-7539(21)00005-1\n10.1016/j.mmcr.2021.02.001\nCase Report\nFirst case of Kluyveromyces marxianus (Candida kefyr) late onset keratitis after lamellar endothelial corneal graft\nAldejohann Alexander M. alexander.aldejohann@hygiene.uni-wuerzburg.dea∗ Theuersbacher Johanna b Haug Lukas c Lamm Olga S. b Walther Grit d Kurzai Oliver ad Hillenkamp Jost b Kampik Daniel b a Julius-Maximilians-University, Institute for Hygiene and Microbiology, Josef-Schneider- Str.2, 97080, Würzburg, Germany\nb University Hospital of Würzburg, Department of Ophthalmology, Josef- Schneider-Str. 11, 97080, Würzburg, Germany\nc Julius-Maximilians-University, Institute of Pathology, Josef-Schneider-Str. 2, 97080, Würzburg, Germany\nd National Reference Center for Invasive Fungal Infections NRZMyk, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI), Adolf-Reichwein-Str. 23, 07745, Jena, Germany\n∗ Corresponding author. alexander.aldejohann@hygiene.uni-wuerzburg.de\n12 2 2021 \n6 2021 \n12 2 2021 \n32 21 24\n16 12 2020 18 1 2021 8 2 2021 © 2021 The Authors. Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2021This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).We present a case of Kluyveromyces marxianus keratitis nine months after Descement's membrane endothelial keratoplasty (DMEK) in a patient with Fuchs endothelial disease. Endothelial scraping revealed this rare yeast infection at the interface between graft and host cornea. Immediate antifungal treatment with intracameral and corneal intrastromal injections of voriconazole and amphotericin B remained unsuccessful, requiring penetrating keratoplasty. This case highlights the challenging management of keratomycosis in patients with endothelial grafts.\n\nKeywords\nFungal keratitsKluyveromyces marxianus (Candida kefyr)DMEKCorneal transplantationVoriconazoleAmphotericin B\n==== Body\n1 Introduction\nKeratomycosis is a severe sight-threatening eye infection, conferred by both Candida\nspecies and filamentous fungi, which imposes a significant health issue of growing global concern [[1], [2], [3], [4], [5], [6]]. While keratomycosis is a relatively common event in tropical and subtropical regions, the incidence of fungal keratitis remains rare in moderate climate countries within Europe [2,5,6]. However, between 2003 and 2017 a 5-fold increase has been observed in different European countries, from 0.32 to 1.53 cases per million inhabitants per year [3,4].\n\nEtiologically, “independent” (i.e. social, economic, regional) and personal risk factors including corneal trauma, usage of contact lenses, prolonged usage of steroid eyedrops, ocular surface diseases and previous corneal transplants can be differentiated [[1], [2], [3]]. Though contaminations of transplants with Candida\nspecies leading to keratitis or endophthalmitis after partial or full keratoplasty are rare events, differences in tissue preparation and storage standards of corneal transplants might serve as a possible explanation. Furthermore, the fortification of storage media with antifungal substances is handled divergently in eye banks across Europe and the US [7].\n\nThe transplantation of a lamellar endothelial corneal graft (DMEK, descemet membrane endothelial keratoplasty) is a less invasive and less immunogenic standard technique in comparison to full thickness keratoplasty [8]. The diseased corneal host tissue is exchanged by a donor lamellar graft comprising the basal lamina with the endothelial cell monolayer. Yeast infections after graft insertion have been reported [7,9]. Especially in treatment of Fuchs endothelial dystrophy DMEK has increasingly evolved to a standard procedure due to good long-term efficacy and fast increase of visual acuity [10,11]. Fuchs dystrophy is characterized by bilateral loss of corneal endothelial cells causing vision loss due to corneal edema. If medical treatment is unsuccessful, corneal transplantation is required.\n\nThe dairy yeast and facultative opportunistic fungal pathogen Kluyveromyces marxianus (syn.: Candida kefyr) -formerly Candida pseudotropicalis- is rarely associated with human infection and scarcely described as transient eye flora [12,13]. Here we present a case of keratomycosis caused by Kluyveromyces marxianus after DMEK.\n\n2 Case presentation\nA 69-year-old male patient suffering from Fuchs endothelial dystrophy predominantly affecting the right eye was admitted to the ophthalmology department for elective DMEK, which was performed without any complications (day 0). Notably, 13 years earlier, the patient had undergone cataract surgery with insertion of an artificial lens as well as a trabeculectomy for pseudoexfoliation (PEX) glaucoma. In PEX glaucoma, metabolism of the extracellular matrix is disturbed. The deposition of fibrillary material causes instability of the lens zonula and an increase in intraocular pressure.\n\nAfter DMEK surgery, dexamethasone eye drops (1mg/ml) were applied six times a day, tapered weekly till day 42, to prevent rejection and to prolong graft survival. The cornea cleared and visual acuity increased from 0.15 (20/125) to 0.5 (20/25) within the following three weeks.\n\nAfter a symptom-free period of three months, a PEX-related luxation of the artificial lens occurred requiring lens exchange with implantation of an iris-fixated, retropupillar intraocular lens (day 104). The cornea remained clear postoperatively, visual acuity was 0.5 (20/25).\n\nAlmost nine months after DMEK (day 264), sudden pain of the right eye set in. Redness and corneal edema were initially interpreted as graft rejection and steroid eye drops were administered (day 279–285: prednisolone acetate 10 mg/ml four times daily; later changed to preservative-free dexamethasone eye drops 1 mg/ml three times daily, day 286–288).\n\nAs vision deteriorated further the patient was referred to our ophthalmology department on day 288. A dense whitish paracentral corneal infiltrate became evident, accompanied by an entirely opaque cornea due to stromal edema (Fig. 1A). Optical coherence tomography revealed a hyperdensity of 1.3 mm in diameter localized between graft and host cornea (Fig. 1B).Fig. 1 Late onset Kluyveromyces marxianus keratitis after lamellar corneal transplantation (DMEK, descemet membrane endothelial keratoplasty).\n\nA. Clinical findings nearly 9 months (288 days) after DMEK surgery: Paracentral corneal infiltrate with surrounding corneal opacity due to epithelial and stromal edema.\n\nB. Cross-section of the cornea by in vivo optical coherence tomography reveals localization of the infiltrate (1291 μm in diameter) between graft lamella and host cornea (Ep: epithelium, S: stroma, En: endothelial transplant lamella).\n\nC. Fungal structures (red arrows) in Grocott stain with surrounding mild inflammation. (Ep: epithelium, S: stroma, En: endothelial transplant lamella). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nBased on these findings we decided to broaden the diagnostic approach by tapping the anterior chamber and acquire an endothelial scraping in the area of the DMEK lamella harbouring the suspicious infiltrate. Local therapy consisted of an hourly alternating antibiotic regimen (day 288–291: ofloxacin 3 mg/ml and gentamicin sulphate 5 mg/ml).\n\nWhile initial Gram staining of the scraping material showed no evidence of microbial pathogens, typical small yeast-like white colonies were observed both on chromogenic media (CHROMagar, Becton Dickinson, USA), blood and chocolate agar after 24 hours of incubation at 36 °C. The species was then identified as Kluyveromyces marxianus by Matrix-Assisted Laser Desorption/Ionisation-Time of Flight (MALDI-TOF) mass spectrometry (MS) (Biomerieux Paris, France, VITEK MS database version 3.2) and finally confirmed via sequencing the internal transcribed spacer of the ribosomal DNA (ITS-rDNA). The ITS sequence of the isolate showed 100% identity with that of the ex-type strain of Kluyveromyces marxianus CBS 712 (GenBank accession number NR_111,251). The strain is deposited in the Jena Microbial Resource Collection (JMRC:NRZ:2921).\n\nImmediate susceptibility testing was performed by VITEK 2 automated system (Biomerieux, Paris, France) using an AST-YS08 testing cartridge (acc. to CLSI). Additionally, Sensititre Yeast One YO10 microbroth dilution (acc. to CLSI) and a EUCAST broth microdilution were conducted (Table 1).Table 1 Kluyveromyces marxianus (syn.: Candida kefyr) susceptibility testing results after 24h. Antifungal agents: anidulafungin (AND), amphotericin B (AMB), micafungin (MIC), caspofungin (CAS), 5-flucytosine (5-FC), posaconazole (POS), voriconazole (VOR), itraconazole (IT), fluconazole (FLU).\n\nTable 1Testing method\tAcc. to reference method\tMinimal inhibitory concentrations (MICs) of antifungal agent (μg/ml)\t\nAND\tAMB\tMIC\tCAS\t5-FC\tPOS\tVOR\tIT\tFLU\t\nVITEK 2\tCLSI\t–\t0.5\t0.12\t–\t–\t–\t≤0.12\t–\t1\t\nYO\tCLSI\t0.12\t1\t0.12\t0.12\t≤0.06\t0.12\t≤0.06\t0.12\t0.5\t\nBroth Microdilution\tEUCAST\t0.03\t0.125\t–\t–\t–\t≤0.016\t≤0.016\t≤0.016\t0.5\t\n\n\nA combination therapy of oral fluconazole (day 291 onwards: 400 mg daily loading dose; 200 mg daily maintenance dose) and hourly eye drops with voriconazole (1%) were begun followed by regular voriconazole (2%) injections. A total of four voriconazole injections were administered intracamerally, intrastromally and subconjunctivally (day 292, 294, 299, 301).\n\nUnfortunately, the infiltrate remained refractory to this treatment, even after regimen was switched to amphotericin B (50 μg/ml in 0.1ml) injections (day 305). On day 306, emergency full thickness keratoplasty had to be performed, again followed by intracameral application of amphotericin B.\n\nThe explanted graft revealed a slightly discontinuous Descemet membrane, whereas the multilayered corneal epithelium showed no significant abnormalities. Histopathology confirmed Candida infection. Fungal structures (red arrows) were identified in both PAS and Grocott stain with surrounding mild inflammation (Fig. 1C).\n\nAfter keratoplasty, the new graft showed no evidence of recurrence. As prophylaxis, antifungal therapy was continued with hourly application of topical voriconazole (1%) and two intracameral injections of amphotericin B (50 μg/ml in 0.1ml, day 319 and 322). For the remaining follow-up period up to day 354, findings were stable without signs of fungal activity, so that antimycotic topical and systemic therapy was discontinued.\n\n3 Discussion\nYeast infection is a rare complication of DMEK, occurring in 0.15% of the cases [14]. In the majority, causative pathogens can be obtained from direct biopsy. However, recent studies indicate that Candida-positive cultures of the corneal donor rim (tissue left over from transplantation) may be a valuable parameter in predicting fungal keratitis prior to the onset of clinical symptoms [7]. However, our patient developed no evidence of infection even four weeks after surgery, and neither did the donor rim show any signs of infection and was therefore discarded. This procedure is supported by the fact that longer preservation time is not necessarily correlated with higher incidences of donor rim contamination. In fact, only a small fraction of cases with positive donor rim cultures develop post-keratoplasty infection [15]. Therefore, it remains debatable whether the patient would have benefited from a prolonged donor cornea conservation.\n\nKluyveromyces marxianus is a rare but severe and life-threatening cause of bloodstream infection, which is underlined by the fact that Kluyveromyces marxianus candidiasis is associated with a higher mortality in ICU patients compared to C. albicans [16]. Hematologic malignancies are considered as a risk factor. Interestingly, a seasonal peak of colonisation and infection is observed during summertime, which might be related to a lack of refrigeration in dairy products [13].\n\nIn our case the patient developed first symptoms of keratitis nine months after DMEK. Fontana et al. described onset of bacterial or fungal keratitis as late as four months after surgery [17]. The special localization of the yeast sequestered between graft and host cornea could influence the late onset of infection and makes it less accessible by topical or systemic therapy [7,9]. However, therapeutic approaches do exist combining systemic therapy with multiple intrastromal and intracameral antimycotic injections, avoiding full thickness keratoplasty in Candida lamellar infection [9].\n\nDespite some Kluyveromyces marxianus in vitro data, no official breakpoints are established due to the paucity of clinical, pharmaceutical and epidemiological information [18]. Only EUCAST provides one fluconazole non-species related breakpoint for Candida based upon PK/PD data, which is defined as susceptible ≤2 μg/ml.\n\nOur antifungal regimen included oral administration of fluconazole accompanied by intracameral and intrastromal injections of voriconazole, which was considered effective -at least in vitro- according to the susceptibility data (Table 1).\n\nPrevious case reports clearly indicate that intracorneal injections of voriconazole are useful alternatives challenging deep stromal Candida infections, especially when full thickness keratoplasty is clinically thought to be too invasive at that particular timepoint [19]. Voriconazole is reported effective against different Candida species in-vitro, but overall pharmacokinetic and pharmacodynamic data is limited. Even so, experimental studies suggest a demand of repeated drug administration at the site of infection, due the risk of accelerated loss of concentration below MIC of common fungi, which we met with multiple intracarmal and intrastromal injections [20]. Fluconazole was given as an attempt to further strengthen local azole concentrations, being aware that corneal drug penetrations of systemically added antifungals are usually poor.\n\nNotably, comparing both EUCAST and CLSI methodologies performed on different testing devices (in-house broth microdilution versus semiautomatic- and automatic commercial broth microdilution), obtained minimum inhibitory concentrations (MICs) are in a similar range.\n\nA change to amphotericin B was considered as a last attempt for medical treatment. It is debatable whether this change should have been considered earlier or even in first place, but it illustrates the dilemma of susceptibility testing in vitro and the concordant effect in vivo at the site of infection.\n\nNonetheless, graft removal was inevitable, underlining the complexity of treating this rare infection by constantly re-balancing the value of antifungal therapy with the lack of in vivo breakpoints against surgical measures, which will ultimately remove the infected focus but result in a new full thickness graft with a risk of reinfection and other complications.\n\nFurther interdisciplinary clinical studies and case reports are warranted not only to elucidate the role of Kluyveromyces marxianus as a rare pathogen but also to develop new treatment strategies for this challenging infection.\n\nFunding source\nThe German National Reference Center NRZMyk is funded by the Robert Koch Institute from funds provided by the 10.13039/501100003107German Ministry of Health (grant no. 1369-240).\n\nConsent\nWritten informed consent was obtained from the patient or legal guardian(s) for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nDeclaration of competing interest\nThere are none.\n\nAcknowledgements\nWe thank Anastasia Besenfelder, Sabrina Mündlein for generating the susceptibility data and Ronny Martin, Yano Axel Pöhlmann for critically reviewing the manuscript.\n==== Refs\nReferences\n1 Roth M. Daas L. Renner-Wilde A. Cvetkova-Fischer N. Saeger M. Herwig-Carl M. The German keratomycosis registry : initial results of a multicenter survey Ophthalmologe 116 10 2019 957 966 30810837 \n2 Walther G. Stasch S. Kaerger K. Hamprecht A. Roth M. Cornely O.A. Fusarium keratitis in Germany J. Clin. Microbiol. 55 10 2017 2983 2995 28747368 \n3 Farrell S. McElnea E. Moran S. Knowles S. Murphy C.C. Fungal keratitis in the republic of Ireland Eye 31 10 2017 1427 1434 28524886 \n4 Tuft S.J. Tullo A.B. Fungal keratitis in the United Kingdom 2003-2005 Eye 23 6 2009 1308 1313 18836409 \n5 Satpathy G. Ahmed N.H. Nayak N. Tandon R. Sharma N. Agarwal T. Spectrum of mycotic keratitis in north India: sixteen years study from a tertiary care ophthalmic centre J Infect Public Health 12 3 2019 367 371 30600158 \n6 Khor W.B. Prajna V.N. Garg P. Mehta J.S. Xie L. Liu Z. The asia cornea society infectious keratitis study: a prospective multicenter study of infectious keratitis in asia Am. J. Ophthalmol. 195 2018 161 170 30098351 \n7 Beckman K.A. Milner M.S. Majmudar P.A. Luchs J.I. Late-onset fungal interface keratitis following endothelial keratoplasty with positive donor fungal culture Am J Ophthalmol Case Rep 18 2020 100707 32368689 \n8 Hos D. Tuac O. Schaub F. Stanzel T.P. Schrittenlocher S. Hellmich M. Incidence and clinical course of immune reactions after descemet membrane endothelial keratoplasty: retrospective analysis of 1000 consecutive eyes Ophthalmology 124 4 2017 512 518 28094043 \n9 Tu E.Y. Hou J. Intrastromal antifungal injection with secondary lamellar interface infusion for late-onset infectious keratitis after DSAEK Cornea 33 9 2014 990 993 25055150 \n10 Boynton G.E. Woodward M.A. Evolving techniques in corneal transplantation Curr Surg Rep 3 2 2015 \n11 Matthaei M. Schrittenlocher S. Hos D. Siebelmann S. Bucher F. Schaub F. 10 years of Descemet membrane endothelial keratoplasty in Fuchs endothelial corneal dystrophy : what have we learned? Ophthalmologe 116 3 2019 236 242 30367230 \n12 Gugnani H.C. Gupta S. Talwar R.S. Role of opportunistic fungi in ocular infections in Nigeria Mycopathologia 65 1–3 1978 155 166 745623 \n13 Dufresne S.F. Marr K.A. Sydnor E. Staab J.F. Karp J.E. Lu K. Epidemiology of Candida kefyr in patients with hematologic malignancies J. Clin. Microbiol. 52 6 2014 1830 1837 24622105 \n14 Augustin V.A. Weller J.M. Kruse F.E. Tourtas T. Fungal interface keratitis after descemet membrane endothelial keratoplasty Cornea 37 11 2018 1366 1369 30157050 \n15 Mian S.I. Aldave A.J. Tu E.Y. Ayres B.D. Jeng B.H. Macsai M.S. Incidence and outcomes of positive donor rim cultures and infections in the cornea preservation time study Cornea 37 9 2018 1102 1109 29912040 \n16 Lortholary O. Renaudat C. Sitbon K. Madec Y. Denoeud-Ndam L. Wolff M. Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002-2010) Intensive Care Med. 40 9 2014 1303 1312 25097069 \n17 Fontana L. Moramarco A. Mandarà E. Russello G. Iovieno A. Interface infectious keratitis after anterior and posterior lamellar keratoplasty. Clinical features and treatment strategies. A review Br. J. Ophthalmol. 103 3 2019 307 314 30355718 \n18 Nagy F. Bozo A. Toth Z. Daroczi L. Majoros L. Kovacs R. In vitro antifungal susceptibility patterns of planktonic and sessile Candida kefyr clinical isolates Med. Mycol. 56 4 2018 493 500 28992253 \n19 Mamas N. Andreanos K. Chatzistefanou K. Petrou P. Brouzas D. Kymionis G. Supradescemetic voriconazole injection for Candida parapsilosis keratitis Int. Ophthalmol. 38 2 2018 849 854 28421398 \n20 Shen Y.C. Wang M.Y. Wang C.Y. Tsai T.C. Tsai H.Y. Lee H.N. Pharmacokinetics of intracameral voriconazole injection Antimicrob. Agents Chemother. 53 5 2009 2156 2157 19258273\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2211-7539",
"issue": "32()",
"journal": "Medical mycology case reports",
"keywords": "Amphotericin B; Corneal transplantation; DMEK; Fungal keratits; Kluyveromyces marxianus (Candida kefyr); Voriconazole",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "21-24",
"pmc": null,
"pmid": "33665066",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "32368689;25055150;28747368;19258273;25097069;30098351;745623;24622105;26101726;28094043;30367230;29912040;28524886;30600158;28421398;28992253;30810837;30157050;30355718;18836409",
"title": "First case of Kluyveromyces marxianus (Candida kefyr) late onset keratitis after lamellar endothelial corneal graft.",
"title_normalized": "first case of kluyveromyces marxianus candida kefyr late onset keratitis after lamellar endothelial corneal graft"
} | [
{
"companynumb": "DE-ALVOGEN-2021-ALVOGEN-116778",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nMethadone administration has increased in pediatric clinical settings. This review is an attempt to ascertain an equianalgesic dose ratio for methadone in the pediatric population using standard adult dose conversion guidelines.\n\n\nMETHODS\nUS tertiary children's hospital.\n\n\nMETHODS\nHospitalized pediatric patients, 0-18 years of age.\n\n\nMETHODS\nA retrospective chart review was conducted for patients who were converted from their initial opioid therapy regimen (morphine, hydromorphone, and/or fentanyl) to methadone. The primary endpoint was whether or not a dose correction was needed for methadone in the 6 days following conversion using standard dose conversion charts for adults. Documented clinical signs of withdrawal, unrelieved pain, or oversedation were examined.\n\n\nRESULTS\nThe majority (53.7 percent) of the 199 children were converted to methadone on intensive care units prior extubation or postextubation. The mean conversion ratio was 23.7 mg of oral morphine to 1 mg of oral methadone (median, 18.8 mg:1 mg, SD=25.7). Most patients experienced an adequate conversion (n=115, 57.8 percent), while 83 (41.7 percent) appeared undermedicated, and one child was oversedated. There were no associations found with conversion ratios for initial morphine dose, days to conversion, or effect of withdrawal of concomitant agents with potential for withdrawal.\n\n\nCONCLUSIONS\nOpioid conversion to methadone is commonly practiced at our institution; however, dosing was significantly lower compared to adult conversion ratios, and more than 40 percent of children were undermedicated. The majority of children in this study received opioids for sedation while intubated and ventilated; therefore, safe and efficacious pediatric methadone conversion rates remain unclear. Prospective studies are needed.",
"affiliations": "Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.;Scientific Investigator, Department of Pain Medicine, Palliative Care and Integrative Medicine, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.;Career Scientist, Head of Design and Analytics Core, Research and Sponsored Programs, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.;Medical Director, Department of Pain Medicine, Palliative Care and Integrative Medicine, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota; Associate Professor, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.",
"authors": "Fife|Alexandra|A|;Postier|Andrea|A|;Flood|Andrew|A|;Friedrichsdorf|Stefan J|SJ|",
"chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-7489",
"issue": "12(2)",
"journal": "Journal of opioid management",
"keywords": null,
"medline_ta": "J Opioid Manag",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D000701:Analgesics, Opioid; D002648:Child; D002675:Child, Preschool; D003243:Consciousness; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D062787:Drug Overdose; D057915:Drug Substitution; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007297:Inpatients; D007442:Intubation, Intratracheal; D008691:Methadone; D008910:Minnesota; D010146:Pain; D010607:Pharmacy Service, Hospital; D012121:Respiration, Artificial; D012189:Retrospective Studies; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome; D062606:Tertiary Care Centers; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101234523",
"other_id": null,
"pages": "123-30",
"pmc": null,
"pmid": "27194197",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methadone conversion in infants and children: Retrospective cohort study of 199 pediatric inpatients.",
