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"abstract": "M. abscessus complex prosthetic joint infections (PJI) of the knee are rare. We present a patient with an M. abscessus subsp. massiliense, a nontuberculous mycobacterium (NTM), peri-prosthetic knee infection who presented with wound drainage followed by sepsis. The published peer-reviewed literature on knee PJIs due to this organism is reviewed to highlight its clinical presentation,symptomatology, microbiology, surgical interventions, antimicrobial regimens, and outcomes.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic, Jacksonville, Florida, USA.;Division of Infectious Diseases, Mayo Clinic, Jacksonville, Florida, USA.;Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, Florida, USA.;Division of Allergy, Mayo Clinic, Jacksonville, Florida, USA.;Division of Infectious Diseases, Mayo Clinic, Jacksonville, Florida, USA.",
"authors": "Nengue|Lydie|L|;Diaz|Mark Anthony A|MAA|;Sherman|Courtney E|CE|;Bhasin|Arveen|A|;Libertin|Claudia R|CR|",
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"fulltext": "\n==== Front\nJ Bone Jt InfectJ Bone Jt InfectjbjiJournal of Bone and Joint Infection2206-3552Ivyspring International Publisher Sydney 10.7150/jbji.36286jbjiv04p0223Case ReportMycobacterium abscessus Prosthetic Joint Infections of the Knee Nengue Lydie 1Diaz Mark Anthony A. 1Sherman Courtney E. 2Bhasin Arveen 3Libertin Claudia R. 1✉1 Division of Infectious Diseases, Mayo Clinic, Jacksonville, Florida, USA2 Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, Florida, USA3 Division of Allergy, Mayo Clinic, Jacksonville, Florida, USA✉ Corresponding author: Claudia R. Libertin, MD, CPE. Professor of Medicine, Division of Infectious Diseases, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, USA, Tel: 904-953-2390; Fax 904-953-0017, [email protected] Interests: The authors have declared that no competing interest exists.\n\n2019 25 9 2019 4 5 223 226 14 1 2019 4 5 2019 © The author(s)2019This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.M. abscessus complex prosthetic joint infections (PJI) of the knee are rare. We present a patient with an M. abscessus subsp. massiliense, a nontuberculous mycobacterium (NTM), peri-prosthetic knee infection who presented with wound drainage followed by sepsis. The published peer-reviewed literature on knee PJIs due to this organism is reviewed to highlight its clinical presentation,symptomatology, microbiology, surgical interventions, antimicrobial regimens, and outcomes.\n\nMycobacterium abscessusProsthetic Joint InfectionsKnee ArthroplastyRapidly Growing MycobacteriaNon-tuberculous mycobacterium.\n==== Body\nIntroduction\nM. abscessus subsp. massiliense is a member of the Rapidly Growing Mycobacteria (RGM). RGM-infections propose a diagnostic and therapeutic challenge to clinicians because of the organism's growth rate, lack of isolation on routine bacterial cultures, and unique resistance to most traditional anti-tuberculous agents. Post-traumatic non-healing wound infections with poor response to broad-spectrum antibiotics should alert physicians to consider the presence of a non-tuberculous mycobacterial (NTM) disease. The backbone therapy, if susceptible, is a macrolide antibiotic. Infected hardware removal is essential for cure. Patients should also be aware of the complexity of the treatment course that includes prolonged antimicrobial therapy and many associated adverse drug reactions.\n\nCase Presentation\nAn 82-year-old Caucasian male with degenerative joint disease and hypertension presented with progressive right knee pain. He underwent a right total knee arthroplasty (TKA) after failed multiple trials of local steroid injections to alleviate pain and swelling. His surgery was complicated by poor wound healing, joint swelling, and drainage from the surgical site as early as the first week post-TKA. He developed a fever higher than 102°F, hypotension of 90/62mm Hg, and syncope after 7 weeks post-TKA requiring emergent hospitalization and fluid resuscitation. Vancomycin (1 g every 12 hours IV) and cefepime (2 g every 8 hours IV) were empirically started. Debridement and implant retention (DAIR) for the infected TKA occurred. After a week, 3 out of 3 intraoperative synovial fluid cultures yielded Mycobacterium abscessus subsp. massiliense. Susceptibilities were sent to the National Jewish Health in Denver, Colorado (Table 1, Isolate #1). A two-drug combination with Azithromycin 500 mg oral daily and Cefoxitin 3 g every 6 hours IV was started. Cefoxitin was discontinued after two weeks due to drug rash; Tigecycline (50 mg IV daily after 100 mg loading dose) replaced Cefoxitin. He was maintained on the two-drug regimen (Azithromycin and Tigecycline) for approximately three months after which he was placed on chronic suppressive therapy of oral Ciprofloxacin 750 mg once daily.\n\nDue to persistent severe knee pain, he self-referred to our institution for an infectious diseases consultation. At that time, all antibiotics were stopped. Allergology service was consulted to determine if Cefoxitin re-challenge would be an option, and surgery was consulted for a diagnostic arthrocentesis. M. abscessus subsp. massiliense was isolated after 19 days on BBL Mycobacteria Growth Indicator Tube and Remel Middlebrook 7H11/Mitchison 7H11 Selective Biplate agar. The isolate was identified as Mycobacterium abscessus group using MALD-TOF platform (Table 1, Isolate #2). He declined immediate two-stage revision for the infected TKA, but opted to take oral Azithromycin (500 mg daily orally) suppressive monotherapy to attend a major life event. (Figure 1)\n\nAfter 2 months on Azithromycin, he underwent the initial part of the two-stage revision arthroplasty beginning with hardware removal and placement of an antibiotic impregnated static cement spacer (10 g of amikacin per Simplex P 80 grams). Intraoperative cultures yielded the same organism. (Table 1, Isolate #3) An audiogram done before initiating treatment documented a baseline sensorineural hearing loss, which never worsened during his 8 month antimicrobial therapy. A three-drug regimen consisted of 2 parenteral antibiotics (Tigecycline 50 mg daily and Amikacin 25 mg/kg three times weekly) with oral Azithromycin 500 mg daily. Gastrointestinal symptoms and syncope limited tigecycline use while Cefoxitin was complicated by the recurrence of rash and resistance on susceptibilities. Linezolid 600 mg oral twice daily with dosing adjustments made to as low as 300 mg daily to keep platelet levels above > 100,000 per microliter replaced Cefoxitin. Linezolid (300 mg oral daily) and Azithromycin (500 mg oral daily) were continued for two more months to complete a total duration of eight months of antimicrobial therapy post-hardware removal. Complete blood count, creatinine, liver function test, sedimentation, C-Reactive protein and amikacin drug levels (peaks/troughs) were monitored twice weekly with periodic audiometry testing throughout the duration of therapy.\n\nRepeat arthrocentesis and cultures for bacteria, fungi, and mycobacteria done after three months of completion of all antimicrobials yielded no growth. Follow-up of ESR and CRP showed a greater than 5-fold decline from original values. Four sets of intra-operative cultures during TKA re-implantation a month after the repeat arthrocentesis were negative for the NTM-infection (NTMI). There was no evidence of microbiological and clinical relapse of the NTMI after more than 6-months of follow-up.\n\nDiscussion\nNTM species are ubiquitous organisms found in the environment. The source of the bacterium was not identified in this case, but the two possible sources of infection are his prior corticosteroid injections or initial TKA surgery. The use of contaminated injections inoculation during the process of mixing the steroids, or upon the injection procedure have been reported sources of joint and cutaneous infections for NTMI.1 Contamination during the procedure or early post-op soilage of surgical field, application of infected prosthesis, use of contaminated water, or shedding from transient NTM colonization can all be other causes of an NTMI.2 In an investigation of an outbreak of NTM PJI in Oregon from 2010 - 2016, infections were even associated with the presence of a surgical instrument representative present in the operating room during the procedures.3\n\nReview of the literature 4-9 yields a total of 7 additional cases of M. abscessus PJI of the knee (Table S1). The clinical presentations of RGM PJIs are similar to musculoskeletal NTMI of the lower extremities where subacute arthritis may progress to osteomyelitis.10 All 8 cases (Table S1 in Supplementary Material) were greater than 60 years of age and female (median age 71 years; range 48-83 years) except case 8. All patients were normal hosts. The time interval between the prosthesis implantation and the onset of symptoms varied tremendously, ranging from days to 3 years (median = 24 weeks). As reported by Diaz et al10., there is a gap in the interval between symptom presentation and diagnosis of NTMI in lower extremities that was evident also with PJIs. The main reasons for the diagnostic delay were nonspecific characteristics of infection, lack of familiarity with NTMI, and lack of clinical suspicion of NTMI until the infection does not resolve after antimicrobials. Two cases are early onset PJIs, and five are delayed PJI of the knee. One patient died in hospice. Of note, cases before 2013 may not be counted in this review based on changes made to the classification and nomenclature of the M. abscessus complex between 1992 and 2013. Previously, M. abscessus and M. chelonae were considered a single specie, but M. abscessus was reclassified as an individual specie in 2002.10 The distinction between closely related species such as M. chelonae and M. abscessus complex relied on phenotypic differences, which were few. Consequently, the number of cases before 2013 may be impacted by nomenclature changes.\n\nAlthough unusual, septic arthritis with the development of concurrent systemic sepsis has been associated with poor outcomes in terms of infection recurrence and arthritis progression.11 Debridements of TKA without hardware removal can lead to treatment failure and longer durations of therapy. Antimicrobial treatment regimens are complex and directed by susceptibility data, when available. Of note, M. abscessus complex is typically resistant to most antimicrobial agents. The Clinical and Laboratory Standards Institute recommends testing RGM for susceptibility to various antimicrobials such as those listed in Table 1. Amikacin, Cefoxitin, and Clarithromycin have the best in-vitro antimycobacterial activity and are commonly used in the cases. Macrolides are the cornerstone of treatment and were used throughout the eight months of therapy (Figure 1) in our case. Isolates of M. abscessus subsp. abscessus may have resistant MICs after extended incubation, which is the result of an inducible methylase gene erm(41) which confers macrolide resistance.12 Therefore, testing of clinically significant isolates of RGM for erm(41) gene inducibility for 14 days for Clarithromycin at a reference laboratory is indicated. Clofazimine is a second-line alternative used for MDR-TB (Multi Drug Resistant-Tuberculosis) and other NTMI. None of the PJI cases used clofazimine. Novartis no longer has an Expanded Access Program for NTM infections.\n\nThe recommended duration of therapy for osteoarticular NTMI is 6 to 12 months.10 Table S1 notes the various lengths of combination antimicrobials given for M. abscessus knee PJIs. Our case demonstrates that post-TKA-resection, 8 months of therapy was curative. A two-staged orthopedic procedure combined with negative cultures following a 2-month antimicrobial holiday is advised before re-implantation. With hardware removal and prolonged antimicrobial therapy, all cases clinically and microbiologically were cured of M. abscessus PJI.\n\nIn conclusion, NTM PJI is an emerging infectious disease. Diagnosis should be suspected especially in non-healing infections poorly responsive to broad spectrum antibiotics. Patients and clinicians should be aware that early, aggressive and prolonged interventions are keys to treatment. By the same token, clinical and drug monitoring are essential to compliance and completion of the regimen.\n\nSupplementary Material\nSupplementary Table S1.\n\nClick here for additional data file.\n\n Figure 1 Timeline of Management and Interventions for M. abscessus subsp. massiliense Knee PJI at Both Institutions\n\nTable 1 Mycobacterium abscessus subsp. massiliense susceptibility reports\n\nAntibiotic\tIsolate #1:\nMIC (ug/mL)1\tInterpretation\tIsolate #2:\nMIC\n(ug/mL)²\tInterpretation\tIsolate #3:\nMIC\n(ug/mL) 2\tInterpretation\t\nCefoxitin\t32\tI\t64\tI\t128\tR\t\nImipenem\t8\tI\t32\tR\t64\tR\t\nCiprofloxacin\t4\tR\t>4\tR\t>4\tR\t\nMoxifloxacin\t>4\tR\t8\tR\t>8\tR\t\nClarithromycin\t0.5\tS\t0.25\tS\t0.5\tS\t\nAmikacin\t16\tS\t16\tS\t16\tS\t\nTobramycin\t>16\t\t>16\tR\t>16\tR\t\nDoxycycline\t>16\tR\t>16\tR\t>16\tR\t\nMinocycline\tNot tested\t\t>8\tR\t>8\tR\t\nTigecycline\t1\tS\t0.12\t\t0.25\t\t\nTMP/SMX\t>4/76\tR\t8/152\tR\t>8/152\tR\t\nLinezolid\t>16\tR\t16\tI\t8\tS\t\nAzithromycin\t≤16\tS\tNot tested\t\tNot tested\t\t\nClofazimine\t≤0.5\tS\tNot tested\t\tNot tested\t\t\nIsolate #1: Isolate from incision and drainage of soft tissue and bone with polyethylene exchange of right knee done 2 months after original TKA\n\nIsolate #2: Isolate from arthrocentesis\n\nIsolate #3: Isolate cultured from the right knee\n==== Refs\n1 Jung SY Kim BG Kwon D Park JH Youn SK Jeon S An outbreak of joint and cutaneous infections caused by non-tuberculous mycobacteria after corticosteroid injection International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 2015 36 62 9 26026822 \n2 Buser GL LM Cassidy P Outbreak of Nontuberculous Mycobacteria Joint Prosthesis Infections, Oregon, USA, 2010-2016 Emerging Infectious Diseases 2019 25 5 849 855 31002056 \n3 Genevieve LB Matthew RL Cassidy PM Heather M-M Zintars GB Paul RC Outbreak of Nontuberculous Mycobacteria Joint Prosthesis Infections, Oregon, USA, 2010-2016 Emerging Infectious Disease journal 2019 25 849 \n4 Kim M Ha CW Jang JW Park YB Rapidly growing non-tuberculous mycobacteria infection of prosthetic knee joints: A report of two cases The Knee 2017 24 869 75 28551202 \n5 Wang SX Yang CJ Chen YC Lay CJ Tsai CC Septic arthritis caused by Mycobacterium fortuitum and Mycobacterium abscessus in a prosthetic knee joint: case report and review of literature Internal medicine (Tokyo, Japan) 2011 50 2227 32 \n6 Amit P Rastogi S Marya S Prosthetic knee joint infection due to Mycobacterium abscessus Indian journal of orthopaedics 2017 51 337 42 28566789 \n7 Eid AJ Berbari EF Sia IG Wengenack NL Osmon DR Razonable RR Prosthetic joint infection due to rapidly growing mycobacteria: report of 8 cases and review of the literature Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2007 45 687 94 17712751 \n8 Spanyer JM Foster S Thum-DiCesare JA Kwon YM Burke DW Nelson SB Mycobacterium abscessus: A Rare Cause of Periprosthetic Knee Joint Infection American journal of orthopedics (Belle Mead, NJ) 2018 47 \n9 Mushatt DM Witzig RS Successful treatment of Mycobacterium abscessus infections with multidrug regimens containing clarithromycin Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 1995 20 1441 2 7620048 \n10 Diaz MAA Huff TN Libertin CR Nontuberculous mycobacterial infections of the lower extremities: A 15-year experience Journal of Clinical Tuberculosis and Other Mycobacterial Diseases 2019 15 100091 \n11 Jung S-W Kim D-H Shin S-J Kang B-Y Eho Y-J Yang S-W Septic arthritis associated with systemic sepsis International Orthopaedics 2018 42 1 7 28717843 \n12 Nash KA Brown-Elliott BA Wallace RJ A Novel Gene, erm(41), Confers Inducible Macrolide Resistance to Clinical Isolates of Mycobacterium abscessus but Is Absent from Mycobacterium chelonae Antimicrobial Agents and Chemotherapy 2009 53 1367 19171799\n\n",
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"keywords": "Knee Arthroplasty; Mycobacterium abscessus; Non-tuberculous mycobacterium.; Prosthetic Joint Infections; Rapidly Growing Mycobacteria",
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"title": "Mycobacterium abscessus Prosthetic Joint Infections of the Knee.",
"title_normalized": "mycobacterium abscessus prosthetic joint infections of the knee"
}
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"abstract": "A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug-induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin-7.5 g dL(-1) , platelet count-20 × 10(9) /L, LDH-698 U L(-1) , creatinine-3.12 mg dL(-1) . No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348-E352, 2016. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Medicine, Mayo Clinic, Rochester, Minnesota.;Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.;Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.;Department of Clinical Therapeutics, National and Kapodistrian, University of Athens, School of Medicine, Athens, Greece.;Department of Clinical Therapeutics, National and Kapodistrian, University of Athens, School of Medicine, Athens, Greece.;Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, Missouri.;Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, Missouri.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.;Division of Hematology, Mayo Clinic, Rochester, Minnesota.",
"authors": "Yui|Jennifer C|JC|;Van Keer|Jan|J|;Weiss|Brendan M|BM|;Waxman|Adam J|AJ|;Palmer|Matthew B|MB|;D'Agati|Vivette D|VD|;Kastritis|Efstathios|E|;Dimopoulos|Meletios A|MA|;Vij|Ravi|R|;Bansal|Dhruv|D|;Dingli|David|D|;Nasr|Samih H|SH|;Leung|Nelson|N|",
"chemical_list": "D009842:Oligopeptides; D061988:Proteasome Inhibitors; D000069286:Bortezomib; C524865:carfilzomib",
"country": "United States",
"delete": false,
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"issue": "91(9)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000069286:Bortezomib; D005260:Female; D006461:Hemolysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D012189:Retrospective Studies; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "E348-52",
"pmc": null,
"pmid": "27286661",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Proteasome inhibitor associated thrombotic microangiopathy.",
"title_normalized": "proteasome inhibitor associated thrombotic microangiopathy"
}
|
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"abstract": "Fasting hypoglycemia is a known complication of mercaptopurine (6MP) maintenance therapy for acute lymphoblastic leukemia (ALL). It is associated with high levels of the methylated metabolite 6-methyl-mercaptopurine (6MMP). Symptoms of hypoglycemia include morning tremulousness, nausea and vomiting. We have previously shown that switching 6MP dosing from evening to morning resolved hypoglycemia by reducing 6MMP; however, the reduction of 6MMP was only transient, potentially resulting in return of hypoglycemia. In children and adults with Crohn's disease, co-prescribing allopurinol with 6MP blocks the activity of thiopurine methytransferase (TPMT), reducing 6MMP and improving its tolerance. As a consequence of inhibiting TPMT, 6MP is shunted toward the production of 6-thioguanine nucleotide (6TGN), which will result in pancytopenia if the dose of 6MP is not reduced. We demonstrate that allopurinol with a reduced dose of 6MP in two patients with ALL and 6MMP-associated hypoglycemia resulted in a complete and sustained suppression of 6MMP and rapid reversal of hypoglycemia and its symptoms.",
"affiliations": "University of California, Berkeley, Berkeley, CA, 94720, USA.;Department of Pediatric Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USA.",
"authors": "Zhang|Melissa|M|;Bostrom|Bruce|B|0000-0001-7974-1271",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D000493:Allopurinol; D015122:Mercaptopurine",
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"fulltext": "\n==== Front\nF1000ResF1000ResF1000ResearchF1000Research2046-1402F1000 Research Limited London, UK 3082844410.12688/f1000research.17760.2Clinical Practice ArticleArticlesAllopurinol reverses mercaptopurine-induced hypoglycemia in patients with acute lymphoblastic leukemia [version 2; peer review: 2 approved]\n\nZhang Melissa Data CurationVisualizationWriting – Original Draft Preparation1Bostrom Bruce ConceptualizationFormal Analysishttps://orcid.org/0000-0001-7974-1271a2\n1 University of California, Berkeley, Berkeley, CA, 94720, USA\n2 Department of Pediatric Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USAa [email protected] competing interests were disclosed.\n\n21 11 2019 2019 8 17612 11 2019 Copyright: © 2019 Zhang M and Bostrom B2019This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Fasting hypoglycemia is a known complication of mercaptopurine (6MP) maintenance therapy for acute lymphoblastic leukemia (ALL). It is associated with high levels of the methylated metabolite 6-methyl-mercaptopurine (6MMP). Symptoms of hypoglycemia include morning tremulousness, nausea and vomiting. We have previously shown that switching 6MP dosing from evening to morning resolved hypoglycemia by reducing 6MMP; however, the reduction of 6MMP was only transient, potentially resulting in return of hypoglycemia. In children and adults with Crohn’s disease, co-prescribing allopurinol with 6MP blocks the activity of thiopurine methytransferase (TPMT), reducing 6MMP and improving its tolerance. As a consequence of inhibiting TPMT, 6MP is shunted toward the production of 6-thioguanine nucleotide (6TGN), which will result in pancytopenia if the dose of 6MP is not reduced. We demonstrate that allopurinol with a reduced dose of 6MP in two patients with ALL and 6MMP-associated hypoglycemia resulted in a complete and sustained suppression of 6MMP and rapid reversal of hypoglycemia and its symptoms.\n\nmercaptopurineallopurinolhypoglycemiamorning nauseathiopurine methyltransferaseThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\nAdditional reference added on the first published use of allopurinol to modulate thiopurine therapy\n==== Body\nIntroduction\nMercaptopurine (6MP) maintenance therapy is critical for the cure of ALL. There is no acceptable alternative. In general, 6MP is well tolerated with minimal side-effects such as facial or generalized rash and asymptomatic elevations of hepatic transaminases. Occasionally, more serious side effects, such as direct hyperbilirubinemia, pancreatitis, and fasting hypoglycemia, may occur, requiring discontinuation or reduction in the dose of 6MP\n1.\n\nPreviously, we had shown that 6MP induced fasting hypoglycemia is related to elevated levels of red cell 6-methyl-mercaptopurine (6MMP)\n2. We also showed that altering the administration time of 6MP from evening to morning or splitting the dose to twice a day results in lower 6MMP concentrations and resolution of hypoglycemia symptoms. However, in some of the patients there was a rebound in 6MMP, which may result in recurrence of symptomatic hypoglycemia.\n\nAllopurinol has been used by gastroenterologists for many years in patients with inflammatory bowel disease who have elevations of alanine aminotransferase (ALT) or gastrointestinal symptoms from the use of 6MP or azathioprine\n3–\n6. Recently, pediatric patients with ALL have been treated with allopurinol to reduce elevated 6MMP levels resulting in pancreatitis, hepatotoxicity, or inability to get absolute neutrophil count in target range despite increasing the dose of 6MP\n7–\n9.\n\nCase series\nThe electronic medical records of two children with ALL who developed symptomatic hypoglycemia on maintenance therapy were reviewed. After an extensive risk-benefit discussion with parents, they were started on allopurinol with a reduced dose of 6MP.\n\nThiopurine metabolites were measured with a CLIA-approved test (\nwww.prometheuslabs.com). The reference values for this assay only apply to patients with inflammatory bowel disease on azathioprine or 6MP and not for ALL patients on 6MP. Unpublished data on 200 patients with ALL from day 85 of the first maintenance cycle on Children’s Oncology Group COG1922 demonstrated the 5\nth, 50\nth, and 95\nth percentiles for 6MMP are 320, 4900, and 19,000 pmol/ 8×10\n8 RBC, respectively. The 5\nth, 50\nth, and 95\nth percentiles for 6TGN are 75, 260, and 690 pmol/ 8×10\n8 RBC, respectively\n10. This two-patient case report was reviewed by Children’s Minnesota Institutional Review Board and deemed not research allowing publication.\n\nCase 1\nPatient UPN 1 is an African-American girl who was diagnosed with B-lineage ALL at age 10 years. She was enrolled on high-risk protocol Children’s Oncology Group (COG) AALL1131 (ClinicalTrials.gov Identifier:\nNCT02883049), but was taken off protocol after induction due to desire to use triple intrathecal therapy for blasts in diagnostic cytospin (CNS-2 status). Germline testing for methylene tetrahydrofolate reductase (MTHFR C667T) and thiopurine methyltransferase (TPMT) were homozygous normal.\n\nMaintenance therapy doses were started at 6MP (62 mg/m\n2/day) and MTX (15 mg/m\n2/week). On day 57 of maintenance, the dose of 6MP was increased to 75 mg/m\n2/day with no change in the methotrexate (MTX) dose. On day 73, she presented to the emergency department with shaking. Upon questioning she disclosed having episodes of morning shaking, nausea and vomiting for about a month. Serum glucose was 3.18 mmol/L (53 mg/dL). The hemoglobin A1C level was 4.9%. Thiopurine metabolites showed an extremely elevated 6MMP level of 41,000 pmol/8×10\n8 RBC and 6TGN level of 456 pmol/ 8×10\n8 RBC. She was neutropenic with absolute neutrophil count (ANC) of 0.462 × 10\n9 cells/L so oral chemotherapy was halted.\n\nOn day 98, 6MP was restarted at 30 mg/m\n2/day along with 50 mg of allopurinol given with each dose of 6MP. MTX was also restarted at the previous dose. The episodes of morning nausea, vomiting, and shakes resolved. No further episodes of hypoglycemia were seen. On day 142, the ANC was 0.29 ×10\n9 cells/L, so oral chemotherapy was halted. Subsequently the hemoglobin level fell to 57 g/L and platelets to 82,000/µl. On day 163, 6MP was restarted at 15 mg/m\n2/day with 50 mg allopurinol and the previous MTX dose, which continued to the end of therapy without interruption. MTX dose remained unchanged at 75 mg/m\n2/week and 6MP was increased to 18 mg/m\n2/day to keep ANC within the target range (0.5–2 ×10\n8/L). The patient remains in remission 24 months off therapy.\nFigure 1 contains details of oral chemotherapy doses and laboratory values.\n\nFigure 1. Treatment regimen for patient in Case 1.\nOn the horizontal axis is the day of maintenance therapy from the start to completion. On the vertical axis are the red cell thiopurine metabolite values and drug doses. Interruption in drug doses is noted by a break in the line. For graph clarity, 6-methyl-mercaptopurine (6MMP) values were divided by 100 and 6-thioguanine nucleotide (6TGN) values by 10. After introduction of allopurinol, the 6MMP levels rapidly fell to undetectable levels with stable 6TGN. Following the initial introduction of allopurinol in patient 1 the mercaptopurine (6MP) and methotrexate (MTX) doses required interruption due to neutropenia which did not recur with a dose reduction of 6MP. As expected the myelosuppression was associated with a very elevated 6TGN level.