"title_normalized": "methadone conversion in infants and children retrospective cohort study of 199 pediatric inpatients"
} | [
{
"companynumb": "US-MYLANLABS-2016M1045852",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nCardiac implantable electronic device (CIED) leads frequently develop echogenic masses. However, the nature of these masses is not well understood. In patients in whom atrial fibrillation (AF) catheter ablation is planned, there is concern that transseptal puncture may result in cerebrovascular embolism of these masses. The optimal therapeutic strategy in this setting remains undefined.\n\n\nMETHODS\nWe describe six patients identified over a 6-year period (2008-2014) with device lead-based masses prior to or at the time of AF ablation. We examined the anticoagulation strategy and periprocedural management based on mass identification.\n\n\nRESULTS\nIn all six patients (age 39-73; four males), the device lead mass was found in the right atrium. The average mass size was 11 ± 1.3 mm. The majority of patients were already on anticoagulation (5/6; 83 %), and an intensified anticoagulation regimen was initiated (INR goal 3.0). In all six patients, the size of the device lead mass decreased on repeat imaging. In two sixths (33 %) patients, the lead-based mass completely resolved within 2 months. The remaining four patients had persistent lead-based masses (average follow-up of 10.9 ± 9.6 months).\n\n\nCONCLUSIONS\nWe describe a series of patients with CIED lead-based masses found at the time of ablation. These cases illustrate that lead-based masses can disappear while patients are on high-intensity anticoagulation, most compatible with a thrombotic origin. These early data will need to be assessed in larger cohorts for further validation and evaluation of safety.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, USA.;Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, USA.;Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, USA.;Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, USA.;Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, USA.;Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN, USA. asirvatham.samuel@mayo.edu.",
"authors": "Lenz|Charles J|CJ|;DeSimone|Christopher V|CV|;Ponamgi|Shiva P|SP|;Sugrue|Alan|A|;Sinak|Lawrence J|LJ|;Chandrasekaran|Krishnaswamy|K|;Packer|Douglas L|DL|;Asirvatham|Samuel J|SJ|",
"chemical_list": "D000925:Anticoagulants",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10840-016-0110-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1383-875X",
"issue": "46(3)",
"journal": "Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing",
"keywords": "Anticoagulation; Cardiac implantable electronic device; Catheter ablation; Lead thrombus; Lead-based masses",
"medline_ta": "J Interv Card Electrophysiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D016022:Case-Control Studies; D017115:Catheter Ablation; D017147:Defibrillators, Implantable; D004567:Electrodes, Implanted; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010138:Pacemaker, Artificial; D019990:Perioperative Care; D011292:Premedication; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "9708966",
"other_id": null,
"pages": "237-43",
"pmc": null,
"pmid": "26898212",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "20048212;15145112;25767086;24685669;19572951;10874278;19995881;14522574;17100678;23844971;21788588;2419868;18570298;24771226;20053426;15511419;22389422;20348141;19684037;18568395;23946264",
"title": "Cardiac implantable electronic device lead-based masses and atrial fibrillation ablation: a case-based illustration of periprocedural anticoagulation management strategies.",
"title_normalized": "cardiac implantable electronic device lead based masses and atrial fibrillation ablation a case based illustration of periprocedural anticoagulation management strategies"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-55290BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
}... |
{
"abstract": "We describe a case report of a 30-year-old bodybuilder suffering acute myocardial infarction (AMI). He had been taking stanozolol and testosterone for two months. The coronary angiogram showed high thrombotic burden in the left anterior descending artery without underlying atherosclerosis. Few case reports of AMI in athletes taking anabolic androgenic steroids (AASs) have been reported so far. AAS-related AMI is possibly underreported in the medical literature due to the desire of the affected individuals to hide AAS use. Physicians should always consider the possibility of AAS abuse in the context of a young athlete suffering AMI. AASs can predispose to AMI through the acceleration of coronary atherosclerosis. Additionally, thrombosis without underlying atherosclerosis or vasospasm is highly possible to cause AMI in AAS users. Complications after AMI may be more frequent in AAS users.",
"affiliations": "Laboratory of Physiology, Medical School, University of Ioannina, Greece georgios.christou@yahoo.gr.;First Department of Cardiology, University Hospital of Ioannina, Greece.;First Department of Cardiology, University Hospital of Ioannina, Greece.;First Department of Cardiology, University Hospital of Ioannina, Greece.",
"authors": "Christou|Georgios A|GA|;Christou|Konstantinos A|KA|;Nikas|Dimitrios N|DN|;Goudevenos|John A|JA|",
"chemical_list": "D045930:Anabolic Agents",
"country": "England",
"delete": false,
"doi": "10.1177/2047487316651341",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2047-4873",
"issue": "23(16)",
"journal": "European journal of preventive cardiology",
"keywords": "Anabolic steroids; athletes; bodybuilding; myocardial infarction",
"medline_ta": "Eur J Prev Cardiol",
"mesh_terms": "D000328:Adult; D045930:Anabolic Agents; D056352:Athletes; D004300:Doping in Sports; D004452:Echocardiography; D004562:Electrocardiography; D006801:Humans; D008297:Male; D000072657:ST Elevation Myocardial Infarction; D013008:Somatotypes",
"nlm_unique_id": "101564430",
"other_id": null,
"pages": "1785-1796",
"pmc": null,
"pmid": "27184497",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acute myocardial infarction in a young bodybuilder taking anabolic androgenic steroids: A case report and critical review of the literature.",
"title_normalized": "acute myocardial infarction in a young bodybuilder taking anabolic androgenic steroids a case report and critical review of the literature"
} | [
{
"companynumb": "GR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-117330",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"dr... |
{
"abstract": "Serotonin syndrome is gaining attention in perioperative and chronic pain settings due to the growing prevalence of multimodal therapies that increase serotonin levels and thereby heighten patient risk. A patient's genetic make-up may further increase the risk of serotonin syndrome. A case of serotonin syndrome on emergence after general anesthesia is presented. A subsequent cytochrome P4502D6 genetic test result suggested a potential alteration in metabolism. For this patient, who was taking combination antidepressant medications and receiving common perioperative medicines, additive pharmacodynamic effects converged with a pharmacogenetic predisposition, resulting in serotonin syndrome.",
"affiliations": "Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: beatty.nicole@mayo.edu.;Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.",
"authors": "Beatty|Nicole C|NC|;Nicholson|Wayne T|WT|;Langman|Loralie J|LJ|;Curry|Timothy B|TB|;Eisenach|John H|JH|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "25(8)",
"journal": "Journal of clinical anesthesia",
"keywords": "Duloxetine; Multimodal therapy; P4502D6 chromosome; Perioperative serotonin syndrome; Pharmacogenetics",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000768:Anesthesia, General; D019389:Cytochrome P-450 CYP2D6; D004347:Drug Interactions; D000068736:Duloxetine Hydrochloride; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D013876:Thiophenes",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "662-5",
"pmc": null,
"pmid": "24096103",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacogenetic workup of perioperative serotonin syndrome.",
"title_normalized": "pharmacogenetic workup of perioperative serotonin syndrome"
} | [
{
"companynumb": "US-PAR PHARMACEUTICAL, INC-2014SCPR009311",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional"... |
{
"abstract": "Purpose Patients with relapsed metastatic germ cell tumor (GCT) can be cured with second-line and even third-line regimens. We report survival outcomes of patients treated with high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplantation (PBSCT) at Indiana University between 2004 and 2014. Patients and Methods We conducted a retrospective analysis of 364 consecutive patients with GCT who progressed after cisplatin-based combination chemotherapy and were subsequently treated with HDCT and PBSCT. Three hundred forty-one patients received two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. Twenty-three patients received only a single course of HDCT because of progressive disease or toxicity. Cox proportional hazards models were used to test predictors of disease progression. Results The median age was 32 years (range, 17 to 70 years). With a median follow-up of 3.3 years, the 2-year progression-free survival (PFS) was 60% (95% CI, 55% to 65%) and the 2-year overall survival was 66% (95% CI, 60% to 70%). Three hundred three patients received HDCT as second-line therapy with a 2-year PFS of 63% (95% CI, 57% to 68%), and 61 patients received HDCT as third-line or later therapy with a 2-year PFS of 49% (95% CI, 36% to 61%). In a multivariable analysis, factors associated with disease progression included use of HDCT as third-line or later therapy, platinum-refractory disease, mediastinal primary tumor site, nonseminoma histology, intermediate- or poor-risk disease at the time of GCT diagnosis, and human chorionic gonadotropin ≥ 1,000 mIU/mL at initiation of HDCT. There were nine treatment-related deaths. Secondary leukemia developed in five patients. Conclusion This large single-institution study demonstrates that patients with relapsed metastatic GCT are curable by HDCT plus PBSCT even when used in third-line or later therapy.",
"affiliations": "All authors: Indiana University School of Medicine, Indianapolis, IN.;All authors: Indiana University School of Medicine, Indianapolis, IN.;All authors: Indiana University School of Medicine, Indianapolis, IN.;All authors: Indiana University School of Medicine, Indianapolis, IN.;All authors: Indiana University School of Medicine, Indianapolis, IN.;All authors: Indiana University School of Medicine, Indianapolis, IN.",
"authors": "Adra|Nabil|N|;Abonour|Rafat|R|;Althouse|Sandra K|SK|;Albany|Costantine|C|;Hanna|Nasser H|NH|;Einhorn|Lawrence H|LH|",
"chemical_list": "D006063:Chorionic Gonadotropin; D005047:Etoposide; D016190:Carboplatin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2016.69.5395",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "35(10)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D006063:Chorionic Gonadotropin; D003131:Combined Modality Therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005047:Etoposide; D006801:Humans; D007938:Leukemia; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D019233:Retreatment; D012186:Retroperitoneal Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors; D018239:Seminoma; D015996:Survival Rate; D013736:Testicular Neoplasms; D013997:Time Factors; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "1096-1102",
"pmc": null,
"pmid": "27870561",
"pubdate": "2017-04-01",
"publication_types": "D016428:Journal Article",
"references": "26786931;9053482;8874322;7786590;2544687;15928070;9667270;20194867;7738621;21444870;18270356;22291076;2154858;20956623;25030752;16170162;25409373;10340903;11013274;8381163;17652649;3633952",
"title": "High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience.",
"title_normalized": "high dose chemotherapy and autologous peripheral blood stem cell transplantation for relapsed metastatic germ cell tumors the indiana university experience"
} | [
{
"companynumb": "US-PFIZER INC-2016411379",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Asparaginase (Asp) and corticosteroid (CS) treatment in patients with acute lymphoblastic leukaemia (ALL) is associated with an increased risk of thrombotic events.\n\n\n\nCharacterization of global haemostatic phenotypes of patients with ALL during Asp therapy.\n\n\n\nThrombin generation (TG) was monitored in platelet-poor plasma of 56 children treated for a B lineage ALL (36 with native, 20 with PEG Asp) using 1 pM tissue factor and 4 μM phospholipids, with and without thrombomodulin. Protein C activity (PC), free protein S (PS), antithrombin (AT) and fibrinogen levels were also measured.\n\n\n\nElevated endogenous thrombin potential (ETP) and peak of TG were noted at diagnosis, throughout the Induction phase and Late Intensification but was significantly less for PEG than for native Asp (P < 0.001), while age, sex, type of corticosteroid during Induction and molecular response had no significant effect. The reduction of ETP after addition of thrombomodulin was significantly lower in ALL children compared with that in controls, suggesting impairment in PS/PC pathway. Three patients experienced thrombosis: two treated with native and one with PEG Asp. The two patients with native Asp had, at the time of thrombosis, a prothrombotic profile.\n\n\n\nTreatment with Asp, in combination with CS, enhances TG in children with ALL, more significantly with native than PEG Asp, which is present early at diagnosis, persists during Induction and reappears during Late Intensification. This is consistent with the high incidence of thrombotic events described during these phases of therapy. The less pronounced effect of PEG Asp remains to be elucidated.",
"affiliations": "Laboratory of hematology, CHU Brugmann, LHUB-ULB, ULB Université libre de Bruxelles, Brussels, Belgium.;Laboratory of hematology, CHU Brugmann, LHUB-ULB, ULB Université libre de Bruxelles, Brussels, Belgium.;Hematology-Oncology Unit, Hôpital Universitaire des Enfants Reine Fabiola, ULB Université libre de Bruxelles, Brussels, Belgium.;Hematology-Oncology Unit, Hôpital Universitaire des Enfants Reine Fabiola, ULB Université libre de Bruxelles, Brussels, Belgium.;Hematology-Oncology Unit, Hôpital Universitaire des Enfants Reine Fabiola, ULB Université libre de Bruxelles, Brussels, Belgium.;Hematology-Oncology Unit, Hôpital Universitaire des Enfants Reine Fabiola, ULB Université libre de Bruxelles, Brussels, Belgium.;Laboratory of hematology, CHU Brugmann, LHUB-ULB, ULB Université libre de Bruxelles, Brussels, Belgium.",
"authors": "Rozen|Laurence|L|;Noubouossie|Denis|D|;Dedeken|Laurence|L|;Huybrechts|Sophie|S|;Lê|Phu Quoc|PQ|;Ferster|Alina|A|;Demulder|Anne|A|",
"chemical_list": "D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C042705:pegaspargase; D013917:Thrombin; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26228",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(2)",
"journal": "Pediatric blood & cancer",
"keywords": "acute lymphoblastic leukaemia; asparaginase; coagulation; haemostatic potential; thrombin generation",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D001215:Asparaginase; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006487:Hemostasis; D006801:Humans; D007223:Infant; D008297:Male; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D013917:Thrombin; D013927:Thrombosis",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "294-301",
"pmc": null,
"pmid": "27605400",
"pubdate": "2017-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase: A cohort study.",
"title_normalized": "different profile of thrombin generation in children with acute lymphoblastic leukaemia treated with native or pegylated asparaginase a cohort study"
} | [
{
"companynumb": "BE-MYLANLABS-2017M1025367",
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"occurcountry": "BE",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "OBJECTIVE\nInfliximab (IFX) is a monoclonal antibody used to treat patients with Crohn's disease (CD). Intra-abdominal abscess formation is a major complication of CD with negative effects on patient prognosis. We have analyzed risk factors for abscess formation in CD patients treated with IFX.\n\n\nMETHODS\nCD patients who received IFX between January 2000 and April 2011 at Keio University Hospital were analyzed retrospectively. Risk factors for abscess formation were assessed by univariate and multivariate logistic regression analyses.\n\n\nRESULTS\nIntra-abdominal abscess was seen in 15 of 258 patients. Univariate analyses showed serum C-reactive protein (CRP) concentration at 14 weeks after initiation of IFX (p = 0.021), serum albumin concentration at week 0 (p = 0.022) and week 14 (p = 0.004), the presence of anal lesions (p = 0.036), progression of intestine deformation (p = 0.015) and early loss of response to IFX (p < 0.0001) to be risk factors. Multivariate analysis showed that CRP concentration at 14 weeks [odds ratio (OR) 1.361] and loss of IFX response within 6 months (OR 5.361) were independent risk factors.\n\n\nCONCLUSIONS\nAbscess formation should be suspected in patients with symptoms of CD recurrence during IFX therapy. Uncontrolled CRP concentration and early loss of response to IFX are risk factors.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.",
"authors": "Yoneno|Kazuaki|K|;Hisamatsu|Tadakazu|T|;Matsuoka|Katsuyoshi|K|;Okamoto|Susumu|S|;Takayama|Tetsuro|T|;Ichikawa|Riko|R|;Sujino|Tomohisa|T|;Miyoshi|Jun|J|;Takabayashi|Kaoru|K|;Mikami|Yohei|Y|;Mizuno|Shinta|S|;Wada|Yasuyo|Y|;Yajima|Tomoharu|T|;Naganuma|Makoto|M|;Inoue|Nagamu|N|;Iwao|Yasushi|Y|;Ogata|Haruhiko|H|;Hasegawa|Hirotoshi|H|;Kitagawa|Yuko|Y|;Hibi|Toshifumi|T|;Kanai|Takanori|T|",
"chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D000069285:Infliximab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000360618",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-2823",
"issue": "89(3)",
"journal": "Digestion",
"keywords": null,
"medline_ta": "Digestion",
"mesh_terms": "D018784:Abdominal Abscess; D000911:Antibodies, Monoclonal; D002097:C-Reactive Protein; D003424:Crohn Disease; D018450:Disease Progression; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0150472",
"other_id": null,
"pages": "201-8",
"pmc": null,
"pmid": "24803137",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk and management of intra-abdominal abscess in Crohn's disease treated with infliximab.",
"title_normalized": "risk and management of intra abdominal abscess in crohn s disease treated with infliximab"
} | [
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"companynumb": "JP-JNJFOC-20120304604",
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"activesubstancename": "INFLIXIMAB"
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{
"abstract": "High-fidelity mannequin-based simulation is frequently used to compliment medical student education during clinical clerkships. However, psychiatric educators have not broadly adopted this modality, focusing rather on standardized patient actors. We developed and delivered a simulation case involving a patient with alcohol withdrawal and lithium toxicity followed by a debriefing session to medical students at the end of their psychiatric clerkship.\n\n\n\nThe case involves a 40-year-old male truck driver with a history of bipolar disorder who presents to the emergency room after a truck accident. The patient is in alcohol withdrawal, which responds to benzodiazepines. A workup reveals that the patient also has lithium toxicity related to the co-ingestion of lithium and naproxen for pain. Participants learn to evaluate and treat alcohol withdrawal, consider medical comorbidities and legal consequences, and complete a brief intervention for substance use. This case requires a simulation mannequin.\n\n\n\nTo date, 150 second-, third-, and fourth-year medical students have participated in this case and 76 have been surveyed. Participants have provided a postsession rating of 4.49 on a 5-point Likert scale (1 = strongly disagree and 5 = strongly agree) on a question about enjoyment, and 3.93 on a question about confidence with evaluation and treatment of patients in alcohol withdrawal.\n\n\n\nPsychiatric education currently underutilizes mannequin-based simulation compared to other medical disciplines. Mannequin simulation is feasible and effective in psychiatric education, especially in cases involving medical complexity, as shown in this novel case involving a patient with alcohol withdrawal and lithium toxicity.",
"affiliations": "Forensic Psychiatry Fellow, Department of Psychiatry, Yale School of Medicine.;Associate Professor, Department of Psychiatry, Yale School of Medicine.;Clinical Instructor, Department of Emergency Medicine, Yale School of Medicine.;Clinical Instructor, Department of Emergency Medicine, Yale School of Medicine.;Associate Professor, Department of Psychiatry, Yale School of Medicine.;Associate Professor, Department of Psychiatry, Yale School of Medicine.",
"authors": "Bhalla|Ish P|IP|;Wilkins|Kirsten M|KM|;Moadel|Tiffany|T|;Wong|Ambrose H|AH|0000-0001-7471-1647;Trevisan|Louis A|LA|;Fuehrlein|Brian|B|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001569:Benzodiazepines; D009288:Naproxen; D008094:Lithium",
"country": "United States",
"delete": false,
"doi": "10.15766/mep_2374-8265.10649",
"fulltext": "\n==== Front\nMedEdPORTALMedEdPORTALMEPMedEdPORTAL : the Journal of Teaching and Learning Resources2374-8265Association of American Medical Colleges 10.15766/mep_2374-8265.10649Original PublicationAlcohol Withdrawal and Lithium Toxicity: A Novel Psychiatric Mannequin-Based Simulation Case for Medical Students Bhalla Ish P. 1*Wilkins Kirsten M. 2Moadel Tiffany 3https://orcid.org/0000-0001-7471-1647Wong Ambrose H. 3Trevisan Louis A. 2Fuehrlein Brian 21 Forensic Psychiatry Fellow, Department of Psychiatry, Yale School of Medicine2 Associate Professor, Department of Psychiatry, Yale School of Medicine3 Clinical Instructor, Department of Emergency Medicine, Yale School of Medicine*Corresponding author: ish.bhalla@yale.edu2017 01 11 2017 13 1064919 7 2017 10 10 2017 Copyright © 2017 Bhalla et al.2017Bhalla et al.This is an open-access publication distributed under the terms of the Creative Commons Attribution-NonCommercial-Share Alike license.Introduction\nHigh-fidelity mannequin-based simulation is frequently used to compliment medical student education during clinical clerkships. However, psychiatric educators have not broadly adopted this modality, focusing rather on standardized patient actors. We developed and delivered a simulation case involving a patient with alcohol withdrawal and lithium toxicity followed by a debriefing session to medical students at the end of their psychiatric clerkship.\n\nMethods\nThe case involves a 40-year-old male truck driver with a history of bipolar disorder who presents to the emergency room after a truck accident. The patient is in alcohol withdrawal, which responds to benzodiazepines. A workup reveals that the patient also has lithium toxicity related to the co-ingestion of lithium and naproxen for pain. Participants learn to evaluate and treat alcohol withdrawal, consider medical comorbidities and legal consequences, and complete a brief intervention for substance use. This case requires a simulation mannequin.\n\nResults\nTo date, 150 second-, third-, and fourth-year medical students have participated in this case and 76 have been surveyed. Participants have provided a postsession rating of 4.49 on a 5-point Likert scale (1 = strongly disagree and 5 = strongly agree) on a question about enjoyment, and 3.93 on a question about confidence with evaluation and treatment of patients in alcohol withdrawal.\n\nDiscussion\nPsychiatric education currently underutilizes mannequin-based simulation compared to other medical disciplines. Mannequin simulation is feasible and effective in psychiatric education, especially in cases involving medical complexity, as shown in this novel case involving a patient with alcohol withdrawal and lithium toxicity.\n\nKeywords\nPsychiatryAlcohol Use DisorderMannequin SimulationLithium Toxicity\n==== Body\nEducational Objectives\nBy the end of this session, learners will be able to:\n1. Evaluate a patient with a complex psychiatric presentation in an emergency setting.\n\n2. Formulate an initial work-up and treatment plan for a patient with alcohol withdrawal and lithium toxicity.\n\n3. Describe the pharmacokinetics of both lithium and alcohol, including how these drug-drug interactions can present clinically.\n\n4. Communicate effectively with team members by working together to collectively complete the simulation.\n\n5. Employ a brief intervention for alcohol use disorder by gathering history and clarifying jargon regarding the nature of alcohol use.\n\n6. Discuss legal and ethical ramifications of maintaining confidentiality versus public safety.\n\n\n\nIntroduction\nHigh fidelity mannequin-based simulation technology has been shown to be effective in teaching health care practice and delivery in various medical disciplines, including anesthesia and emergency medicine.1–3 As a specialty that relies on thorough history-taking, mental status examinations, and nonverbal cues such as body language and facial expressions, psychiatry continues to prefer the use of standardized patient actors rather than mannequin simulation in educational design.4 However, mannequin simulators can represent the physiologic aspects of a patient's illness where live actors cannot, and can allow for the demonstration of real-time autonomous reactions to interventions and therapies.5 Full-scale, high-fidelity simulated environments using mannequin simulators can be uniquely effective when complex, rare, or potentially dangerous clinical scenarios need to be accurately portrayed in an immersive clinical setting.6 There is some evidence, in fact, that supports the effectiveness of mannequin-based simulation in psychiatry, though there is not a significant amount of literature on the subject.7,8\n\nPatients with psychiatric illness and addiction often have comorbid medical problems or medication side effects that should be carefully considered, especially in emergency settings. Not all medical students are given the opportunity to evaluate and treat patients with such comorbidities in an emergency room during their psychiatry clerkship. Medical simulators are generally available at U.S. medical schools and often underutilized by psychiatry. Thus, we designed a case utilizing a mannequin to simulate an emergency department encounter of a patient with bipolar disorder, alcohol-use disorder, and lithium-induced acute kidney injury to allow students to explore the diagnosis and management of a psychiatric patient with ongoing medical complications. We chose to develop a case that emphasizes overlap between medical and psychiatric conditions to challenge students to think broadly about medical problems that may arise in patients with psychiatric problems.\n\nA search of MedEdPORTAL and did not find any other psychiatric case that utilized high-fidelity mannequin technology. As previously stated, our case involves a common, yet complex, presentation of a patient experiencing comorbid alcohol use and medical complications. While this is a common clinical scenario encountered by physicians, not all medical students have the opportunity to care for such patients during their brief rotation on psychiatry. We hope that this will be the first of many psychiatric cases utilizing high-fidelity mannequin technology.\n\nThe case was delivered as a component of a half-day teaching session at the end of a 12-week integrated primary care/psychiatry clerkship. Our overall goal was to provide an opportunity for experiential learning where students manage psychiatric diagnoses in the broader context of a medically complex patient who concurrently requires therapeutic intervention for both metabolic and behavioral health issues. During their psychiatry clerkship, students have learned about how to employ a brief intervention for hazardous alcohol use, which they are later encouraged to use during this case. All students participated in an introduction to simulation session, which oriented them to the simulation mannequin, the simulation environment, and its capabilities prior to the start of their clerkships.\n\nMethods\nEquipment/Environment\nThis simulation took place within an on-site medical school affiliated simulation center, in an immersive simulation room designed to function as a large adult emergency department patient care room. A SimMan 3G high-fidelity mannequin by Laerdal Medical served as the patient, connected to an adjacent vital sign monitor that simulated real-time physiologic parameters such as heart rate, cardiac rhythm strip, blood pressure monitoring, pulse oximetry, and temperature. The case was preprogrammed and the scenario program was run by a trained simulation technician. A facilitator sat in a room behind a one-way mirror and played the voice of the patient. An initial triage note and other available clinical information (e.g., laboratory results, imaging studies, and collateral information) was displayed in the room on an adjacent monitor as it became available.\n\nThe Simulation Case File (Appendix A) includes details regarding the history and physical, instructor notes, and a description of the ideal case flow. Laboratory studies (Appendix B) are also included. Collateral information from the patient's wife is available for students to review (Appendix C).\n\nPersonnel\nStudents participated in groups of four to six individuals. There were two case facilitators; an in-room facilitator served as the moderator and a patient-voice facilitator who played the voice of the patient in an adjacent control room behind a one-way mirror using a microphone. The in-room facilitator paused the case from time to time to provide instructive feedback through broad questioning to steer the case in a direction leading to a comprehensive differential diagnosis (Appendix D). Both facilitators debriefed with students at the end of the session and provided feedback on their performance and medical management. We used senior psychiatry residents and psychiatry faculty members as facilitators. In addition, a simulation technician was also present in the control room to assist with the operation of the computerized scenario and the display of clinical information on the monitors in real time.\n\nAssessment\nBefore the day began, participants were informed about the formative nature of the simulation within the end-of-clerkship session, and notified that performance did not affect their grade in the clerkship. Students completed surveys before and after the simulation to assess their level of confidence with treating alcohol withdrawal and in delivering a brief addiction intervention in an emergency setting.\n\nDebriefing\nThe simulation session lasted approximately 25–30 minutes, and was followed by a 20–25-minute debriefing session. The debriefing session followed a standard semistructured script in concordance with a blended approach to maximize learner engagement.9,10 First, the facilitators allowed time for participants to reflect on their experience working as part of a team and with the simulation case itself. Facilitators then reviewed the learning objectives from the case and stimulated a discussion on alcohol use disorders, pathophysiology of lithium and nonsteroidal anti-inflammatory drugs (NSAIDs), and legal and ethical considerations (Appendix E).\n\nResults\nAll students were given the opportunity to complete an anonymous postsession evaluation. To date, approximately 150 students have participated in a total of 30 simulation sessions using this case. Of these, 76 completed a postsession survey. After the session, students rated their enjoyment of the session as 4.49 (SD = 0.8), and confidence regarding their ability to identify and initiate management of a patient in alcohol withdrawal as 3.93 (SD = 0.9) overall on a 5-point Likert scale where 1 = strongly disagree and 5 = strongly agree. Examples of student comments from the evaluation include the following statements:\n• “I thought the substance use emergency department simulation was great — very realistic, good practice making decisions under pressure.”\n\n• “Loved the simulation! It was really fun and I learned a lot. It was also interesting thinking out loud with classmates because you see how they approach patient care and their way of thinking.”\n\n• “Hands-on work always appreciated.”\n\n• “Really enjoyed the simulation… I found it very helpful… to perform the group mannequin simulation to work in groups, practice emergency management, and see how other students talk to patients. I appreciated the feedback that we received.”\n\n• “Simulation with mannequin made me realize how I was not exposed to an emergency department/consult setting.”\n\n• “It would be helpful to have smaller groups.”\n\n\n\nDiscussion\nMannequin simulation is not commonly used in psychiatry education or training. We have developed a case and administered it to undergraduate medical students during an end-of-clerkship teaching session. Our case demonstrates that mannequin-based simulation can be a useful tool in undergraduate psychiatry education. It provides students the ability to practice identifying psychiatric distress in a medical setting, to evaluate the overlap and interaction between medical and mental health disorders, and to manage psychiatric complaints medically. We have successfully utilized this mannequin-based simulator to teach high-yield topics encountered in psychiatry, which include alcohol use disorder and withdrawal, medication side effects and toxicity (e.g., acute renal failure), ethical and legal dilemmas faced by physicians, and cognitive bias in formation of differential diagnoses.11 While delivering this case, we found that students prefer the challenge of treating a medically and psychiatrically complex patient with guidance from facilitators.\n\nLimitations of our case involve the inability of the mannequin to simulate symptoms of alcohol withdrawal. For example, the mannequin can reproduce a tonic-clonic seizure, but not the mild 6 to 10 Hz alcohol withdrawal tremor. In lieu of the physical finding, facilitators simply tell the students that the patient has a slight tremor. Another limitation is that the group interview format is unrealistic in most clinical settings. However, this approach is more practical and emphasizes team-working skills. The case as described has been modified based on feedback from participants. Originally, we did not include the lithium toxicity component, and procedurally, this case originally simulated alcohol withdrawal only. Based on the feedback from facilitators and participants, we found that the case was too straight-forward. We decided to add the element of bipolar disorder to the case in order to challenge students to think beyond one differential, as many patients are more complex. We chose bipolar disorder because of the pharmacokinetics of lithium and NSAIDs. We think that other cases of psychiatric complexity could also be effectively simulated with mannequin technology.\n\nPotential future simulation cases in psychiatry may involve altered mental status.7 They could also involve substance use such as overdose, intoxication, and withdrawal; or medication side effects and toxidromes including serotonin syndrome/neuroleptic malignant syndrome. Future simulation cases in psychiatry could also cover interventional psychiatry, including electroconvulsive therapy. The current literature focuses on standardized patient actors for psychiatric education, mainly through objective structured clinical examinations (OSCEs).12,13 This report provides preliminary evidence to show the potential for mannequin-based simulation in psychiatry. Future studies may assess the potential for mannequin-based simulation in evaluative capacities, in teaching students in psychiatry how to work and communicate effectively in teams, and in psychiatric resident education. Future studies are warranted to investigate the quantitative and qualitative efficacy of mannequin simulation in psychiatry compared to traditional standardized patients.\n\nAppendices\nA. Simulation Case File.docx\n\nB. Laboratory Studies.docx\n\nC. Collateral.docx\n\nD. Differential Diagnosis.docx\n\nE. Debriefing.docx\n\nAll appendices are peer reviewed as integral parts of the Original Publication.\n\n Disclosures\nNone to report.\n\nFunding/Support\nNone to report.\n\nEthical Approval\nThis publication contains data obtained from human subjects and received ethical approval.\n==== Refs\nReferences\n1. Cook DA , Hatala R , Brydges R , et al. Technology-enhanced simulation for health professions education: a systematic review and meta-analysis . JAMA. \n2011 ;306 (9 ):978 –988 . https://doi.org/10.1001/jama.2011.123421900138 \n2. Ilgen JS , Sherbino J , Cook DA \nTechnology-enhanced simulation in emergency medicine: a systematic review and meta-analysis . Acad Emerg Med. \n2013 ;20 (2 ):117 –127 . https://doi.org/10.1111/acem.1207623406070 \n3. Kennedy J , Hill T , Gephardt G , Cantrell M , Thompson T \nHybrid simulations using standardized patients and high fidelity mannequins for anaphylaxis and asthma treatments in an office setting . MedEdPORTAL. \n2012 ;8 :9239 \nhttps://doi.org/10.15766/mep_2374-8265.9239\n4. Abdool PS , Nirula L , Bonato S , Rajji TK , Silver IL \nSimulation in undergraduate psychiatry: exploring the depth of learner engagement . Acad Psychiatry. \n2017 ;41 (2 ):251 –261 . https://doi.org/10.1007/s40596-016-0633-927882523 \n5. Hamstra S , Philibert I \nSimulation in graduate medical education: understanding uses and maximizing benefits . J Grad Med Educ. \n2012 ;4 (4 ):539 –540 . https://doi.org/10.4300/JGME-D-12-00260.124294437 \n6. Owen H , Mugford B , Follows V , Plummer JL \nComparison of three simulation-based training methods for management of medical emergencies . Resuscitation. \n2006 ;71 (2 ):204 –211 . https://doi.org/10.1016/j.resuscitation.2006.04.00716987587 \n7. Sperling JD , Clark S , Kang Y \nTeaching medical students a clinical approach to altered mental status: simulation enhances traditional curriculum . Med Educ Online. \n2013 ;18 (1 ):19775 \nhttps://doi.org/10.3402/meo.v18i0.19775\n8. Murray BA \nThe use of high-fidelity simulation in psychiatric and mental health nursing clinical education . Int J Health Sci Educ. \n2014 ;2 (1 ):3 .\n9. Sawyer T , Eppich W , Brett-Fleegler M , Grant V , Cheng A \nMore than one way to debrief: a critical review of healthcare simulation debriefing methods . Simul Healthc. \n2016 ;11 (3 ):209 –217 . https://doi.org/10.1097/SIH.000000000000014827254527 \n10. Eppich W , Cheng A \nPromoting excellence and reflective learning in simulation (PEARLS): development and rationale for a blended approach to health care simulation debriefing . Simul Healthc. \n2015 ;10 (2 ):106 –115 . https://doi.org/10.1097/SIH.000000000000007225710312 \n11. Norman GR , Monteiro SD , Sherbino J , Ilgen JS , Schmidt HG , Mamede S \nThe causes of errors in clinical reasoning: cognitive biases, knowledge deficits, and dual process thinking . Acad Med. \n2017 ;92 (1 ):23 –30 . https://doi.org/10.1097/ACM.000000000000142127782919 \n12. McNaughton N , Ravitz P , Wadell A , Hodges BD \nPsychiatric education and simulation: a review of the literature . Can J Psychiatry. \n2008 ;53 (2 ):85 –93 . https://doi.org/10.1177/07067437080530020318357926 \n13. Dave S \nSimulation in psychiatric teaching . Adv Psychiatr Treat. \n2012 ;18 (4 ):292 –298 . https://doi.org/10.1192/apt.bp.110.008482\n\n",
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"issn_linking": "2374-8265",
"issue": "13()",
"journal": "MedEdPORTAL : the journal of teaching and learning resources",
"keywords": "Alcohol Use Disorder; Lithium Toxicity; Mannequin Simulation; Psychiatry",
"medline_ta": "MedEdPORTAL",
"mesh_terms": "D000063:Accidents, Traffic; D000328:Adult; D000437:Alcoholism; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001569:Benzodiazepines; D001714:Bipolar Disorder; D002982:Clinical Clerkship; D006801:Humans; D008094:Lithium; D008297:Male; D018986:Motor Vehicles; D009288:Naproxen; D010146:Pain; D016544:Patient Simulation; D013337:Students, Medical; D011795:Surveys and Questionnaires",
"nlm_unique_id": "101714390",
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"pmc": null,
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"pubdate": "2017-11-01",
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"references": "24294437;27782919;27254527;25710312;23406070;16987587;23561054;18357926;21900138;27882523",
"title": "Alcohol Withdrawal and Lithium Toxicity: A Novel Psychiatric Mannequin-Based Simulation Case for Medical Students.",
"title_normalized": "alcohol withdrawal and lithium toxicity a novel psychiatric mannequin based simulation case for medical students"
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"abstract": "Pulmonary vein (PV) stenosis is a rare but serious complication of PV isolation. It usually develops 3-6 months after the procedure, but may rarely develop in the acute phase. We present a case of symptomatic PV stenosis within 48 hours after antral PV isolation. Following the initiation of medical treatment including a glucocorticoid, acute changes in the PV wall regressed and the patient's complaint of dyspnea at rest improved rapidly. In addition, long-term renin-angiotensin-aldosterone system (RAAS) blockers were given. The complaint did not recur during follow-up and PV stenosis was mild at 6 months.",
"affiliations": "Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.;Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.;Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.;Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.;Department of Chest Diseases, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.;3 Department of Radiology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.",
"authors": "Ulus|Taner|T|;Dural|Muhammet|M|;Şener|Emre|E|;Meşe|Pelin|P|;Kurt|Emel|E|;Aydın|Nevin|N|",
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"fulltext_license": null,
"issn_linking": "1941-6911",
"issue": "12(5)",
"journal": "Journal of atrial fibrillation",
"keywords": "Atrial fibrillation; Corticosteroid; Pulmonary vein",
"medline_ta": "J Atr Fibrillation",
"mesh_terms": null,
"nlm_unique_id": "101514767",
"other_id": null,
"pages": "2261",
"pmc": null,
"pmid": "32435356",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26987915;19463436;15683534;27492534;25172325;25027177;15511245;29759432;27796513;15028044;19054246;27793993",
"title": "Medical treatment of a symptomatic acute pulmonary vein stenosis following antral pulmonary vein isolation.",
"title_normalized": "medical treatment of a symptomatic acute pulmonary vein stenosis following antral pulmonary vein isolation"
} | [
{
"companynumb": "TR-PFIZER INC-2020323873",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DABIGATRAN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nRecent imaging studies demonstrated the usefulness of quantitative computed tomographic (CT) analysis assessing pulmonary hypertension (PH) in patients with chronic obstructive lung disease (COPD-PH). The aim of this study was to investigate whether it would be also valuable for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.\n\n\nMETHODS\nWe analyzed a correlation between the extent of cystic destruction (LAA%) and total cross-sectional areas of small pulmonary vessels less than 5 mm(2) (%CSA <5) in many CT slices from each of four COPD-PH patients before and after the initiation of pulmonary vasodilator. To evaluate those generalized data from patients with COPD, we evaluated multiple slices from 42 patients whose PH was not clinically suspicious. We also selected five PH patients with idiopathic interstitial pneumonia (IIP-PH) and analyzed serial changes of pulmonary artery enlargement (PA:A ratio).\n\n\nRESULTS\nIn 42 COPD patients without PH, LAA% had a statistically significant negative correlation with %CSA <5. However, three of four COPD-PH patients manifested no such correlation. In two patients, clinical findings were dramatically improved after the initiation of pulmonary vasodilator. Notably, LAA% and %CSA <5 in those patients correlated significantly after its treatment. In COPD-PH, the PA:A ratio was significantly decreased after the initiation of pulmonary vasodilator therapy (1.25 ± 0.13 vs. 1.13 ± 0.11, p = 0.019), but not in IIP-PH.\n\n\nCONCLUSIONS\nOur study demonstrates that the use of quantitative CT analysis is a plausible and beneficial tool for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.",
"affiliations": "Division of Respiratory Medicine, Department of Internal Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. kando@juntendo.ac.jp.;Department of Pulmonology, Nagano Red Cross Hospital, 5-22-1 Wakasato, Nagano, Nagano, 380-8582, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.;Department of Pulmonology, Koshigaya Municipal Hospital, 10-47 Higashi-koshigaya, Koshigaya, Saitama, 343-8577, Japan.;Department of Cardiovascular Medicine, Koshigaya Municipal Hospital, 10-47 Higashi-koshigaya, Koshigaya, Saitama, 343-8577, Japan.;Department of Pulmonology, Koshigaya Municipal Hospital, 10-47 Higashi-koshigaya, Koshigaya, Saitama, 343-8577, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.",
"authors": "Ando|Katsutoshi|K|;Kuraishi|Hiroshi|H|;Nagaoka|Tetsutaro|T|;Tsutsumi|Takeo|T|;Hoshika|Yoshito|Y|;Kimura|Toru|T|;Ienaga|Hiroki|H|;Morio|Yoshiteru|Y|;Takahashi|Kazuhisa|K|",
"chemical_list": "D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D014665:Vasodilator Agents; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D000077300:Bosentan",
"country": "United States",
"delete": false,
"doi": "10.1007/s00408-015-9813-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0341-2040",
"issue": "193(6)",
"journal": "Lung",
"keywords": "Chronic obstructive pulmonary disease; Computed tomography; Pulmonary hypertension; Pulmonary vasodilator",
"medline_ta": "Lung",
"mesh_terms": "D000368:Aged; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D005080:Exercise Test; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery; D011653:Pulmonary Diffusing Capacity; D029424:Pulmonary Disease, Chronic Obstructive; D011658:Pulmonary Fibrosis; D000068677:Sildenafil Citrate; D013449:Sulfonamides; D000068581:Tadalafil; D014057:Tomography, X-Ray Computed; D014665:Vasodilator Agents; D014797:Vital Capacity",
"nlm_unique_id": "7701875",
"other_id": null,
"pages": "911-8",
"pmc": null,
"pmid": "26453478",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "12615615;15565748;24918967;23265910;24085320;22964373;18094009;25393421;19875684;17761614;11463591;19749199;22938715;19875683;18448495;23734820",
"title": "Potential Role of CT Metrics in Chronic Obstructive Pulmonary Disease with Pulmonary Hypertension.",
"title_normalized": "potential role of ct metrics in chronic obstructive pulmonary disease with pulmonary hypertension"
} | [
{