\n\nCase 2\nPatient UPN 2 is a Caucasian girl diagnosed with B-lineage ALL at 3 years of age. Genotyping for TPMT was normal and MTHFR C677T was heterozygous. She was enrolled on the standard risk protocol COG AALL0932 (ClinicalTrials.gov Identifier:\nNCT01190930) and removed from the protocol when allopurinol was started.\n\nAround day 124 of maintenance, she had problems with morning vomiting daily. She had been on full dose 6MP (75 mg/m\n2/day) and MTX (20 mg/m\n2/week) since the start of maintenance with no interruptions. On day 229, she was diagnosed steroid-induced hyperglycemia with rebound hypoglycemia. Hemoglobin A1C was normal. Home glucose monitoring was started. Glucose levels were noted to be elevated after completion of a 5-day dexamethasone pulse. Metformin 500 mg extended release every morning was started with a subsequent dexamethasone pulse on day 255, with the resolution of steroid induced hyperglycemia. However symptomatic hypoglycemia continued.\n\n Thiopurine metabolite levels were drawn, which showed an extremely high 6MMP level (32,718 pmol/8×10\n8 RBC) with a 6TGN level of 182 pmol/8×10\n8 RBC. She then was switched to morning dosing of 6MP, based on prior publication\n2. She continued to have symptoms of morning hypoglycemia, which was confirmed on five low serum glucose values over a 40-day period (values of 46, 44, 42, 37, and 36 mg/dL = 2.8, 2.7, 2.6, 2.5, 2.2, and 2.2 mmol/L).\n\nAfter extensive discussion with the parents concerning the risks and benefits of the treatment, she was taken off COG 0932 protocol per physician preference and started on allopurinol 50 mg daily with reduced dose 6MP (12 mg/m\n2/day) and MTX (11 mg/m\n2/day) on day 316 of maintenance. Within 2 weeks she had no hypoglycemia symptoms and no low glucose values on home testing. On day 392 the doses were increased to 6MP (20 mg/m\n2/day and MTX (17 mg/m\n2/week) to keep ANC in the target range (0.5-2 × 10\n8/L). Metformin was continued for 5 months during dexamethasone pulses. Metformin was omitted the last 5 months of maintenance, without rebound hyperglycemia, which was completed on day 547. She remains in remission 24 months off therapy.\nFigure 2 contains details of oral chemotherapy doses and laboratory values.\n\nFigure 2. Treatment regimen for patient in Case 2.\nOn the horizontal axis is the day of maintenance therapy from the start to completion. On the vertical axis are the red cell thiopurine metabolite values and drug doses. For graph clarity, 6-methyl-mercaptopurine (6MMP) values were divided by 100 and 6-thioguanine nucleotide (6TGN) values by 10. After introduction of allopurinol, the 6MMP levels rapidly fell to undetectable levels with stable 6TGN. Of note the high glucose values during dexamethasone pulses resolved after introduction of metformin on day 255.\n\nDiscussion\n6MP is a pro-drug that is metabolized in nucleated cells to form 6TGN, which is felt to be the active anti-leukemic metabolite. Alternatively, 6MP can also undergo oxidation through a pathway catalyzed by xanthine oxidase/dehydrogenase and aldehyde oxidase to form thiouric acid, which is excreted in urine. It is also metabolized in nucleated cells by TPMT, producing 6MMP. In patients with inflammatory bowel disease, high levels of 6MMP (>5300 pmol/8×10\n8 RBCs) have been associated with hepatotoxicity, decreased therapeutic efficacy, and symptoms of hypoglycemia\n11.\n\nPreviously we showed that switching 6MP from evening to morning administration reduced elevated 6MMP levels and resolved symptomatic hypoglycemia\n2. The mechanism of this effect is not fully known, but the most reasonable interpretation is inhibition of TPMT activity. The current study is an extension of that observation, showing that co-administration of a low dose allopurinol (50 mg) once a day with a reduced dose of 6MP (~20 mg/m\n2/day) also resolves 6MMP-induced symptomatic hypoglycemia without any rebound of 6MMP levels, as we saw with switching the administration time of 6MP. A reduction in the dose of 6MP is needed because on average the 6MMP to 6TGN ratio during ALL maintenance is approximately 25 to 1, per unpublished data from the COG9506 study\n12.\n\nApproximately 90% of people, including the patients in this study, have wild-type\nTPMT, the genotype responsible for high levels of TPMT activity. These patients require higher doses of 6MP to reach therapeutic levels of 6TGN. It is unknown what proportion of these patients will develop the symptoms related to elevated 6MMP\n8.\n\nAllopurinol was first developed by Gertrude Elion to potentiate the therapeutic index of oral 6MP for treatment of leukemia. Albeit allopurinol stimulated the anti-tumor activity of 6MP, it was associated with increased hematologic toxicity. Allopurinol use with 6MP was abandoned in the 1960s and fell into the niche of managing gout. However, our data shows success of co-prescription of allopurinol to reverse hypoglycemia in children with ALL by reducing 6MMP\n13.\n\nSeinen\net al. demonstrated that allopurinol inhibited xanthine oxidase/dehydrogenase and increased hypoxanthine guanine phosphoribosal transferase in blood samples from patients taking 6MP who were started on allopurinol\n14. Notably, they did not show change in TPMT activity but did show a slight increase in 6TGN and significant decrease in 6MMP. However, Blaker\net al. demonstrated inhibition of TPMT by a metabolite of allopurinol thioxanthine (2-hydroxymercaptopurine)\nin vitro\n11. Our data shows that the same mechanism of allopurinol to inhibit TPMT to treat hepatotoxicity in IBD can be applied to reverse symptoms of hypoglycemia by lowering 6MMP levels. Both patients exhibited a reduction of 6MMP to undetectable levels following co-prescription of allopurinol with 6MP.\n\nOf concern is the theoretical possibility that reducing production of 6MMP may have a negative effect on leukemia therapy. An\nin vitro study with MOLT-4 ALL cells showed that knocking down TPMT expression did not affect sensitivity to 6MP, and that increasing the 6MMP to 6TGN ratio in the MOLT-4 ALL cell line by adding S-adenosylmethionine (SAM) decreases cytotoxicity of 6MP\n15,\n16. These two prior studies suggest 6MMP is not an active metabolite in the treatment of leukemia. However, another\nin vitro study showed that transfection with\nTPMT gene increased sensitivity to 6MP in human CCRF-CEM cell lines, probably through inhibition of\nde novo purine synthesis by methylmercaptopurine nucleotide\n17. To our knowledge, no studies on animals or humans, including currently unpublished results from the COG1922/B925 study, have demonstrated a correlation of intracellular levels of 6MMP with a decrease in ALL relapse. Thus, we are left with conflicting\nin vitro data and no patient data suggesting that 6MMP is necessary to cure ALL. Indeed, when prescribed by itself, allopurinol is also known to inhibit\nde novo purine synthesis, similar to the effect of 6MMP, suggesting it may have anti-leukemic effects. Following the submission of our manuscript the senior author reviewed for publication a two patient report further confirming our observations\n18. In our opinion, the benefit of preventing symptomatic 6MMP-induced hypoglycemia, and the likely reduction or omission of 6MP, outweighs the unproven theoretical possibility of interfering with ALL therapy.\n\nWe recently became aware of the first reported use of allopurinol to modulate thiopurine therapy. They used a reduced dose of azathioprine as part of a combination immunosuppressive regimen for cadaveric renal transplant. The addition of allopurinol to the three drug combination of azathiopurine, cyclosporine and prednisolone reduced rejection episodes from 73% in historical controls to 8% without excessive bone marrow toxicity\n19.\n\nData availability\nDeidentified clinical values for each patient by day are available on figshare. DOI:\nhttps://doi.org/10.6084/m9.figshare.7666409\n20.\n\nData are available under the terms of the\nCreative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nConsent\nWritten informed consent for publication of their clinical details was obtained from the parents of the patients.\n\n10.5256/f1000research.19418.r44317Reviewer response for version 1 Rytting Michael E. 1Referee\n1 Departments of Pediatrics and Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA\nCompeting interests: No competing interests were disclosed.\n\n26 2 2019 Copyright: © 2019 Rytting ME2019This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapproveThis report on two patients with hypoglycemia and increased 6MMP provides an interesting discussion of management of this unusual but significant problem. The description of the use of allopurinol along with the biochemical rationale for using the drug is very helpful, and should be of value to pediatric hematologists. The discussion, including the possibility of altering the effectiveness of chemotherapy, is fair and balanced, as well.\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.19418.r44316Reviewer response for version 1 O'Brien Maureen 12Refereehttps://orcid.org/0000-0002-9054-4321\n1 Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA\n2 University of Cincinnati School of Medicine, Cincinnati, OH, USA\nCompeting interests: No competing interests were disclosed.\n\n20 2 2019 Copyright: © 2019 O'Brien M2019This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapproveThe authors provide an interesting report of the use of allopurinol to decrease 6-MMP levels and ameliorate 6MP-induced hypoglycemia. Their experience in these two cases is supported by other recent case reports with similar results. This article provides good background and discussion of the mechanism, as well as guidance regarding the risks of myelosuppression with this therapy and the need for 6MP dose reduction and close monitoring. \n\n The authors should review the therapy details closely, particularly related to dosing. For patient #1 they state that the methotrexate dose was 75mg/m\n2 which is clearly a typo, but draws into question if other doses provided are correct.\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n==== Refs\n1 \nSchmiegelow K Nielsen SN Frandsen TL :\nMercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. \nJ Pediatr Hematol Oncol. \n2014 ;36 (7 ):503 –517 .\n10.1097/MPH.0000000000000206 \n\n24936744 \n2 \nMelachuri S Gandrud L Bostrom B :\nThe association between fasting hypoglycemia and methylated mercaptopurine metabolites in children with acute lymphoblastic leukemia. \nPediatr Blood Cancer. \n2014 ;61 (6 ):1003 –1006 .\n10.1002/pbc.24928 \n24415675 \n3 \nSparrow MP Hande SA Friedman S :\nAllopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. \nAliment Pharmacol Ther. \n2005 ;22 (5 ):441 –446 .\n10.1111/j.1365-2036.2005.02583.x \n16128682 \n4 \nSmith MA Blaker P Marinaki AM :\nOptimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. \nJ Crohns Colitis. \n2012 ;6 (9 ):905 –912 .\n10.1016/j.crohns.2012.02.007 \n22386736 \n5 \nMin MX Weinberg DI McCabe RP :\nAllopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use. \nJ Clin Pharm Ther. \n2014 ;39 (2 ):107 –111 .\n10.1111/jcpt.12125 \n24438369 \n6 \nIhekweazu FD Kellermayer R :\nAllopurinol: a useful adjunct to thiopurine therapy for pediatric ulcerative colitis in the biologic era. \nJ Pediatr Gastroenterol Nutr. \n2014 ;59 (1 ):22 –24 .\n10.1097/MPG.0000000000000344 \n24590210 \n7 \nZerra P Bergsagel J Keller FG :\nMaintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis. \nPediatr Blood Cancer. \n2016 ;63 (4 ):712 –715 .\n10.1002/pbc.25841 \n26878433 \n8 \nGiamanco NM Cunningham BS Klein LS :\nAllopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity. \nJ Pediatr Hematol Oncol. \n2016 ;38 (2 ):147 –151 .\n10.1097/MPH.0000000000000499 \n26808368 \n9 \nBrackett J Schafer ES Leung DH :\nUse of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism. \nPediatr Blood Cancer. \n2014 ;61 (6 ):1114 –1117 .\n10.1002/pbc.24913 \n24376133 \n10 \nBostrom BC Sensel MR Sather HN :\nDexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. \nBlood. \n2003 ;101 (10 ):3809 –17 .\n10.1182/blood-2002-08-2454 \n12531809 \n11 \nBlaker PA Arenas-Hernandez M Smith MA :\nMechanism of allopurinol induced TPMT inhibition. \nBiochem Pharmacol. \n2013 ;86 (4 ):539 –547 .\n10.1016/j.bcp.2013.06.002 \n23770457 \n12 \nBell BA Brockway GN Shuster JJ :\nA comparison of red blood cell thiopurine metabolites in children with acute lymphoblastic leukemia who received oral mercaptopurine twice daily or once daily: a Pediatric Oncology Group study (now The Children's Oncology Group). \nPediatr Blood Cancer. \n2004 ;43 (2 ):105 –9 .\n10.1002/pbc.20089 \n15236274 \n13 \nElion GB :\nNobel lecture in physiology or medicine--1988. The purine path to chemotherapy. \nIn Vitro Cell Dev Biol. \n1989 ;25 (4 ):321 –30 .\n2654122 \n14 \nSeinen ML van Asseldonk DP de Boer NK :\nThe effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study. \nJ Crohns Colitis. \n2013 ;7 (10 ):812 –819 .\n10.1016/j.crohns.2012.12.006 \n23317929 \n15 \nKarim H Ghalali A Lafolie P :\nDifferential role of thiopurine methyltransferase in the cytotoxic effects of 6-mercaptopurine and 6-thioguanine on human leukemia cells. \nBiochem Biophys Res Commun. \n2013 ;437 (2 ):280 –6 .\n10.1016/j.bbrc.2013.06.067 \n23811272 \n16 \nMilek M Karas Kuzelicki N Smid A :\nS-adenosylmethionine regulates thiopurine methyltransferase activity and decreases 6-mercaptopurine cytotoxicity in MOLT lymphoblasts. \nBiochem Pharmacol. \n2009 ;77 (12 ):1845 –1853 .\n10.1016/j.bcp.2009.03.006 \n19428339 \n17 \nDervieux T Blanco JG Krynetski EY :\nDiffering contribution of thiopurine methyltransferase to mercaptopurine\nversus thioguanine effects in human leukemic cells. \nCancer Res. \n2001 ;61 (15 ):5810 –5816 .\n11479220 \n18 \nMiller MB Brackett J Schafer ES :\nPrevention of mercaptopurine-induced hypoglycemia using allopurinol to reduce methylated thiopurine metabolites. \nPediatr Blood Cancer. \n2018 ;66 (4 ):e27577 .\n10.1002/pbc.27577 \n30548777 \n19 \nChocair P Duley J Simmonds HA :\nLow-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen. \nLancet. \n1993 ;342 (8863 ):83 –4 .\n10.1016/0140-6736(93)91287-v \n8100914 \n20 \nBostrom B :\n6MP Allopurinol hypoglycemia patient data SPSS .\nfigshare. Fileset.2019 \n10.6084/m9.figshare.7666409.v1\n\n",
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"issn_linking": "2046-1402",
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"keywords": "allopurinol; hypoglycemia; mercaptopurine; morning nausea; thiopurine methyltransferase",
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"mesh_terms": "D000493:Allopurinol; D000964:Antimetabolites, Antineoplastic; D001786:Blood Glucose; D015190:Blood Glucose Self-Monitoring; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D015122:Mercaptopurine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16128682;24415675;23811272;30548777;24438369;19428339;8100914;11479220;26808368;23317929;15236274;22386736;12531809;24590210;24936744;26878433;24376133;23770457;2654122",
"title": "Allopurinol reverses mercaptopurine-induced hypoglycemia in patients with acute lymphoblastic leukemia.",
"title_normalized": "allopurinol reverses mercaptopurine induced hypoglycemia in patients with acute lymphoblastic leukemia"
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},
{
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}
],
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{
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},
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}
],
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},
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"literaturereference": "ZHANG M, BOSTROM B. ALLOPURINOL REVERSES MERCAPTOPURINE-INDUCED HYPOGLYCEMIA IN PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA. F1000 RESEARCH. 2019?8:176-176. DOI:10.12688/F1000RESEARCH.17760.1",
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"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190422",
"receivedate": "20190418",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16210543,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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}
] |
{
"abstract": "Recent studies suggest an increased risk for Pneumocystis jirovecii pneumonia (PJP) in adults receiving short-interval rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy for diffuse large cell B cell lymphoma (DLBCL). This retrospective study evaluates precise PJP incidence and the efficacy of anti-PJP prophylaxis in DLBCL. Patients with DLBCL, aged ≥18 years and treated between December 2004 and December 2010, were included. Details of treatment-related respiratory infections, focusing on PJP incidence, risk factors and prophylaxis, were assessed. A total of 132 patients were analyzed; 47 were treated with rituximab-CHOP therapy every 21 days (R-CHOP-21) and 85 were treated every 14 days (R-CHOP-14). The incidence of treatment-related respiratory infections was higher in patients receiving R-CHOP-14. PJP was diagnosed in 5 patients: 4 in the R-CHOP-14 (6.6%) and 1 in the R-CHOP-21 cohort (2.6%), using triplex polymerase chain reaction (PCR) for PJ in bronchoalveolar fluid. None of the patients receiving P.jirovecii prophylaxis (n = 33) developed PJP, compared with 6.6% of those treated with R-CHOP-14 without such prophylaxis. An older age and R-CHOP administered every 14 rather than every 21 days increased the PJP risk. Trimethoprim/sulfamethoxazole prophylaxis is found to be highly efficient in preventing this life-threatening complication and, therefore, should be recommended for patients receiving the R-CHOP-14 regimen.",
"affiliations": "Division of Pulmonary Medicine, Rambam Health Care Campus, Haifa, Israel.",
"authors": "Hardak|Emilia|E|;Oren|Ilana|I|;Dann|Eldad J|EJ|;Yigla|Mordechai|M|;Faibish|Tal|T|;Rowe|Jacob M|JM|;Avivi|Irit|I|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000334113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "127(2)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014750:Vincristine",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "110-4",
"pmc": null,
"pmid": "22178955",
"pubdate": "2012",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The increased risk for pneumocystis pneumonia in patients receiving rituximab-CHOP-14 can be prevented by the administration of trimethoprim/sulfamethoxazole: a single-center experience.",
"title_normalized": "the increased risk for pneumocystis pneumonia in patients receiving rituximab chop 14 can be prevented by the administration of trimethoprim sulfamethoxazole a single center experience"
}
|
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{
"abstract": "Stevens-Johnson syndrome is a rare immunologic reaction that may involve skin or various mucosal surfaces. The etiology may range from multiple pharmacologic agents to viral infections. Associated findings can range from minimal skin and mucosal involvement to extensive dermal exfoliation, nephritis, lymphadenopathy, hepatitis, and multiple serologic abnormalities. We report a 36 year-old caucasian male who developed a pruritic, raised maculopapular eruption on Day 17 of intravenous vancomycin for treatment of probable bacterial endocarditis. The vancomycin was discontinued. The patient had received a prosthetic aortic valve subsequent to acute rheumatic valve disease 20 years earlier, but had been well until development of endocarditis. The rash became more extensive to involve the torso, abdomen, legs, and arms. His fever persisted, and he developed neutropenia and eosinophilia. Axillary and inguinal lymphadenopathy, pharyngeal irritation, lip swelling, conjunctival injection, and elevated liver function studies also developed following cessation of the vancomycin. Eight days after eruption and fever began, corticosteroid therapy was instituted, with subsequent improvement of symptoms in less than 24 hours. Allergic reactions to vancomycin have included Stevens-Johnson syndrome rarely, and only one other case of adenopathy has been recorded. Most reactions have been in patients with severe renal insufficiency. We believe this patient is the first case of vancomycin-induced Stevens-Johnson syndrome in a previously healthy patient to be complicated by lymphadenopathy, hepatitis, and multiple serologic abnormalities.",
"affiliations": "Department of Medicine, Northwestern University Medical School, Chicago, IL 60611-3008, USA.",
"authors": "Alexander|I I|II|;Greenberger|P A|PA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.2500/108854196778645029",
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"issn_linking": "1088-5412",
"issue": "17(2)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D006801:Humans; D008297:Male; D013262:Stevens-Johnson Syndrome; D014640:Vancomycin",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "75-8",
"pmc": null,
"pmid": "8934797",
"pubdate": "1996",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Vancomycin-induced Stevens-Johnson syndrome.",
"title_normalized": "vancomycin induced stevens johnson syndrome"
}
|
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{
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"reactionmeddraversionpt": "21.0",
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{
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"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
}
],
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},
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"literaturereference": "ALEXANDER, I.. VANCOMYCIN-INDUCED STEVENS-JOHNSON SYNDROME. J ALLERGY CLIN IMMUNOL. 1996?97 (1):343",
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{
"abstract": "Protothecosis is a rare algal infection, affecting primarily immunocompromised hosts. Optimal management is unclear: in-vitro antimicrobial breakpoints are not established and therapeutic decisions are primarily based on case reports. We present a case of cutaneous Prototheca wickerhamii infection in an immunosuppressed 63 year old male, successfully treated with liposomal amphotericin and prolonged itraconazole. Inoculation may have been through frequent hot-tub use, highlighting hot-tub exposure as an infection risk for the immunocompromised host.",
"affiliations": "Sydney Children's Hospital, Sydney 2031, Australia.;Marie Bashir Institute for Infectious Diseases, University of Sydney, Sydney 2006, Australia.;Westmead Millenium Institute, Sydney 2145, Australia.;Westmead Hospital, Sydney 2145, Australia.",
"authors": "McMullan|Brendan|B|;Pollett|Simon|S|;Biswas|Chayanika|C|;Packham|Donald|D|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.mmcr.2016.08.001",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(16)30042-210.1016/j.mmcr.2016.08.001Case ReportSuccessful treatment of cutaneous protothecosis with liposomal amphotericin and oral itraconazole McMullan Brendan [email protected]⁎Pollett Simon bBiswas Chayanika cPackham Donald da Sydney Children’s Hospital, Sydney 2031, Australiab Marie Bashir Institute for Infectious Diseases, University of Sydney, Sydney 2006, Australiac Westmead Millenium Institute, Sydney 2145, Australiad Westmead Hospital, Sydney 2145, Australia⁎ Corresponding author. [email protected] 8 2016 6 2016 03 8 2016 12 21 23 7 6 2016 2 8 2016 3 8 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Protothecosis is a rare algal infection, affecting primarily immunocompromised hosts. Optimal management is unclear: in-vitro antimicrobial breakpoints are not established and therapeutic decisions are primarily based on case reports. We present a case of cutaneous Prototheca wickerhamii infection in an immunosuppressed 63 year old male, successfully treated with liposomal amphotericin and prolonged itraconazole. Inoculation may have been through frequent hot-tub use, highlighting hot-tub exposure as an infection risk for the immunocompromised host.\n\nKeywords\nPrototheca wickerhamiiProtothecosisCutaneousLiposomal amphotericinItraconazole\n==== Body\n1 Introduction\nHuman protothecosis is an algal infection due to environmentally ubiquitous achlorophyllic algae: Prototheca species. Prototheca wickerhamii and Prototheca zopfii are the species reported in human infections, and infection occurs predominantly in the immunocompromised, for whom outcomes are often poor [1]. The optimal management of cases remains unclear with in-vitro minimum inhibitory concentrations (MICs) of antimicrobials difficult to interpret, and no clinical breakpoints established. Published case reports to date are relatively uncommon [2], thus reports of risk factors, clinical presentation and outcomes of potential therapies are valuable for future research into therapy.\n\n2 Case\nA 63-year-old male presented with two weeks of right lower limb swelling, erythema and ulceration. The patient recalled frequent use of a home hot-tub over the preceding months before presentation.\n\nHis medical history included dermatomyositis with associated pulmonary fibrosis, Type 2 diabetes mellitus, peripheral neuropathy, stage III chronic kidney disease, dilated congestive cardiac failure with moderate systolic dysfunction, atrial fibrillation, and compensated chronic liver disease due to primary biliary cirrhosis. He was not known to have HIV infection but testing was not performed for this. In addition to his chronic co-morbidities, the patient had a history of abdominal wall Mycobacterium chelonae infection requiring debridement and multidrug therapy 3 years previously; and disseminated Mycobacterium haemophilum requiring prolonged antimicrobials 2 years previously. Both mycobacterial infections were considered cured at the time of his presentation.\n\nMedications on presentation included long term prednisolone 30 mg daily, in addition to intermittent higher doses up to 35 mg over the preceding 6 months for presumed flares of his inflammatory lung disease. Other medications included beta-blockers, diuretics, digoxin, ursodeoxycholic acid and subcutaneous insulin.\n\nOn examination at presentation to hospital (day 0), the patient was febrile at 38.5° Celsius, haemodynamically stable and normoglycemic on presentation. Inspection of the right lower leg (Fig. 1) revealed a 15 cm region of erythema and warmth with central ulceration and several surrounding dark bullae.\n\nLaboratory results revealed raised inflammatory markers with a leukocyte count of 12.6×109/L with a left shift, and a C-reactive protein of 32 mg/L. Renal function indices were abnormal with an eGFR of 37 mL/min/1.73 m2.\n\nThe patient was provisionally diagnosed with a right lower limb soft tissue infection and acute on chronic renal failure. Ticarcillin-clavulanate 3.1 g four times daily was commenced. Swabs of the ulcer were sent for general microscopy and culture, with no organisms seen on Gram stain. A biopsy of the ulcer edge was performed and sent for mycobacterial and fungal cultures. Direct microscopy on the biopsy showed no fungal elements, and no acid-fast bacilli were demonstrated on Ziehl-Neelsen stain. Biopsy sample PCR for methicillin-resistant Staphylococcus aureus (MRSA) was positive and renally dose-adjusted vancomycin was commenced.\n\nOne week following presentation there was no improvement of the right lower limb soft tissue infection. New bullae and ulceration had formed on the medial aspect of the leg. At this time yeast-like organisms were grown from biopsy enrichment cultures (cooked meat broth), along with MRSA, with no growth on primary plates (Horse Blood Columbia Agar and Chocolate Agar). Subcultures of the yeast-like organisms produced creamy colonies on Sabouraud's Dextrose Agar (SDA) and pale purple colonies 1–2 mm in diameter at 2 days’ incubation on Candida CHROMagar™ (CHROMagar, France). These were Gram-positive and had morula forms, characteristic of Prototheca spp. on wet preparation (Fig. 2). RapID™ Yeast Plus (Thermo Fisher Scientific Remel Products, USA) provided an “adequate identification” for Prototheca wickerhamii and API 20C AUX (BioMérieux, France) provided an “excellent identification” for Prototheca wickerhamii. Antifungal susceptibilities were performed by broth microdilution using the Sensititre Yeast-One Test Panel (Trek Diagnostic Systems, USA). The MICs for fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, micafungin, 5-fluorocytosine, and amphotericin B were 128, 0.5, 0.25, 0.25, >8, >8, >8, >64 and 0.25 mg/liter, respectively. Blood cultures were negative. The Prototheca isolate was later retrieved for isavuconazole susceptibility testing. It was grown on SDA for 24 h at 30 °C. Susceptibility testing for isavuconazole was performed in a 96-well round-bottom plate using standard broth microdilution assay, according to the Clinical and Laboratory Standards Institute (CLSI) document M27-A3 for yeast [3]. The concentration range for isavuconazole was 0.06–32 mg/L. Results were obtained by reading the plates visually after 48 and 72 h incubation at 37 °C. The MIC of isavuconazole was read as the lowest concentration of the drug at which there was 100% inhibition of growth. The MIC obtained for isavuconazole against Prototheca was 0.5 mg/L after both 48 and 72 h incubation periods.\n\nThe patient was diagnosed with cutaneous protothecosis and intravenous liposomal amphotericin was commenced at 3 mg per kg based on ideal body weight. Other antibiotics were discontinued and prednisone therapy was reduced to 20 mg. By day three of amphotericin (day 10 post admission), however, renal function had deteriorated with an eGFR of 22 mL/min/1.73 m2 and liposomal amphotericin was ceased. Oral itraconazole 200 mg twice daily was commenced with recovery of renal function to baseline over the following week before discharge. Over the next three months, the ulcers improved slowly and a repeat biopsy of the residual lateral ulcer was did not isolate Prototheca species on cultures or microscopy. The patient tolerated the oral therapy well. By 6 months the right lower limb ulceration had healed with a minor residual area of granulation and superficial desquamation.\n\n3 Discussion\nPrototheca species are achlorophyllic algae found in soil and water [1]. Human infections due to Prototheca species are rare, with only 160 cases (as described by Todd et al.) up to mid-2011, since the first report in 1964 [2]. Since this report, a further 41 cases have been reported, perhaps suggesting human protothecosis is being increasingly diagnosed. All human cases of protothecosis, where organisms were identified to species level, have been caused by either P. wickerhamii or P. zopfii species. Protothecosis predominantly occurs in adults, although infections in children are described [2]. Inoculation is thought to occur via occult or overt skin trauma, especially in the context of contaminated water [1], [2]. This patient in this case reported frequent hot-tub exposure and this was felt to be the likely environmental exposure, although a sample of the hot-tub water was not available for microbiological testing. Hot tubs have been associated with other cutaneous and systemic infections, particularly with mycobacteria [4], [5] and Pseudomonas aeruginosa\n[6]. Confirmed or suspected protothecosis acquisition from hot-tub use has not been described before.\n\nClinical presentations of protothecosis may be broadly divided into the categories of cutaneous and systemic (including disseminated disease). The spectrum of cutaneous protothecosis is broad and constitutes the majority of cases reported, with wide range of findings including ulcers (as with our case), erosions, crusting, papules, plaques and pustules [7]. Olecranon bursitis is a notable manifestation and has been considered a distinct entity [8]. A wide range of systemic manifestations has been reported, including abdominal infections, pneumonia, bloodstream infection and central nervous system infection [2], [9], [10], [11]. Peritoneal catheter and other device infections are also described [2], [12], [13]. Disseminated disease is reported generally in the immunosuppressed, frequently with exogenous steroid use, as with this case [2]. Other immunosuppressants described in association with protothecosis include chemotherapy for malignancy or transplantation [13], [14]. Non-iatrogenic immunosuppressing risk conditions include chronic renal failure and diabetes mellitus [11], [15], the latter which was seen in this case.\n\nCulture and microscopy are essential in the approach to the diagnosis of protothecosis. Prototheca species typically form creamy yeast-like colonies on Sabouraud's media [15], [16], as was seen in this case. On wet preparation, they can be distinguished from yeast by the absence of budding, and presence of small sporangia with endospores forming characteristic ‘spoked wheels’ on microscopy of cultures, as illustrated in Fig. 2\n[16]. Diagnosis may also be made in histopathologic sections, with morulae often visible with stains used to detect fungus, such as Periodic Acid Schiff stain or Grocott's modification of Gomori methenamine silver [1]. Commercial systems which may correctly identify Prototheca include the API 20C or API 20C AUX (bio-Mérieux, Marcy L'Etoile, France) as well as Vitek 2 (bio-Mérieux), but the API 32C (bio-Mérieux) does not include these organisms in its database [17]. Molecular techniques have been used to identify Prototheca species in human clinical samples, including ribosomal internal transcribed spacer (ITS) sequencing [18] and 26S rRNA gene sequencing [17]. Successful identification with mass spectrometry has been reported [19] but, as clinical isolates of Prototheca spp. are uncommon, these are not well represented in current databases, leading to potential for failed identification or misidentification [13], [14].\n\nThe natural history of isolated skin disease is an indolent progressive course [7], though there are reports of spontaneous resolution [2], [20]. In the immunosuppressed, cutaneous lesions may disseminate and this form of protothecosis has high mortality [2]. Such prognoses underscore the need for prompt diagnosis and rapid treatment of even apparently isolated skin disease, particularly in the context of immunosuppression [17], [21].\n\nMedical treatment for protothecosis most commonly includes antifungal agents and/or tetracyclines [1], [2]. Reported treatment success rates are higher for cutaneous disease (73%) and olecranon bursitis (83%) and low for disseminated disease (33%) [2]. There are no established antimicrobial breakpoints for susceptibility or resistance but Prototheca species generally appear to be susceptible to amphotericin in-vitro [1], with variable susceptibility to triazoles. In-vitro synergy has been reported for tetracycline [1], and recently in-vitro susceptibility to miltefosine and terbinafine, with resistance to echinocandins reported [13]. Intravenous amphotericin, either alone or in combination with other agents, has the highest reported treatment success rates to date: 77% and 86%, respectively [2]. Triazoles, especially itraconazole, have been reported as successful treatments, but failure with these is commonly reported, including with cutaneous disease, which prompted our induction with amphotericin therapy for this case. To our knowledge, there are no reports of isavuconazole susceptibility testing for Prototheca spp. We found a relatively low MIC of 0.5 mg/L in our clinical isolate, suggesting this agent may merit further study as a treatment option for protothecosis. Consideration may be given to surgery in isolated cutaneous disease or olecranon bursitis. Reduction of immunosuppression is also a consideration, as corticosteroids in particular appear to increase susceptibility to Prototheca infection [2].\n\nIn our case, we believe prompt microbiological diagnosis, delivery of amphotericin followed by itraconazole therapy and reduction of immunosuppression contributed to the successful outcome. The patient was cautioned about hot-tub use as a potential source of protothecosis or mycobacterial disease.\n\nConflict of interest\nThere are none.\n\nAcknowledgments\nDr. Shrada Subedi, Westmead Hospital, for assistance with acquisition of clinical data. Dr. Catriona Halliday, Clinical Mycology Reference Laboratory, Westmead Hospital, for assistance with isavuconazole susceptibility testing.\n\nFig. 1 Right leg ulcer from which Prototheca wickerhamii was subsequently grown.\n\nFig. 1Fig. 2 Wet preparation microscopy of P. wickerhamii isolates demonstrating characteristic morula forms.\n\nFig. 2\n==== Refs\nReferences\n1 Lass-Flörl C. Mayr A. Human protothecosis Clin. Microbiol. Rev. 20 2007 230 242 17428884 \n2 Todd J.R. King J.W. Oberle A. Matsumoto T. Odaka Y. Fowler M. Protothecosis: report of a case with 20-year follow-up, and review of previously published cases Med. Mycol. 50 2012 673 689 22571772 \n3 Clinical and Laboratory Standards Institute, M27-A3. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Approved Standard—Third Edition, Wayne, PA, USA, 2008.\n4 Edson R.S. Terrell C.L. Brutinel W.M. Wengenack N.L. Mycobacterium intermedium granulomatous dermatitis from hot tub exposure Emerg. Infect. Dis. 12 2006 821 823 16704844 \n5 Piersimoni C. Extrapulmonary infections associated with nontuberculous mycobacteria in immunocompetent persons Emerg. Infect. Dis. 2009 1351 1358 19788801 \n6 Yu Y. Cheng A.S. Wang L. Dunne W.M. Bayliss S.J. Hot tub folliculitis or hot hand-foot syndrome caused by Pseudomonas aeruginosa J. Am. Acad. Dermatol. 57 2007 596 600 17658195 \n7 Mayorga J. Barba-Gómez J.F. Verduzco-Martínez A.P. Muñoz-Estrada V.F. Welsh O. Protothecosis Clin. Dermatol. 30 2012 432 436 22682193 \n8 Pednekar M. Chandra P.A. Margulis Y. Chandra A.B. Schiff C. Protothecal olecranon bursitis: an unusual algal infection Am. J. Med. Sci. 342 2011 424 21804360 \n9 Żak I. Jagielski T. Kwiatkowski S. Bielecki J. Prototheca wickerhamii as a cause of neuroinfection in a child with congenital hydrocephalus. First case of human protothecosis in Poland Diagn. Microbiol. Infect. Dis. 74 2012 186 189 22858361 \n10 Tan R.M.R. Aw M.M. Quak S.H. Chan S.M. Pulmonary protothecosis in a pediatric liver transplant patient J. Pediatr. Infect. Dis. 3 2014 e31 e34 \n11 Min Z. Moser S.A. Pappas P.G. Prototheca wickerhamii algaemia presenting as cholestatic hepatitis in a patient with systemic lupus erythematosus – a case report and literature review Med. Mycol. Case Rep. 2 2013 19 22 24432207 \n12 Sykora T. Horakova J. Buzzasyova D. Sladekova M. Poczova M. Sufliarska S. Protothecal peritonitis in child after bone marrow transplantation: case report and literature review of paediatric cases New Microbes New Infect. 2 2014 156 160 25566393 \n13 Macesic N. Fleming S. Kidd S. Madigan V. Chean R. Ritchie D. Protothecosis in hematopoietic stem cell transplantation: case report and review of previous cases Transpl. Infect. Dis. 16 2014 490 495 24797402 \n14 Bandaranayake T.D. Paniz Mondolfi A. Peaper D.R. Malinis M.F. Prototheca wickerhamii algaemia: an emerging infection in solid organ transplant recipients Transpl. Infect. Dis. 17 2015 599 604 26040253 \n15 Zhang Q.-Q. Li L. Zhu L.-P. Zhao Y. Wang Y.-R. Zhu J.-H. Cutaneous protothecosis in patient with diabetes mellitus and review of published case reports Mycopathologia 173 2011 163 171 21964624 \n16 Okazaki C. Wakusawa C. Chikama R. Murakami K. Hitomi H. Satoh K. A case of cutaneous protothecosis in a Polyarteritis nodosa patient and review of cases reported in Japan Dermatol. Online J. 17 2011 2 21971267 \n17 McMullan B. Muthiah K. Stark D. Lee L. Marriott D. Prototheca wickerhamii mimicking yeast: a cautionary tale J. Clin. Microbiol. 49 2011 3078 3081 21653770 \n18 Hirose N. Nishimura K. Inoue-Sakamoto M. Masuda M. Ribosomal internal transcribed spacer of Prototheca wickerhamii has characteristic structure useful for identification and genotyping PLoS One 8 2013 e81223 24312279 \n19 von Bergen M. Eidner A. Schmidt F. Murugaiyan J. Wirth H. Binder H. Identification of harmless and pathogenic algae of the genus Prototheca by MALDI-MS Proteomics Clin. Appl. 3 2009 774 784 21136986 \n20 Boyce F. Longcrier D.L. Young J.W. Partlow K. Prototheca as a pathogen Clin. Microbiol. Newsl. 1 1979 4 5 \n21 Murata M. Ito T. Nagae K. Nakano-Nakamura M. Nishida R. Takei K. Disseminated protothecosis manifesting with multiple, rapidly-progressing skin ulcers: successful treatment with amphotericin B Eur. J. Dermatol. 25 2015 208 209 25906086\n\n",
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"issue": "12()",
"journal": "Medical mycology case reports",
"keywords": "Cutaneous; Itraconazole; Liposomal amphotericin; Prototheca wickerhamii; Protothecosis",
"medline_ta": "Med Mycol Case Rep",
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"pubdate": "2016-06",
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"title": "Successful treatment of cutaneous protothecosis with liposomal amphotericin and oral itraconazole.",
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{
"abstract": "BACKGROUND\nSevere short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly.\n\n\nOBJECTIVE\nTo identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure.\n\n\nMETHODS\nClinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene.\n\n\nMETHODS\nAn academic pediatric endocrinology clinic.\n\n\nMETHODS\nTwo adult siblings (male patient [P1] and female patient 2 [P2]) presented with a history of severe postnatal growth failure (adult heights: P1, -6.8 SD score; P2, -4 SD score), microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28.\n\n\nMETHODS\nSingle nucleotide polymorphism microarray and exome sequencing.\n\n\nRESULTS\nCombined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect.\n\n\nCONCLUSIONS\nIn this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non-homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition.",
"affiliations": "Cincinnati Center for Growth Disorders (C.d.B., S.F.A., V.H., A.D.), Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Institute of Maternal and Child Research (V.M.), Faculty of Medicine, University of Chile, 226-3 Santiago, Chile; Laboratory for Diagnostic Genome Analysis (H.A.v.D., M.L.), Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Department of Genetics (N.S.V., D.C.v.G.), Erasmus MC, 3015 CE Rotterdam, The Netherlands; Center for Autoimmune Genomics and Etiology (A.P.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Pediatrics Division (H.G.), Faculty of Medicine, Pontificia Universidad Catolica de Chile Santiago, 340 Santiago, Chile; Division of Developmental Biology (Y.K.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Institute of Human Development (D.H., P.C.), University of Manchester and Manchester Academic Health Sciences Centre, Manchester M13 9PL, United Kingdom; and Department of Pediatrics (J.M.W.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.",
"authors": "de Bruin|Christiaan|C|;Mericq|Verónica|V|;Andrew|Shayne F|SF|;van Duyvenvoorde|Hermine A|HA|;Verkaik|Nicole S|NS|;Losekoot|Monique|M|;Porollo|Aleksey|A|;Garcia|Hernán|H|;Kuang|Yi|Y|;Hanson|Dan|D|;Clayton|Peter|P|;van Gent|Dik C|DC|;Wit|Jan M|JM|;Hwa|Vivian|V|;Dauber|Andrew|A|",
"chemical_list": "D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2015-1098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "100(5)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000328:Adult; D001827:Body Height; D004268:DNA-Binding Proteins; D059472:Exome; D005260:Female; D006801:Humans; D007006:Hypogonadism; D008297:Male; D024821:Metabolic Syndrome; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D035781:Siblings",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "E789-98",
"pmc": null,
"pmid": "25742519",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "9736627;21396581;15613856;16357942;16625094;21358632;21358633;21775435;21979914;21998596;22354167;22354170;23144622;22858719;23442139;23100014;23760025;24123394;24389050;24629483;24065112;24582502;24793695;24793696;25344692;25480036;10786799;11870614;12640452;16757976;18174396;19240156;19833883;20192759;21131973;21270239;9875844",
"title": "An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome.",
"title_normalized": "an xrcc4 splice mutation associated with severe short stature gonadal failure and early onset metabolic syndrome"
}
|
[
{
"companynumb": "PHHY2015US065725",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "021588",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "GASTROINTESTINAL STROMAL TUMOUR",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IMATINIB"
}
],
"patientagegroup": null,
"patientonsetage": "36",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Gastrointestinal stromal tumour",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Gastrointestinal disorder",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DAUBER A, BRUIN C, MERICQ V, ANDREW AF, DUYVENVOORDE HA, VERKAIK NS ET AL.. AN XRCC4 SPLICE MUTATION ASSOCIATED WITH SEVERE SHORT STATURE, GONADAL FAILURE, AND EARLY-ONSET METABOLIC SYNDROME. JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. 2015;100-5:E789-E798",
"literaturereference_normalized": "an xrcc4 splice mutation associated with severe short stature gonadal failure and early onset metabolic syndrome",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150605",
"receivedate": "20150605",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11166158,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
{
"abstract": "OBJECTIVE\nSildenafil has been shown to preserve alveolar growth and lung angiogenesis in a rat model of bronchopulmonary dysplasia. We conducted a proof-of-concept randomised controlled pilot study to assess the feasibility of oral sildenafil treatment in extremely preterm infants with evolving bronchopulmonary dysplasia.\n\n\nMETHODS\nPreterm infants <28 weeks gestational age were eligible if they were mechanically ventilated on day 7 of life. Infants were randomised to a 4-weeks course of either oral sildenafil (3 mg/kg/day) or placebo solution. Pre-discharge cardiorespiratory outcomes and medication side effects were collected.\n\n\nRESULTS\nTwenty infants were randomised, 10 received sildenafil (mean gestational age 24 + 5 weeks (SD 4.9 days), mean weight 692 g (SD 98)) and 10 received placebo (mean gestational age 24 + 5 weeks (SD 6.5 days), mean weight 668 g (SD 147)). One infant in the sildenafil group did not receive treatment because of an early pneumoperitoneum. Two infants did not complete the study (transferred out). Of the remaining seven treated infants, three died (two from respiratory-related causes). One infant in the control group died from a non-respiratory cause. Sildenafil did not reduce length of invasive (median 688 versus 227 h) or non-invasive ventilation (median 1609 versus 1416 h). More infants in the sildenafil group required postnatal steroid treatment. One infant developed hypotension following sildenafil administration and was excluded after three doses.\n\n\nCONCLUSIONS\nIn this pilot study, oral sildenafil treatment did not improve any short-term respiratory outcomes in extremely preterm infants.",
"affiliations": "Mercy Hospital for Women, Department of Paediatrics , Melbourne, Victoria , Australia and.",
"authors": "König|Kai|K|;Barfield|Charles P|CP|;Guy|Katelyn J|KJ|;Drew|Sandra M|SM|;Andersen|Chad C|CC|",
"chemical_list": "D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate",
"country": "England",
"delete": false,
"doi": "10.3109/14767058.2013.818650",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": "27(5)",
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": null,
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": "D001997:Bronchopulmonary Dysplasia; D018450:Disease Progression; D064420:Drug-Related Side Effects and Adverse Reactions; D005240:Feasibility Studies; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D008297:Male; D010865:Pilot Projects; D010879:Piperazines; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D016896:Treatment Outcome; D014665:Vasodilator Agents",
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "439-44",
"pmc": null,
"pmid": "23796045",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study.",
"title_normalized": "the effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants a randomised controlled pilot study"
}
|
[
{
"companynumb": "AU-PFIZER INC-2012086342",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SILDENAFIL CITRATE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "021845",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "FILM-COATED TABLET",
"drugdosagetext": "1 MG/KG, 3X/DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BRONCHOPULMONARY DYSPLASIA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "3",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "REVATIO"
}
],
"patientagegroup": "2",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KONIG, K.. THE EFFECT OF SILDENAFIL ON EVOLVING BRONCHOPULMONARY DYSPLASIA IN EXTREMELY PRETERM INFANTS: A RANDOMISED CONTROLLED PILOT STUDY. JOURNAL OF MATERNAL-FETAL + NEONATAL MEDICINE. 2014;27 (5):439-444",
"literaturereference_normalized": "the effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants a randomised controlled pilot study",
"qualification": "1",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20141212",
"receivedate": "20120416",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 8514734,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150529"
}
] |
{
"abstract": "Highly active antiretroviral therapy (HAART) has dramatically lowered rates of mother-to-child HIV transmission among patients with access to treatment. Barriers to complete viral suppression increase rates of transmission, even with only low levels of viral replication. Here, we present the case of a pregnant patient who developed a detectable viral load in pregnancy, thought to be related to calcium supplement consumption or emesis while using a dolutegravir-based HAART regimen. Ultimately, with adjustments, the patient again reached an undetectable viral load and had an uncomplicated perinatal and neonatal outcome. We discuss new data on the use of dolutegravir in pregnancy and precautions for maintaining viral suppression while on antiretroviral therapy in pregnancy.",
"affiliations": "Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina, USA [email protected].;Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.;Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.",
"authors": "Federspiel|Jerome|J|http://orcid.org/0000-0003-0321-6280;Bukhari|Melanie J|MJ|;Hamill|Matthew M|MM|http://orcid.org/0000-0002-1277-819X",
"chemical_list": "D019380:Anti-HIV Agents; D004366:Nonprescription Drugs; D014815:Vitamins; D002119:Calcium Carbonate",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236655",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "HIV / AIDS; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002119:Calcium Carbonate; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D004366:Nonprescription Drugs; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D019562:Viral Load; D014815:Vitamins; D014839:Vomiting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33408101",
"pubdate": "2021-01-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interactions between highly active antiretroviral therapy and over-the-counter agents: a cautionary note.",
"title_normalized": "interactions between highly active antiretroviral therapy and over the counter agents a cautionary note"
}
|
[
{
"companynumb": "US-BAYER-2021-041915",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM CARBONATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "999999",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SUPPLEMENTATION THERAPY",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CALCIUM CARBONATE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOLUTEGRAVIR"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MINERALS\\VITAMINS"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugrecurrence": null,
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"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PRENATAL VITAMINS [MINERALS NOS;VITAMINS NOS]"
}
],
"patientagegroup": "5",
"patientonsetage": "35",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "HIV viraemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Labelled drug-drug interaction medication error",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FEDERSPIEL J, BUKHARI MJ, HAMILL MM. INTERACTIONS BETWEEN HIGHLY ACTIVE ANTIRETROVIRAL THERAPY AND OVER?THE?COUNTER AGENTS: A CAUTIONARY NOTE. BMJ CASE REPORTS. 2021?14:1:ARTICLE NUMBER: E236655",
"literaturereference_normalized": "interactions between highly active antiretroviral therapy and over the counter agents a cautionary note",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210205",
"receivedate": "20210205",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18853884,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210420"
},
{
"companynumb": "US-SA-2021SA035103",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CALCIUM CARBONATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "3",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SUPPLEMENTATION THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CALCIUM CARBONATE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "020164",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "THROMBOSIS PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ENOXAPARIN SODIUM."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ABACAVIR SULFATE\\DOLUTEGRAVIR SODIUM\\LAMIVUDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "3",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK (PILL)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HIV INFECTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ABACAVIR;DOLUTEGRAVIR;LAMIVUDINE"
}
],
"patientagegroup": "5",