"companynumb": "JP-ACTELION-A-CH2016-141576",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BOSENTAN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nVisceral fat is the pathogenesis of Crohn's disease and is associated with disease status.\n\n\nOBJECTIVE\nThis study aimed to evaluate the effect of the visceral fat on mucosal healing in patients with Crohn's disease after infliximab induction therapy DESIGN:: This was a retrospective study.\n\n\nMETHODS\nThe study was conducted in a tertiary referral hospital.\n\n\nMETHODS\nBetween 2011 and 2017, 97 patients with Crohn's disease with the presence of ulcers underwent infliximab therapy.\n\n\nMETHODS\nWe studied them retrospectively. Mucosal healing was the end point. Patients composed 2 groups: mucosal healing and no mucosal healing. Univariate, multivariate, and receiver operating characteristic curve analyses determined the predictive value of the visceral fat area.\n\n\nRESULTS\nUnivariate analysis showed a statistically significant difference in the smoking history between the groups. Mucosal healing rates after infliximab were lower among active smokers (p = 0.022). Healed patients had significantly less visceral fat area before therapy (47.76 ± 4.94 vs 75.88 ± 5.55; p = 0.000) and a lower mesenteric fat index (0.52 ± 0.04 vs 0.89 ± 0.07; p = 0.000). There was no significant difference in the subcutaneous fat area (87.39 ± 5.01 vs 93.31 ± 6.95; p = 0.500). Multivariate analysis showed that only visceral fat area (OR = 0.978 (95% CI, 0.964-0.992); p = 0.002) and smoking history (OR = 0.305 (95% CI, 0.089-0.996); p = 0.041) were independent factors for mucosal healing. Receiver operating characteristic curve analysis showed predictive cutoff values of 61.5 cm and 0.62 for visceral fat area and mesenteric fat index.\n\n\nCONCLUSIONS\nThis was a retrospective study.\n\n\nCONCLUSIONS\nThere was an association between increased visceral fat area and attenuated mucosal healing after infliximab therapy in biologically naive patients with Crohn's disease, indicating a need for earlier increased infliximab doses among patients with increased visceral fat. See Video Abstract at http://links.lww.com/DCR/A590.",
"affiliations": "Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.",
"authors": "Shen|Weisong|W|;Cao|Lei|L|;Li|Yi|Y|;Cai|Xingchen|X|;Ge|Yuanyuan|Y|;Zhu|Weiming|W|",
"chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1097/DCR.0000000000001074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3706",
"issue": "61(6)",
"journal": "Diseases of the colon and rectum",
"keywords": null,
"medline_ta": "Dis Colon Rectum",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003424:Crohn Disease; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa; D050152:Intra-Abdominal Fat; D008297:Male; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014945:Wound Healing; D055815:Young Adult",
"nlm_unique_id": "0372764",
"other_id": null,
"pages": "706-712",
"pmc": null,
"pmid": "29722729",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Visceral Fat Is Associated With Mucosal Healing of Infliximab Treatment in Crohn's Disease.",
"title_normalized": "visceral fat is associated with mucosal healing of infliximab treatment in crohn s disease"
} | [
{
"companynumb": "CN-JNJFOC-20180605896",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nThe aim of the study was to assess the feasibility and acceptability of acupuncture's augmentation of lidocaine therapy in the treatment of provoked localized vulvodynia (PLV).\n\n\nMETHODS\nFor 12 weeks, women with moderate to severe PLV were randomized to either 18 sessions of traditional acupuncture (TA) or non-TA (NTA). All participants applied lidocaine 5% cream 4 times daily to the vestibule. Feasibility was assessed by recruitment, enrollment, assessment completion, and blinding. Acceptability was assessed by study visit attendance and satisfaction. The primary outcome was change in tampon test scores from baseline to week 12 and follow-up at week 24.\n\n\nRESULTS\nNineteen women enrolled and 14 completed the study. Five withdrew because of lidocaine reaction (n = 2), inability to insert tampon (n = 1), starting a new medication (n = 1), or change in vulvar diagnosis (n = 1). Participants in both groups reported pain reduction for 12 weeks. There was no statistically significant difference between groups. Women in the TA group (n = 7) experienced less pain from baseline to 12 weeks (mean difference [MD] = 42.4 ± 19.4 and MD = 35.7 ± 17.8 at week 24). In the non-TA group (n = 7), women experienced a within-group MD of 28.7 ± 28.5 at 12 weeks and an MD of 36.7 ± 17.7.\n\n\nCONCLUSIONS\nIn this early-phase research, acupuncture augmentation of lidocaine was acceptable. The study procedures, with modifications, may be feasible for future investigation. Both acupuncture techniques showed a favorable effect; however, the contribution to pain relief is undetermined.",
"affiliations": "Osher Center for Integrative Medicine, University of California San Francisco, San Francisco, CA.;Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR.;Department of Nursing, University of Texas, Austin, TX.;Osher Center for Integrative Medicine, University of California San Francisco, San Francisco, CA.;Department of Obstetrics and Gynecology, Oregon Health & Science University, San Francisco, CA.",
"authors": "Hullender Rubin|Lee E|LE|;Mist|Scott D|SD|;Schnyer|Rosa N|RN|;Chao|Maria T|MT|;Leclair|Catherine M|CM|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/LGT.0000000000000489",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1089-2591",
"issue": "23(4)",
"journal": "Journal of lower genital tract disease",
"keywords": null,
"medline_ta": "J Low Genit Tract Dis",
"mesh_terms": "D026881:Acupuncture; D000293:Adolescent; D000328:Adult; D000779:Anesthetics, Local; D005260:Female; D006801:Humans; D008012:Lidocaine; D008875:Middle Aged; D010342:Patient Acceptance of Health Care; D016896:Treatment Outcome; D056650:Vulvodynia; D055815:Young Adult",
"nlm_unique_id": "9704963",
"other_id": null,
"pages": "279-286",
"pmc": null,
"pmid": "31592976",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Acupuncture Augmentation of Lidocaine for Provoked, Localized Vulvodynia: A Feasibility and Acceptability Study.",
"title_normalized": "acupuncture augmentation of lidocaine for provoked localized vulvodynia a feasibility and acceptability study"
} | [
{
"companynumb": "US-DENTSPLY PHARMACEUTICAL-2020SCDP000023",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditiona... |
{
"abstract": "Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction.",
"affiliations": "Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA.",
"authors": "Sall|D|D|;Wang|J|J|;Rashkin|M|M|;Welch|M|M|;Droege|C|C|;Schauer|D|D|",
"chemical_list": "D019440:Anti-Obesity Agents; D007783:Lactones; D000077403:Orlistat",
"country": "England",
"delete": false,
"doi": "10.1111/cob.12075",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1758-8103",
"issue": "4(6)",
"journal": "Clinical obesity",
"keywords": "Hepatic failure; liver transplant; orlistat",
"medline_ta": "Clin Obes",
"mesh_terms": "D019440:Anti-Obesity Agents; D005260:Female; D006801:Humans; D007783:Lactones; D017114:Liver Failure, Acute; D008875:Middle Aged; D009765:Obesity; D000077403:Orlistat",
"nlm_unique_id": "101560587",
"other_id": null,
"pages": "342-7",
"pmc": null,
"pmid": "25826164",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Orlistat-induced fulminant hepatic failure.",
"title_normalized": "orlistat induced fulminant hepatic failure"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2015GSK010931",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ORLISTAT"
},
"drugadditional": null,... |
{
"abstract": "Ruxolitinib is a dual janus kinase 1 (JAK1)/JAK2 inhibitor used to treat splenomegaly and symptoms associated with myelofibrosis (MF). Current therapeutic options for symptomatic MF include supportive care, myelosuppressive therapy (such as hydroxycarbamide) and janus kinase (JAK) inhibitors (in particular ruxolitinib). Allogeneic stem cell transplantation remains the only potentially curative treatment for MF, and younger transplant-eligible patients should still be considered for allogeneic stem cell transplantation; however, this is applicable only to a small proportion of patients. There is now increasing and extensive experience of the efficacy and safety of ruxolitinib in MF, both in clinical trials and in 'real-world' practice. The drug has been shown to be of benefit in intermediate-1 risk patients with symptomatic splenomegaly or other MF-related symptoms, and higher risk disease. Optimal use of the drug is required to maximise clinical benefit, requiring an understanding of the balance between dose-dependent responses and dose-limiting toxicities. There is also increasing experience in the use of ruxolitinib in the pre-transplantation setting. This paper aims to utilise several 'real-life' cases to illustrate several strategies that may help to optimise clinical practice.",
"affiliations": "Royal Prince Alfred Hospital, and, Sydney, NSW, Australia.;The Royal Melbourne Hospital, Melbourne, Victoria, Australia.;Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.;Liverpool Hospital, Sydney, NSW, Australia.;Royal Brisbane Hospitals, Brisbane, Queensland, Australia.;Jarrett Street Specialist Centre, North Gosford, NSW, Australia.;Princess Alexandra Hospital, Brisbane, Queensland, Australia.;SA Pathology, Royal Adelaide Hospital, Brisbane, South Australia, Australia.",
"authors": "Ho|P Joy|PJ|;Bajel|Ashish|A|;Burbury|Kate|K|;Dunlop|Lindsay|L|;Durrant|Simon|S|;Forsyth|Cecily|C|;Perkins|Andrew C|AC|;Ross|David M|DM|",
"chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053613:Janus Kinase 1; D053614:Janus Kinase 2",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.13341",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "47(3)",
"journal": "Internal medicine journal",
"keywords": "drug-related side effects and adverse reactions; janus kinases; primary myelofibrosis; prognosis; ruxolitinib",
"medline_ta": "Intern Med J",
"mesh_terms": "D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D017410:Practice Guidelines as Topic; D055728:Primary Myelofibrosis; D011720:Pyrazoles; D011743:Pyrimidines; D013163:Splenomegaly; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "262-268",
"pmc": null,
"pmid": "28260257",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case-based discussion of clinical problems in the management of patients treated with ruxolitinib for myelofibrosis.",
"title_normalized": "a case based discussion of clinical problems in the management of patients treated with ruxolitinib for myelofibrosis"
} | [
{
"companynumb": "AU-INCYTE CORPORATION-2017IN001976",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RUXOLITINIB"
},
"drugadditional": nu... |
{
"abstract": "The proper clinical evaluation of pituitary and adrenal disorders depends on the accurate measurement of plasma ACTH. The modern two-site sandwich ACTH immunoassay is a great improvement compared with older methods but still has the potential for interferences such as heterophile antibodies and pro-opiomelanocortin (POMC) and ACTH fragments. We report the cases of five patients in whom the diagnosis or differential diagnosis of Cushing syndrome was confounded by erroneously elevated results from the Siemens ACTH Immulite assay [ACTH(Immulite)] that were resolved using the Roche Cobas or Tosoh AIA [ACTH(Cobas) and ACTH(AIA), respectively]. In one case, falsely elevated ACTH(Immulite) results owing to interfering antibodies resulted in several invasive differential diagnostic procedures (including inferior petrosal sinus sampling), MRI, and unnecessary pituitary surgery. ACTH(Cobas) measurements were normal, and further studies excluded the diagnosis of Cushing syndrome. In three cases, either Cushing disease or occult ectopic ACTH were suspected owing to elevated ACTH(Immulite) results. However, adrenal (ACTH-independent) Cushing syndrome was established using ACTH(AIA) or ACTH(Cobas) and proved surgically. In one case, ectopic ACTH was suspected owing to elevated ACTH(Immulite) results; however, the ACTH(Cobas) findings led to the diagnosis of alcohol-induced hypercortisolism that resolved with abstinence. We have concluded that ACTH(Immulite) results can be falsely increased and alternate ACTH assays should be used in the diagnosis or differential diagnosis of clinical disorders of the hypothalamic-pituitary-adrenal axis.",
"affiliations": "Department of Medicine, New York University School of Medicine, New York, New York.;Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York.;Neuroendocrine Unit, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York.;Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, Wisconsin.;Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.",
"authors": "Greene|Loren Wissner|LW|0000-0003-1796-3631;Geer|Eliza B|EB|0000-0003-3722-1889;Page-Wilson|Gabrielle|G|0000-0002-4064-1211;Findling|James W|JW|;Raff|Hershel|H|0000-0002-5128-8476",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/js.2019-00027",
"fulltext": "\n==== Front\nJ Endocr SocJ Endocr SocjesJournal of the Endocrine Society2472-1972Endocrine Society Washington, DC js_20190002710.1210/js.2019-00027Case ReportAdrenalAssay-Specific Spurious ACTH Results Lead to Misdiagnosis, Unnecessary Testing, and Surgical Misadventure—A Case Series http://orcid.org/0000-0003-1796-3631Greene Loren Wissner 12http://orcid.org/0000-0003-3722-1889Geer Eliza B 3http://orcid.org/0000-0002-4064-1211Page-Wilson Gabrielle 4Findling James W 567http://orcid.org/0000-0002-5128-8476Raff Hershel hraff@mcw.edu789101 Department of Medicine, New York University School of Medicine, New York, New York2 Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York3 Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York4 Neuroendocrine Unit, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York5 Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, Wisconsin6 Department of Community Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin7 Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin8 Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin9 Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin10 Endocrine Research Laboratory, Aurora St. Luke’s Medical Center, Aurora Research Institute, Milwaukee, WisconsinCorrespondence: Hershel Raff, PhD, Endocrine Research Laboratory, Aurora St. Luke’s Medical Center, Aurora Research Institute, 2801 West KK River Parkway, MOB 260, Milwaukee, Wisconsin 53215. E-mail: hraff@mcw.edu.01 4 2019 20 2 2019 3 4 763 772 18 1 2019 15 2 2019 Copyright © 2019 Endocrine Society2019This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Abstract\nThe proper clinical evaluation of pituitary and adrenal disorders depends on the accurate measurement of plasma ACTH. The modern two-site sandwich ACTH immunoassay is a great improvement compared with older methods but still has the potential for interferences such as heterophile antibodies and pro-opiomelanocortin (POMC) and ACTH fragments. We report the cases of five patients in whom the diagnosis or differential diagnosis of Cushing syndrome was confounded by erroneously elevated results from the Siemens ACTH Immulite assay [ACTH(Immulite)] that were resolved using the Roche Cobas or Tosoh AIA [ACTH(Cobas) and ACTH(AIA), respectively]. In one case, falsely elevated ACTH(Immulite) results owing to interfering antibodies resulted in several invasive differential diagnostic procedures (including inferior petrosal sinus sampling), MRI, and unnecessary pituitary surgery. ACTH(Cobas) measurements were normal, and further studies excluded the diagnosis of Cushing syndrome. In three cases, either Cushing disease or occult ectopic ACTH were suspected owing to elevated ACTH(Immulite) results. However, adrenal (ACTH-independent) Cushing syndrome was established using ACTH(AIA) or ACTH(Cobas) and proved surgically. In one case, ectopic ACTH was suspected owing to elevated ACTH(Immulite) results; however, the ACTH(Cobas) findings led to the diagnosis of alcohol-induced hypercortisolism that resolved with abstinence. We have concluded that ACTH(Immulite) results can be falsely increased and alternate ACTH assays should be used in the diagnosis or differential diagnosis of clinical disorders of the hypothalamic–pituitary–adrenal axis.\n\nCushing syndromeimmunoassay interferencediagnosisadrenocorticotropinRobert Wood Johnson Foundation10.13039/10000086771951Aurora Research Institute10.13039/100013762\n==== Body\nThe accurate measurement of plasma ACTH is necessary for the proper diagnosis, differential diagnosis, and monitoring of hypothalamic–pituitary–adrenal axis disorders, including Cushing syndrome, adrenal insufficiency, and congenital adrenal hyperplasia [1]. The development of the two-site “sandwich” immunometric assay for ACTH has greatly improved the sensitivity, specificity, and performance of this assay [2–5]. However, two-site immunometric assays are susceptible to interference, including the presence of heterophile antibodies and hormone fragments or precursors [4, 6–10].\n\nA recent case series raised serious concerns about the performance of the Siemens Immulite ACTH assay [ACTH(Immulite)] [11]. The ACTH(Immulite) had yielded falsely elevated results, which had led to unnecessary testing and misdiagnosis [11]. Since 2012, we have been accumulating a series of cases highlighting serious issues with this assay. The purpose of the present report was to highlight this problem and provide endocrinologists with the clinical context and suggest a corrective course of action.\n\n1. Case Series\nDetails of the 5 patients have been summarized in Table 1. The relevant laboratory specific-assay reference ranges have been provided parenthetically. The same method could have slightly different reference ranges depending on in which reference laboratory the assay had been validated and performed. The relevant ACTH immunometric assays reported were the ACTH(Immulite) (Siemens Healthcare Diagnostics, Tarrytown, NY) [12], Roche Cobas [ACTH(Cobas)] (Roche Diagnostics, Indianapolis, IN) [13], and Tosoh AIA [ACTH(AIA)] (Tosoh Bioscience, San Francisco, CA) [14]. The institutional review boards (IRBs) approved the present study. Patients 1, 2, and 3 provided written informed consent for specialty testing through Columbia University Medical Center (patient 1) and Memorial Sloan Kettering Cancer Center (patients 2 and 3). The NYU School of Medicine IRB and the Medical College of Wisconsin IRB determined that IRB approval and written informed consent were not required for patients 1, 4, and 5.\n\nTable 1. Summary of Cases\n\nCase\tReason for Referral\tInitial Adrenal Testing\tACTH(Immulite)\tImaging\tAdditional Testing and Procedures\tInitial Diagnosis\tACTH (2nd Method)\tFinal Diagnosis\t\n1\tWeight gain Hypertension Fatigue Anxiety Bruising Irregular menses Infertility\tNormal AM cortisol, elevated LNSC and UFC, positive LDDST Elevated ACTH(Immulite) after LDDST and HDDST\tElevated (122–203 pg/mL)\tNormal pituitary MRI ×2 3rd MRI positive\tIPSS ACTH(Immulite) positive (Table 2) Pituitary surgery (neoplasm ACTH staining negative)\tCushing disease\tACTH(Cobas) normal (16–38 pg/mL)\tNo Cushing syndrome\t\n2\tStriae Weight gain Moon facies Gestational diabetes\tElevated UFC, LNSC, LDDST\tNormal (40 pg/mL) and elevated (62 pg/mL)\tPituitary MRI, 5-mm microadenoma Abdominal MRI, adrenal nodule DOTATE negative ×2\tJVS ACTH(Immulite) no gradient IPSS ACTH(Immulite) no gradient Adrenal vein sampling Left adrenal vein cortisol > right Serum DHEAS low\tOccult ectopic ACTH-dependent Cushing syndrome\tACTH(AIA) decreased (2–5 pg/mL)\tAdrenal (ACTH-independent) Cushing syndrome\t\n3\tFatigue Muscle weakness Hypertension Prediabetes Osteoporosis Renal calculi\tNormal/elevated UFC Elevated LNSC Positive LDDST\tElevated (78–143 pg/mL)\tRight adrenal nodule Pituitary MRI 1–2-mm lesion MIBG uptake in adrenal nodule DOTATATE normal\tJVS ACTH(Immulite) elevated but no gradient IPSS ACTH(AIA) low and no gradient\tOccult ectopic ACTH-dependent Cushing syndrome\tACTH(AIA) decreased (2–4 pg/mL)\tAdrenal (ACTH-independent) Cushing syndrome\t\n4\tWeight gain Facial rounding Hirsutism Striae Supraclavicular fullness\tElevated UFC, LNSC Positive LDDST\tNormal (17–21 pg/mL)\tPossible 3-mm pituitary lesion Right adrenal mass (HU 40)\t\tCushing disease\tACTH(Cobas) decreased (1 pg/mL)\tAdrenal (ACTH-independent) Cushing syndrome\t\n5\tEtOH abuse Cirrhosis Bruising Muscle atrophy Edema\tNormal UFC Elevated LNSC Positive LDDST\tElevated (367–1031 pg/mL)\tPituitary MRI normal\t\tEctopic ACTH syndrome\tACTH(Cobas) decreased (7 pg/mL) ACTH(AIA) normal (14 pg/mL)\tEthanol-induced hypercortisolism\t\nTo convert ACTH to pmol/L, multiply by 0.2202.\n\nAbbreviations: EtOH, ethanol; HDDST, high-dose DST suppression test; HU, Hounsfield units; IPSS, inferior petrosal sinus sampling; JVS, jugular venous sampling; LDDST, low-dose DST suppression test; MIBG, metaiodobenzylguanidine; UFC, urine free cortisol.\n\nA. Patient 1\nA 21-year-old woman had presented after evaluations by several other physicians. She reported a 20- to 23-kg weight gain after taking clomiphene alone or combined with dexamethasone for irregular menses with infertility. She had a history of hypertension, headaches, fever, insomnia, fatigue, abdominal pain, rashes, edema, early satiety, mild anorexia, and easy bruisability.\n\nThe early morning plasma ACTH(Immulite) levels were consistently elevated [122 and 203 pg/mL (reference range, 6 to 50) and 89 and 95 pg/mL (reference range, 6 to 58)]. The morning serum cortisol values were normal [12.5 µg/dL (reference range, 4.5 to 23.0) and 14.1 µg/dL (reference range, 4.0 to 22.0)], as were the late night salivary cortisol (LNSC) levels [<0.04 µg/dL (reference range, <0.09)]. Urinary free cortisol (UFC) values, measured using liquid chromatography–mass spectrometry/mass spectrometry, were elevated [54 µg/24 h (reference range, <45) and 98 µg/24 h (reference range, <50)] with elevated urine volumes (>2400 mL) and creatinine clearance [>131 mL/min (reference range, 80 to 130)], suggesting an overcollection of urine. Low-dose (1 mg) overnight dexamethasone (DST) suppressed morning serum cortisol to 0.8 µg/dL (reference range, <2.0). High dose (8 mg) overnight DST also resulted in suppressed morning serum cortisol (0.6 µg/dL) and an undetectable UFC. However, the corresponding plasma ACTH(Immulite) concentrations after low- and high-dose overnight DST remained elevated [83 and 84 pg/mL (reference range, 6 to 50), respectively]. The findings from normal-resolution (performed twice) and high-resolution pituitary MRI scans with and without gadolinium were unremarkable.\n\nBecause the elevated plasma ACTH results were inconsistent with the other clinical results, further evaluation of possible ACTH(Immulite) assay interference was undertaken. The result for the ACTH(Immulite) after pretreatment with a heterophile blocking reagent was 518 pg/mL, which differed by >50% from the untreated ACTH(Immulite) result (104 pg/mL), indicating the possible presence of heterophile antibody interference. This testing was repeated on a fresh plasma sample several months later, and the results were similar. Dilutions of plasma using the ACTH(Immulite) assay were linear. Elevated plasma ACTH(Immulite) results [122 pg/mL (reference range, 9.0 to 46.0)] had decreased to 27 pg/mL after treatment of the plasma sample with a 25% (w/v) buffered phosphate solution of polyethylene glycol 6000 (Sigma-Aldrich, St. Louis, MO) [15], consistent with the precipitation of interfering immunoglobulins. The plasma pro-opiomelanocortin (POMC) concentration [14.2 fmol/mL (reference range, 7 to 38)] was not suggestive of ectopic ACTH secretion [16].