"patientonsetage": "35",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood HIV RNA increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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},
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"receivedate": "20210215",
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},
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},
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"transmissiondate": "20210420"
},
{
"companynumb": "US-VIIV HEALTHCARE LIMITED-GB2021GSK007142",
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{
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{
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},
{
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{
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},
{
"reactionmeddrapt": "Vomiting",
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},
{
"reactionmeddrapt": "Inappropriate schedule of product administration",
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},
{
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},
{
"reactionmeddrapt": "Live birth",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Exposure during pregnancy",
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"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "FEDERSPIEL J, BUKHARI MJ, HAMILL MW. INTERACTIONS BETWEEN HIGHLY ACTIVE ANTIRETROVIRAL THERAPY AND OVER?THE?COUNTER AGENTS: A CAUTIONARY NOTE. BMJ CASE REPORTS. 2021?14 (1)",
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"reportercountry": "US"
},
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"receiptdate": "20210125",
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},
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"sender": {
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},
"serious": 1,
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"transmissiondate": "20210419"
}
] |
{
"abstract": "A 24-year-old man known to consume illegal drugs was found dead in his apartment. A reclosable plastic zipper bag containing several hundred milligrams of a brown powder was found close to the dead body and the first assumption of the investigators was death due to heroin intoxication. Therefore, a legal autopsy was ordered. The following toxicological analysis revealed ocfentanil in urine and in the brown powder. Four different approaches for the determination of the ocfentanil concentrations in peripheral whole blood are described. Enrichment of ocfentanil from the powder was realized. With this reference, it was possible to determine the ocfentanil concentration in the seized powder to be 0.91%. Concentrations of ocfentanil were also determined in the sampled body fluids using the standard addition procedure. In peripheral blood 9.1 µg/L, in heart blood 27.9 µg/L and in urine 480 µg/L were measured. In addition, the antidepressant citalopram, the neuroleptic quetiapine and cannabinoids were found in urine and subsequently quantified in peripheral blood.",
"affiliations": "Forensic Chemistry and Toxicology, Institute of Legal Medicine of the University of Basel, Pestalozzistrasse 22, CH-4056 Basel, Switzerland [email protected].;Forensic Chemistry and Toxicology, Institute of Legal Medicine of the University of Basel, Pestalozzistrasse 22, CH-4056 Basel, Switzerland.;Forensic Chemistry and Toxicology, Institute of Legal Medicine of the University of Basel, Pestalozzistrasse 22, CH-4056 Basel, Switzerland.;Institute of Chemistry and Bioanalytics, University of Applied Sciences Northwestern Switzerland (FHNW), Gruendenstrasse 40, CH-4132 Muttenz, Switzerland.;Institute of Chemistry and Bioanalytics, University of Applied Sciences Northwestern Switzerland (FHNW), Gruendenstrasse 40, CH-4132 Muttenz, Switzerland.;Institute of Chemistry and Bioanalytics, University of Applied Sciences Northwestern Switzerland (FHNW), Gruendenstrasse 40, CH-4132 Muttenz, Switzerland.;Institute of Pathology and Legal Medicine, Canton Hospital Grisons, Loëstrasse 170, CH-7000 Chur, Switzerland.;Forensic Chemistry and Toxicology, Institute of Legal Medicine of the University of Basel, Pestalozzistrasse 22, CH-4056 Basel, Switzerland.",
"authors": "Dussy|F E|FE|;Hangartner|S|S|;Hamberg|C|C|;Berchtold|C|C|;Scherer|U|U|;Schlotterbeck|G|G|;Wyler|D|D|;Briellmann|T A|TA|",
"chemical_list": "D002186:Cannabinoids; D013287:Illicit Drugs; D010880:Piperidines; D015283:Citalopram; D000069348:Quetiapine Fumarate; D000082:Acetaminophen; C071395:ocfentanil",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkw096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "40(9)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000082:Acetaminophen; D001344:Autopsy; D001826:Body Fluids; D002138:Calibration; D002186:Cannabinoids; D002851:Chromatography, High Pressure Liquid; D015283:Citalopram; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D010880:Piperidines; D000069348:Quetiapine Fumarate; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D055815:Young Adult",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "761-766",
"pmc": null,
"pmid": "27650310",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An Acute Ocfentanil Fatality: A Case Report with Postmortem Concentrations.",
"title_normalized": "an acute ocfentanil fatality a case report with postmortem concentrations"
}
|
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{
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},
{
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"medicinalproduct": "CAFFEINE."
}
],
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}
],
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},
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"qualification": "3",
"reportercountry": "CH"
},
"primarysourcecountry": "CH",
"receiptdate": "20170718",
"receivedate": "20170718",
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},
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},
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"seriousnessdeath": 1,
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"transmissiondate": "20171127"
},
{
"companynumb": "CH-TEVA-764428ROM",
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{
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"medicinalproduct": "CAFFEINE."
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{
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"medicinalproduct": "PARACETAMOL"
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{
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"medicinalproduct": "QUETIAPINE."
}
],
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{
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}
],
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},
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},
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},
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},
{
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{
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},
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"drugdosagetext": "UNKNOWN",
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"medicinalproduct": "OCFENTANYL"
}
],
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"reaction": [
{
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{
"abstract": "BACKGROUND\nObesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated.\n\n\nMETHODS\nThe authors evaluated the relation between BMI and outcomes in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group that included chemotherapy regimens with doxorubicin and cyclophosphamide, including E1199, E5188, and E3189. Results are expressed as hazard ratios (HRs) from Cox proportional hazards models (HR >1 indicates a worse outcome). All P values are 2-sided.\n\n\nRESULTS\nWhen evaluated as a continuous variable in trial E1199, increasing BMI within the obese (BMI, ≥ 30 kg/m(2)) and overweight (BMI, 25-29.9 kg/m(2)) ranges was associated with inferior outcomes in hormone receptor-positive, human epidermal growth receptor 2 (HER-2)/neu-negative disease for disease-free survival (DFS; P = .0006) and overall survival (OS; P = .0007), but not in HER-2/neu-overexpressing or triple-negative disease. When evaluated as a categorical variable, obesity was associated with inferior DFS (HR, 1.24; 95% confidence interval [CI], 1.06-1.46; P = .0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P = .002) in hormone receptor-positive disease, but not other subtypes. In a model including obesity, disease subtype, and their interaction, the interaction term was significant for OS (P = .02) and showed a strong trend for DFS (P = .07). Similar results were found in 2 other trials (E5188, E3189).\n\n\nCONCLUSIONS\nIn a clinical trial population that excluded patients with significant comorbidities, obesity was associated with inferior outcomes specifically in patients with hormone receptor-positive operable breast cancer treated with standard chemohormonal therapy.",
"affiliations": "Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA. [email protected]",
"authors": "Sparano|Joseph A|JA|;Wang|Molin|M|;Zhao|Fengmin|F|;Stearns|Vered|V|;Martino|Silvana|S|;Ligibel|Jennifer A|JA|;Perez|Edith A|EA|;Saphner|Tom|T|;Wolff|Antonio C|AC|;Sledge|George W|GW|;Wood|William C|WC|;Fetting|John|J|;Davidson|Nancy E|NE|",
"chemical_list": "D011960:Receptors, Estrogen; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.27527",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "118(23)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D015992:Body Mass Index; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009765:Obesity; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "5937-46",
"pmc": null,
"pmid": "22926690",
"pubdate": "2012-12-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "10791773;18280327;15894097;15328174;16450399;21115859;17939036;17179478;16236737;19731015;14519753;8874335;17635889;19501243;20547990;20071471;18437560;20571870;9667255;20935336;12829800;18635428;7981391;19474385;16087950;18420499;15761078;16331345;11553815;20620929;17159189;21115856;16236738;20404251",
"title": "Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer.",
"title_normalized": "obesity at diagnosis is associated with inferior outcomes in hormone receptor positive operable breast cancer"
}
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"literaturereference": "SPARANO JA, WANG M, ZHAO F, STEARNS V, MARTINO S, LIGIBEL JA, ET AL. OBESITY AT DIAGNOSIS IS ASSOCIATED WITH INFERIOR OUTCOMES IN HORMONE RECEPTOR-POSITIVE OPERABLE BREAST CANCER. CANCER 01-DEC-2012;118 (NO. 23):5937-5946.",
"literaturereference_normalized": "obesity at diagnosis is associated with inferior outcomes in hormone receptor positive operable breast cancer",
"qualification": "1",
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"abstract": "OBJECTIVE\nTo compare the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS) versus azathioprine (AZA) in patients with active systemic lupus erythematosus (SLE) disease.\n\n\nMETHODS\nA multicentre, 24-month, superiority, open-label, randomised controlled trial (NCT01112215) was conducted with 240 patients (120 per arm) receiving either EC-MPS (target dose: 1440 mg/day) or AZA (target dose: 2 mg/kg/day) in addition to prednisone and/or antimalarials. The primary endpoint was the proportion of patients achieving clinical remission, assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG), at 3 and 24 months. Secondary endpoints included time to clinical remission, BILAG A and B flare rates, time to flare, corticosteroid reduction and adverse events (AEs).\n\n\nRESULTS\nProportion of patients achieving clinical remission (clinical SLEDAI=0) was higher in the EC-MPS group at 3 (32.5% vs 19.2%; treatment difference, 13.3 (CI 2.3 to 24), p=0.034) and 24 months (71.2% vs 48.3%; treatment difference, 22.9 (CI 10.4 to 34.4), p<0.001). EC-MPS was superior with respect to time to clinical remission (HR 1.43; 95% CI 1.07 to 1.91; p=0.017). BILAG A/B and B flares occurred more frequently in the AZA group (71.7% vs 50%, p=0.001 and 21.67% vs 8.3%, p=0.004, respectively). EC-MPS was superior with respect to time to first BILAG A/B (HR 1.81; 95% CI 1.3 to 2.56; p=0.0004) and BILAG A flare (HR 2.84; 95% CI 1.37 to 5.89; p=0.003). AEs were similar in both groups except for leucopenia that occurred more frequently with AZA.\n\n\nCONCLUSIONS\nEC-MPS was superior to AZA in treating SLE and preventing further relapses.\n\n\nBACKGROUND\nNCT01112215; Results.",
"affiliations": "Autoimmune Disease Unit, Internal Medicine Department, Research Institute Vall d'Hebrón Hospital, Barcelona, Spain.;Autoimmune Diseases Unit, Internal Medicine Department, Miguel Servet Hospital, Zaragoza, Spain.;Autoimmune Diseases Unit, Internal Medicine Department, Miguel Servet Hospital, Zaragoza, Spain.;Clinical Pharmacology Department, Vall d'Hebrón Hospital, Barcelona, Spain.;Internal Medicine Department, Bellvitge University Hospital, Barcelona, Spain.;Internal Medicine Department, Sant Joan de Reus University Hospital, Reus, Spain.;Internal Medicine Department, Granollers University Hospital, Granollers, Spain.;Department of Rheumatology Unit, Granollers University Hospital, Granollers, Spain.;Internal Medicine Department, Mataró Hospital, Mataro, Spain.;Autoimmune Disease Unit, Internal Medicine Department, Research Institute Vall d'Hebrón Hospital, Barcelona, Spain.",
"authors": "Ordi-Ros|Josep|J|;Sáez-Comet|Luis|L|;Pérez-Conesa|Mercedes|M|;Vidal|Xavier|X|;Mitjavila|Francesca|F|;Castro Salomó|Antoni|A|;Cuquet Pedragosa|Jordi|J|;Ortiz-Santamaria|Vera|V|;Mauri Plana|Montserrat|M|;Cortés-Hernández|Josefina|J|",
"chemical_list": "D000962:Antimalarials; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D009173:Mycophenolic Acid; D001379:Azathioprine; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2016-210882",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "76(9)",
"journal": "Annals of the rheumatic diseases",
"keywords": "Outcomes research; Systemic Lupus Erythematosus; Treatment",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D000962:Antimalarials; D001379:Azathioprine; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011241:Prednisone; D012074:Remission Induction; D013608:Tablets, Enteric-Coated",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1575-1582",
"pmc": null,
"pmid": "28450313",
"pubdate": "2017-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Enteric-coated mycophenolate sodium versus azathioprine in patients with active systemic lupus erythematosus: a randomised clinical trial.",
"title_normalized": "enteric coated mycophenolate sodium versus azathioprine in patients with active systemic lupus erythematosus a randomised clinical trial"
}
|
[
{
"companynumb": "PHHY2017ES127552",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
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"drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS",
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{
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"medicinalproduct": "PREDNISONE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Cervix carcinoma",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
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}
],
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},
"primarysource": {
"literaturereference": "ORDI-ROS J, SAEZ-COMET L, PEREZ-CONESA M, VIDAL X, MITJAVILA F, SALOMO AC ET AL.. ENTERIC-COATED MYCOPHENOLATE SODIUM VERSUS AZATHIOPRINE IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS: A RANDOMISED CLINICAL TRIAL.. ANNALS OF THE RHEUMATIC DISEASES. 2017;1-8",
"literaturereference_normalized": "enteric coated mycophenolate sodium versus azathioprine in patients with active systemic lupus erythematosus a randomised clinical trial",
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"transmissiondate": "20171127"
}
] |
{
"abstract": "Intestinal obstruction is a common acute presentation of advanced rectal cancer, which could be managed with surgical or non-surgical techniques including metallic stenting. Bevacizumab has been gaining popularity in the treatment of advanced colorectal cancer (CRC) in combination with different chemotherapeutic agents, to improve the overall survival rate; however, data regarding the adverse effects of bevacizumab in combination with other treatment modalities have been insufficient. Herein, we present a case of a 37-year-old man diagnosed with advanced rectal cancer with concurrent liver and lung metastases. He was started on Xelox (capecitabine plus oxaliplatin) chemotherapy in combination with bevacizumab for palliative care. He developed an episode of bowel obstruction, which was managed with emergent placement of a metallic stent. Soon after that, the patient presented emergently with signs and symptoms of intestinal perforation. He underwent emergent surgical intervention with stoma creation and a complicated hospital course. Despite the oncological benefits of bevacizumab for treating metastatic CRC, complications can occur resulting in a devastating outcome, with intestinal perforation being the most serious rare complication.",
"affiliations": "Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU.;Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU.",
"authors": "Akeel|Nouf|N|;Toonsi|Wafaa A|WA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.12831",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12831\nGeneral Surgery\nOncology\nGastrointestinal Perforation With an Intraluminal Stent and Bevacizumab use in Advanced Metastatic Colorectal Cancer\nMuacevic Alexander Adler John R Akeel Nouf 1 Toonsi Wafaa A 1 \n1 \nSurgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU \n\nNouf Akeel [email protected]\n21 1 2021 \n1 2021 \n13 1 e1283121 1 2021 Copyright © 2021, Akeel et al.2021Akeel et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/50090-gastrointestinal-perforation-with-an-intraluminal-stent-and-bevacizumab-use-in-advanced-metastatic-colorectal-cancerIntestinal obstruction is a common acute presentation of advanced rectal cancer, which could be managed with surgical or non-surgical techniques including metallic stenting. Bevacizumab has been gaining popularity in the treatment of advanced colorectal cancer (CRC) in combination with different chemotherapeutic agents, to improve the overall survival rate; however, data regarding the adverse effects of bevacizumab in combination with other treatment modalities have been insufficient. Herein, we present a case of a 37-year-old man diagnosed with advanced rectal cancer with concurrent liver and lung metastases. He was started on Xelox (capecitabine plus oxaliplatin) chemotherapy in combination with bevacizumab for palliative care. He developed an episode of bowel obstruction, which was managed with emergent placement of a metallic stent. Soon after that, the patient presented emergently with signs and symptoms of intestinal perforation. He underwent emergent surgical intervention with stoma creation and a complicated hospital course. Despite the oncological benefits of bevacizumab for treating metastatic CRC, complications can occur resulting in a devastating outcome, with intestinal perforation being the most serious rare complication.\n\ngastrointestinal perforationintraluminal stentbevacizumabmetastatic cancercolorectal cancercase reportThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nColorectal cancer (CRC) is considered the third most common malignancy worldwide, affecting 1.4 million humans each year. Its wide distribution and natural history make it the fourth leading cause of cancer deaths globally [1]. \n\nRectal cancer represents 35% of the total incidence of CRC in the European Union [2]. Presentations range from asymptomatic, incidental findings to locally advanced and metastatic disease, where complications have already occurred. Studies found that 25% of patients present late in stage 4, 85% of whom initially present with intestinal obstruction that manifests as vomiting, obstipation, or abdominal distention. Management of advanced cases includes a variety of surgical and non-surgical options, which may either be curative or palliative. However, poor overall survival and a survival deficit persist for up to one year after surgical intervention as candidates are usually older and have other comorbidities [3].\n\nOne of the acceptable surgical therapeutic options to relieve symptoms of obstruction related to advanced CRC in emergency situations is the Hartmann procedure with colostomy creation. Although this approach has been the gold standard for managing emergency situations over the past two decades, its complications are devastating [4]. Self-expanding metallic stents (SEMS) have gained popularity in the management of distal malignant obstruction, either for palliation or as a bridge to surgery for resectable tumors, allowing relief of the obstruction without stoma formation [5]. Although SEMS have success rates exceeding 90% and mortality rates as low as 1%, the possibility of developing [6] a life-threatening perforation raises the mortality rates to approximately 20%-30% [7], despite an overall perforation incidence of 4% [6].\n\nBevacizumab (Avastin®), a monoclonal antibody that blocks vascular endothelial growth factor, is an important mediator of tumor angiogenesis [8]. Studies have demonstrated that bevacizumab significantly improves the overall survival in patients with advanced metastatic CRC [9].\n\nA study of patients with advanced CRC who were treated with bevacizumab in combination with chemotherapy and surgical interventions with a total of three years surveillance found that, for all patients who were treated with bevacizumab, most adverse effects were hematological (neutropenia and leukopenia). No severe bevacizumab-related toxicities were noted in this study, including bleeding, gastric-intestinal perforation, and thromboembolism. Despite its oncological benefits, bevacizumab can result in rare complications such as bowel perforation, a life-threatening condition with poor survival and devastating outcomes [10].\n\nCase presentation\nA 37-year-old man was diagnosed with advanced rectosigmoid adenocarcinoma with concurrent lung and liver metastasis and received palliative Xelox (capecitabine plus oxaliplatin) chemotherapy in combination with bevacizumab. He presented to the emergency department at King Abdelaziz Hospital in the Kingdom of Saudi Arabia, with symptoms suggestive of intestinal obstruction. He was managed with placement of a metal stent and discharged in a good condition. Three weeks later, a few days after he finished his 7th and last cycle of chemotherapy, he presented to the emergency department again complaining of a two-day history of abdominal pain. Physical examination found a rigid peritonitic abdomen, tachycardia of 110, and blood pressure of 110/60. His lab results were unremarkable, and initial erect and supine abdominal radiographs showed bowel loops distended within normal limits, no air-fluid level, and no free air. His abdominal and pelvic CT scans with intravenous and oral contrast revealed a stent in its proper position with the superior anterior part indenting the anterior rectal wall, which led us to suspect perforation (Figures 1-3). Free fluid with free air was also noted in the sub-hepatic and right pelvic regions. \n\nFigure 1 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (sagittal view)\nFigure 2 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (axial view)\nFigure 3 CT scan of the abdomen demonstrating the rectal stent in its place but intending the anterior rectal wall; note the free air in the abdomen (coronal view)\nThe patient underwent exploratory laparotomy, which revealed fecal material in the peritoneal cavity. Abdominal exploration showed a perforation at the rectosigmoid junction with the stent exposed (Figure 4). After peritoneal lavage, a loop colostomy was created and a pelvic drain was inserted. The post-operative course was complicated by a pelvic abscess and partial wound dehiscence. Moreover, he developed multiple attacks of rectal bleeding that were controlled through palliative radiotherapy. The total length of hospital stay was two months after which the patient was discharged in a satisfactory condition. Following this admission, he was lost to follow up.\n\nFigure 4 Intraoperative picture of the perforated anterior rectal wall\nDiscussion\nOne might expect that combining chemotherapy, bevacizumab, and a self-expanding metal stent would increase the perforation rates. However, the paucity of the literature on this special circumstance limits judgment.\n\nThe oncological benefits of bevacizumab in combination with chemotherapy were demonstrated in a phase III trial by Chen et al. [11]. They reported that the addition of bevacizumab to irinotecan/5-fluorouracil/leucovorin as a first-line therapy for metastatic CRC was associated with a significantly increased response rate, progression-free survival, and survival rates.\n\nMultiple studies have demonstrated the risk of perforation in similar conditions, i.e., advanced obstructed rectal cancer combined with metal stent placement, neoadjuvant chemotherapy, and bevacizumab therapy. One study that enrolled all of the patients with advanced CRC who were treated in their institute over an 11-year period, found no significant difference in the incidence of gastrointestinal perforation between the groups that underwent chemotherapy alone and chemotherapy plus bevacizumab, chemotherapy and chemotherapy plus bevacizumab, or chemotherapy alone and no chemotherapy (p = 0.21, p = 0.63, and p = 0.42, respectively) [12]. \n\nThe predisposing factors that are most commonly suggested for bevacizumab-related perforation are peptic ulcer disease, diverticulitis, chemotherapy-induced colitis, a history of abdominal radiation, and abdominal carcinomatosis have been discussed in many articles as independent risk factors; however, there are no associations that have been sufficiently established [13]. Saif et al. [14] reported that the incidence of bowel perforation tends to be higher in candidates with a recent history of colonoscopy or sigmoidoscopy. None of these factors were present in our case except for the patient having a history of bowel obstruction that was treated with a metal stent three weeks prior to the perforation, which may have posed an additional risk of perforation. However, there have been cases reported of bevacizumab-induced bowel perforation in patients that were treated for non-small cell lung cancer despite the absence of evidence of metastatic spread to the abdomen or other predisposing risks for perforation [15].