\n\nDespite the normal low-dose DST described and the lack of evidence for cyclical Cushing syndrome, her symptoms and consistently elevated plasma ACTH(Immulite) levels led the patient to self-refer to yet another physician at another medical center, resulting in a third pituitary MRI scan with findings suggestive of a right superior pituitary microadenoma. This led to inferior petrosal sinus (IPS) sampling (IPSS) [17, 18] using the ACTH(Immulite) assay, which showed an IPS to peripheral gradient and lateralization to the left side (Table 2). Because the IPSS results ruled out ectopic Cushing syndrome and suggested the diagnosis of Cushing disease, pituitary surgery was performed. No adenoma was found, and the anatomic pathology report of the tissue removed (which included immunohistochemistry for GH, prolactin, ACTH, FSH, LH, and TSH) was consistent with normal anterior pituitary tissue.\n\nTable 2. Patient 1: IPSS ACTH(Immulite) Results\n\nTime (min)a\tLeft Petrosal, pg/mL\tRight Petrosal, pg/mL\tPeripheral, pg/mL\t\nBaseline\t149 (2.8)\t77 (1.5)\t53\t\n2\t320 (5.3)\t194 (3.2)\t60\t\n5\t338 (2.6)\t172 (1.3)\t130\t\n10\t488 (7.3)\t391(5.8)\t67\t\n15\t459 (5.7)\t231(2.9)\t80\t\nTo convert pg/ml to pmol/L, multiply by 0.2202. Data in parentheses are IPS/peripheral ACTH(I) ratios.\n\na Represents time after injection of CRH.\n\nPostoperative secondary adrenal insufficiency did not ensue. Her morning serum cortisol was 6.0 µg/dL (reference range, 6.7 to 22.6) and plasma ACTH(Immulite) level was 18.8 pg/mL (reference range, 7.2 to 63.3). At 1 week after surgery, serum cortisol was 11.8 µg/dL; however, the plasma ACTH(Immulite) level was again elevated (73 pg/mL). A pituitary MRI scan performed 2 months after pituitary surgery suggested a residual pituitary adenoma and/or postoperative changes. At 2 months postoperatively, the serum cortisol was normal 8.2 µg/dL (reference range, 4.5 to 23.0), but the plasma ACTH(Immulite) level was still elevated [79 pg/mL (reference range, 6 to 58)]. The serum cortisol continued to be normal at 5 months postoperatively [8.2 µg/dL (reference range, 4.5 to 23)], but the plasma ACTH(Immulite) level remained elevated [62 pg/mL (reference range, 6 to 58)]. When the possibility of issues with the ACTH(Immulite) assay was raised, the same sample was analyzed using the ACTH(Cobas) method and the level was found to be normal [35 pg/mL (reference range, 7.2 to 63)]. Commercial heterophile antibody blocking reagents failed to alter the ACTH(Cobas) results, and serial dilutions showed only a small deviation from linearity, indicating the absence of antibody interference with the ACTH(Cobas) assay. Additional follow-up data have confirmed that this patient did not have Cushing syndrome.\n\nB. Patient 2\nA 30-year-old woman had presented in her third trimester of pregnancy with violaceous abdominal striae. In retrospect, she noted weight gain and moon facies before conceiving, and she had developed gestational diabetes during her pregnancy. She delivered a healthy boy by cesarean section at 38 weeks. Subsequent testing confirmed the diagnosis of Cushing syndrome with markedly elevated UFC (537 µg/24 h) and LNSC [0.45 and 0.38 µg/dL (reference range, <0.09)] and a nonsuppressed 1-mg overnight DST serum cortisol concentration [20.6 µg/dL (reference range, <2.0)]. Random plasma ACTH(Immulite) concentrations were either high normal or elevated [40 and 62 pg/mL (reference range, <58)], consistent with ACTH-dependent Cushing syndrome.\n\nA pituitary MRI scan showed a 5-mm microadenoma. The jugular venous sampling [19–21] plasma ACTH(Immulite) values did not demonstrate a central to peripheral gradient, with a baseline and CRH-stimulated peripheral plasma ACTH(Immulite) of 34 pg/mL and 38 pg/mL, respectively, and baseline and CRH-stimulated jugular vein ACTH(Immulite) level of 38 to 40 pg/mL and 39 pg/mL, respectively. Imaging for a potential ectopic ACTH using chest and abdominal MRI showed a 2.5 × 2.4-cm left adrenal nodule. The results of a DOTATATE scan were unremarkable, showing only physiologic uptake in the pituitary and adrenal glands. IPSS [17, 18] was performed at a different institution and, similarly, did not show a central to peripheral ACTH(Immulite) gradient, with an elevated 24-hour UFC on the day of the test (304 µg/24 h). The peripheral and IPS plasma ACTH(Immulite) levels were 30 to 60 pg/mL.\n\nOwing to the normal or elevated basal plasma ACTH(Immulite) values in the setting of hypercortisolemia and the lack of a central to peripheral plasma ACTH(Immulite) gradient during jugular venous and IPSS without any anatomic evidence of an ectopic source of ACTH, she was given a provisional diagnosis of occult ectopic ACTH-dependent Cushing syndrome. She was treated with metyrapone for 9 months and improved clinically with normalization of the 24-hour UFC and LNSC values. A repeat DOTATATE scan was again negative. Adrenal vein sampling was conducted to assess for the possibility of an ACTH-producing adrenal lesion, which led to unexpected findings [22]. The plasma ACTH(Immulite) concentration in the inferior vena cava was within the reference range and was similar from both adrenal gland veins and the inferior vena cava (21 to 28 pg/mL), consistent with a non–ACTH-producing adrenal nodule. However, the serum cortisol was much greater from the left vs the right adrenal vein (211.0 vs 26.6 µg/dL, respectively), suggesting a cortisol-producing adrenal neoplasm. Furthermore, the serum dehydroepiandrosterone sulfate (DHEAS) level had been consistently low [22 µg/dL (reference range, 65 to 380) and 26 µg/dL (reference range, 31 to 228)], suggesting a primary adrenal etiology of Cushing syndrome.\n\nWhile the patient was taking metyrapone, the plasma ACTH(Immulite) result was normal [37 pg/mL (reference range, <60)], with normal serum cortisol (11.6 µg/dL) and UFC (21 µg/24 h) levels. Still taking metyrapone, the plasma ACTH level using a different method [ACTH(AIA)] was subnormal [4.6 pg/mL (reference range, 7.4 to 64.3)], with a normal serum cortisol (10.3 µg/dL). Metyrapone was then discontinued, and the plasma ACTH(AIA) level was still low (2.4 pg/mL), but the serum cortisol and UFC had increased (18.5 µg/dL and 764 µg/24 h, respectively).\n\nBecause of the subnormal ACTH(AIA) results and findings from previous adrenal imaging studies, adrenal (ACTH-independent) Cushing syndrome was diagnosed, and the patient underwent unilateral adrenalectomy. The pathologic findings were consistent with a benign adrenal cortical adenoma. The postoperative serum cortisol was very low (0.5 µg/dL), consistent with secondary adrenal insufficiency. At the last follow-up examination, she was in remission and taking a physiologic oral hydrocortisone replacement, with marked weight loss and clinical improvement.\n\nC. Patient 3\nA 55-year-old woman had presented with fatigue and muscle weakness in the setting of hypertension, prediabetes, osteoporosis, and renal calculi. A previous abdominal CT scan had incidentally identified a 2.1-cm right adrenal nodule with enhancement characteristic for an adenoma. A subsequent evaluation revealed an elevated 1-mg DST serum cortisol (26.7 µg/dL) and variable UFC (22.4 to 132.0 µg/24 h). The plasma ACTH(Immulite) was elevated [78 pg/mL (reference range, <50) and 143 pg/mL (reference range, <58)], consistent with ACTH-dependent Cushing syndrome.\n\nA pituitary MRI scan showed a possible 1- to 2-mm lesion but the finding was not definitive. Metaiodobenzylguanidine demonstrated uptake in the adrenal nodule, and DOTATATE showed only physiologic uptake in the pituitary and adrenal glands. Jugular venous sampling with CRH administration did not identify a central to peripheral gradient, with a peak stimulated jugular vein plasma ACTH(Immulite) of 124 pg/mL and peak peripheral plasma ACTH of 127 pg/mL. These findings were consistent with occult ectopic Cushing syndrome. However, using an alternate assay method, the plasma ACTH(AIA) was low [3.9 pg/mL (reference range, 7.4 to 64.3)], suggesting ACTH-independent Cushing syndrome.\n\nBecause of the discordant ACTH results, IPSS was performed with the ACTH(AIA) assay method, and the results were markedly and consistently less than the reference range (2 to 4 pg/mL). Repeat studies confirmed a subnormal plasma ACTH(AIA) level [3.3 pg/mL (reference range, 7.4 to 64.3)] and elevated LNSC (0.34 µg/dL and 0.41 µg/dL (reference range, <0.09)].\n\nAfter 3 years of evaluations by multiple physicians, adrenal (ACTH-independent) Cushing syndrome was finally diagnosed, and unilateral adrenalectomy was performed. The pathologic examination findings were consistent with adrenal cortical adenoma. The postoperative serum cortisol was low (2.0 µg/dL), consistent with secondary adrenal insufficiency. At the last follow-up examination, she was in remission and taking an oral hydrocortisone replacement.\n\nD. Patient 4\nA 23-year-old woman had been referred for IPSS to confirm the suspicion of Cushing disease. The patient had experienced a rapid 14-kg weight gain during a 9-month period in a truncal distribution associated with facial rounding, hirsutism, supraclavicular fullness, and striking violaceous abdominal striae. She did not have hypertension or diabetes. She was not taking any medications.\n\nPrevious studies had showed an elevated LNSC [0.38 µg/dL (reference range, <0.11)] and UFC (127 µg/24 h (reference range, <45)] and a nonsuppressed overnight 1-mg DST serum cortisol level [14.4 µg/dL (reference range, <1.8)]. Previous basal plasma ACTH(Immulite) concentrations were within the reference range [17 and 21 pg/mL (reference range, 10 to 54)], which had suggested ACTH-dependent Cushing syndrome and had led to the referral for IPSS. A pituitary MRI scan showed a faint 3-mm area of diminished contrast enhancement in the left pituitary gland (seen on only one image). The basal morning serum cortisol was 17.8 µg/dL (reference range, 5 to 18).\n\nThe basal morning plasma ACTH was repeated with ACTH(Cobas) and was very low [1.0 pg/mL (reference range, 10 to 52)], with a subnormal serum DHEAS [5 µg/dL (reference range, 148 to 407)]. A peripheral CRH test (1 µg/kg ovine CRH intravenously) showed a very low basal ACTH(Cobas) concentration [1 pg/mL (reference range, 10 to 52)], which did not increase after CRH, suggesting ACTH-independent hypercortisolism. The basal serum cortisol was 17.3 µg/dL (reference range, 5 to 18) and also did not increase after CRH.\n\nAn abdominal CT scan showed a 2.5 × 2.2-cm right adrenal mass with a noncontrast Hounsfield unit of 40 and absolute contrast washout of 63%. The patient underwent successful laparoscopic right adrenalectomy, followed by secondary adrenal insufficiency. Her ACTH-independent hypercortisolism promptly resolved, and her hypothalamic–pituitary–adrenal axis had fully recovered by 18 months after surgery.\n\nE. Patient 5\nA 59-year-old woman had been referred for IPSS for ACTH-dependent hypercortisolism. She had a 25-year history of an alcohol abuse disorder (8 to 10 alcohol drinks daily), stage IV cirrhosis with portal hypertension and ascites, and chronic hyponatremia. In the previous year, she had lost 14-kg and had easy bruising, severe muscle atrophy and weakness, and substantial lower extremity edema. She was cachectic and appeared chronically ill. She had excessive lanugo hair, multiple ecchymoses on her arms, severe proximal muscle weakness, and 2+ pretibial edema.\n\nThe LNSC was elevated [0.58 and 2.6 µg/dL (reference range, <0.14)]; however, the UFC was within the reference range [34 µg/24 h (reference range, <45)]. Overnight 1-mg DST yielded a nonsuppressed morning serum cortisol [8.9 µg/dL (reference range, <1.8)]. The previous plasma ACTH(Immulite) concentrations were markedly elevated [367 to 1031 pg/mL (reference range, 10 to 60)], which had led to the referral for IPSS. A pituitary MRI scan showed cerebral atrophy and cerebellar volume loss but a normal pituitary gland. Ectopic ACTH syndrome was suspected.\n\nBefore IPSS was performed, a peripheral CRH test (1 µg/kg IV) was performed initially, using the ACTH(Cobas) and ACTH(AIA) because the clinician was suspicious of the previously elevated ACTH(Immulite) results (Table 3). These results dramatically illustrate the problem we have demonstrated in our study. The ACTH(Cobas) and ACTH(AIA) responses to CRH were consistent with the blunted responses previously demonstrated in patients with alcohol-induced hypercortisolism [23]. These samples were then subsequently analyzed using ACTH(Immulite) and were markedly increased and inconsistent with the clinical diagnosis of alcohol-induced hypercortisolism. These findings confirmed the conjecture that the previous ACTH(Immulite) results were incorrect and made the likelihood of alcoholic-induced hypercortisolism very high. In anticipation of a possible liver transplantation, the patient discontinued all alcohol use. Nine months later, her late-night salivary cortisol levels were normal [0.09 and 0.08 µg/dL (reference range, <0.14)], confirming the diagnosis of alcohol-induced hypercortisolism [24].\n\nTable 3. Patient 5: Peripheral CRH Test Results (1 µg/kg Ovine CRH IV After Baseline Sample at 9:35 am)\n\nTime (min)\tPlasma ACTH (pg/mL)\tSerum Cortisol (µg/dL)\t\nACTH(Cobas)\tACTH(AIA)\tACTH(Immulite)\t\nBaseline\t7.3\t14.2\t835\t16.8\t\n15\t11.2\t23.7\t914\t21.2\t\n30\t12.3\t22.1\t879\t22.4\t\n60\t14.1\t26.9\t825\t25.3\t\nTo convert ACTH (pg/mL) to pmol/L, multiply by 0.2202; to convert cortisol (µg/dL) to nmol/L, multiply by 27.6.\n\n2. Discussion\nThe present case series has illuminated and amplified serious issues with the ACTH(Immulite) assay [11]. Because many high-volume reference laboratories in the United States use this assay, we believe it is critical to inform physicians, especially endocrinologists and endocrine surgeons, of this ACTH assay problem. Since the assembly of our case series, multiple other instances of diagnostic confusion related to this assay have been brought to our attention, many of which resulted in prolonged and unnecessary endocrine testing and procedures for suspected Cushing syndrome, creating a potential patient safety problem. With the large series of patients recently reported and several previous case reports detailing spurious ACTH results with the ACTH(Immulite) assay [6, 8, 10, 11], we believe that our five patients are not isolated or unique and their cases represent a much larger problem, with many cases either unrecognized or unreported. Endocrinologists are very reliant on specialized test results. For several of our patients, the evaluation continued undaunted even when the laboratory findings were not concordant.\n\nThe documentation of heterophile antibody assay interference and/or the absence of a pituitary or ectopic source of ACTH did not deter the continued evaluation because many clinicians were persuaded by the inappropriately normal or elevated ACTH(Immulite) results. Repetitive and invasive differential diagnostic testing (e.g., jugular vein sampling and IPSS) and expensive 68Ga-DOTATATE positron emission tomography/CT testing ensued. Furthermore, in patient 1, the seemingly “positive” IPS/P gradients with the appropriate CRH stimulation ratios [17, 25] had seemed to confirm the pituitary location of ACTH hypersecretion, which, in turn, led to unnecessary pituitary surgery. In some cases, patients, disturbed by the persistently “abnormal” laboratory results, took it on themselves to pursue further endocrine testing and definitive treatment, which led to misdiagnosis and extensive unnecessary and expensive procedures. If the dramatically increased ACTH(Immulite) results in patient 5 during the peripheral CRH test (Table 3) were the only ACTH results available, this patient would have likely proceeded to have undergone unnecessary IPSS and perhaps even pituitary surgery. However, this did not occur because the assays were performed with ACTH(Cobas) and ACTH(AIA). This illustrates the important rule that IPSS should never be performed unless the diagnosis of ACTH-dependent Cushing syndrome is certain because normal subjects can have ACTH responses to CRH and ACTH IPS/P ratios that overlap with those of patients with Cushing disease [26, 27].\n\nDonegan et al. [11] suggested that the presence of heterophile antibodies was responsible for some of the falsely increased ACTH(Immulite) results. The case of patient 1 confirmed that the ACTH(Immulite) is susceptible to heterophile antibody interference. However, heterophile antibodies are not always revealed by proprietary blocking reagents, leaving open the possibility that they could have been responsible for more incorrect ACTH(Immulite) results than previously thought [8]. Polyethylene glycol precipitation represents an alternative strategy for detecting immunoassay interference, because treatment of plasma and serum samples with polyethylene glycol has repeatedly been shown to precipitate immunoglobulins, including heterophile antibodies, as demonstrated in patient 1 [28].\n\nAnother possible cause is a substantial difference in the epitopes against which the two anti-ACTH antibodies used in the different immunometric assays are directed (Table 4). At first, we thought the correct results from the ACTH(Cobas) had been because it uses monoclonal, rather than animal polyclonal, antibodies and/or that the ACTH(Cobas) antibody epitopes are smaller and do not overlap. However, the ACTH(AIA) also uses animal polyclonal antibodies with larger epitopes, although they are shorter and nonoverlapping compared with the ACTH(Immulite) antibodies. In contrast to the ACTH(AIA), which uses only goat antibodies, the ACTH(Immulite) method uses both rabbit and mouse antibodies, which might make the method more susceptible to interference [7, 8]. We do not believe this phenomenon is related to biotin interference because that would artificially lower, rather than increase, the ACTH results [29].\n\nTable 4. N- and C-Terminal Antibody Epitopes (Inclusive Amino Acid Numbers) of the Different ACTH Assays\n\nAssay\tMonoclonal or Polyclonal\tN-Terminal\tC-Terminal\t\nACTH(Cobas)\tMonoclonal\t9-12\t36-39\t\nACTH(Immulite)\tPolyclonal\t1-24 (rabbit)\t18-39 (mouse)\t\nACTH(AIA)\tPolyclonal\t1-16 (goat)\t24-39 (goat)\t\nACTH(Cobas) and ACTH(Immulite) antibody information provided by Mark A. Cervinski, PhD (Department of Pathology, Dartmouth-Hitchcock Medical Center) and reported with his permission; ACTH(AIA) antibody information provided by Barbara Petro (Tosoh Bioscience, Inc.) and reported with her permission.\n\nPatients 2 and 4, who ultimately had a diagnosis of adrenal (ACTH-independent) Cushing syndrome, had had low serum DHEAS concentrations. This makes the diagnosis of ACTH-dependent Cushing syndrome very unlikely [30] and should have raised the specter of a spuriously elevated plasma ACTH, in particular, because these patients had a unilateral adrenal mass. Also, in patient 5, it would be highly unusual for a patient with ectopic ACTH with plasma ACTH concentrations >350 pg/mL to have normal UFC results [31].\n\nIn conclusion, despite substantial endocrine and imaging data suggesting otherwise, elevated ACTH(Immulite) results led to unnecessary testing and potentially harmful invasive procedures, including pituitary surgery. Because the ACTH(Immulite) assay is used by most clinical laboratories, this presents a substantial problem for the endocrine community. It is imperative that physicians know which ACTH assay is in use in their practice. We believe that an alternate ACTH assay such as the ACTH(Cobas) or ACTH(AIA) should be used in the diagnosis and differential diagnosis of patients with suspected disorders of pituitary-adrenal function.\n\nAcknowledgments\nThe authors thank Drs. Joely Straseski (ARUP Laboratories), Mark A. Cervinski (Dartmouth-Hitchcock Medical Center), Barbara Petro (Tosoh Bioscience), and Sharon Wardlaw (Columbia University Medical Center, Neuroendocrine Unit) and the Mayo Clinical Laboratories and ARUP Laboratories for their invaluable assistance. The present study has been accepted in abstract form for a poster presentation at the Endocrine Society 2019 meetings.\n\n\nFinancial\nSupport: The present study was supported by the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program (grant 71951 to G.P.-W.) and the Aurora Research Institute (to H.R.).\n\n\nDisclosure Summary: E.B.G. has received consulting fees from Strongbridge, Corcept, Pfizer and grants from Novartis Pharmaceuticals, Ionis Pharmaceuticals Inc., Strongbridge, and Chiasma. G.P.-W. has received consulting fees from Strongbridge. J.W.F. has received consulting fees from Corcept Therapeutics, and Novartis Pharmaceuticals and has been a research investigator for Corcept Therapeutics and Novartis Pharmaceuticals. H.R. has received consulting fees and a research grant from Cerium Pharmaceuticals. The remaining author has nothing to disclose.\n\nAbbreviations:\nACTH(AIA)Tosoh AIA\n\nACTH(Cobas)Roche Cobas\n\nACTH(Immulite)Siemens ACTH Immulite assay\n\nDSTdexamethasone\n\nIPSinferior petrosal sinus\n\nIPSSinferior petrosal sinus sampling\n\nIRBinstitutional review board\n\nLNSClate night salivary cortisol\n\nPOMPpro-opiomelanocortin\n\nUFCurinary free cortisol\n==== Refs\nReferences and Notes\n1. \nRaff H , Sharma ST , Nieman LK \nPhysiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia . Compr Physiol . 2014 ;4 (2 ):739 –769 .24715566 \n2. \nFindling JW , Engeland WC , Raff H \nThe use of immunoradiometric assay for the measurement of ACTH in human plasma . Trends Endocrinol Metab . 1990 ;1 (6 ):283 –287 .18411131 \n3. \nLindsay JR , Shanmugam VK , Oldfield EH , Remaley AT , Nieman LK \nA comparison of immunometric and radioimmunoassay measurement of ACTH for the differential diagnosis of Cushing’s syndrome . J Endocrinol Invest . 2006 ;29 (11 ):983 –988 .17259795 \n4. \nTalbot JA , Kane JW , White A \nAnalytical and clinical aspects of adrenocorticotrophin determination . Ann Clin Biochem . 2003 ;40 (Pt 5 ):453 –471 .14503983 \n5. \nRaff H , Findling JW \nA new immunoradiometric assay for corticotropin evaluated in normal subjects and patients with Cushing’s syndrome . Clin Chem . 1989 ;35 (4 ):596 –600 .2539271 \n6. \nBolstad N , Kazaryan AM , Revheim ME , Distante S , Johnsrud K , Warren DJ , Nustad K , Edwin B \nA man with abdominal pain: enough evidence for surgery ? Clin Chem . 2012 ;58 (8 ):1187 –1190 .22843812 \n7. \nBolstad N , Warren DJ , Nustad K \nHeterophilic antibody interference in immunometric assays . Best Pract Res Clin Endocrinol Metab . 2013 ;27 (5 ):647 –661 .24094636 \n8. \nGrasko J , Willliams R , Beilin J , Glendenning P , Fermoyle S , Vasikaran S \nA diagnostic conundrum: heterophilic antibody interference in an adrenocorticotropic hormone immunoassay not detectable using a proprietary heterophile blocking reagent . Ann Clin Biochem . 2013 ;50 (Pt 5 ):433 –437 .23873871 \n9. \nRaff H , Findling JW , Wong J \nShort loop adrenocorticotropin (ACTH) feedback after ACTH-(1-24) injection in man is an artifact of the immunoradiometric assay . J Clin Endocrinol Metab . 1989 ;69 (3 ):678 –680 .2547830 \n10. \nChoy KW , Teng J , Wijeratne N , Tan CY , Doery JC \nImmunoassay interference complicating management of Cushing’s disease: the onus is on the clinician and the laboratory . Ann Clin Biochem . 2017 ;54 (1 ):183 –184 .27303060 \n11. \nDonegan DM , Algeciras-Schimnich A , Hamidi O , Young WF , Nippoldt T , Bancos I , Erickson D \nCorticotropin hormone assay interference: a case series . Clin Biochem . 2019 ;63 :143 –147 .30423322 \n12. RRID. AB_2783635. https://scicrunch.org/resolver/AB_2783635.\n13. RRID. AB_2783634. https://scicrunch.org/resolver/AB_2783634.\n14. RRID. AB_2783633. https://scicrunch.org/resolver/AB_2783633.