\n\nAs in our case, stenting could be an additional risk for patients on bevacizumab. The European Society of Gastrointestinal Endoscopy (ESGE) clinical guidelines provides strong recommendations for the use of self-expanding metal stents as palliative care for advanced obstructed colon cancer, except for in patients using bevacizumab; however, the evidence to substantiate this recommendation is of low quality [16]. \n\nThe timing of systemic chemotherapy administration in relation to stent insertion and the number of cycles may influence the risk of perforation; however, this idea has not yet been well established. A study reported that receiving chemotherapy after stent insertion, regardless of bevacizumab use, raises the incidence of perforation to 11% compared to only 6% in patients who received systemic therapy before the procedure, regardless of bevacizumab use [12]. One reasonable explanation for this is that, the different tumor responses to therapies result in a weakened intestinal wall and subsequent erosion of the applied stent; however, despite its occurrence, this concept could not be applied to therapies after stenting and it requires more justifiable explanations [17].\n\nConclusions\nThere are multiple modalities that can be used to manage obstructed CRC. For patients treated with bevacizumab, the risk of perforation increases, which should be taken into consideration despite it being a rare complication. Stenting on the other hand carries an additional risk of perforation, not to mention that many possible factors could augment or diminish bevacizumab’s perforation risk. This includes interpersonal differences such as demographics, disease onset and course, histological type, and location. In addition, the different treatment modalities, types of chemotherapeutic agents, timing of administration, and the period separating the last dose from the surgical procedure should be considered; however, the scarcity of these conditions has not yet been made clear. Further studies are required to investigate the different associated factors and their possible contributions to similar conditions.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n1 Global cancer incidence and mortality rates and trends--an update Cancer Epidemiol Biomarkers Prev Torre LA Siegel RL Ward EM Jemal A 16 27 25 2016 26667886 \n2 Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol Glynne-Jones R Wyrwicz L Tiret E Brown G Rödel C Cervantes A Arnold D 263 29 2018 \n3 Endoscopic stenting of colonic tumours Best Pract Res Clin Gastroenterol Baron TH Kozarek RA 209 229 18 2004 15123093 \n4 Colonic stent vs. emergency surgery for management of acute left-sided malignant colonic obstruction: a decision analysis Gastrointest Endosc Targownik LE Spiegel BM Sack J Hines OJ Dulai GS Gralnek IM Farrell JJ 865 874 60 2004 15604999 \n5 Acute colorectal obstruction: treatment with self-expandable metallic stents before scheduled surgery--results of a multicenter study Radiology Mainar A De Gregorio Ariza MA Tejero E 65 69 210 1999 9885588 \n6 Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectal obstruction Am J Gastroenterol Sebastian S Johnston S Geoghegan T Torreggiani W Buckley M 2051 2057 99 2004 https://journals.lww.com/ajg/Abstract/2004/10000/Pooled_Analysis_of_the_Efficacy_and_Safety_of.33.aspx 15447772 \n7 Presentation, treatment, and multivariate analysis of risk factors for obstructive and perforative colorectal carcinoma Am J Surg Alvarez JA Baldonedo RF Bear IG Truan N Pire G Alvarez P 376 382 190 2005 16105522 \n8 Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer Nat Rev Drug Discov Ferrara N Hillan KJ Gerber HP Novotny W 391 400 3 2004 15136787 \n9 Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200 J Clin Oncol Giantonio BJ Catalano PJ Meropol NJ 1539 1544 25 2007 17442997 \n10 Neoadjuvant oxaliplatin and capecitabine combined with bevacizumab plus radiotherapy for locally advanced rectal cancer: results of a single‐institute phase II study Cancer Commun Yu X Wang QX Xiao WW 1 9 38 2018 \n11 Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301 J Clin Oncol Chen HX Mooney M Boron M 3354 3360 24 2006 16849749 \n12 Colonic perforation with intraluminal stents and bevacizumab in advanced colorectal cancer: retrospective case series and literature review Can J Surg Imbulgoda A MacLean A Heine J Drolet S Vickers MM 167 171 58 2015 25799132 \n13 Managing patients treated with bevacizumab combination therapy Oncology Gordon MS Cunningham D 25 33 69 2005 16301833 \n14 Gastrointestinal perforation due to bevacizumab in colorectal cancer Ann Surg Oncol Saif MW Elfiky A Salem RR 1860 1869 14 2007 17356952 \n15 Bevacizumab-induced bowel perforation J Am Osteopath Assoc Sliesoraitis S Tawfik B 437 441 111 2011 21803880 \n16 Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline Endoscopy van Hooft JE van Halsema EE Vanbiervliet G 990 1053 46 2014 25325682 \n17 Gastrointestinal perforation during treatment with erlotinib plus bevacizumab in two patients with non-small cell lung cancer exhibiting epidermal growth factor receptor mutations: a case report Oncol Lett Yamaguchi T Gotoh Y Hattori H Katsuno H Imaizumi K 1046 1050 16 2018 29963181\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(1)",
"journal": "Cureus",
"keywords": "bevacizumab; case report; colorectal cancer; gastrointestinal perforation; intraluminal stent; metastatic cancer",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e12831",
"pmc": null,
"pmid": "33628692",
"pubdate": "2021-01-21",
"publication_types": "D002363:Case Reports",
"references": "15447772;26667886;21803880;9885588;25325682;16105522;29963181;17442997;25799132;15123093;17356952;15604999;29741565;15136787;16849749;16301833;29784042",
"title": "Gastrointestinal Perforation With an Intraluminal Stent and Bevacizumab use in Advanced Metastatic Colorectal Cancer.",
"title_normalized": "gastrointestinal perforation with an intraluminal stent and bevacizumab use in advanced metastatic colorectal cancer"
}
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{
"abstract": "Mycobacterial spindle cell pseudotumor (MSP) is a rare benign lesion characterized by a proliferation of bland spindle-shaped histiocytes with vague granulomatous formation, positive for acid-fast bacilli staining. This lesion is usually reported in the lymph nodes and skin of immunocompromised patients; only 6 cases primary in the lung have been reported in the English literature to this date. In this article, we present the case of a 42-year-old female status post failed kidney-pancreas transplant with subsequent multiple kidney transplants, on chronic immunosuppression, who developed a mass in the left lower lobe consistent with MSP. Mycobacterium xenopi was identified in lung tissue culture, an association never previously described in literature. This case report alerts for the possible association of this rare form of non-tuberculous mycobacteria in the pathogenesis of MSP and highlights the importance of this differential diagnosis in lung masses of immunocompromised patients.",
"affiliations": "Rush University Medical Center, Chicago, IL, USA.;Rush University Medical Center, Chicago, IL, USA.;Rush University Medical Center, Chicago, IL, USA.;Rush University Medical Center, Chicago, IL, USA.;Rush University Medical Center, Chicago, IL, USA.;Rush University Medical Center, Chicago, IL, USA.;Rush University Medical Center, Chicago, IL, USA.",
"authors": "Furlan|Karina|K|https://orcid.org/0000-0001-6383-2240;Rohra|Prih|P|;Mir|Fatima|F|;Sethi|Shenon|S|;Almajnooni|Abdullah|A|;Gattuso|Paolo|P|;Moore|Nicholas|N|https://orcid.org/0000-0002-9734-8905",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1066896919879745",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1066-8969",
"issue": "28(3)",
"journal": "International journal of surgical pathology",
"keywords": "Mycobacterium xenopi; immunocompromised patients; lung infection; mycobacteria; posttransplant patients; pseudotumor of the lung; spindle cell tumor of the lung",
"medline_ta": "Int J Surg Pathol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008171:Lung Diseases; D009165:Mycobacterium Infections, Nontuberculous; D019912:Mycobacterium xenopi",
"nlm_unique_id": "9314927",
"other_id": null,
"pages": "316-320",
"pmc": null,
"pmid": "31601138",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mycobacterium Spindle Cell Pseudotumor Caused by Mycobacterium xenopi: A First Described Association of a Rare Entity Presenting in the Lung.",
"title_normalized": "mycobacterium spindle cell pseudotumor caused by mycobacterium xenopi a first described association of a rare entity presenting in the lung"
}
|
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{
"abstract": "Metformin-associated lactic acidosis (MALA) carries a high mortality rate. It is seen in patients with type 2 diabetes on metformin or patients who attempt suicide with metformin overdose. We present the case of a man in his early 20s with type 2 diabetes, hypertension and hypothyroidism who presented with agitation, abdominal pain and vomiting after ingesting 50-60 g of metformin; he developed severe lactic acidosis (blood pH 6.93, bicarbonate 7.8 mEq/L, lactate 28.0 mEq/L). He was managed with intravenous 8.4% bicarbonate infusion and continuous venovenous haemodiafiltration. He also developed acute renal failure (ARF) requiring intermittent haemodialysis and continuous haemodiafiltration. MALA is uncommon and causes changes in different vital organs and even death. The primary goals of therapy are restoration of acid-base status and removal of metformin. Early renal replacement therapy for ARF can result in rapid reversal of the acidosis and good recovery, even with levels of lactate normally considered to be incompatible with survival.",
"affiliations": "Diabetes and Endocrine Centre, Hadfield Wing, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK [email protected].;Critical Care Department, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Critical Care Department, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Diabetes and Endocrine Centre, Hadfield Wing, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.",
"authors": "Goonoo|Mohummad Shaan|MS|http://orcid.org/0000-0003-2793-309X;Morris|Rebecca|R|;Raithatha|Ajay|A|;Creagh|Fionuala|F|",
"chemical_list": "D001639:Bicarbonates; D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin; D013974:Thyroxine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235608",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(9)",
"journal": "BMJ case reports",
"keywords": "diabetes; fluid electrolyte and acid-base disturbances; intensive care; renal intervention; toxicology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000140:Acidosis, Lactic; D058186:Acute Kidney Injury; D001639:Bicarbonates; D000079664:Continuous Renal Replacement Therapy; D003924:Diabetes Mellitus, Type 2; D062787:Drug Overdose; D005919:Glomerular Filtration Rate; D006801:Humans; D007004:Hypoglycemic Agents; D007037:Hypothyroidism; D019344:Lactic Acid; D008297:Male; D008687:Metformin; D006435:Renal Dialysis; D013974:Thyroxine; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32878828",
"pubdate": "2020-09-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin-associated lactic acidosis: reinforcing learning points.",
"title_normalized": "metformin associated lactic acidosis reinforcing learning points"
}
|
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},
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},
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},
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"reactionoutcome": "6"
},
{
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}
],
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},
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"literaturereference": "GOONOO MS, MORRIS R, RAITHATHA A, CREAGH F. METFORMIN?ASSOCIATED LACTIC ACIDOSIS: REINFORCING LEARNING POINTS. BMJ CASE REP. 2020? 13(9).",
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},
{
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},
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},
{
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},
{
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},
{
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},
{
"reactionmeddrapt": "Coagulopathy",
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},
{
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},
{
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}
],
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"literaturereference": "GOONOO MS, MORRIS R, RAITHATHA A, CREAGH F. METFORMIN?ASSOCIATED LACTIC ACIDOSIS: REINFORCING LEARNING POINTS. BMJ CASE REPORTS. 2020?13(9). DOI:10.1136/BCR?2020?235608",
"literaturereference_normalized": "metformin associated lactic acidosis reinforcing learning points",
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"reportercountry": "COUNTRY NOT SPECIFIED"
},
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"receiptdate": "20200928",
"receivedate": "20200928",
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20201103"
},
{
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{
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
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{
"reactionmeddrapt": "Agitation",
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"reactionoutcome": "2"
},
{
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute kidney injury",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Intentional overdose",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Vomiting",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Haemodynamic instability",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "GOONOO M, MORRIS R, RAITHATHA A, CREAGH F. METFORMIN-ASSOCIATED LACTIC ACIDOSIS: REINFORCING LEARNING POINTS. BMJ CASE REP.. 2020?13(9)",
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"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20201015",
"receivedate": "20170322",
"receiver": {
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},
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"safetyreportversion": 5,
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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}
] |
{
"abstract": "Rothia spp. are Gram-positive cocco-bacilli that cause a wide range of serious infections, especially in immunocompromised hosts. Risk factors for Rothia mucilaginosa (previously known as Stomatococcus mucilaginosus) bacteremia include prolonged and profound neutropenia, malignancy, and an indwelling vascular foreign body. Here, we describe 67 adults at the Mayo Clinic in Rochester, MN, from 2002 to 2012 with blood cultures positive for Rothia. Twenty-five of these patients had multiple positive blood cultures, indicating true clinical infection. Among these, 88% (22/25) were neutropenic, and 76% (19/25) had leukemia. Common sources of bacteremia were presumed gut translocation, mucositis, and catheter-related infection. One patient died with Rothia infection. Neutropenic patients were less likely to have a single positive blood culture than were nonneutropenic patients. Antimicrobial susceptibility testing was performed on 21% of the isolates. All of the tested isolates were susceptible to vancomycin and most beta-lactams; however, four of six tested isolates were resistant to oxacillin. There was no difference between the neutropenic and nonneutropenic patients in need of intensive care unit care, mortality, or attributable mortality.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Pharmacy, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA [email protected].",
"authors": "Ramanan|Poornima|P|;Barreto|Jason N|JN|;Osmon|Douglas R|DR|;Tosh|Pritish K|PK|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.01270-14",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "52(9)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D001769:Blood; D015331:Cohort Studies; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D007938:Leukemia; D008297:Male; D008826:Microbial Sensitivity Tests; D008835:Micrococcaceae; D008875:Middle Aged; D008910:Minnesota; D012189:Retrospective Studies; D016019:Survival Analysis; D055815:Young Adult",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "3184-9",
"pmc": null,
"pmid": "24951810",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "17565469;1775836;22506572;1562654;3558716;23659597;1521887;17886126;14616756;17588235;9827277;8268348;23483615;7695321;23467598;21205990;15877090;23357608",
"title": "Rothia bacteremia: a 10-year experience at Mayo Clinic, Rochester, Minnesota.",
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{
"abstract": "GVHD as a complication of SOT presents both a diagnostic and therapeutic challenge. Typically affecting the skin, gastrointestinal tract, and liver, GVHD occurs when donor lymphocytes engrafted in recipient tissues are activated by host antigen-presenting cells resulting in cytokine release and donor cell-mediated cytotoxicity to host tissue. Here, we describe a 5-year-old girl who developed fatal, refractory GVHD after isolated intestinal transplantation when recipient immune cells failed to repopulate the allograft in the setting of CMV viremia. Persistence of the donor immune cells in the allograft mucosa, rather than engraftment in the recipient bone marrow, likely perpetuated this refractory GVHD. Early diagnosis and intervention are critical to reduce morbidity and mortality. Thus, periodic monitoring of peripheral blood and allograft mucosal chimerism with sensitive detection methods may allow early detection and potentially curative enterectomy in similar cases of refractory GVHD.",
"affiliations": "Division of Pediatric Hematology/Oncology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Pathology Department, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.;Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.",
"authors": "Stanley|Kaitlin|K|0000-0002-6130-4724;Ranganathan|Sarangarajan|S|;Mazariegos|George|G|0000-0002-2624-8632;Bond|Geoffrey|G|;Soltys|Kyle|K|;Ganoza|Armando|A|;Jones|Katie|K|;Cieply|Kathleen|K|;Sindhi|Rakesh|R|0000-0001-8525-6694",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13350",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(2)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001853:Bone Marrow; D002675:Child, Preschool; D046528:Chimerism; D017809:Fatal Outcome; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D007413:Intestinal Mucosa; D007422:Intestines; D008297:Male; D012778:Short Bowel Syndrome; D014019:Tissue Donors",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13350",
"pmc": null,
"pmid": "30672115",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Donor mucosal immunocytes perpetuate refractory GVHD after intestinal transplantation without engrafting in recipient bone marrow: Case report and review of the literature.",
"title_normalized": "donor mucosal immunocytes perpetuate refractory gvhd after intestinal transplantation without engrafting in recipient bone marrow case report and review of the literature"
}
|
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{
"abstract": "In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.\n\n\n\nPatients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.\n\n\n\nAs of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).\n\n\n\nDuvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.",
"affiliations": "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. [email protected].;Department of Haematology, Flinders Medical Centre and Flinders University, Bedford Park, South Australia, Australia.;St James's University Hospital, Leeds, United Kingdom.;Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.;Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.;Oncology/Hematology Care, Cincinnati, Ohio.;Hematology/Oncology Division, Columbia University Medical Center, New York, New York.;1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary.;St Vincent's Hospital and University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.;Department of Internal Medicine III, Ulm University, Ulm, and Department of Internal Medicine I, Saarland University, Homburg, Germany.;Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy.;Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona, Spain.;Verastem Oncology, Needham, Massachusetts.;Verastem Oncology, Needham, Massachusetts.;Verastem Oncology, Needham, Massachusetts.;Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.",
"authors": "Davids|Matthew S|MS|;Kuss|Bryone J|BJ|;Hillmen|Peter|P|0000-0001-5617-4403;Montillo|Marco|M|;Moreno|Carol|C|;Essell|James|J|;Lamanna|Nicole|N|;Nagy|Zsolt|Z|;Tam|Constantine S|CS|;Stilgenbauer|Stephan|S|;Ghia|Paolo|P|0000-0003-3750-7342;Delgado|Julio|J|;Lustgarten|Stephanie|S|;Weaver|David T|DT|;Youssoufian|Hagop|H|;Jäger|Ulrich|U|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007546:Isoquinolines; D011687:Purines; C586691:duvelisib; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C486018:PIK3CD protein, human; C546760:PIK3CG protein, human; C527517:ofatumumab",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-19-3061",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "26(9)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D018592:Cross-Over Studies; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007546:Isoquinolines; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011687:Purines; D016879:Salvage Therapy; D015996:Survival Rate",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "2096-2103",
"pmc": null,
"pmid": "31964785",
"pubdate": "2020-05-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL in the DUO Crossover Extension Study.",
"title_normalized": "efficacy and safety of duvelisib following disease progression on ofatumumab in patients with relapsed refractory cll or sll in the duo crossover extension study"
}
|
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"abstract": "Methotrexate-associated lymphoproliferative disorders are categorized as \"other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4-8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8+ cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8+ cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus+ tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8+ cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.",
"affiliations": "Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan. [email protected].;Department of Pathology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan.;Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.;Department of Pathology, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Pathology, Saitama Medical University International Medical Center, Saitama, Japan.;Division of Pathophysiology, Okayama University Graduate School of Health Sciences, Okayama, Japan.;Department of Pathology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan.;Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.;Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan.;Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan.;Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.",
"authors": "Satou|Akira|A|;Tabata|Tetsuya|T|;Miyoshi|Hiroaki|H|http://orcid.org/0000-0002-2356-3725;Kohno|Kei|K|;Suzuki|Yuka|Y|;Yamashita|Daisuke|D|;Shimada|Kazuyuki|K|;Kawasaki|Tomonori|T|;Sato|Yasuharu|Y|;Yoshino|Tadashi|T|;Ohshima|Koichi|K|;Takahara|Taishi|T|;Tsuzuki|Toyonori|T|http://orcid.org/0000-0002-4855-4366;Nakamura|Shigeo|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1038/s41379-019-0264-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-3952",
"issue": "32(8)",
"journal": "Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc",
"keywords": null,
"medline_ta": "Mod Pathol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007119:Immunoblastic Lymphadenopathy; D007166:Immunosuppressive Agents; D016411:Lymphoma, T-Cell, Peripheral; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D012189:Retrospective Studies; D016176:T-Lymphocyte Subsets; D013602:T-Lymphocytes, Cytotoxic",
"nlm_unique_id": "8806605",
"other_id": null,
"pages": "1135-1146",
"pmc": null,
"pmid": "30952973",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases.",
"title_normalized": "methotrexate associated lymphoproliferative disorders of t cell phenotype clinicopathological analysis of 28 cases"
}
|
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},
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{
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{
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},
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}
] |
{
"abstract": "Extended-release dipyridamole plus aspirin is widely used for secondary prevention of ischemic stroke, although the molecular pharmacodynamics of dipyridamole are not completely determined. Adverse effects of fixed-dose combination of aspirin and dipyridamole include headache, bleeding, and gastrointestinal events. Previously, intravenous infusion of dipyridamole in cardiac stress testing has been associated with cardiogenic shock and pulmonary edema. Herein, we report a case study of a 72-year-old man, presented with a transient ischemic attack who suffered a circulatory collapse after an oral dose of 200 mg extended-release dipyridamole. The possible molecular mechanisms of dipyridamole on the cardiovascular system are reviewed. This is the first case report of a circulatory collapse induced by an oral intake of dipyridamole.",
"affiliations": "Department of Neurology, Tampere University Hospital, Tampere, Finland. Electronic address: [email protected].;Department of Neurology, Tampere University Hospital, Tampere, Finland.;Department of Surgery, Division of Vascular Surgery, Tampere University Hospital, Tampere, Finland.",
"authors": "Jolma|Pasi|P|;Ollikainen|Jyrki|J|;Uurto|Ilkka|I|",
"chemical_list": "D003692:Delayed-Action Preparations; D010975:Platelet Aggregation Inhibitors; D004176:Dipyridamole",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.08.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "27(12)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Adverse effect; collapse; dipyridamole; stroke",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D003692:Delayed-Action Preparations; D004176:Dipyridamole; D006801:Humans; D002546:Ischemic Attack, Transient; D008297:Male; D010975:Platelet Aggregation Inhibitors; D012769:Shock",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "3460-3462",
"pmc": null,
"pmid": "30185396",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oral Dipyridamole-Associated Circulatory Collapse.",
"title_normalized": "oral dipyridamole associated circulatory collapse"
}
|
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},
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},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "ASPIRIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN\\DIPYRIDAMOLE"
},
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"drugadministrationroute": "048",
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"drugdosageform": null,
"drugdosagetext": "FORMULATION: EXTENDED RELEASE",
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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},
{
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},
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"drugdosagetext": "1 DROP PER DAY",
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"drugindication": "GLAUCOMA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LATANOPROST."
}
],
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"patientonsetage": "72",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Circulatory collapse",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cyanosis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JOLMA P, OLLIKAINEN J, UURTO I. ORAL DIPYRIDAMOLE?ASSOCIATED CIRCULATORY COLLAPSE. JOURNAL OF STROKE AND CEREBROVASCULAR DISEASES. 2018?.",
"literaturereference_normalized": "oral dipyridamole associated circulatory collapse",
"qualification": "1",
"reportercountry": "FI"
},
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"receiptdate": "20180917",
"receivedate": "20180917",
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},
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"transmissiondate": "20181010"
},
{
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{
"abstract": "A 72-year-old woman with metastatic ER/PR-positive breast cancer who had been on ribociclib and letrozole for 1 year developed severe life-threatening colitis. She presented to emergency department with features of acute abdomen and diarrhoea. The diagnosis of colitis was confirmed radiologically as well as by histopathological examination of the biopsy specimen and the patient clinically improved after withholding ribociclib and receiving corticosteroids compatible with ribociclib-induced colitis. The mechanism of injury in CDK 4/6 inhibitor-induced colitis is unknown but may be related to recruitment of inflammatory cells. Whether the development of colitis is associated with tumour response is an interesting and unanswered question.",
"affiliations": "Medical Oncology Department, Queen Elizabeth Hospital, Birmingham, UK [email protected].;Medical Oncology Department, Queen Elizabeth Hospital, Birmingham, UK.;Medical Oncology Department, Queen Elizabeth Hospital, Birmingham, UK.;Medical Oncology Department, Queen Elizabeth Hospital, Birmingham, UK.",
"authors": "Malik|Azhar Abbas|AA|;Abbas|Haider|H|;Oo|Zin Mar|ZM|;Lim|Zerlene|Z|http://orcid.org/0000-0002-6134-374X",
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"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242766",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "Breast cancer; Unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000631:Aminopyridines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003092:Colitis; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D005260:Female; D006801:Humans; D000077289:Letrozole; D011687:Purines; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34312131",
"pubdate": "2021-07-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "CDK4/6 inhibitor-induced colitis: a case report and review of the literature.",
"title_normalized": "cdk4 6 inhibitor induced colitis a case report and review of the literature"
}
|
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}
},
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}
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{
"abstract": "Post-transplant hyperglycaemia of diabetic patients may cause recurrent diabetic kidney disease (DKD) in kidney allografts. We report a patient with slowly progressive DKD with calcineurin inhibitor toxicity (CNI) toxicity after the kidney transplantation. A 28-year-old female with type 1 diabetes mellitus underwent successful kidney transplantation from her mother in April 2003, and the kidney graft survived for more than 10 years. She was treated with combined immunosuppressive therapy consisting of cyclosporine and mycophenolate mofetil. After transplantation, she continued to take insulin injection four times per day, but her glycosylated haemoglobin (HbA1c) was above 10%. Protocol allograft kidney biopsies performed 5 and 10 years after transplantation revealed the recurrence of slowly progressive diabetic kidney disease. In addition, arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity (CNI) was detected with progression. Post-transplant hyperglycaemia causes recurrent diabetic kidney disease (DKD) in kidney allografts, but its progression is usually slow. For long-term management, it is important to prevent the progression of the calcineurin inhibitor arteriolopathy, as well as maintain favourable glycaemic control.",
"affiliations": "Department of Medicine, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Pathology, Kidney Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Medicine, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Pathology, Kidney Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Surgery, Kidney Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Surgery, Kidney Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.;Department of Medicine, Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.",
"authors": "Nyumura|Izumi|I|;Honda|Kazuho|K|;Babazono|Tetsuya|T|;Horita|Shigeru|S|;Murakami|Toru|T|;Fuchinoue|Shohei|S|;Uchigata|Yasuko|Y|",
"chemical_list": "D015415:Biomarkers; D001786:Blood Glucose; D065095:Calcineurin Inhibitors; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D007328:Insulin; C517652:hemoglobin A1c protein, human",
"country": "Australia",
"delete": false,
"doi": "10.1111/nep.12454",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5358",
"issue": "20 Suppl 2()",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": "calcineurin inhibitor toxicity (CIN); diabetic kidney disease (DKD); type 1 diabetes",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D000328:Adult; D050379:Arteriolosclerosis; D015415:Biomarkers; D001706:Biopsy; D001786:Blood Glucose; D065095:Calcineurin Inhibitors; D003922:Diabetes Mellitus, Type 1; D003928:Diabetic Nephropathies; D018450:Disease Progression; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D007328:Insulin; D007668:Kidney; D016030:Kidney Transplantation; D019520:Living Donors; D008854:Microscopy, Electron; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9615568",
"other_id": null,
"pages": "90-2",
"pmc": null,
"pmid": "26031596",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrence of diabetic kidney disease in a type 1 diabetic patient after kidney transplantation.",
"title_normalized": "recurrence of diabetic kidney disease in a type 1 diabetic patient after kidney transplantation"
}
|
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},
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
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},
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": null,
"patientonsetage": "28",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Kidney fibrosis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diabetic end stage renal disease",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal tubular atrophy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Arterial injury",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "NYUMURA I, HONDA K, BABAZONO T, HORITA S, MURAKAMI T, FUCHINOUE S ET AL. RECURRENCE OF DIABETIC KIDNEY DISEASE IN A TYPE 1 DIABETIC PATIENT AFTER KIDNEY TRANSPLANTATION. NEPHROLOGY. 2015;20(SUPPL2):90-92",
"literaturereference_normalized": "recurrence of diabetic kidney disease in a type 1 diabetic patient after kidney transplantation",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20150612",
"receivedate": "20150611",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 2,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "This case report highlights the potential severity of bisphosphonate-associated reactions.\n\n\nMETHODS\nA 76-year-old lady underwent several hospital admissions for investigation of fever associated with rigors, abdominal pain, and vomiting.\n\n\nCONCLUSIONS\nDespite multiple investigations, no cause was found, but the timing of the symptoms coincided with monthly risedronate administration.",
"affiliations": "Austin Health, 145 Studley Road, Heidelberg, Australia, [email protected].",
"authors": "Shah|Sonali|S|;Jeremiah|Cameron|C|;Johnson|Douglas|D|;Baker|Scott|S|",
"chemical_list": "D004164:Diphosphonates; D000068296:Risedronic Acid; D012968:Etidronic Acid",
"country": "England",
"delete": false,
"doi": "10.1007/s11657-015-0213-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "10()",
"journal": "Archives of osteoporosis",
"keywords": null,
"medline_ta": "Arch Osteoporos",
"mesh_terms": "D018784:Abdominal Abscess; D000368:Aged; D004164:Diphosphonates; D012968:Etidronic Acid; D005260:Female; D006801:Humans; D010024:Osteoporosis; D000068296:Risedronic Acid; D018805:Sepsis",
"nlm_unique_id": "101318988",
"other_id": null,
"pages": "213",
"pmc": null,
"pmid": "25792348",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Risedronate as an intra-abdominal sepsis mimic: a case report.",
"title_normalized": "risedronate as an intra abdominal sepsis mimic a case report"
}
|
[
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-95650",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"medicinalproduct": "METHOTREXATE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
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"drugdosagetext": "LOW DOSE",
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"drugindication": "POLYMYALGIA RHEUMATICA",
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"medicinalproduct": "PREDNISOLONE."
},
{
"actiondrug": "1",
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"activesubstancename": "RISEDRONATE SODIUM"
},
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"drugdosagetext": "150 MG, MONTHLY",
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}
],
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"reactionmeddrapt": "Chills",
"reactionmeddraversionpt": "18.0",
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},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Vomiting",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Diarrhoea",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Confusional state",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Sinus tachycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "SHAH S, JEREMIAH C, JOHNSON D, BAKER S. RISEDRONATE AS AN INTRA-ABDOMINAL SEPSIS MIMIC: A CASE REPORT. ARCH-OSTEOPOROS. 2015;10 (1)",
"literaturereference_normalized": "risedronate as an intra abdominal sepsis mimic a case report",
"qualification": "3",
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},
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},
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"transmissiondate": "20150821"
},
{
"companynumb": "AU-MYLANLABS-2015M1012916",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISEDRONATE SODIUM"
},
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"medicinalproduct": "RISEDRONATE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sinus tachycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Chills",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Confusional state",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHAH S, JEREMIAH C, JOHNSON D, BAKER S. RISEDRONATE AS AN INTRA-ABDOMINAL SEPSIS MIMIC: A CASE REPORT. ARCH-OSTEOPOROS 2015; 10:NO. 9.",
"literaturereference_normalized": "risedronate as an intra abdominal sepsis mimic a case report",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20150420",
"receivedate": "20150420",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
{
"abstract": "A female patient in her seventies affected by a signet-ring cell carcinoma G3pT4N3 (24/29), with lymphovascular invasion, HER2-negative. After completing three cycles of first-line systemic treatment in combination with cisplatin (CDDP) + 5-fluorouracil (5FU), a new systemic therapy line with paclitaxel + Cyramza (ramucirumab) was planned. On the day after the first administration the patient manifested a Standford type A aortic dissection (AD), with a diameter of around 6.5 cm and dissection flap originating in the ascending aorta below the brachiocephalic trunk, extended to the whole descending aorta until the carrefour. The causal relationship between adverse drug reactions and Cyramza, calculated using the Naranjo algorithm, led to a result of 'probable' correlation between ramucirumab and AD. The endothelial dysfunction associated with vascular endothelial growth factor pathway inhibitors (VPIs) would seem to be the most plausible explanation for such events: it causes thromboembolic events and cardiovascular complications.",
"affiliations": "Hospital Pharmacy Department, ASST Bergamo EST, Alzano Lombardo, Italy.;Scuola di Specializzazione Farmacia Ospedaliera, Università degli Studi di Milano, Milan, Italy.;Hospital Pharmacy Department, ASST Bergamo EST, Alzano Lombardo, Italy.;Oncology Department, ASST Bergamo EST, Seriate, Italy.;Hospital Pharmacy Department, ASST Bergamo EST, Alzano Lombardo, Italy.;Hospital Pharmacy Department, ASST Bergamo EST, Alzano Lombardo, Italy.",
"authors": "Zenoni|Davide|D|0000-0002-1060-5252;Beretta|Flavio Niccolò|FN|;Martinelli|Vanessa|V|;Iaculli|Alessandro|A|;Benzoni Fratelli|Maria Teresa|MT|;Bonzi|Delia|D|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C543333:ramucirumab",
"country": "England",
"delete": false,
"doi": "10.1136/ejhpharm-2019-001879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2047-9956",
"issue": "27(2)",
"journal": "European journal of hospital pharmacy : science and practice",
"keywords": "adverse effects; cardiology; chemotherapy; gastrointestinal tumours; oncology",
"medline_ta": "Eur J Hosp Pharm",
"mesh_terms": "D000368:Aged; D000784:Aneurysm, Dissecting; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001014:Aortic Aneurysm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous",
"nlm_unique_id": "101578294",
"other_id": null,
"pages": "117-120",
"pmc": null,
"pmid": "32133140",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25662791;21621130;18525305;18607842;17309856;28223329;24094768;19875754;26887374;23065042;22199439;29724300;17145990;18603160;25351639;17964363;30085888;12917408",
"title": "Aortic dissection after ramucirumab infusion.",
"title_normalized": "aortic dissection after ramucirumab infusion"
}
|
[
{
"companynumb": "IT-MYLANLABS-2020M1034120",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
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"drugauthorizationnumb": null,
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"medicinalproduct": "5-FLUOROURACIL /00098801/"
},
{
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},
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"medicinalproduct": "PACLITAXEL."
},
{
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},
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"drugdosagetext": "WITH 75% DOSAGE",
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"medicinalproduct": "CISPLATIN."
},
{
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"activesubstancename": "RAMUCIRUMAB"
},
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"drugauthorizationnumb": null,
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"drugenddate": "2018",
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"drugstartdateformat": "602",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CYRAMZA"
}
],
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"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Gastrointestinal toxicity",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZENONI D, BERETTA FN, MARTINELLI V, IACULLI A, BENZONI FRATELLI MT, BONZI D. AORTIC DISSECTION AFTER RAMUCIRUMAB INFUSION. EJHP-SP 2020?27(2):117-120.",
"literaturereference_normalized": "aortic dissection after ramucirumab infusion",
"qualification": "1",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20200402",
"receivedate": "20200402",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17616590,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200713"
},
{
"companynumb": "IT-TEVA-2020-IT-1218852",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"abstract": "BACKGROUND\nQuinine can cause diverse and severe immune-mediated adverse reactions, including thrombotic microangiopathy (TMA). Our objective was to describe the presenting features and long-term outcomes of patients with quinine-induced TMA.\n\n\nMETHODS\nA case series of 19 patients with quinine-induced TMA treated with plasma exchange.\n\n\nMETHODS\nPatients with quinine-induced TMA initially suspected of having thrombotic thrombocytopenic purpura (TTP) were identified among patients enrolled in the Oklahoma TTP-Hemolytic Uremic Syndrome Registry.\n\n\nRESULTS\nThe clinical course of the initial episode and morbidity and mortality following recovery.\n\n\nMETHODS\nThe diagnosis of quinine-induced TMA was confirmed by documentation of quinine-dependent antibodies reactive with platelets or neutrophils and/or by previous quinine-associated systemic symptoms. Clinical data from the initial episode and long-term follow-up were described, focusing on kidney function.\n\n\nRESULTS\n19 of the 509 patients enrolled in the registry in 1989 to 2015 had quinine-induced TMA. 18 patients had quinine-dependent antibodies reactive with platelets and/or neutrophils (1 patient died before testing); 8 patients had a history of quinine-associated systemic symptoms. All patients were white; 18 were women. Quinine exposure was in pill form for 18 patients and as tonic water for 1. All patients had microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. All were initially misdiagnosed as having TTP or hemolytic uremic syndrome, and adverse reactions to quinine were not initially suspected. 1 patient died before treatment began; 17 of the 18 surviving patients required dialysis. 14 patients developed chronic kidney disease, 3 of whom developed end-stage renal disease. 8 patients died.\n\n\nCONCLUSIONS\nPatients for whom plasma exchange was not requested were not identified.\n\n\nCONCLUSIONS\nQuinine-induced TMA causes severe acute kidney injury that commonly results in chronic kidney disease.",
"affiliations": "Department of Biostatistics and Epidemiology, College of Public Health, Oklahoma City, OK; Hematology-Oncology Section, Department of Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK.;Nephrology Service, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, MD.;Department of Biostatistics and Epidemiology, College of Public Health, Oklahoma City, OK.;Department of Biostatistics and Epidemiology, College of Public Health, Oklahoma City, OK; Hematology-Oncology Section, Department of Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK. Electronic address: [email protected].",
"authors": "Page|Evaren E|EE|;Little|Dustin J|DJ|;Vesely|Sara K|SK|;George|James N|JN|",
"chemical_list": "D009125:Muscle Relaxants, Central; D011803:Quinine",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2017.05.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "70(5)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Thrombotic microangiopathy (TMA); acute kidney injury (AKI); adverse event; case series; chronic kidney disease (CKD); kidney function; quinine; quinine-induced TMA; registry study; thrombotic thrombocytopenic purpura (TTP)",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000743:Anemia, Hemolytic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central; D009825:Oklahoma; D010951:Plasma Exchange; D011803:Quinine; D012042:Registries; D006435:Renal Dialysis; D013921:Thrombocytopenia; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "686-695",
"pmc": null,
"pmid": "28780041",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Quinine-Induced Thrombotic Microangiopathy: A Report of 19 Patients.",
"title_normalized": "quinine induced thrombotic microangiopathy a report of 19 patients"
}
|
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},
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},
{
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},
{
"reactionmeddrapt": "Cardiovascular disorder",
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},
{
"reactionmeddrapt": "Cerebrovascular accident",
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},
{
"reactionmeddrapt": "End stage renal disease",
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},
{
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}
],
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},
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},
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},
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},
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"medicinalproduct": "QUININE SULFATE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Thrombotic microangiopathy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PAGE EE, LITTLE DJ, VESELY SK, GEORGE JN. QUININE-INDUCED THROMBOTIC MICROANGIOPATHY: A REPORT OF 19 PATIENTS. AM-J-KIDNEY-DIS 2017;70(5):686-695.",
"literaturereference_normalized": "quinine induced thrombotic microangiopathy a report of 19 patients",
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"reportercountry": "US"
},
"primarysourcecountry": "US",
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"receivedate": "20171129",
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},
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},
{
"companynumb": "US-MYLANLABS-2017M1073531",
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{
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},
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"reaction": [
{
"reactionmeddrapt": "Thrombotic microangiopathy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "PAGE EE, LITTLE DJ, VESELY SK, GEORGE JN. QUININE-INDUCED THROMBOTIC MICROANGIOPATHY: A REPORT OF 19 PATIENTS. AM-J-KIDNEY-DIS 2017;70(5):686-695.",
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},
"primarysourcecountry": "US",
"receiptdate": "20171121",
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}
] |
{
"abstract": "Tumor lysis syndrome (TLS) is an uncommon, but well described, clinical entity that typically occurs following chemotherapy in patients with rapidly growing hematological malignancies. It is rarely described in patients with solid tumors. We report a case of TLS in a patient with metastatic adenocarcinoma of the prostate after treatment with paclitaxel chemotherapy.",
"affiliations": "Department of Urology, University of Washington, WA, USA.",
"authors": "Wright|Jonathan L|JL|;Lin|Daniel W|DW|;Dewan|Puneet|P|;Montgomery|R Bruce|RB|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017430:Prostate-Specific Antigen; D017239:Paclitaxel",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1442-2042.2005.01196.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-8172",
"issue": "12(11)",
"journal": "International journal of urology : official journal of the Japanese Urological Association",
"keywords": null,
"medline_ta": "Int J Urol",
"mesh_terms": "D000230:Adenocarcinoma; D000972:Antineoplastic Agents, Phytogenic; D019046:Bone Marrow Neoplasms; D001859:Bone Neoplasms; D006417:Hematuria; D006801:Humans; D006869:Hydronephrosis; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D006435:Renal Dialysis; D051437:Renal Insufficiency; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "9440237",
"other_id": null,
"pages": "1012-3",
"pmc": null,
"pmid": "16351664",
"pubdate": "2005-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tumor lysis syndrome in a patient with metastatic, androgen independent prostate cancer.",
"title_normalized": "tumor lysis syndrome in a patient with metastatic androgen independent prostate cancer"
}
|
[
{
"companynumb": "US-PFIZER INC-2018035127",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "076131",
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"drugdosageform": null,
"drugdosagetext": "UNK",
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"drugenddateformat": null,
"drugindication": "PROSTATE CANCER METASTATIC",
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"medicinalproduct": "PACLITAXEL."