\n15. \nSmith TP , Suliman AM , Fahie-Wilson MN , McKenna TJ \nGross variability in the detection of prolactin in sera containing big big prolactin (macroprolactin) by commercial immunoassays . J Clin Endocrinol Metab . 2002 ;87 (12 ):5410 –5415 .12466327 \n16. \nPage-Wilson G , Freda PU , Jacobs TP , Khandji AG , Bruce JN , Foo ST , Meece K , White A , Wardlaw SL \nClinical utility of plasma POMC and AgRP measurements in the differential diagnosis of ACTH-dependent Cushing’s syndrome . J Clin Endocrinol Metab . 2014 ;99 (10 ):E1838 –E1845 .25013995 \n17. \nFindling JW , Kehoe ME , Shaker JL , Raff H \nRoutine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing’s syndrome: early recognition of the occult ectopic ACTH syndrome . J Clin Endocrinol Metab . 1991 ;73 (2 ):408 –413 .1649842 \n18. \nFindling JW , Kehoe ME , Raff H \nIdentification of patients with Cushing’s disease with negative pituitary adrenocorticotropin gradients during inferior petrosal sinus sampling: prolactin as an index of pituitary venous effluent . J Clin Endocrinol Metab . 2004 ;89 (12 ):6005 –6009 .15579751 \n19. \nDoppman JL , Oldfield EH , Nieman LK \nBilateral sampling of the internal jugular vein to distinguish between mechanisms of adrenocorticotropic hormone-dependent Cushing syndrome . Ann Intern Med . 1998 ;128 (1 ):33 –36 .9424979 \n20. \nIlias I , Chang R , Pacak K , Oldfield EH , Wesley R , Doppman J , Nieman LK \nJugular venous sampling: an alternative to petrosal sinus sampling for the diagnostic evaluation of adrenocorticotropic hormone-dependent Cushing’s syndrome . J Clin Endocrinol Metab . 2004 ;89 (8 ):3795 –3800 .15292307 \n21. \nRadvany MG , Quinones-Hinojosa A , Gallia GL , Wand GS , Salvatori R \nVenous sampling for Cushing disease: comparison of internal jugular vein and inferior petrosal sinus sampling . Endocr Pract . 2016 ;22 (9 ):1057 –1061 .27214296 \n22. \nHayes AR , Grossman AB \nThe ectopic adrenocorticotropic hormone syndrome: rarely easy, always challenging . Endocrinol Metab Clin North Am . 2018 ;47 (2 ):409 –425 .29754641 \n23. \nWand GS , Dobs AS \nAlterations in the hypothalamic-pituitary-adrenal axis in actively drinking alcoholics . J Clin Endocrinol Metab . 1991 ;72 (6 ):1290 –1295 .2026749 \n24. \nFindling JW , Raff H \nDiagnosis of endocrine disease: differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome) . Eur J Endocrinol . 2017 ;176 (5 ):R205 –R216 .28179447 \n25. \nOldfield EH , Doppman JL , Nieman LK , Chrousos GP , Miller DL , Katz DA , Cutler GB Jr, Loriaux DL \nPetrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome . N Engl J Med . 1991 ;325 (13 ):897 –905 .1652686 \n26. \nRaff H , Findling JW \nA physiologic approach to diagnosis of the Cushing syndrome . Ann Intern Med . 2003 ;138 (12 ):980 –991 .12809455 \n27. \nYanovski JA , Cutler GB Jr, Doppman JL , Miller DL , Chrousos GP , Oldfield EH , Nieman LK \nThe limited ability of inferior petrosal sinus sampling with corticotropin-releasing hormone to distinguish Cushing’s disease from pseudo-Cushing states or normal physiology . J Clin Endocrinol Metab . 1993 ;77 (2 ):503 –509 .8393887 \n28. \nSturgeon CM , Viljoen A \nAnalytical error and interference in immunoassay: minimizing risk . Ann Clin Biochem . 2011 ;48 (Pt 5 ):418 –432 .21750113 \n29. \nSamarasinghe S , Meah F , Singh V , Basit A , Emanuele N , Emanuele MA , Mazhari A , Holmes EW \nBiotin interference with routine clinical immunoassays: understand the causes and mitigate the risks . Endocr Pract . 2017 ;23 (8 ):989 –998 .28534685 \n30. \nDennedy MC , Annamalai AK , Prankerd-Smith O , Freeman N , Vengopal K , Graggaber J , Koulouri O , Powlson AS , Shaw A , Halsall DJ , Gurnell M \nLow DHEAS: a sensitive and specific test for the detection of subclinical hypercortisolism in adrenal incidentalomas . J Clin Endocrinol Metab . 2017 ;102 (3 ):786 –792 .27797672 \n31. \nAron DC , Raff H , Findling JW \nEffectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome . J Clin Endocrinol Metab . 1997 ;82 (6 ):1780 –1785 .9177382\n\n",
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"issue": "3(4)",
"journal": "Journal of the Endocrine Society",
"keywords": "Cushing syndrome; adrenocorticotropin; diagnosis; immunoassay interference",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
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"title": "Assay-Specific Spurious ACTH Results Lead to Misdiagnosis, Unnecessary Testing, and Surgical Misadventure-A Case Series.",
"title_normalized": "assay specific spurious acth results lead to misdiagnosis unnecessary testing and surgical misadventure a case series"
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"abstract": "Sepedonium sp . is a saprophytic fungus that inhabits soil and plant material. Few cases of infection with this fungus have been reported. We describe a case of a child who received haploidentical stem cell transplantation. The patient developed Sepedonium sp . infection after graft failure accompanied by cytomegalovirus infection. This was associated with two genotypes corresponding to a gB1 and gB3 mixture, which suggested involvement of two strains. Throughout the clinical course, immunosuppression and subsequent development of the fungal infection was observed. Our findings add to the available evidence regarding the potential for acquisition of fungal infection from the environment in patients at high risk because of immunosuppression. To the best of our knowledge, this is the first case of Sepedonium sp . infection following graft failure accompanied by previous cytomegalovirus infection in a patient with hematopoietic stem cell transplantation.",
"affiliations": "1 Área de Virología, Laboratorio de Infectología, Hospital Infantil de México Federico Gómez, Ciudad de México, México.;2 Banco de Sangre, Hospital Las Américas de Ecatepec, Ecatepec Estado de México, México.;3 UMAE Centro Médico Nacional La Raza IMSS, Ciudad de México, México.;4 Departamento de Infectología, Hospital Infantil de México Federico Gómez, México.;5 Laboratorio de Micología, Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, México.;4 Departamento de Infectología, Hospital Infantil de México Federico Gómez, México.;6 Laboratorio de Investigación en Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, México.;6 Laboratorio de Investigación en Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, México.;6 Laboratorio de Investigación en Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, México.",
"authors": "Arellano-Galindo|José|J|;Eugenio|Vázquez-Meraz|VM|;Elva|Jiménez-Hernández|JH|;Jesús|Reséndiz-Sánchez|RS|;María de Los Ángeles|Martínez-Rivera|MR|;Rodolfo Norberto|Jiménez-Juárez|JJ|;Juan|Xicohtencatl-Cortes|XC|;Sara A|Ochoa|O|;Ariadna|Cruz-Córdoba|CC|",
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"fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2860601810.1177/030006051770810310.1177_0300060517708103Case ReportsA saprophytic fungus (Sepedonium) associated with fatal pneumonia in a patient undergoing stem cell transplantation Arellano-Galindo José 1Eugenio Vázquez-Meraz 2Elva Jiménez-Hernández 3Jesús Reséndiz-Sánchez 4María de los Ángeles Martínez-Rivera 5Rodolfo Norberto Jiménez-Juárez 4Juan Xicohtencatl-Cortes 6Sara A. Ochoa 6Ariadna Cruz-Córdoba 61 Área de Virología, Laboratorio de Infectología, Hospital Infantil de México Federico Gómez, Ciudad de México, México2 Banco de Sangre, Hospital Las Américas de Ecatepec, Ecatepec Estado de México, México3 UMAE Centro Médico Nacional La Raza IMSS, Ciudad de México, México4 Departamento de Infectología, Hospital Infantil de México Federico Gómez, México5 Laboratorio de Micología, Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, México6 Laboratorio de Investigación en Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, MéxicoJosé Arellano-Galindo, Area de Virología, Laboratorio de Infectología, Hospital Infantil de México Federico Gómez, Dr. Márquez No. 162, Col Doctores, del Cuauhtémoc Ciudad de México, México. Email: jose.arellano@salud.gob.mx12 6 2017 8 2017 45 4 1430 1434 4 11 2016 12 4 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Sepedonium sp. is a saprophytic fungus that inhabits soil and plant material. Few cases of infection with this fungus have been reported. We describe a case of a child who received haploidentical stem cell transplantation. The patient developed Sepedonium sp. infection after graft failure accompanied by cytomegalovirus infection. This was associated with two genotypes corresponding to a gB1 and gB3 mixture, which suggested involvement of two strains. Throughout the clinical course, immunosuppression and subsequent development of the fungal infection was observed. Our findings add to the available evidence regarding the potential for acquisition of fungal infection from the environment in patients at high risk because of immunosuppression. To the best of our knowledge, this is the first case of Sepedonium sp. infection following graft failure accompanied by previous cytomegalovirus infection in a patient with hematopoietic stem cell transplantation.\n\nSepedoniumcytomegalovirusHSCTgraft failure\n==== Body\nIntroduction\nSepedonium sp. is a saprophytic fungus that inhabits soil and plant material. Few cases of human infection with this fungus have been reported. This fungal infection was described in a patient with AIDS who developed an infection that was resolved with itraconazole.1 Appearance of this type of infection suggests that patients who are immunosuppressed because of AIDS or after transplantation have a high risk of colonization and infection by various microorganisms. By contrast, involvement of cytomegalovirus has been described in cases of rejected hematopoietic stem cell grafts accompanied by immunosuppression that can lead to sepsis.2 We report here a case of a child who received hematopoietic stem cell transplantation (HSCT), but developed Sepedonium sp. infection after graft failure accompanied by previous cytomegalovirus infection.\n\nCase report\nThe patient was a 14-year-old boy who had received haploidentical stem cell transplantation (dosage of 12 × 106/kg of CD34+ cells). The Cytomegalovirus (CMV) serostatus was IgG D+/R+. The regimen of conditioning was described previously by our group.3 Prophylaxis against graft-versus-host was not administrated. Prophylaxis therapy against infection included fluconazole 6 mg/kg from day –5, ciprofloxacin 30 mg/kg daily, acyclovir 1500 mg/kg daily, trimethoprim and sulfamethoxazole 10 mg/kg daily, and immunoglobulin 400 mg/kg.\n\nBlood was collected in EDTA tubes for monitoring CMV reactivation. This was performed using qualitative PCR with primers that were specific for the fourth exon coding for the immediate-early antigen. PCR was used for fungal monitoring using universal primers to the 18 S RNA sequence in blood and biopsy cultures, as well as for hybridization with specific probes for Candida and Aspergillus.4 PCR was used only to detect the presence of a fungal infection, and the fungus was grown on Sabouraud dextrose agar. The patient received an allogenic bone marrow transplantation. CMV DNAemia was detected up to post-HSCT day +28. The genotype was identified as a gB1 and gB3 mixture on day +41 (Figure 1).\nFigure 1. Follow-up of the patient after transplantation.\n\n\n\nThe patient developed a fever on post-HSCT day +31, and ganciclovir therapy was started with a good response. On post-HSCT day +36, the patient began to show signs of acute rejection. This was diagnosed by analysis of the bone marrow, which showed hypoplasia, and non-donor chimeric cells were detected with the Variable Number of Tandem Repeats (VNTR) technique. On post-HSCT day +43, the patient began to show symptoms of pneumonitis. On day +50, a fungal infection was detected in blood by PCR–ELISA, but the agent could not be identified because the amplification product did not show hybridization with Candida or Aspergillus probes. Sequencing was not possible because the required technology was not available in our laboratory. On day +60, a fungus was isolated in a culture of blood and it was identified by macro- and micromorphological characteristics as Sepedonium sp. The patient was administered antimicrobial therapy comprising ceftazidime (2 g every 8 h) plus teicoplanin (400 mg every 8 h on day 1 and 400 mg every day thereafter) for microbial infection and amphotericin 4 mg/kg daily and caspofungin 50 mg daily. However, despite this treatment, the patient developed sepsis and severe lung lesions, which required ventilatory therapy. The patient died on post-HSCT day +75. Sepedonium sp.was isolated in Sabouraud Dextrose Agar (SDA) culture from a lung biopsy and blood (Figures 1 and 2a). In both of these cultures, possible contamination from our laboratory was ruled out because septate and hyaline hyphae were also observed in a lung biopsy. Radiography of the thorax showed bilateral mixed infiltrates (Figure 2b) and axial computed tomography also showed mixed infiltrates (Figure 2c and 2d).\nFigure 2. Culture of Sepedonium sp., and lung radiology and computed tomography\n\n(a) Culture of the fungus from a sample of lung tissue. The morphology of Sepedonium on Sabouraud dextrose agar at 25℃ during 4 days was initially white and membranous, and then became powdery, reverse is tan, and was sometimes light yellow. (b) Anteroposterior radiograph showing bilateral mixed infiltrates with a rounded parahilar region (left, red arrow). (c) Computed tomography showing three zones of consolidation (red arrows). One zone appears as a rounded parahilar region on the left and another is shown on the right. (d) Computed tomography showing a macronodule with a halo sign in the posterior right region (red arrow).\n\n\n\nDiscussion\nHSCT is an alternative of treatment for patients with haematological disorders. However, regeneration of the immune system after HSCT is a slow and prolonged process, and complications can increase the risk of developing microbial infections.\n\nIn CMV infection, we found two genotypes that corresponded to a gB1 and gB3 mixture, which suggested that two strains were involved in the infection. A previous report showed that gB3 is the most common genotype involved in immunosuppression.5\n\nImmunosuppression is a critical state in patients with a bone marrow transplant. In our case, the patient’s immune system had not recovered completely because of graft failure and the consequent severe immunosuppression allowed microbial infection to develop. The patient’s complications began when he developed pneumonitis, and a rare fungal infection was identified in lung tissue. The fungus Sepedonium sp. is acquired from the environment, with only a few cases reported in the past several years. Sepedonium sp. is occasionally reported as an infectious agent located in the skin and lymph nodules. However, reports of this fungal infection do not describe the immune status of the patients or note that the patients are immunocompetent. The effects of fungal isolates in animal models have been described as lesions in the lung, spleen, adrenals, and liver.6 We isolated the fungus from the patient’s lung tissue. Sepedonium sp. has also been reported in skin lesions of an adult patient with AIDS.1 Therefore, it should be suggest that this genus of fungus and due to the lack of immune response, in immunosuppressed patients could develop disseminated infection and the patient died. Sepedonium was recently identified in the peritoneal dialysate from a 60-year-old man with poorly controlled type I diabetes mellitus.7\n\nOur findings add to the evidence regarding the potential for acquisition of fungal infection from the environment in patients at high risk because of immunosuppression. To the best of our knowledge, this is the first case of Sepedonium sp. infection following graft failure accompanied by previous CMV infection in a patient with HSCT.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis work received support from the Hospital Infantil de México Federico Gómez (protocol number: HIM/2014/027 SSA 1148).\n==== Refs\nReferences\n1 Peng K Soo-Hoo T Na S et al. \nSepedonium Species: an Emerging opportunistic Fungal Infection in a Patient with AIDS . Clin Microbiol Newslett \n2003 ; 25 : 20 –22 .\n2 Castagnola E Cappelli B Erba D et al. \nCytomegalovirus Infection after Bone Marrow Transplantation in Children . Hum Immunol \n2004 ; 65 : 416 –422 .15172440 \n3 Vázquez-Meraz JE Arellano-Galindo J Mendoza-García E et al. \nHaploidentical bone marrow transplantation in Mexico . Pediatr Blood Cancer \n2012 ; 59 : 950 –952 .22434694 \n4 Löffler J Hebart H Sepe S et al. \nDetection of PCR-amplified fungal DNA by using a PCR-ELISA system . Med Mycol \n1998 ; 36 : 275 –279 .10075496 \n5 Torok-Storb B Boeckh M Hoy C et al. \nAssociation of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation . Blood \n2002 ; 90 : 2097 –2102 .\n6 Hanssman G Schenken J \nA unique infection in man caused by a new yeast-like organism, a pathogenic member of the genus Sepedonium . Am J Pathol \n1934 ; 10 : 731 –738 .19970175 \n7 Yogo N Shapiro L Erlandson K \nSepedonium intra-abdominal infection: a case report and review of an emerging fungal infection . J Antimicro Chemoth \n2014 ; 69 : 2583 –2585 .\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "45(4)",
"journal": "The Journal of international medical research",
"keywords": "HSCT; Sepedonium; cytomegalovirus; graft failure",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000293:Adolescent; D001203:Ascomycota; D003586:Cytomegalovirus Infections; D017809:Fatal Outcome; D016469:Fungemia; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009181:Mycoses; D011014:Pneumonia",
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"pages": "1430-1434",
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"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "A saprophytic fungus ( Sepedonium) associated with fatal pneumonia in a patient undergoing stem cell transplantation.",
"title_normalized": "a saprophytic fungus sepedonium associated with fatal pneumonia in a patient undergoing stem cell transplantation"
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"abstract": "A three-year-old male patient was admitted to the clinic with proptosis in his right eye. He had a history of fever with an unknown etiology. In examination, right proptosis was observed and an immobile mass was palpated at the lateral wall of the right orbita. Eye movement was unrestricted in all directions and anterior and posterior segment examination was normal in both eyes. On computed tomography, diffuse bone destruction and expansion was observed in the right orbital lateral wall and other cranial bones. Langerhans cell histiocytosis was diagnosed by bone biopsy. Malignancy is an important cause of proptosis in childhood. Pediatric patients who are admitted to clinic with proptosis should be carefully examined and Langerhans cell histiocytosis should also be considered as an etiology.",
"affiliations": "Mersin University Faculty of Medicine, Department of Ophthalmology, Mersin, Turkey.;Mersin University Faculty of Medicine, Department of Pediatrics, Mersin, Turkey.;Mersin University Faculty of Medicine, Department of Ophthalmology, Mersin, Turkey.;Mersin University Faculty of Medicine, Department of Ophthalmology, Mersin, Turkey.;Mersin University Faculty of Medicine, Department of Pathology, Mersin, Turkey.",
"authors": "Vatansever|Mustafa|M|;Vatansever|Esra|E|;Dinç|Erdem|E|;Sarı|Ayça|A|;Kara|Tuba|T|",
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"fulltext": "\n==== Front\nTurk J OphthalmolTurk J OphthalmolTJOTurkish Journal of Ophthalmology2149-86952149-8709Galenos Publishing 10.4274/tjo.500241754Case ReportA Rare Cause of Proptosis in Childhood: Langerhans Cell Histiocytosis Vatansever Mustafa 1*Vatansever Esra 2Dinç Erdem 1Sarı Ayça 1Kara Tuba 31 \nMersin University Faculty of Medicine, Department of Ophthalmology, Mersin, Turkey\n2 \nMersin University Faculty of Medicine, Department of Pediatrics, Mersin, Turkey\n3 \nMersin University Faculty of Medicine, Department of Pathology, Mersin, Turkey\n* Address for Correspondence: Mersin University Faculty of Medicine, Department of Ophthalmology, Mersin, Turkey Phone: +90 324 337 43 00-1200 E-mail: vatansevermustafa@hotmail.com8 2016 15 8 2016 46 4 194 196 25 6 2014 26 9 2014 ©Turkish Journal of Ophthalmology, Published by Galenos Publishing.2016This 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.A three-year-old male patient was admitted to the clinic with proptosis in his right eye. He had a history of fever with an unknown etiology. In examination, right proptosis was observed and an immobile mass was palpated at the lateral wall of the right orbita. Eye movement was unrestricted in all directions and anterior and posterior segment examination was normal in both eyes. On computed tomography, diffuse bone destruction and expansion was observed in the right orbital lateral wall and other cranial bones. Langerhans cell histiocytosis was diagnosed by bone biopsy. Malignancy is an important cause of proptosis in childhood. Pediatric patients who are admitted to clinic with proptosis should be carefully examined and Langerhans cell histiocytosis should also be considered as an etiology.\n\nHistiocytosisproptosisorbital masschildhood\n==== Body\nINTRODUCTION\nLangerhans cell histiocytosis (LCH) is the most common form of histiocytosis, with an annual incidence of 4-5 per million.1 The average age at diagnosis is 30.2 months and the disease occurs in males more often than females.2 Although both genetic and environmental factors have been implicated in its etiology, a clear relationship has not been demonstrated. Eighty percent of LCH patients have bone involvement, and half of these cases occur in the skull and facial bones. Orbital involvement occurs in 20% of LCH patients.3 Swelling is usually the first sign of cranial involvement due to bone expansion. The probability of organ involvement rises with lower age of disease onset; liver, lung and bone marrow involvement are associated with worse prognosis.4 Malignancy is etiologically important in terms of the prognosis of pediatric proptosis, and 22% of orbital lesions in pediatric patients are malignant.5 LCH is detected in 1-7% of orbital biopsies.6 Here we present a case presenting with proptosis which was diagnosed as LCH as a result of tests.\n\nCASE REPORT\nThe ophthalmology clinic was consulted regarding a 3-year-old male patient with proptosis of the right eye. It was learned that the patient had a 4-month history of persistent subfebrile temperature; tests revealed pancytopenia and hepato-splenomegaly. He was being followed in the pediatric inpatient clinic to establish an etiologic cause. On examination, the patient was able to track a light source, his eye movement was unrestricted in all directions, and anterior and posterior segment examinations were normal. Proptosis was observed in the right eye (Figure 1). An immovable mass of 1x2 cm was palpated in the lateral wall of the right orbita. Computed tomography (CT) revealed diffuse bone destruction and expansion in the right orbital lateral wall and other cranial bones (Figure 2). Microcystic formations were observed on thoracic CT (Figure 3). Suspecting histiocytosis based on the clinical and radiological findings, skeletal scintigraphy was performed. Pathologic involvement was observed in the walls of both orbita and the pelvis. The diagnosis was confirmed by pelvic bone marrow biopsy (Figure 4), which stained positive for CD1a. A treatment protocol of oral prednisolone (40 mg/m2/day) and intravenous vinblastin (6 mg/m2) was initiated. When this protocol failed, treatment was changed to a rescue protocol of cytosine arabinozid (1 g/m2/day) + chlorodeoxyadenosine (8.9 mg/m2/day). Despite some treatment response, the patient died due to pneumonia secondary to neutropenia.