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Tumour lysis syndrome",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WRIGHT, J.. TUMOR LYSIS SYNDROME IN A PATIENT WITH METASTATIC, ANDROGEN INDEPENDENT PROSTATE CANCER. INT J UROL. 2005?12:1012-1013",
"literaturereference_normalized": "tumor lysis syndrome in a patient with metastatic androgen independent prostate cancer",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180126",
"receivedate": "20180126",
"receiver": {
"receiverorganization": "FDA",
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},
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"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "OBJECTIVE\nBased on the significant prolongation of progression-free survival in a randomized phase III trial, RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors, Third Trial), everolimus has been approved for the management of advanced, progressive pancreatic neuroendocrine tumors (pNET). Here, we describe 15 participants in RADIANT-3 who were treated with everolimus at our study center. We report the long-term survival of a subset of patients.\n\n\nMETHODS\nPatients with advanced, progressive pNET were randomly assigned to the everolimus arm of RADIANT-3 or received everolimus as open-label treatment after experiencing progression on placebo or during the unblinded phase.\n\n\nRESULTS\nFive patients on everolimus (5-10 mg/day) had stable disease for >43 to >76 months after initiating treatment. Three patients achieved stable disease for 19-25 months, but died of progressive malignancy thereafter. Seven patients had stable disease for ≤11 months after initiating everolimus therapy.\n\n\nCONCLUSIONS\nPatients with advanced, progressive pNET can obtain long-term benefit from daily oral treatment with everolimus.",
"affiliations": "Markey Cancer Center/University of Kentucky, Lexington, Ky., USA.",
"authors": "Wolin|Edward M|EM|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000369780",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "60(3)",
"journal": "Chemotherapy",
"keywords": null,
"medline_ta": "Chemotherapy",
"mesh_terms": "D000328:Adult; D000368:Aged; D018450:Disease Progression; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D020123:Sirolimus",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "143-50",
"pmc": null,
"pmid": "25766415",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term everolimus treatment of patients with pancreatic neuroendocrine tumors.",
"title_normalized": "long term everolimus treatment of patients with pancreatic neuroendocrine tumors"
}
|
[
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
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"drugdosagetext": "10 MG, QD",
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"drugindication": "PANCREATIC NEUROENDOCRINE TUMOUR",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "EVEROLIMUS"
}
],
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"patientonsetage": "54",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Upper respiratory tract infection",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Joint swelling",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Herpes zoster",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Rash erythematous",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oedema peripheral",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hyperglycaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WOLIN EM.. LONG-TERM EVEROLIMUS TREATMENT OF PATIENTS WITH PANCREATIC NEUROENDOCRINE TUMORS.. CHEMOTHERAPY. 2015;60:143-150",
"literaturereference_normalized": "long term everolimus treatment of patients with pancreatic neuroendocrine tumors",
"qualification": "3",
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},
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"receivedate": "20150529",
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
},
{
"companynumb": "PHHY2015US064285",
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"occurcountry": "US",
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{
"actiondrug": null,
"activesubstance": {
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},
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"drugdosagetext": "10 MG, QD",
"drugenddate": "20091230",
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}
],
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"patientonsetage": "59",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Cholangitis acute",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Gastrooesophageal reflux disease",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight decreased",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal pain upper",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hyperglycaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dermatitis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Device occlusion",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WOLIN EM. LONG-TERM EVEROLIMUS TREATMENT OF PATIENTS WITH PANCREATIC NEUROENDOCRINE TUMORS.. CHEMOTHERAPY. 2014;60:143-150",
"literaturereference_normalized": "long term everolimus treatment of patients with pancreatic neuroendocrine tumors",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150601",
"receivedate": "20150601",
"receiver": {
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},
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},
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},
{
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{
"abstract": "Despite the occurrence of serious side effects, the use of cyclosporin A after organ transplantation has increased because of its ability to effectively suppress allograft rejection. Its use in the treatment of ophthalmic disease has also recently increased. Central nervous system toxicity due to cyclosporin A is a significant but apparently clinically reversible side effect. A liver transplant patient in whom cortical blindness from profound neurotoxicity was the initial presentation is described. Neurologic abnormalities, including cortical blindness, resolved completely after discontinuation of cyclosporin A. However, pathologic studies performed 8.5 months after the initial transplant revealed residual central nervous system demyelination.",
"affiliations": "Department of Ophthalmology, Mayo Clinic Foundation, Rochester, Minnesota 55905.",
"authors": "Wilson|S E|SE|;de Groen|P C|PC|;Aksamit|A J|AJ|;Wiesner|R H|RH|;Garrity|J A|JA|;Krom|R A|RA|",
"chemical_list": "D003524:Cyclosporins",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0272-846X",
"issue": "8(4)",
"journal": "Journal of clinical neuro-ophthalmology",
"keywords": null,
"medline_ta": "J Clin Neuroophthalmol",
"mesh_terms": "D001766:Blindness; D001921:Brain; D003524:Cyclosporins; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009778:Occipital Lobe; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8109051",
"other_id": null,
"pages": "215-20",
"pmc": null,
"pmid": "2977135",
"pubdate": "1988-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cyclosporin A-induced reversible cortical blindness.",
"title_normalized": "cyclosporin a induced reversible cortical blindness"
}
|
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"reactionmeddrapt": "Toxic optic neuropathy",
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{
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"summary": null
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"primarysource": {
"literaturereference": "WILSON, S.. CYCLOSPORIN A-INDUCED REVERSIBLE CORTICAL BLINDNESS. JOURNAL OF CLINICAL NEURO-OPHTHALMOLOGY. 1988?8 (4):215-220",
"literaturereference_normalized": "cyclosporin a induced reversible cortical blindness",
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{
"abstract": "Low-grade endometrial stromal sarcoma (LGESS) is a rare malignancy. The tumor is reportedly responsive to hormonal therapy, most commonly with medroxyprogesterone acetate (MPA), but the effectiveness of aromatase inhibitors for recurrent LGESS remains unclear. The present study reports a case of stage IC LGESS presenting with abnormal uterine bleeding, and also provides a review of the literature. Following a total abdominal hysterectomy and bilateral salpingo-oophorectomy, MPA therapy was initiated; treatment was successful, but discontinued 19 months later due to disruptive side effects. A further 2 months later, the patient presented with recurrent disease and received chemotherapy. MPA treatment was restarted with a partial response. A second recurrence, 4 years later, presented with lung and para-aortic lymph node metastases. The patient responded to treatment with the aromatase inhibitor letrozole. The patient has since exhibited stable disease and remained free of symptoms for 7 years. This case suggests that aromatase-inhibitor treatment may be effective for recurrent LGESS as a second-line treatment.",
"affiliations": "Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Organ Pathology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.;Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.",
"authors": "Nakamura|Kohei|K|;Nakayama|Kentaro|K|;Ishikawa|Masako|M|;Ishikawa|Noriyoshi|N|;Katagiri|Hiroshi|H|;Katagiri|Atsuko|A|;Ishibashi|Tomoka|T|;Sato|Emi|E|;Iida|Kohji|K|;Sultana|Razia|R|;Kyo|Satoru|S|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2016.5186",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2016.5186OL-0-0-5186ArticlesLetrozole as second-line hormonal treatment for recurrent low-grade endometrial stromal sarcoma: A case report and review of the literature Nakamura Kohei 1Nakayama Kentaro 1Ishikawa Masako 1Ishikawa Noriyoshi 2Katagiri Hiroshi 1Katagiri Atsuko 1Ishibashi Tomoka 1Sato Emi 1Iida Kohji 1Sultana Razia 1Kyo Satoru 11 Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan2 Department of Organ Pathology, Shimane University School of Medicine, Izumo, Shimane 6938501, JapanCorrespondence to: Dr Kentaro Nakayama, Department of Obstetrics and Gynecology, Shimane University School of Medicine, Enyacho 89-1, Izumo, Shimane 6938501, Japan, E-mail: [email protected] 2016 26 9 2016 26 9 2016 12 5 3856 3860 24 4 2015 03 8 2016 Copyright: © Nakamura et al.2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Low-grade endometrial stromal sarcoma (LGESS) is a rare malignancy. The tumor is reportedly responsive to hormonal therapy, most commonly with medroxyprogesterone acetate (MPA), but the effectiveness of aromatase inhibitors for recurrent LGESS remains unclear. The present study reports a case of stage IC LGESS presenting with abnormal uterine bleeding, and also provides a review of the literature. Following a total abdominal hysterectomy and bilateral salpingo-oophorectomy, MPA therapy was initiated; treatment was successful, but discontinued 19 months later due to disruptive side effects. A further 2 months later, the patient presented with recurrent disease and received chemotherapy. MPA treatment was restarted with a partial response. A second recurrence, 4 years later, presented with lung and para-aortic lymph node metastases. The patient responded to treatment with the aromatase inhibitor letrozole. The patient has since exhibited stable disease and remained free of symptoms for 7 years. This case suggests that aromatase-inhibitor treatment may be effective for recurrent LGESS as a second-line treatment.\n\nlow-grade endometrial stromal sarcomahormonal therapymedroxyprogesterone acetatearomatase inhibitorsurvival\n==== Body\nIntroduction\nEndometrial stromal sarcoma (ESS) is an uncommon malignancy, accounting for <1% of all uterine carcinomas and 7–15% of all uterine sarcomas (1). ESS is classified as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS) and undifferentiated uterine sarcoma (2). LGESS shows minimal to no cytological atypia and low mitotic activity (usually <5 mitoses per 10 high-power fields (HPFs). HGESS shows high mitotic activity (typically >10 per 10 HPFs) and is typically very striking. LGESS is generally a slow-growing malignancy with an indolent clinical course, but with a tendency for late recurrence, while HGESS is more aggressive, frequently metastasizes and has an extremely poor outcome.\n\nAlthough no universal staging system exists for ESS, the International Federation of Gynecology and Obstetrics surgical staging system for endometrial cancer is typically used (2). Total abdominal hysterectomy and bilateral salpingo-oophorectomy is recommended as the primary treatment, with debulking recommended when extrauterine disease is apparent. The role of chemotherapy, radiation or hormonal treatment as adjuvant therapy has not yet been established. A number of studies have demonstrated estrogen and progesterone receptor expression in LGESS (3,4). Furthermore, LGESS has previously been shown to be responsive to hormonal therapy, including aromatase inhibitors and megestrol acetate (3,5,6). Studies have shown that synthesized progestins, including medroxyprogesterone acetate (MPA), are an effective conservative treatment for endometrial cancer (7,8).\n\nIn our previous study, we reported the cases of 2 patients with metastatic LGESS lesions who experienced prolonged survival following treatment with MPA (9). However, to the best of our knowledge, only 5 case reports detailing recurrent LGESS treated with aromatase inhibitors are reported in the literature. The present study reports a case of recurrent LGESS that was treated with surgery, followed by MPA for 2 years as first-line therapy and the aromatase inhibitor letrozole for 6 years as second-line hormonal therapy. The patient has survived for 13 years since the initial surgery.\n\nCase report\nA 58-year-old (gravida 2, para 2) woman was referred to Shimane University School of Medicine (Izumo, Japan) in May 2002 due to persistent abnormal vaginal bleeding. The patient reported a history of rheumatoid arthritis, but no other significant past medical or surgical history. Endometrial curettage revealed LGESS, based on the characteristics of the cells observed, which resembled the stromal cells of proliferative endometrium. In consequence, a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed in May 2002. The resected specimens were sectioned (section thickness, 3 µm), and stained with hematoxylin and eosin. Subsequently, the specimens were immunohistochemically stained with the following antibodies: Anti-cluster of differentiation (CD) 10 (1:1; pre-diluted rabbit monoclonal; clone SP67; Roche Diagnostics, Basel, Switzerland); anti-estrogen receptor (1:1; pre-diluted rabbit monoclonal; clone SP1; Roche Diagnostics); anti-progesteron receptor (1:1; pre-diluted rabbit monoclonal; clone 1E2; Roche Diagnostics); anti-h-caldesmon (1:50; mouse monoclonal; clone h-CD; Dako, Glostrup, Denmark); anti-cytokeratin AE1/AE3/PCK26 (1:1; pre-diluted; clone AE1/AE3/PCK26; Roche Diagnostics); anti-cytokeratin Cam5.2 (1:2; mouse monoclonal; clone Cam5.2; Roche Diagnostics); anti-desmin (1:100; mouse monocolonal; clone D33; Dako); anti-α-smooth muscle actin (1:100; mouse monoclonal; clone 1A4; Dako); anti-Melan A (1:1; pre-diluted mouse monoclonal; clone A103; Dako); and anti-human melanoma black-45 (1:50; mouse monoclonal; clone HMB-45; Dako). The histopathological result was of stage IC, low-grade ESS of the corpus uteri (Fig. 1). In addition, immunostaining revealed that the tumor tissue was positive for estrogen receptor (Fig. 2), progesterone receptor (Fig. 3) and CD10, and negative for h-caldesmon, AE1/AE3, Cam5.2, desmin, α-smooth muscle actin, Melan A and human melanoma black 45.\n\nPost-operatively, the patient was started on 600 mg daily MPA as adjuvant therapy. The patient experienced no recurrence for 19 months, but was forced to discontinue MPA at that time, as it worsened the rheumatoid arthritis symptoms. Another 2 months later, computed tomography (CT) revealed enlargement of the common iliac lymph nodes. The patient underwent chemotherapy with 6 cycles of doxorubicin (25 mg/m2 on days 1–2) and ifosfamide (1 mg/m2 on days 1–5) every 3 weeks, along with lymph-node radiation. Three months after completing chemotherapy, MPA was restarted as the rheumatoid arthritis symptoms had improved. The lymph nodes gradually decreased in size and this partial response was maintained for 3 years.\n\nIn January 2008, CT revealed a mass in the left lung measuring 19×13 mm (Fig. 4) and a para-aortic lymph node enlarged to 20×12 mm, compressing the right common iliac vein. MPA treatment was discontinued at this point and the patient underwent a secondary complete resection of the lung tumor. Similarly to the endometrial curettage result, the histopathological result confirmed disease metastasis. Post-operatively, informed consent was obtained for treatment with 2.5 mg daily letrozole. The patient has continued letrozole treatment to this date, and has remained asymptomatic and progression-free for 7 years.\n\nDiscussion\nESS is classified as low grade, high grade and undifferentiated based on morphology and mitotic rate. Although LGESS exhibits a relatively indolent behavior, the possibility of late recurrences and distant metastases exists (10). The risk of recurrence is believed to be as much as 50%, although such tumors usually grow slowly and the recurrence occurs late (10). In a previous large case series, the time between diagnosis or hysterectomy and recurrence was reported as between 3 months and 23 years, with a median time of 3 years (10). In the largest clinical study to date on LGESS, the median time between hysterectomy and relapse was recorded as 5.4 years for stage I disease and 9 months for disease at stages III–IV (11). In our previous series, the median disease-free time was 50 months (12).\n\nLymphadenectomy has not been determined to confer long-term survival in patients with LGESS (13,14). The patient in the present study was diagnosed with LGESS following surgery, which did not include either pelvic or para-aortic lymphadenectomy. Although there has been no systematic study on the advantages of adjuvant chemotherapy in LGESS, a number of retrospective analyses have shown that doxorubicin and ifosfamide combination chemotherapy exhibit a certain degree of efficacy (15–18). The present patient experienced a partial response to doxorubicin and ifosfamide-containing chemotherapy and MPA following the first recurrence.\n\nThere are few reports on the effectiveness of aromatase inhibitors in patients with recurrent LGESS due to the rarity of the disease. To the best of our knowledge, there are only 5 case reports describing aromatase inhibitors as either first- or second-line treatment for recurrent LGESS (5,19–22). Table I shows the demographic features of the patients in these cases, including the patient featured in the present study.\n\nSeveral studies have described estrogen and progesterone receptor expression in ESS tumors, and have evaluated the efficacy of progestins as a treatment modality (2,23–26). In all previous patients treated with aromatase inhibitors, immunostaining was positive for estrogen and progesterone receptors; this also applied to the present patient. All studies in the present literature review have suggested the effectiveness of aromatase inhibitors, including letrozole and anastrozole, in the treatment of recurrent LGESS (5,19–22). No definitive conclusions about treatment with aromatase inhibitors can be drawn, but this option should be taken into consideration for patients with recurrent LGESS and positive immunostaining for estrogen and progesterone receptors. We recommend that immunostaining be performed when the tumor is first determined to be ESS.\n\nAromatase inhibitors were used as second-line treatment in 3 previous studies and as first-line treatment in only 1 study by Leunen et al (5). Therefore, no conclusions can be drawn as to the priority of MPA or aromatase inhibitors as first-line treatment. Due to their efficacy, further studies are warranted to evaluate aromatase inhibitors as first-line hormonal therapy in these neoplasms.\n\nIn summary, the present case reported a recurrent LGESS that responded to treatment with the aromatase inhibitor letrozole, and our experience suggests that aromatase inhibitor treatment may be effective for patients with recurrent LGESS. A number of additional case studies will be necessary to confirm these findings and support the suggested treatment.\n\nFigure 1. Cells resembling the stromal cells of proliferative endometrium arranged around small arterioles. Magnification, (A) ×100 and (B) ×400.\n\nFigure 2. Immunohistochemical staining positive for estrogen receptor (magnification, ×200).\n\nFigure 3. Immunohistochemical staining positive for progesterone receptor (magnification, ×200).\n\nFigure 4. Contrast-enhanced computed tomography of the lungs showing a metastatic lesion (arrow).\n\nTable I. Previous cases of recurrent low-grade endometrial stromal sarcoma treated with aromatase inhibitors.\n\nFirst author, year\tPatient age at diagnosis, years\tTumor stage\tImmunostaining\tInterval from diagnosis to recurrence, months\tSite of recurrent lesion\tFirst-line treatment for recurrence\tSecond-line treatment for recurrence\tSurvival since initial diagnosis, years\tSurvival since use of aromatase inhibitor, years\t(Ref.)\t\nLeunen et al 2004\t76\t–\tER(+), PR(+)\t300\tPelvis\tAromatase inhibitor (letrozole)\t–\t28\t3\t(5)\t\nSpano et al 2003\t44\t–\tER(+), PR(+)\t 3\tLung, rectum\tHRT\tAromatase inhibitor (aminoglutethimide)\t16\t8\t(19)\t\n\t34\t–\tER(+), PR(+)\t 12\tLung\tHRT\tAromatase inhibitor (letrozole)\t11\t2\t\t\nLeiser et al 2004\t48\tI\tER(+), PR(+)\t 18\tPelvis\tChemotherapy (BEP)\tMegestrol acetate + aromatase inhibitor (anastrozole)\t4.5\t2\t(20)\t\nMaluf et al 2001\t51\t–\tER(+), PR(+)\t 60\tPelvis, subcutaneous nodules, subcapsular liver implant\tMPA\tAromatase inhibitor (letrozole)\t 8\t0.75\t(21)\t\nShoji et al 2011\t34\tI\tER(+), PR(+)\t 60\tPelvis, ovary, peritoneum\tMPA\tAromatase inhibitor (anastrozole)\t21\t2\t(22)\t\nCurrent patient\t58\tIC\tER(+), PR(+)\t 19\tLung, para-aortic lymph node\tMPA and chemotherapy (ICA)\tAromatase inhibitor (letrozole)\t13\t7\t\t\nER, estrogen receptor; PR, progesterone receptor; MPA, medroxyprogesterone acetate; HRT, hormonal replacement therapy; BEP, bleomycin + etoposide + cisplatin; ICA, ifosfamide + carboplatin + doxorubicin.\n==== Refs\nReferences\n1 Echt G Jepson J Steel J Langholz B Luxton G Hernandez W Astrahan M Petrovich Z Treatment of uterine sarcomas Cancer 66 35 39 1990 10.1002/1097-0142(19900701)66:1<35::AID-CNCR2820660108>3.0.CO;2-V 2354406 \n2 Kurman RJ Carcangiu ML Herrington S Young RH World Health Organization Classification of Tumours of Female Reproductive Organs 4th IARC Press Lyon, France \n3 Tsukamoto N Kamura T Matsukuma K Imachi M Uchino H Saito T Ono M Endolymphatic stromal myosis: A case with positive estrogen and progesterone receptors and good response to progestins Gynecol Oncol 20 120 128 1985 10.1016/0090-8258(85)90132-5 3965374 \n4 Sabini G Chumas JC Mann WJ Steroid hormone receptors in endometrial stromal sarcomas. A biochemical and immunohistochemical study Am J Clin Pathol 97 381 386 1992 10.1093/ajcp/97.3.381 1371902 \n5 Leunen M Breugelmans M De Sutter P Bourgain C Amy JJ Low-grade endometrial stromal sarcoma treated with the aromatase inhibitor letrozole Gynecol Oncol 95 769 771 2004 10.1016/j.ygyno.2004.07.063 15582003 \n6 Pink D Lindner T Mrozek A Kretzschmar A Thuss-Patience PC Dörken B Reichardt P Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: Single center experience with 10 cases and review of the literature Gynecol Oncol 101 464 469 2006 10.1016/j.ygyno.2005.11.010 16368128 \n7 Kaku T Yoshikawa H Tsuda H Sakamoto A Fukunaga M Kuwabara Y Hataeg M Kodama S Kuzuya K Sato S Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: Central pathologic review and treatment outcome Cancer Lett 167 39 48 2001 10.1016/S0304-3835(01)00462-1 11323097 \n8 Ushijima K Yahata H Yoshikawa H Konishi I Yasugi T Saito T Nakanishi T Sasaki H Saji F Iwasaka T Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women J Clin Oncol 25 2798 2803 2007 10.1200/JCO.2006.08.8344 17602085 \n9 Ishibashi M Nakayama K Shamima Y Katagiri A Iida K Nakayama N Miyazaki K Two cases of endometrial stromal sarcoma (ESS) in which survival was prolonged by administration of MPA Gan To Kagaku Ryoho 35 857 861 2008 (In Japanese) 18487930 \n10 Stadsvold JL Molpus KL Baker JJ Michael K Remmenga SW Conservative management of a myxoid endometrial stromal sarcoma in a 16-year-old nulliparous woman Gynecol Oncol 99 243 245 2005 10.1016/j.ygyno.2005.06.039 16054205 \n11 Amant F Moerman P Cadron I Neven P Berteloot P Vergote I The diagnostic problem of endometrial stromal sarcoma: Report on six cases Gynecol Oncol 90 37 43 2003 10.1016/S0090-8258(03)00207-5 12821339 \n12 Nakayama K Ishikawa M Nagai Y Yaegashi N Aoki Y Miyazaki K Prolonged long-term survival of low-grade endometrial stromal sarcoma patients with lung metastasis following treatment with medroxyprogesterone acetate Int J Clin Oncol 15 179 183 2010 10.1007/s10147-010-0040-2 20217451 \n13 Shah JP Bryant CS Kumar S Ali-Fehmi R Malone JM Jr Morris RT Lymphadenectomy and ovarian preservation in low-grade endometrial stromal sarcoma Obstet Gynecol 112 1102 1108 2008 10.1097/AOG.0b013e31818aa89a 18978112 \n14 Thomas MB Keeney GL Podratz KC Dowdy SC Endometrial stromal sarcoma: Treatment and patterns of recurrence Int J Gynecol Cancer 19 253 256 2009 10.1111/IGC.0b013e3181999c5f 19396004 \n15 Haberal A Kayikçioğlu F Boran N Calişkan E Ozgül N Köse MF Endometrial stromal sarcoma of the uterus: Analysis of 25 patients Eur J Obstet Gynecol Reprod Biol 109 209 213 2003 10.1016/S0301-2115(03)00078-2 12860344 \n16 Omura GA Blessing JA Major F Lifshitz S Ehrlich CE Mangan C Beecham J Park R Silverberg S A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: A gynecologic oncology group study J Clin Oncol 3 1240 1245 1985 3897471 \n17 Pautier P Genestie C Fizazi K Morice P Mottet C Haie-Meder C Le Cesne A Lhommé C Cisplatin-based chemotherapy regimen (DECAV) for uterine sarcomas Int J Gynecol Cancer 12 749 754 2002 10.1046/j.1525-1438.2002.01144.x 12445254 \n18 Kim WY Lee JW Choi CH Kang H Kim TJ Kim BG Lee JH Bae DS Low-grade endometrial stromal sarcoma: A single center's experience with 22 cases Int J Gynecol Cancer 18 1084 1089 2008 10.1111/j.1525-1438.2007.01159.x 18179547 \n19 Spano JP Soria JC Kambouchner M Piperno-Neuman S Morin F Morere JF Martin A Breau JL Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma Med Oncol 20 87 93 2003 10.1385/MO:20:1:87 12665689 \n20 Leiser AL Hamid AM Blanchard R Recurrence of prolactin-producing endometrial stromal sarcoma with sex-cord stromal component treated with progestin and aromatase inhibitor Gynecol Oncol 94 567 571 2004 10.1016/j.ygyno.2004.03.025 15297205 \n21 Maluf FC Sabbatini P Schwartz L Xia J Aghajanian C Endometrial stromal sarcoma: Objective response to letrozole Gynecol Oncol 82 384 388 2001 10.1006/gyno.2001.6238 11531300 \n22 Shoji K Oda K Nakagawa S Kawana K Yasugi T Ikeda Y Takazawa Y Kozuma S Taketani Y Aromatase inhibitor anastrozole as a second-line hormonal treatment to a recurrent low-grade endometrial stromal sarcoma: A case report Med Oncol 28 771 774 2011 10.1007/s12032-010-9511-6 20354812 \n23 Chu MC Mor G Lim C Zheng W Parkash V Schwartz PE Low-grade endometrial stromal sarcoma: Hormonal aspects Gynecol Oncol 90 170 176 2003 10.1016/S0090-8258(03)00258-0 12821359 \n24 Piver MS Rutledge FN Copeland L Webster K Blumenson L Suh O Uterine endolymphatic stromal myosis: A collaborative study Obstet Gynecol 64 173 178 1984 6738952 \n25 Katz L Merino MJ Sakamoto H Schwartz PE Endometrial stromal sarcoma: A clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors Gynecol Oncol 26 87 97 1987 10.1016/0090-8258(87)90074-6 3792939 \n26 Scribner DR Jr Walker JL Low-grade endometrial stromal sarcoma preoperative treatment with Depo-Lupron and Megace Gynecol Oncol 71 458 460 1998 10.1006/gyno.1998.5174 9887250\n\n",