\n\nDISCUSSION\nMalignant infiltrations are one of the primary diagnoses that should be considered in pediatric proptosis. Particularly in cases of proptosis accompanied by signs like leukocoria, restricted eye motility, sudden-onset asymmetric eye position, afferent pupil defect, and pseudohypopyon, malignancies should be seriously considered and must be excluded. Twenty-two percent of orbital lesions seen in pediatric patients are malignant lesions, with 65% of these being primary, 29% secondary and 6% metastatic lesions.5 The differential diagnosis for proptosis should include medulloepithelioma as a primary ocular tumor; rhabdomyosarcoma and optic nerve glioma as primary orbital tumors; fibroma, fibrous dysplasia and osteosarcoma as orbital bone tumors; and leukemia, lymphoma and neuroblastoma as metastatic tumors.7\n\nLCH is a malignancy characterized by abnormal proliferation of Langerhans cells, but its etiology is not fully understood. Skeletal involvement occurs in 80% of LCH cases; the cranial bones are involved in more than half of these patients, while about 20% exhibit orbital involvement.3 The most common cranial finding is a mass located at the zygomaticofrontal suture, as in our patient. Initial ocular signs of LCH include proptosis, ptosis, eyelid edema and redness around the eyes.8 As in the current case, patients may present with proptosis alone. Direct imaging is the most effective way to visualize skeletal involvement in LCH, and typically reveals lytic lesions. Pulmonary involvement of LCH begins as nodular lesions that develop with disease progression into thin-walled cystic structures which are easily detected by high-resolution CT.9 Biopsy of these nodular lesions is recommended for histopathologic confirmation of pulmonary LCH. However, the Histiocytosis Society reported that the observation of typical cystic lesions on high-resolution CT is sufficient to diagnose pulmonary involvement.10 Our patient presented with typical lytic bone lesions as well as microcystic pulmonary lesions, so lung biopsy was deemed unnecessary. The Histiocytosis Society also created a guideline for diagnosing splenic and hepatic involvement through clinical examination and ultrasonography, without histopathologic sampling.\n\nLCH most often arises in childhood but onset is known to occur in patients of every age group. Prognosis worsens with lower age at diagnosis. Clinical manifestation varies from benign unifocal skeletal involvement to aggressively malignant multisystem disease. Prognosis is poor in cases with disease spread and organ dysfunction.11 For patients with unifocal skeletal involvement, local treatment or observation may be adequate.8,12 However, these patients should be followed closely due to the risk of progression to multisystem disease. Systemic chemotherapeutic agents are used to treat multisystem LCH. The current case exhibited multifocal skeletal involvement; despite the absence of hematopoietic, hepatic, splenic, or pulmonary involvement, he was considered at risk for multisystem disease and systemic chemotherapy was initiated. Patients with hematopoietic, hepatic, splenic or pulmonary involvement are considered at risk for multisystem disease in the risk stratification system of the Histiocytosis Society, and treatment protocols were designed accordingly.10 The prognosis of LCH patients with multisystem involvement is poor.\n\nDue to the inability of pediatric patients to express themselves and the subtlety of the signs and symptoms of orbital malignancy, the families of these patients may overlook or disregard their symptoms. This may lead to delayed diagnosis and worse prognosis. Unfortunately, our patient’s family disregarded his proptosis and orbital mass.\n\nCONCLUSION\nAll pediatric patients presenting with proptosis should undergo a thorough examination, and the possibility of an underlying malignancy should be considered even in cases with subtle signs. It should be kept in mind that LCH is among these malignancies and that an initial diagnosis is possible with careful radiologic imaging.\n\nEthics\nInformed Consent: It was taken.\n\nPeer-review: Externally and internally peer-reviewed.\n\nSurgical and Medical Practices: Mustafa Vatansever, Esra Vatansever, Erdem Dinç, Ayça Sarı, Tuba Kara, Concept: Mustafa Vatansever, Esra Vatansever, Erdem Dinç, Ayça Sarı, Tuba Kara, Design: Mustafa Vatansever, Esra Vatansever, Erdem Dinç, Ayça Sarı, Tuba Kara, Data Collection or Processing: Mustafa Vatansever, Esra Vatansever, Erdem Dinç, Ayça Sarı, Tuba Kara, Analysis or Interpretation: Mustafa Vatansever, Esra Vatansever, Erdem Dinç, Ayça Sarı, Tuba Kara, Literature Search: Mustafa Vatansever, Esra Vatansever, Erdem Dinç, Ayça Sarı, Tuba Kara, Writing: Mustafa Vatansever, Esra Vatansever, Erdem Dinç, Ayça Sarı, Tuba Kara.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nFigure 1 Mild proptosis of the right eye and expansion of the lateral wall of the right orbita\nFigure 2 Multiple lytic lesions detected in the cranial bones on computed tomography\nFigure 3 Microcystic formations visible on pulmonary computed tomography\nFigure 4 a) Characteristic Langerhans cells (hematoxylin & eosin, x200) and b) cytoplasmic CD1a staining (x200) in the patient’s bone marrow biopsy\n==== Refs\nReferences\n1 Nicholson HS Egeler RM Nesbitt ME The epidemiology of Langerhans cell histiocytosis Hematol Oncol Clin North Am 1998 12 379 384 9561907 \n2 Braier J Chantada G Rosso D Bernaldez P Amaral D Latella A Balancini B Masautis A Goldberg J Langerhans cell histiocytosis: retrospective evaluation of 123 patients at a single institution Pediatr Hematol Oncol 1999 16 377 385 10505313 \n3 Moore AT Pritchard J Taylor DS Histiocytosis X: an ophthalmological review Br J Ophthalmol 1985 69 7 14 3871158 \n4 Lahey ME Histiocytosis X-an analysis of prognostic factors J Pediatr 1975 87 184 189 1151558 \n5 Johansen S Heegard S Bogeskov L Prause JU Orbital space occupying lesions in Denmark 1974-1997 Acta Opththalmol Scand 2000 78 547 552 \n6 Henderson JW Farrow GM Orbital Tumors (2nd ed) New York NY; Brian C Decker (Thieme Stratton) 1980 580 584 \n7 Rao AA Naheedy JH Chen JY Robins SL Ramkumar HL A clinical update and radiologic review of pediatric orbital and ocular tumors J Oncol 2013 2013 975908 23577029 \n8 Kiratli H Tarlan B Söylemezoglu F Langerhans cell histiocytosis of the orbit Eur J Ophthalmol 2013 23 578 583 23483503 \n9 Brauner MW Grenier P Tijani K Battesti JP Valeyre D Pulmonary Langerhans cell histiocytosis: evolution of lesions on CT scans Radiology 1997 204 497 502 9240543 \n10 [Internet] https://www.histiocytesociety.org/document.doc?id=290 \n11 Henter JI Tondini C Pritchard J Histiocyte disorders Crit Rev Oncol Hematol 2004 50 157 174 15157664 \n12 Yüksel D Sungur G Erden O Ünlübay D Duman S Orbita Tutulumu Gösteren Langerhans Hücreli Histiositozis: İki Olgu Sunumu Turk J Ophthalmol 2004 3 168 172\n\n",
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"issue": "46(4)",
"journal": "Turkish journal of ophthalmology",
"keywords": "Histiocytosis; childhood; orbital mass; proptosis",
"medline_ta": "Turk J Ophthalmol",
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"title": "A Rare Cause of Proptosis in Childhood: Langerhans Cell Histiocytosis.",
"title_normalized": "a rare cause of proptosis in childhood langerhans cell histiocytosis"
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"abstract": "A malignant tumor can cause hypercoagulation and it also often coexists with thrombosis. Cisplatin-based chemotherapy can also induce adverse vascular effects, including arterial thrombosis. We herein report a case of acute arterial thrombosis in a patient undergoing postoperative adjuvant cisplatin-based chemotherapy for completely resected lung cancer. The patient complained of acute leg pain after chemotherapy, and computed tomography revealed multiple thrombi from the thoracic to popliteal arteries. Arterial thrombosis during adjuvant chemotherapy is extremely rare; however, careful clinical observation of patients receiving cisplatin-based chemotherapy is important, because arterial thrombosis, even in the absence of the primary malignant tumor, is possible.",
"affiliations": "General Education Center, The University of Tokyo Hospital, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Vascular Surgery, The University of Tokyo Hospital, Japan.;Department of Vascular Surgery, The University of Tokyo Hospital, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan.",
"authors": "Sato|Chihiro|C|;Okuda|Kenichi|K|;Tamiya|Hiroyuki|H|;Yamamoto|Kota|K|;Hoshina|Katsuyuki|K|;Narumoto|Osamu|O|;Urushiyama|Hirokazu|H|;Noguchi|Satoshi|S|;Amano|Yosuke|Y|;Watanabe|Kosuke|K|;Mitani|Akihisa|A|;Kage|Hidenori|H|;Tanaka|Goh|G|;Yamauchi|Yasuhiro|Y|;Takai|Daiya|D|;Nagase|Takahide|T|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2922524610.2169/internalmedicine.8996-17Case ReportAcute Arterial Thrombosis during Postoperative Adjuvant Cisplatin-based Chemotherapy for Completely Resected Lung Adenocarcinoma Sato Chihiro 1Okuda Kenichi 2Tamiya Hiroyuki 2Yamamoto Kota 3Hoshina Katsuyuki 3Narumoto Osamu 2Urushiyama Hirokazu 2Noguchi Satoshi 2Amano Yosuke 2Watanabe Kosuke 2Mitani Akihisa 2Kage Hidenori 2Tanaka Goh 2Yamauchi Yasuhiro 2Takai Daiya 24Nagase Takahide 2\n1 General Education Center, The University of Tokyo Hospital, Japan\n2 Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan\n3 Department of Vascular Surgery, The University of Tokyo Hospital, Japan\n4 Department of Clinical Laboratory, The University of Tokyo Hospital, JapanCorrespondence to Dr. Hiroyuki Tamiya, TAMIYAH-INT@h.u-tokyo.ac.jp\n\n8 12 2017 15 2 2018 57 4 557 561 6 2 2017 5 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A malignant tumor can cause hypercoagulation and it also often coexists with thrombosis. Cisplatin-based chemotherapy can also induce adverse vascular effects, including arterial thrombosis. We herein report a case of acute arterial thrombosis in a patient undergoing postoperative adjuvant cisplatin-based chemotherapy for completely resected lung cancer. The patient complained of acute leg pain after chemotherapy, and computed tomography revealed multiple thrombi from the thoracic to popliteal arteries. Arterial thrombosis during adjuvant chemotherapy is extremely rare; however, careful clinical observation of patients receiving cisplatin-based chemotherapy is important, because arterial thrombosis, even in the absence of the primary malignant tumor, is possible. \n\narterial thrombosiscisplatinlung cancerresected\n==== Body\nIntroduction\nA malignant tumor can cause hypercoagulation and it also often coexists with thrombosis (a phenomenon known as Trousseau's syndrome) (1). Chemotherapy for malignant diseases can also promote thrombogenicity; cisplatin-based chemotherapy, for example, has been shown to elicit thromboembolic events (TEEs), such as aortic thrombosis, myocardial and cerebral infarction, and deep vein thrombosis (2). Although arterial thrombosis during cancer chemotherapy has been described (3-6), chemotherapy-induced arterial thrombosis in patients with a completely resected cancer has been rarely seen.\n\nWe herein report a case of acute arterial thrombosis that occurred during adjuvant cisplatin-based chemotherapy administered after complete resection of lung cancer.\n\nCase Report\nA 68-year-old man was referred to our hospital because of abnormal chest computed tomography (CT) findings (Fig. 1). He had undergone appendectomy at 26 years of age and colon polypectomy (adenoma) at 62 years of age, but had no medical history of TEEs and was in good condition, with an Eastern Cooperative Oncology Group performance status of 0. He had a smoking history of 45 pack-years but no other risk factors for atherosclerosis, such as hypertension, diabetes, dyslipidemia, chronic kidney disease, or a history of cerebral infarction or peripheral artery disease. He had a family history of lung cancer in his sister but was negative for thromboembolic disease. No abnormal findings were observed on a physical examination or electrocardiogram. A blood test showed no abnormalities, including his lipid profiles, plasma glucose, serum creatinine, levels of carcinoembryonic antigen (4.7 ng/mL), and coagulation markers. A contrast-enhanced CT body scan and gadolinium-enhanced magnetic resonance imaging brain scan revealed an abnormal shadow in the right lung and calcification of the abdominal aorta and common iliac artery but no metastatic lesions or thrombi. Lung cancer was suspected, and the patient underwent right lower lobectomy. Histology revealed lung adenocarcinoma (pT2aN1M0, stage IIA) with negative surgical margins. The patient had an uneventful postoperative course and was discharged from the hospital nine days after admission.\n\nFigure 1. Chest computed tomography performed at the diagnosis. A nodular shadow is seen at the right lower lobe (arrow).\n\nOne month after surgery, the patient received the first cycle of an adjuvant chemotherapy regimen consisting of cisplatin (80 mg/m2, intravenously on day 1) and vinorelbine (25 mg/m2, intravenously on days 1 and 8). On day 13 of cycle 1, he complained of acute pain in his right leg and intermittent claudication, which diminished within 1 h. The next day, he again experienced sudden pain and coldness in his right leg while walking. A physical examination showed the absence of pulsation in the right popliteal and dorsalis pedis artery and coldness in the peripheral part of the right lower leg.\n\nContrast-enhanced CT revealed an intramural thrombus extending from the thoracic artery to the abdominal aorta, 90% narrowing of the right common iliac artery, and complete occlusion of the right popliteal artery (Fig. 2). The ankle brachial pressure index (ABI) was 0.33 on the right side and 1.14 on the left. The laboratory findings concerning coagulation were as follows (normal range): fibrin/fibrinogen degradation, 12.7 μg/mL (0.0-4.9); D-dimer, 5.7 μg/mL (0.0-0.9); protein C, 109% (75.0-128.0); protein S, 51.2% (74.0-132.0); von Willebrand factor (vWF) antigen, 280% (50.0-155.0); anti-β2-glycoprotein I antibodies, 1.2 U/mL (0.0-3.5); anticardiolipin IgG antibody, 8 U/mL (0.0-10.0); and lupus anticoagulant, 1.01 (normalized ratio, 0.0-1.3). Echocardiography showed no thrombi in the heart.\n\nFigure 2. Contrast-enhanced computed tomography angiogram at the onset of thromboembolic events showed narrowing of the right common iliac artery and complete occlusion of the right popliteal artery. Enlarged images of the common iliac artery and the right popliteal artery are shown in the boxes.\n\nWe consulted vascular surgeons concerning the treatment of the patient and decided to carry out medication prior to operative treatment since his symptoms were relieved. He was managed conservatively via the administration of unfractionated heparin followed by warfarin, and his symptoms subsided completely after two weeks. Chemotherapy was permanently stopped, and he was discharged from the hospital with warfarin therapy. Positron emission tomography performed 1 month after the first day of chemotherapy showed no evidence of lung cancer relapse. The right-side ABI returned to 1.10 after 2 months. Contrast-enhanced CT performed 115 days after the onset of thrombotic event showed resolution of all arterial thrombi (Fig. 3). The vWF antigen level peaked (576%) 2 weeks and declined to 182% 4 months after the onset of TEEs.\n\nFigure 3. Contrast-enhanced computed tomography scans. (A) At the diagnosis: there was no thrombus. (B) At the onset of thromboembolic events (TEEs): a low-density intraluminal lesion (thrombus) was detected at the level of the descending aorta (long arrow), abdominal aorta (short arrow), and common iliac artery (arrowhead). (C) After the onset of TEEs (day 115): the thrombus was no longer present.\n\nDiscussion\nThe relationship between malignancy and venous thrombosis described by Trousseau suggests that malignancy is associated with an increased risk of venous and arterial TEEs (1). Among the factors that influence the incidence of TEEs in cancer patients (e.g., an increase in the expression of proteins that facilitate coagulation, including tissue factor and plasminogen activator inhibitor type 1), chemotherapy imparts a significant risk. The chemotherapeutic agent cisplatin in particular has been associated with a wide range of TEEs in tongue carcinomas (7), esophageal adenocarcinomas (8), gastric cancers (9), rectosigmoid adenocarcinomas (3,6), lung cancers (3,6), cervical cancers (10), and germ cell tumors (11). Cool et al. reported recurrent arterial thrombosis during cisplatin and etoposide chemotherapy (12), and in a large retrospective analysis, Moore et al. found that 169 of 932 (18.1%) patients experienced a TEE during cisplatin-based chemotherapy for any type of malignancy (2). In the Moore et al. study, most TEEs (88%) occurred within the first 100 days after the initiation of cisplatin treatment, and although deep venous thrombosis and pulmonary embolus were the predominant events, arterial TEEs occurred in 19 of the 169 (11.3%) patients (2). Several cases of arterial TEEs during cisplatin-based chemotherapy for lung cancer have been reported; however, all patients in these cases were cancer-bearing (3-5). To our knowledge, we are the first to report a case of arterial thrombosis that occurred during postoperative adjuvant cisplatin-based chemotherapy in a patient with completely resected lung cancer (i.e., in a non-cancer-bearing patient). Our case strongly suggests an association between cisplatin-based chemotherapy and the development of arterial TEEs.\n\nThe exact mechanism of action by which cisplatin-based chemotherapy causes TEEs has not been clarified. Licciardello et al. correlated vWF levels with arterial thrombosis in cisplatin-treated patients; in their study, the median vWF level increased significantly after cisplatin-based chemotherapy (13). Others reported elevated plasma vWF levels in patients with germ cell tumors receiving cisplatin-based chemotherapy (14). In our case, the level of vWF antigen substantially increased after the occurrence of TEEs, perhaps due to drug-induced endothelial cell damage. Cisplatin may promote vascular endothelial injury, such as vacuolation, subendothelial edema, and the destruction of the internal elastic membrane, via free radical-induced lipid peroxidation (15), platelet phospholipase A2-mediated platelet aggregation (16), or the upregulation of intercellular adhesion molecule-1, tissue-type plasminogen activator, and plasminogen activator inhibitor type 1 (17,18), all of which can induce arterial thrombosis.\n\nCisplatin-induced hypomagnesemia is also a possible risk factor for TEEs; in the study by Vogelzang et al., hypomagnesemia caused thrombosis by eliciting arterial spasms (19). Although we did not measure the magnesium level before the onset of TEEs, we routinely administer magnesium sulfate to prevent hypomagnesemia due to cisplatin. Therefore, it is unlikely that hypomagnesemia contributed to the thrombosis in our case. Furthermore, hypomagnesemia has not been shown to cause large vessel thrombotic effects.\n\nProtein S deficiency predisposes subjects to develop venous thromboembolism (20). Engesser et al. found that venous thrombotic events occurred in 55% of protein S-deficient patients, and the age at the first thrombotic event ranged from 15 to 68 years (mean, 28 years) (21). Borgel et al. reported protein S activity ranging from 5% to 30% in patients who developed thrombotic events (22).\n\nIn our patient, the protein S activity (51.2%) was below the lower limit of normal (74.0-132.0%), however, he did not have a history of any TEEs in the past. In addition, protein S deficiency was not regarded as a risk factor for arterial thromboembolism in a familial protein S deficiency cohort (23,24). Therefore, we suspect that the low protein S activity was not related to the arterial thrombosis in our case.\n\nMale gender, smoking, and age ≥45 years for men are known risk factors for atherosclerotic cardiovascular diseases (25), all of which applied to this case. Furthermore, calcification of the abdominal aorta and common iliac artery was detected in our patient. We therefore speculate that patients with multiple risk factors for cardiovascular diseases and aortic calcification may tend to develop arterial thrombosis when receiving cisplatin-based chemotherapy, even in the absence of the primary malignant tumor. Prophylactic anticoagulation should be considered for cancer patients in high-risk settings. Indeed, prophylactic antithrombotic agents have been shown to reduce the incidence of TEEs in patients with solid cancer who are receiving chemotherapy (26,27). However, the patients included in these trials had metastatic or locally advanced cancers, and most of the TEEs were venous thrombosis. Therefore, the benefit of prophylactic anticoagulation for arterial thrombosis in postoperative adjuvant chemotherapy for completely resected cancer needs to be validated.\n\nIn conclusion, careful clinical observations of patients receiving cisplatin-based chemotherapy is important because of the possible risk of arterial TEEs, even when the primary malignant tumor has been completely resected.\n\n\nWritten informed consent was obtained from the patient for the publication of this case report.\n\nThis work originated at Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nVarki A \nTrousseau's syndrome: multiple definitions and multiple mechanisms . Blood \n110 : 1723 -1729 , 2007 .17496204 \n2. \nMoore RA , Adel N , Riedel E , et al \nHigh incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis . J Clin Oncol \n29 : 3466 -3473 , 2011 .21810688 \n3. \nFernandes DD , Louzada ML , Souza CA , Matzinger F \nAcute aortic thrombosis in patients receiving cisplatin-based chemotherapy . Curr Oncol \n18 : e97 -e100 , 2011 .21505594 \n4. \nChin SO , Lee JJ , Hwang YH , et al \nAortic thrombosis resolved with enoxaparin in a patient treated with cisplatin-based regimen for small cell lung cancer . Int J Hematol \n91 : 892 -896 , 2010 .20428980 \n5. \nHahn SJ , Oh JY , Kim JS , Kim DY \nA case of acute aortic thrombosis after cisplatin-based chemotherapy . Int J Clin Oncol \n16 : 732 -736 , 2011 .21455627 \n6. \nMathews J , Goel R , Evans WK , Shamji F , Stewart DJ \nArterial occlusion in patients with peripheral vascular disease treated with platinum-based regimens for lung cancer . Cancer Chemother Pharmacol \n40 : 19 -22 , 1997 .9137524 \n7. \nRishi A , Ghoshal S \nAcute multiple arterial thrombosis after cisplatin in base of tongue carcinoma: case report . Head Neck \n35 : E269 -E271 , 2013 .22915348 \n8. \nMorlese JF , Jeswani T , Beal I , Wylie P , Bell J \nAcute ventricular and aortic thrombosis post chemotherapy . Br J Radiol \n80 : e75 -e77 , 2007 .17551165 \n9. \nIto S , Nakamura Y , Noumi T , Sasaki Y \nAcute aortic thrombosis during cisplatin based chemotherapy for gastric cancer . Intern Med \n52 : 973 -975 , 2013 .23648716 \n10. \nApiyasawat S , Wongpraparut N , Jacobson L , Berkowitz H , Jacobs LE , Kotler MN \nCisplatin induced localized aortic thrombus . Echocardiography \n20 : 199 -200 , 2003 .12848689 \n11. \nCheng E , Berthold DR , Moore MJ , Duran I \nArterial thrombosis after cisplatinbased chemotherapy for metastatic germ cell tumors . Acta Oncol \n48 : 475 -477 , 2009 .18932096 \n12. \nCool RM , Herrington JD , Wong L \nRecurrent peripheral arterial thrombosis induced by cisplatin and etoposide . Pharmacotherapy \n22 : 1200 -1204 , 2002 .12222560 \n13. \nLicciardello JT , Moake JL , Rudy CK , Karp DD , Hong WK \nElevated plasma von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy . Oncology \n42 : 296 -300 , 1985 .3875817 \n14. \nDieckmann KP , Struss WJ , Budde U \nEvidence for acute vascular toxicity of cisplatin-based chemotherapy in patients with germ cell tumour . Anticancer Res \n31 : 4501 -4505 , 2011 .22199322 \n15. \nIto H , Okafuji T , Suzuki T \nVitamin E prevents endothelial injury associated with cisplatin injection into the superior mesenteric artery of rats . Heart Vessels \n10 : 178 -184 , 1995 .8530321 \n16. \nTogna GI , Togna AR , Franconi M , Caprino L \nCisplatin triggers platelet activation . Thromb Res \n99 : 503 -509 , 2000 .10973681 \n17. \nYu M , Han J , Cui P , et al \nCisplatin up-regulates ICAM-1 expression in endothelial cell via a NF-kappaB dependent pathway . Cancer Sci \n99 : 391 -397 , 2008 .18271937 \n18. \nNuver J , De Haas EC , Van Zweeden M , Gietema JA , Meijer C \nVascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro . Oncol Rep \n23 : 247 -253 , 2010 .19956889 \n19. \nVogelzang NJ , Torkelson JL , Kennedy BJ \nHypomagnesemia, renal dysfunction, and Raynaud's phenomenon in patients treated with cisplatin, vinblastine, and bleomycin . Cancer \n56 : 2765 -2770 , 1985 .2413982 \n20. \nten Kate MK , van der Meer J \nProtein S deficiency: a clinical perspective . Haemophilia \n14 : 1222 -1228 , 2008 .18479427 \n21. \nEngesser L , Broekmans AW , Briet E , Brommer EJ , Bertina RM \nHereditary protein S deficiency: clinical manifestations . Ann Intern Med \n106 : 677 -682 , 1987 .2952034 \n22. \nBorgel D , Gandrille S , Aiach M \nProtein S deficiency . Thromb Haemost \n78 : 351 -356 , 1997 .9198178 \n23. \nBrouwer JL , Veeger NJ , van der Schaaf W , Kluin-Nelemans HC , van der Meer J \nDifference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test-based classification . Br J Haematol \n128 : 703 -710 , 2005 .15725093 \n24. \nLibourel EJ , Bank I , Veeger NJ , et al \nProtein S type III deficiency is no risk factor for venous and arterial thromboembolism in 168 thrombophilic families: a retrospective study . Blood Coagul Fibrinolysis \n16 : 135 -140 , 2005 .15741801 \n25. \nTeramoto T , Sasaki J , Ishibashi S , et al \nCardiovascular disease risk factors other than dyslipidemia. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan - 2012 version . J Atheroscler Thromb \n20 : 733 -742 , 2013 .23892529 \n26. \nPelzer U , Opitz B , Deutschinoff G , et al \nEfficacy of prophylactic low-molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO-004 trial . J Clin Oncol \n33 : 2028 -2034 , 2015 .25987694 \n27. \nAgnelli G , Gussoni G , Bianchini C , et al \nNadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study . Lancet Oncol \n10 : 943 -949 , 2009 .19726226\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "arterial thrombosis; cisplatin; lung cancer; resected",
"medline_ta": "Intern Med",
"mesh_terms": "D000208:Acute Disease; D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D011013:Pneumonectomy; D011150:Popliteal Artery; D011183:Postoperative Complications; D013895:Thoracic Arteries; D013927:Thrombosis",
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"title": "Acute Arterial Thrombosis during Postoperative Adjuvant Cisplatin-based Chemotherapy for Completely Resected Lung Adenocarcinoma.",
"title_normalized": "acute arterial thrombosis during postoperative adjuvant cisplatin based chemotherapy for completely resected lung adenocarcinoma"
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"abstract": "A 68-year-old woman was referred with the diagnosis of symptomatic pHPT (primary hyperparathyroidism). Ultrasonography (US) and 99mTc-MIBI scintigraphy could not clearly identify a parathyroid adenoma. A primary unilateral surgical exploration remained unsuccessful to remove adenomatous parathyroid tissue and the pHPT persisted. 18F-ethylcholine PET/CT showed a left-sided retropharyngeal lesion with intense tracer uptake that could not be detected on US images at first sight. Therefore, additional 18F-ethylcholine PET/US fusion imaging was performed and revealed a poorly definable nodular structure on US that could be unambiguously correlated to the PET finding. Surgical excision confirmed an oncocytic variant of parathyroid adenoma, and parathormone and calcium levels normalized immediately.",
"affiliations": "From the Clinic of Nuclear Medicine, Jena University Hospital, Jena Medical Faculty, Department of Visceral, Vascular, and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.",
"authors": "Seifert|Philipp|P|;Greiser|Julia|J|;Winkens|Thomas|T|;Lorenz|Kerstin|K|;Freesmeyer|Martin|M|",
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"pmid": "34406183",
"pubdate": "2021-08-16",
"publication_types": "D016428:Journal Article",
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"title": "Ectopic Retrolaryngeal Parathyroid Adenoma Detected by 18F-Ethylcholine PET/US Fusion Imaging.",
"title_normalized": "ectopic retrolaryngeal parathyroid adenoma detected by 18f ethylcholine pet us fusion imaging"
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"abstract": "Type A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range <50 ng/dL), free testosterone 2.21 ng/dL (reference range <1.09 ng/dL), normal glucose, and HbA1c of 5.6%. She received a diagnosis of polycystic ovary syndrome (PCOS) and was referred to our Multi-Specialty Adolescent PCOS Program. There, oral glucose tolerance test showed fasting glucose and insulin of 80 mg/dL and 63.1 mIU/mL, respectively. The 2-hour glucose and insulin were 199 mg/dL and 1480 μIU/mL, respectively. Because of hyperandrogenism with severe IR, dysglycemia, and normal lipids, type A IR was considered. Genetic testing revealed a heterozygous mutation in the insulin receptor gene [c.3095G>A(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy improved hyperandrogenism and reduced ovarian size while severe IR persisted. We describe an adolescent with type A IR who experienced resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Given the patient's marked reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropin effect. GnRH agonist therapy should be considered in the treatment of hyperandrogenism in severe cases of IR.",
"affiliations": "Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.;Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.;Division of Nutritional Sciences, Cornell University, Ithaca, New York.;Division of Nutritional Sciences, Cornell University, Ithaca, New York.;Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.",
"authors": "Paprocki|Emily|E|0000-0002-5555-5906;Barral|Romina L|RL|;Vanden Brink|Heidi|H|;Lujan|Marla|M|;Burgert|Tania S|TS|",
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"country": "United States",
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"doi": "10.1210/js.2019-00045",
"fulltext": "\n==== Front\nJ Endocr SocJ Endocr SocjesJournal of the Endocrine Society2472-1972Endocrine Society Washington, DC js_20190004510.1210/js.2019-00045Case ReportDiabetes, Pancreatic and Gastrointestinal HormonesGnRH Agonist Improves Hyperandrogenism in an Adolescent Girl With an Insulin Receptor Gene Mutation http://orcid.org/0000-0002-5555-5906Paprocki Emily epaprocki@cmh.edu1Barral Romina L 1Vanden Brink Heidi 2Lujan Marla 2Burgert Tania S 11 Children’s Mercy Kansas City, University of Missouri–Kansas City School of Medicine, Kansas City, Missouri2 Division of Nutritional Sciences, Cornell University, Ithaca, New YorkCorrespondence: Emily Paprocki, DO, Children’s Mercy Kansas City, Division of Endocrinology/Diabetes, 3101 Broadway Blvd, Kansas City, Missouri 64111. E-mail: epaprocki@cmh.edu.01 6 2019 07 5 2019 3 6 1196 1200 01 2 2019 01 5 2019 Copyright © 2019 Endocrine Society2019This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Abstract\nType A insulin resistance (IR) is caused by heterozygous mutations in the insulin receptor gene. It presents with mild acanthosis nigricans, severe IR, and hyperandrogenism in the absence of obesity or lipodystrophy. Treatment aims to improve insulin sensitivity and decrease androgens. An adolescent girl was evaluated for secondary amenorrhea and prominent hirsutism. She had a normal body mass index, and laboratory testing revealed an elevated LH to FSH ratio (LH 11.6 mIU/mL, FSH 4.2 mIU/mL), testosterone 96 ng/dL (reference range <50 ng/dL), free testosterone 2.21 ng/dL (reference range <1.09 ng/dL), normal glucose, and HbA1c of 5.6%. She received a diagnosis of polycystic ovary syndrome (PCOS) and was referred to our Multi-Specialty Adolescent PCOS Program. There, oral glucose tolerance test showed fasting glucose and insulin of 80 mg/dL and 63.1 mIU/mL, respectively. The 2-hour glucose and insulin were 199 mg/dL and 1480 μIU/mL, respectively. Because of hyperandrogenism with severe IR, dysglycemia, and normal lipids, type A IR was considered. Genetic testing revealed a heterozygous mutation in the insulin receptor gene [c.3095G>A(pGly1032Asp)]. After standard treatment of hirsutism and hyperinsulinism failed, a trial of GnRH agonist therapy improved hyperandrogenism and reduced ovarian size while severe IR persisted. We describe an adolescent with type A IR who experienced resolution of clinical and biochemical hyperandrogenism during GnRH agonist treatment. Given the patient’s marked reduction in testosterone and hirsutism despite persistent hyperinsulinism, this case challenges the idea that insulin increases steroidogenesis independently of gonadotropin effect. GnRH agonist therapy should be considered in the treatment of hyperandrogenism in severe cases of IR.\n\nadolescentGnRHhyperandrogenisminsulin resistanceleuprolideKatherine Berry Richardson GrantP20MD000198- MT\n==== Body\nType A insulin resistance (IR) is severe IR caused by heterozygous mutations in the insulin receptor gene. It presents after puberty with acanthosis nigricans, IR, and hyperandrogenism [1]. Hyperandrogenism in type A IR may result from insulin acting as a cogonadotropin directly increasing androgen synthesis in theca cells via ovarian insulin receptor signaling [2] or indirectly by increasing GnRH-mediated LH release from the pituitary [3]. Clinical hyperandrogenism is a concern for patients, yet there are limited data on treatment options in severe IR syndromes. In a recently published case of type B insulin resistance masquerading as ovarian hyperthecosis, GnRH agonist treatment curtailed hyperandrogenism without ameliorating diabetes [4]. Similarly, we describe an adolescent patient with type A IR who demonstrated resolution of hyperandrogenism during GnRH agonist treatment while severe IR persisted. This case challenges the notion that insulin increases steroidogenesis independently of gonadotropins.\n\n1. Case Presentation\nA 16-year-old Hispanic–African American girl presented with secondary amenorrhea and hirsutism. She attained menarche at age nine with normal cycles until age 13, when menstrual cycles ceased. At age 14, she noticed increased facial hair necessitating daily waxing of her upper lip and chin. Measurements revealed a normal body mass index (BMI) of 23.7 kg/m2. Physical examination was unremarkable except for an elevated Ferriman-Gallwey hirsutism score of 24 and mild acanthosis nigricans. After exclusion of other endocrinopathies, elevated testosterone (Table 1) and secondary amenorrhea led to the diagnosis of polycystic ovary syndrome (PCOS). The patient was subsequently evaluated at the multispecialty adolescent PCOS program 1 month later. Her testosterone levels continued to rise, and a transabdominal ultrasound revealed normal ovarian morphology (based on adult criteria) and no evidence of malignancy. Oral glucose tolerance test (OGTT) showed impaired glucose tolerance (IGT) and a substantially elevated 2-hour insulin level of 1480 μIU/mL (Table 1). Despite prominent IR, her lipid profile was favorable. She was prescribed metformin and a course of medroxyprogesterone to induce withdrawal bleeding.\n\nTable 1. Clinical and Laboratory Evaluation of an Adolescent Girl With an Insulin Receptor Gene Mutation\n\n\tInitial Presentation\t1-mo Follow-Up\t5-mo Follow-Up\t9-mo Follow-Up\t12-mo Leuprolide Initiated\t13-mo Follow-Up\t17-mo Follow-Up\tReference Range\t\nReproductive markers\t\t\t\t\t\t\t\t\t\n Total testosterone, ng/dL\t96\t142\t99\t139\t\t7\t22\t<50\t\n Free testosterone, ng/dL\t2.2\t3.6\t2.7\t3.1\t\t0.2\t\t<1.09\t\n Androstenedione, ng/dL\t\t\t258\t\t\t\t\t80–240\t\n DHEA, ng/dL\t415\t\t\t\t\t\t\t39–481\t\n DHEAS, μg/dL\t\t\t133\t\t\t\t\t50–540\t\n 17-OHP, ng/dL\t178\t\t146\t\t\t\t\t20–265\t\n LH, mIU/mL\t11.6\t12.1\t9.4\t12.7\t\t0.3\t1.0\t—\t\n FSH mIU/mL\t4.2\t4.1\t4.2\t4.5\t\t2.0\t\t—\t\n Ovarian volume, cm3\t\t\t\t\t\t\t\t\t\n Right ovary\t\t5.0\t\t10.6\t\t\t4.4\t10\t\n Left ovary\t\t8.9\t\t8.8\t\t\t5.7\t10\t\n Follicle number per ovary\t\t\t\t\t\t\t\t\t\n Right ovary\t\t18\t\t\t\t\t26\t—\t\n Left ovary\t\t20\t\t\t\t\t18\t—\t\n Follicle number per section\t\t\t\t\t\t\t\t\t\n Right ovary\t\t7\t\t6\t\t\t10\t9\t\n Left ovary\t\t8\t\t19\t\t\t10\t9\t\n Endometrial thickness, cm\t\t0.6\t\t0.7\t\t\t0.6\t1.0\t\nMetabolic markers\t\t\t\t\t\t\t\t\t\n Random cortisol, μg/dL\t\t\t4.7\t\t\t\t\t—\t\n HbA1c, %\t\t5.6\t5.5\t5.4\t\t5.8\t6.4\t<6\t\n OGTT 0-min glucose, mg/dL\t\t80\t\t\t\t84\t91\t<100\t\n OGTT 2-h glucose, mg/dL\t\t199\t\t\t\t159\t181\t<140\t\n OGTT 0-min insulin, μIU/mL\t\t63.1\t\t\t\t397.0\t90.9\t—\t\n OGTT 2-h insulin, μIU/mL\t\t1480\t\t\t\t1326\t1038\t—\t\nTable provides laboratory and transabdominal ultrasound results for the patient at initial presentation and throughout the treatment course at each of her follow-up visits. The shaded column demonstrates the initiation of leuprolide at the patient’s 12-mo follow-up visit, and in the columns to the right (13-mo and 17-mo follow-up visits) she continues on leuprolide treatment. Reference ranges are reported when available based on internal assays.\n\nAbbreviations: DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; 17-OHP, 17-hydroxyprogesterone.\n\nBecause of hyperandrogenism with severe IR, dysglycemia, and favorable lipid profile, type A and type B IR syndromes were considered. Genetic testing revealed a heterozygous mutation in the insulin receptor gene for a missense variant designated c.3095G>A(pGly1032Asp), pointing toward the diagnosis of type A IR.\n\nFive months from initial presentation, the patient reported variable metformin adherence. The medroxyprogesterone challenge had triggered vaginal bleeding for 1 week, but no further cycles had occurred. Facial hair returned by noon after her morning shave and depilation, so spironolactone was added to her treatment. Elevated LH and testosterone levels persisted, and additional androgen levels were measured to rule out other endocrinopathies (Table 1).\n\nNine months after the initial presentation, she still was nonadherent to metformin, had not started spironolactone, and was on her second month of oral contraceptive pill (OCP), which had been started by her primary care physician to induce cyclic bleeding. Hirsutism remained a major concern, and the patient’s mood had worsened to prominent depression. Laboratories showed prominent hyperandrogenemia despite OCP therapy (Table 1). Repeat transabdominal ultrasound revealed an unchanged left ovary and a substantial increase in right ovarian size that was not attributed to a dominant follicle, recent ovulation, or ovarian mass. Sonographic findings related to ovarian size (Table 1) now met the definition of polycystic ovarian morphology (PCOM) based on the recent international guidelines for PCOS in adults [5]. Twelve months after the initial presentation, the team decided to start leuprolide 11.25 mg/mo intramuscular injections to improve treatment adherence and hyperandrogenism while potentially yielding a secondary benefit on insulin resistance.\n\nOne month after leuprolide-induced LH suppression (13-month follow-up, Table 1), dramatic testosterone reduction and hirsutism improvement were noted, but the patient complained of hot flashes, so OCP was restarted. Seventeen months from initial presentation (5 months after leuprolide was started), repeat OGTT still showed IGT and severe IR along with increased HbA1c (Table 1). Ovarian size had decreased substantially in both ovaries, no longer meeting the definition of PCOM (Table 1). Endometrial thickness was normal and unchanged (<1.0 cm, Table 1). Of note, the patient had discontinued OCP after only 1 month.\n\n2. Discussion\nWe describe a case of an adolescent girl with type A IR whose severe hirsutism and biochemical hyperandrogenism were successfully managed on GnRH agonist therapy, despite extreme hyperinsulinemia. Our patient’s dysglycemia and extreme hyperinsulinemia led to genetic testing, which revealed a mutation in the insulin receptor gene [c.3095G>A(pGly1032Asp)]. Although the direct causality cannot be proven, we suspect the mutation is pathogenic because it fits the patient’s clinical picture of type A IR and was not present in the asymptomatic mother’s genetic testing (asymptomatic father not available for testing). The amino acid residue pGly1032 is highly conserved during evolution, and no missense variants at this codon have previously been reported. Yet other heterozygous missense variants in this domain have been reported pathogenic in severe IR [6].\n\nThis case allowed us to examine the frequently debated bidirectional relationship between insulin and hyperandrogenism, often deemed independent of gonadotropin activity. Insulin can act directly on theca cells to drive testosterone production [3]. Even in patients with insulin receptor defects, ovarian sensitivity to insulin remains conserved. It is postulated that excess insulin activates the similarly structured IGF-1 receptors, leading to ovarian hyperandrogenism [7]. Therefore, in the case of severe IR syndromes, we may expect hyperandrogenism to persist even after the gonadotropin stimulus is suppressed. However, our case showed clinical and biochemical hyperandrogenism that responded dramatically to leuprolide despite persistent hyperinsulinism. Our case suggests that LH is necessary to facilitate insulin’s action on steroidogenesis even in severe IR due to a defective insulin receptor. A similar conclusion was drawn in the aforementioned case by Brown et al. [4], which demonstrated the permissive effect of LH in a patient with autoimmune type B IR. Hyperandrogenemia itself can lead to IR, but data are inconsistent on the impact of decreasing androgens in improving insulin sensitivity [3]. Some patients with PCOS and mild IR have shown modest improvements in insulin sensitivity during androgen suppression with GnRH agonists [8]. In our case, prominent IR persisted after marked testosterone suppression.\n\nOf note, our patient’s diagnosis of severe IR would have been missed if OGTT had not been performed. OGTT is not routinely performed in the setting of normal HbA1c, fasting glycemia, and BMI. Supported by previous findings of abnormal glucose tolerance in nonobese adolescents with hyperandrogenism [9], we argue OGTT should be considered in all patients with hyperandrogenism.\n\nThe utility of transabdominal ultrasound for the evaluation of adolescent reproductive health is controversial [5]. There has been some support for use of ovarian size measurement (reviewed in 10]). However, the relevance of follicle counts has remained questionable because of a lack of normative data during adolescence as gathered via modern ultrasound technology. We observed an increase in ovarian volume meeting the adult definition of PCOM in association with persistent hyperandrogenism. Normalization of ovarian volume occurred with resolution of hyperandrogenism. This observation is consistent with ovarian size reflecting hyperandrogenism in adolescents [10]. Transabdominal ultrasound may be helpful in monitoring progression or resolution of hyperandrogenism, particularly in cases where access to reliable biochemical assays is limited.\n\nIn conclusion, we present a case of an adolescent with a mutation in the insulin receptor gene whose hyperandrogenism responded to GnRH agonist therapy. Her persistent, severe IR brings into question the mechanism of insulin causing hyperandrogenism independently of LH. GnRH agonist therapy may be helpful in cases of severe IR syndromes with distressing hirsutism when other modalities are unsuccessful.\n\nAcknowledgments\n\nFinancial Support: Katherine Berry Richardson grant, Children’s Mercy Hospital, Kansas City; National Institutes of Health (P20MD000198-MT, to T.S.B.).\n\n\nDisclosure Summary: The authors have nothing to disclose.\n\nAbbreviations:\nBMIbody mass index\n\nIGTimpaired glucose tolerance\n\nIRinsulin resistance\n\nOCPoral contraceptive pill\n\nOGTToral glucose tolerance test\n\nPCOMpolycystic ovarian morphology\n\nPCOSpolycystic ovary syndrome\n==== Refs\nReferences and Notes\n1. \nSemple RK , Savage DB , Cochran EK , Gorden P , O’Rahilly S \nGenetic syndromes of severe insulin resistance . Endocr Rev . 2011 ;32 (4 ):498 –514 .21536711 \n2. \nFranks S , Gilling-Smith C , Watson H , Willis D \nInsulin action in the normal and polycystic ovary . Endocrinol Metab Clin North Am . 1999 ;28 (2 ):361 –378 .10352923 \n3. \nDiamanti-Kandarakis E , Dunaif A \nInsulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications . Endocr Rev . 2012 ;33 (6 ):981 –1030 .23065822 \n4. \nBrown RJ , Joseph J , Cochran E , Gewert C , Semple R , Gorden P \nType B insulin resistance masquerading as ovarian hyperthecosis . J Clin Endocrinol Metab . 2017 ;102 (6 ):1789 –1791 .27911591 \n5. \nTeede HJ , Misso ML , Costello MF , Dokras A , Laven J , Moran L , Piltonen T , Norman RJ ; International PCOS Network . Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome . Hum Reprod . 2018 ;33 (9 ):1602 –1618 .30052961 \n6. \nImamura T , Takata Y , Sasaoka T , Takada Y , Morioka H , Haruta T , Sawa T , Iwanishi M , Hu YG , Suzuki Y , et al \nTwo naturally occurring mutations in the kinase domain of insulin receptor accelerate degradation of the insulin receptor and impair the kinase activity . J Biol Chem . 1994 ;269 (49 ):31019 –31027 .7983039 \n7. \nMusso C , Cochran E , Moran SA , Skarulis MC , Oral EA , Taylor S , Gorden P \nClinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective . Medicine (Baltimore) . 2004 ;83 (4 ):209 –222 .15232309 \n8. \nElkind-Hirsch KE , Valdes CT , Malinak LR \nInsulin resistance improves in hyperandrogenic women treated with Lupron . Fertil Steril . 1993 ;60 (4 ):634 –641 .8405516 \n9. \nFlannery CA , Rackow B , Cong X , Duran E , Selen DJ , Burgert TS \nPolycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMI . Pediatr Diabetes . 2013 ;14 (1 ):42 –49 .22925367 \n10. \nRackow BW , Vanden Brink H , Hammers L , Flannery CA , Lujan ME , Burgert TS \nOvarian morphology by transabdominal ultrasound correlates with reproductive and metabolic disturbance in adolescents with PCOS . J Adolesc Health . 2018 ;62 (3 ):288 –293 .29217212\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2472-1972",
"issue": "3(6)",
"journal": "Journal of the Endocrine Society",
"keywords": "GnRH; adolescent; hyperandrogenism; insulin resistance; leuprolide",
"medline_ta": "J Endocr Soc",
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"nlm_unique_id": "101697997",
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"pages": "1196-1200",
"pmc": null,
"pmid": "31187077",
"pubdate": "2019-06-01",
"publication_types": "D002363:Case Reports",
"references": "10352923;15232309;21536711;22925367;23065822;27911591;29217212;30052961;7983039;8405516",
"title": "GnRH Agonist Improves Hyperandrogenism in an Adolescent Girl With an Insulin Receptor Gene Mutation.",
"title_normalized": "gnrh agonist improves hyperandrogenism in an adolescent girl with an insulin receptor gene mutation"
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