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"title": "Letrozole as second-line hormonal treatment for recurrent low-grade endometrial stromal sarcoma: A case report and review of the literature.",
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"abstract": "The decision for PJP prophylaxis depends on a physician's evaluation of multiple variables. The high rate of PJP infection described in this article combined with the known impaired T-cell function post Bendamustine treatment justifies considering all patients for PJP prophylaxis when they receive Bendamustine treatment.",
"affiliations": "Department of Haematology, University Hospital Limerick Limerick, Ireland.;Department of Haematology, University Hospital Limerick Limerick, Ireland.;Department of Haematology, University Hospital Limerick Limerick, Ireland.;Graduate Entry Medical School, University of Limerick Limerick, Ireland.;Department of Haematology, University Hospital Limerick Limerick, Ireland ; Graduate Entry Medical School, University of Limerick Limerick, Ireland.;Department of Haematology, University Hospital Limerick Limerick, Ireland ; Graduate Entry Medical School, University of Limerick Limerick, Ireland.;Department of Haematology, University Hospital Limerick Limerick, Ireland ; Graduate Entry Medical School, University of Limerick Limerick, Ireland.",
"authors": "Abkur|Tarig Mohammed|TM|;Saeed|Mamoun|M|;Ahmed|Saad Zeinalabdin|SZ|;McArthur|Ryan|R|;Leahy|Maeve|M|;O'Leary|Hilary|H|;O'Keeffe|Denis|D|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Repccr3Clinical Case Reports2050-09042050-0904BlackWell Publishing Ltd Oxford, UK 10.1002/ccr3.195Case ReportsPneumocystis jiroveci prophylaxis in patients undergoing Bendamustine treatment: the need for a standardized protocol Abkur Tarig Mohammed 1Saeed Mamoun 1Ahmed Saad Zeinalabdin 1McArthur Ryan 2Leahy Maeve 12O'Leary Hilary 12O'Keeffe Denis 121 Department of Haematology, University Hospital LimerickLimerick, Ireland2 Graduate Entry Medical School, University of LimerickLimerick, IrelandCorrespondence Tarig Mohammed Abkur, Department of Haematology, University Hospital Limerick, St. Nessan road, Dooradoyle, CO. Limerick, Ireland. Tel: +353-61-301111; Fax: +353-61-425902; E-mail: [email protected] Information No sources of funding were declared for this study.\n\n4 2015 09 2 2015 3 4 255 259 18 8 2014 24 11 2014 04 12 2014 © 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Key Clinical Message\nThe decision for PJP prophylaxis depends on a physician's evaluation of multiple variables. The high rate of PJP infection described in this article combined with the known impaired T-cell function post Bendamustine treatment justifies considering all patients for PJP prophylaxis when they receive Bendamustine treatment.\n\nBendamustinePneumocystisTrimethoprim/Sulfamethoxazole\n==== Body\nIntroduction\nPneumocystis jiroveci pneumonia (PJP) has been increasingly described as a serious opportunistic infection in HIV-seronegative patients with malignancy, as a consequence of immunosuppression from chemotherapy.\n\nThe standard method for diagnosing PJP is demonstration of Pneumocystis in either bronchoalveolar lavage fluid or induced sputum. Testing with either specimen has a sensitivity ranging from 80 to 95% 1,2. Trimethoprim/sulpfamexazole (TMP/SMX) is the gold standard for treatment and prophylaxis of PJP.\n\nThe death rate due to PJP ranges between 10 and 20% in patients with HIV 3. This infection carries a worse prognosis in the HIV seronegative population with a mortality rate of 30 to 60%, possibly as a consequence of late diagnosis and delayed treatment 4.\n\nBendamustine is an alkylating agent with multiple unique mechanisms of action. It was first synthesized in 1963 by Ozegowski and Krebs and was available only in East Germany until 1990. It is increasingly used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma and non-Hodgkin lymphomas (NHL). Myelosuppression is a common side effect of Bendamustine with severe T-lymphocyte depletion and increased risk of opportunistic infections.\n\nWe describe four cases of PJP in HIV negative individuals as sequelae of Bendamustine/Rituximab (BR) treatment. The use of PJP prophylaxis has been a routine practice in patients undergoing treatment with Bendamustine.\n\nCase Presentations\nCase 1\nA 69-year-old male was diagnosed with stage B CLL in June 2011. One year later, cytotoxic therapy was initiated with Bendamustine (100 mg/m2) on days 1 and 2 and Rituximab (375 mg/m2) on day 1. He presented on day 13 after the third cycle of treatment with dry cough, dyspnea, and a temperature of 38°C. Examination revealed oxygen saturation (SPO2) of 93% on room air. Fine crackles and wheezes were audible at both lung bases.\n\nArterial blood gas (ABG) demonstrated respiratory alkalosis with hypoxemia. Oxygen partial pressure (PO2) was 9.7 kilopascal (Kpa). Blood cultures did not identify any organism. Laboratory results showed lymphopenia, elevated C-reactive protein (CRP), and lactate dehydrogenase (LDH) at 495 U/L (220 upper limit of normal). Chest X-ray (CXR) was suggestive of PJP with a perihilar and mid-zone ground glass pattern (Fig.1). Chest Computed Tomography (CT) supported the diagnosis of PJP (Fig.2).\n\nFigure 1 CXR Showing perihilar and mid-zone ground glass pattern.\n\nFigure 2 CT-Thorax demonstrating perihilar infiltrates consistent with the diagnosis of PJP.\n\nBronchoscopy was normal, but bronchial washings were positive for PJP polymerase chain reaction (PCR). TMP/SMX was initiated at a dosage of 20 mg/kg six hourly intravenously and continued for 21 days. The patient improved and was discharged on the prophylactic dose of TMP/SMX.\n\nCase 2\nA 73-year-old male was diagnosed with marginal zone lymphoma and was treated with Bendamustine (100 mg/m2) and Rituximab (375 mg/m2) as per standard protocol. He presented on day ten after the second cycle of chemotherapy with fever and productive cough. Examination revealed tachycardia at 105 beats per minute and SPO2 of 93% on 40% oxygen. Bronchial breathing and crackles were heard at the left lower zone.\n\nInvestigations showed neutrophil leukocytosis, lymphopenia, renal impairment, high CRP at 192 mg/L and LDH of 300 U/L. ABG demonstrated hypoxemia with PO2 of 8.9 Kpa. Lobar consolidation was evident on CXR (Fig.3). Echocardiogram revealed mild mitral regurgitation, good left ventricular function, and mild left ventricular hypertrophy.\n\nFigure 3 CXR showing consolidation involving the left lower lobe.\n\nDespite treatment with Tazocin and Clarithromycin for a presumed bacterial pneumonia, he remained hypoxic. Subsequently, he was admitted to ICU for management of fast atrial fibrillation. Sputum was positive for PJP by PCR testing. Intravenous TMP/SMX was started on day six post admission at 20 mg/kg six hourly for 14 days with complete resolution of the infection.\n\nCase 3\nA 68-year-old female was diagnosed with stage IV A follicular B-cell non-Hodgkin lymphoma (FL). She was started on Bendamustine (90 mg/m2) and Rituximab (375 mg/m2) as per standard protocol. She developed fever, dry cough, and dyspnea 14 days post the third cycle of treatment. Examination revealed fever, hypotension, and tachypnea. SPO2 was 88 on 40% oxygen. Widespread wheezes were audible on chest auscultation.\n\nCXR showed bilateral upper and mid zone opacification with sparing of both bases (Fig.4). Laboratory investigations revealed lymphopenia, high CRP and LDH of 1090 U/L. The patient received Tazocin without any beneficial effect. Twenty-four hours later, she deteriorated further and remained hypotensive, breathless, and hypoxic. She was transferred to ICU, required intubation and ventilation. PJP was identified by PCR testing in the bronchoalveolar lavage.\n\nFigure 4 CXR showing bilateral upper and mid zone opacification with sparing of the bases.\n\nTreatment with intravenous TMP/SMX was started on day three of admission at 20 mg/kg six hourly and continued for 15 days. She remained on mechanical ventilation for 33 days. Eventually, she was weaned successfully from the ventilator and made a complete recovery.\n\nCase 4\nA 71-year-old female with a diagnosis of CLL was treated with Bendamustine (100 mg/m2) and Rituximab (375 mg/m2) as per standard protocol. She presented to the emergency department on day ten after the first cycle with fever, rigors and vomiting for 2 days. Physical examination revealed a high-grade temperature of 39°C, tachycardia and tachypnea. Her SPO2 was 98% on room air. No other abnormalities were identified on examination.\n\nLaboratory investigations showed lymphopenia, renal impairment, elevated CRP of 42 mg/L and LDH of 305 U/L. ABG on 40% oxygen showed hypoxemia with PO2 of 8.2 Kpa. CXR was suggestive of PJP with large volume perihilar infiltration (Fig.5).\n\nFigure 5 CXR revealing perihilar infiltration.\n\nThe patient was subsequently commenced on intravenous TMP/SMX at 20 mg/kg eight hourly and she was transferred to ICU as she was hypotensive and hypoxemic. Bronchoscopy was deferred as the patient was too unstable. Echocardiogram was normal with good LV function. She developed paroxysmal fast atrial fibrillation, which was managed with Amiodarone infusion. She made an excellent clinical recovery after 14 days of intravenous TMP/SMX with complete resolution of the radiological signs.\n\nDiscussion\nIn patients with hematological malignancies or solid tumors receiving chemotherapy or high-dose steroid therapy, clinicians should be vigilant to the possibility of PJP and consider the need for prophylaxis 5.\n\nLike HIV patients, lymphopenia may place cancer patients at increased risk of opportunistic infections such as PJP. However, in contrast to the HIV population, there has not been agreement regarding PJP prophylaxis in HIV seronegative patients receiving immunosuppressive therapies. In a meta-analysis of randomized controlled trials of PJP prophylaxis in immunocompromised patients without HIV, the meta-analysis concludes that PJP prophylaxis is indicated when the risk of PJP is higher than 3.5% in adults 6.\n\nAll patients described received Bendamustine and Rituximab. Rituximab has rarely been associated with PJP. In the initial trials of Rituximab with combination chemotherapy, over 3000 patients were treated without any cases of PJP described 7. Case reports have described Pneumocystis pneumonia post Rituximab treatment, but the rate of infection is low 8–14.\n\nBendamustine has the potential to induce a reduction in CD4 lymphocyte counts causing a severe T-lymphocyte-mediated immunosuppression. Bendamustine is a recognized risk for opportunistic infection, including PJP 15–18. It may result in grade 3 to 4 lymphopenia in 74% of patients and thus, a recent article has recommended bimonthly monitoring of CD4 T-helper cells with initiation of PJP prophylaxis in patients with counts less than 200/μL 19.\n\nA review of randomized controlled trials (RCTs) found that prophylaxis with TMP/SMX significantly reduced the occurrence of PJP by more than 90% 6. Preventive treatment was not associated with an increased risk of adverse events. Given the low rate of adverse events, which include nausea, skin rash, and myelosuppression, prophylaxis should be considered for patients at risk. According to reports, gastrointestinal symptoms and skin reactions, each occurs in about 3.5% of patients 20. The incidence and severity of the adverse reactions are generally dose dependent. Hematological cytopenias are the most serious side effect, reportedly occurring in less than 0.5% of patients 21. No differences between once daily versus thrice weekly TMP/SMX were seen 18,22.\n\nThe described patient cases provide evidence that PJP can develop in patients without significant evidence of neutropenia and infection and can occur early in treatment. Bendamustine was received by 67 patients between November 2009 and October 2014 in our practice, primarily for low-grade lymphoproliferative disorders. We describe four cases of PJP of 39 patients, who received Bendamustine before PJP prophylaxis was introduced in August 2012. Twenty-eight patients have received Bendamustine since the introduction of PJP prophylaxis without any further cases of PJP.\n\nCurrent guidelines vary without clear, consistent recommendations for PJP prophylaxis in patients receiving Bendamustine. Recent studies have prescribed PJP prophylaxis for patients with prolonged grade III/IV neutropenia 23, based on local practice 24 or based on the CD4 count 19.There is increasing evidence that the majority of patients will develop significant reductions in their CD4 counts post Bendamustine. Recent publications have described PJP post Bendamustine treatment 15–18. On the basis of this series of cases and this increasing evidence of CD4 T-cell suppression, we propose that the safest practice is to ensure that all patients receive PJP prophylaxis from the beginning of treatment with Bendamustine.\n\nConclusion\nThe decision for PJP prophylaxis depends on a physician's evaluation of multiple variables, including corticosteroid, duration, and dosage of other immunosuppressive therapy, underlying pathology and comorbidities that may adversely affect the immune system. The high rate of PJP infection described in this article combined with the known impaired T-cell function post Bendamustine treatment justifies considering all patients for PJP prophylaxis when they receive Bendamustine treatment.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\nBaughman RP Walzer PD Current methods of diagnosis Pneumocystis carinii Pneumonia 1994 2nd edn New York Dekker 381 401 \nHuang L Hecht FM Stansell JD Montanti R Hadley WK Hopewell PC Suspected pneumocystis carinii pneumonia with a negative induced sputum examination. Is early bronchoscopy useful? Am. J. Respir. Crit. Care Med 1995 151 1866 1871 7767533 \nCurtis JR Yarnold PR Schwartz DN Weinstein RA Bennett CL Improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virus related pneumocystis carinii pneumonia Am. J. Respir. Crit. Care Med 2000 162 393 398 10934059 \nSu YS Lu JJ Perng CL Chang FY Pneumocystis jirovecii pneumonia in patients with and without human immunodeficiency virus infection Journal of Microbiology, Immunology, and Infection 2008 41 478 482 \nBolle'e G Sarfati C Thie'ry G Bergeron A de Miranda S Menotti J Clinical picture of Pneumocystis jiroveci pneumonia in cancer patients Chest 2007 132 1305 1310 17934116 \nGreen H Paul M Vidal L Leibovici L Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials Mayo Clin. Proc 2007 82 1052 1059 Sep. 17803871 \nGarcía-Muñoz R Izquierdo-Gil A Muñoz A Roldan Galiacho V Rabasa P Panizo C Lymphocyte recovery is impaired in patients with CLL and indolent NHL treated with bendamustine and rituximab Ann. Hematol 2014 DOI: 10.1007/s00277-014-2135-8 \nHashimoto K Kobayashi Y Asakura Y Mori M Azuma T Maruyama D Pneumocystis jiroveci pneumonia in relation to CD4+ lymphocyte count in patients with B-cell non-Hodgkin lymphoma treated with chemotherapy Leukaemia & Lymphoma 2010 51 1816 1821 \nKurokawa T Kaya H Yoshida T Two cases of Pneumocystis jiroveci pneumonia with non-Hodgkin's lymphoma after CHOP-based chemotherapy containing rituximab J. Clin. Exp. Hematop 2010 50 159 162 21123974 \nBesada E Nossent JC Should Pneumocystis jiroveci prophylaxis be recommended with Rituximab treatment in ANCA-associated vasculitis? Clin. Rheumatol 2013 32 1677 1681 23754241 \nKamel S O'Connor S Lee N Filshie R Nandurkar H Tam CS High incidence of Pneumocystis jirovecii pneumonia in patients receiving biweekly rituximab and cyclophosphamide, adriamycin, vincristine, and prednisone Leuk. Lymphoma 2010 51 797 801 May. 20367135 \nKumar D Gourishankar S Mueller T Cockfield S Weinkauf J Vethanayagam D Pneumocystis jirovecii pneumonia after rituximab therapy for antibody-mediated rejection in a renal transplant recipient Transplant Infectious Disease 2009 11 167 170 18803617 \nShelton E Yong M Cohney S Late onset Pneumocystis pneumonia in patients receiving rituximab for humoral renal transplant rejection Nephrology 2009 14 696 699 19796030 \nKamar N Milioto O Puissant-Lubrano B Esposito L Pierre MC Ould Mohamed A Incidence and Predictive Factors for Infectious Disease after Rituximab Therapy in Kidney-Transplant Patients American Journal of Transplantation 2010 10 89 98 19656128 \nKlippstein A P Schneider C G Sayer H Höffken K Pneumocystis carinii pneumonia as a complication of benamustine monotherapy in a patient with advanced progressive breast cancer J. Cancer Res. Clin. Oncol 2003 129 316 319 12756557 \nReinbolt RE Alam S Layman R Shapiro C Lustberg M PCP in an Atypical Host Clin. Breast Cancer 2012 12 138 141 22133356 \nCarter SJ Bernstein SH Friedberg JW Barr PM Pneumocystis jirovecii pneumonia as a complication of bendamustine in a patient receiving bendamustine plus rituximab for marginal zone lymphoma Leuk. Res 2011 35 e223 e224 Nov. 21824654 \nCheson BD Friedberg JW Kahl BS Van der Jagt RH Tremmel L Bendamustine produces durable responses with an acceptable safety profile in patients with rituximab-refractory indolent non-hodgkin lymphoma Clin. Lymphoma Myeloma Leuk 2010 10 452 457 21189660 \nWolfram B Ghielmini M Bendamustine in Indolent Non-Hodgkin's Lymphoma: a Practice Guide for patient management Oncologist 2013 18 954 964 23900001 \nNHSG 2010 Acute Sector Empirical Antibiotic Guidelines (V2) November \nGoedert JJ Bower M Impact of highly effective antiretroviral therapy on the risk for Hodgkin lymphoma among people with human immunodeficiency virus infection Curr. Opin. Oncol 2012 24 531 536 22729154 \nHughes WT Rivera GK Schell MJ Thornton D Lott L Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis N. Engl. J. Med 1987 316 1627 1632 3495732 \nFischer K Cramer P Busch R Böttcher S Bahlo J Schubert J Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group Journal of Clinical Oncology 2012 30 3209 3216 22869884 \nFreedberg KA Tosteson AN Cohen CJ Cotton DJ Primary prophylaxis for Pneumocystis carinii pneumonia in HIV-infected people with CD4 counts below 200/mm3 : a cost-effectiveness analysis J. Acquir. Immune Defic. Syndr 1991 4 521 1673157\n\n",
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"abstract": "We present an interesting case of encephalopathy in a patient diagnosed with COVID19 pneumonia describing the clinical course and recovery. We hope this unique presentation can contribute to the ever-growing evidence and literature on COVID-19 encephalopathy.",
"affiliations": "D Y Patil Hospital and Medical College, Navi Mumbai, India.;D Y Patil Hospital and Medical College, Navi Mumbai, India.;D Y Patil Hospital and Medical College, Navi Mumbai, India.;D Y Patil Hospital and Medical College, Navi Mumbai, India.",
"authors": "Ganvir|Mayur|M|;Modi|Pranav|P|;Patankar|Ashwini|A|;Uppe|Abhay|A|",
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"fulltext": "\n==== Front\nCurr Health Sci J\nCurr Health Sci J\nCHSJ\nCurrent Health Sciences Journal\n2067-0656\n2069-4032\nMedical University Publishing House Craiova\n\n2021.2.26\n10.12865/CHSJ.47.02.26\nCase Report\nEncephalopathy in the Setting of COVID-19: A Case Report\nGANVIR MAYUR 1\nMODI PRANAV 1\nPATANKAR ASHWINI 1\nUPPE ABHAY 1\n1 D Y Patil Hospital and Medical College, Navi Mumbai, India\nCorresponding Author: Ashwini Patankar Dr. D Y Patil Hospital and Medical CollegeNavi [email protected]\nApr-Jun 2021\n30 6 2021\n47 2 322326\n26 1 2021\n17 6 2021\nCopyright © 2014, Medical University Publishing House Craiova\n2014\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open-access article distributed under the terms of a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License, which permits unrestricted use, adaptation, distribution and reproduction in any medium, non-commercially, provided the new creations are licensed under identical terms as the original work and the original work is properly cited.\nWe present an interesting case of encephalopathy in a patient diagnosed with COVID19 pneumonia describing the clinical course and recovery. We hope this unique presentation can contribute to the ever-growing evidence and literature on COVID-19 encephalopathy.\n\nCOVID-19\nEncephalopathy\nEncephalopathy in COVID-19\n==== Body\npmcIntroduction\n\nSince its outbreak in early 2020, COVID-19 continues to be a major health concern in most parts of the world.\n\nDuring the course of the pandemic, it has been established that COVID-19 also can cause multi-organ involvement including a wide range of neurologic manifestations [1].\n\nViral respiratory infections, in general, have a frequent association with encephalopathy and COVID-19 has often been associated with encephalopathy in as many as 31.8% of patients [1,2].\n\nThe outcomes of viral encephalopathy are usually grave and are accompanied by various complications such as seizures, vertigo, ataxia, dysarthria, dysphagia and dysphonia [3,4,5].\n\nSimilarly, patients developing COVID-19 encephalopathy have a risk of developing acute as well as long term neurological sequelae that must be identified early provided with prompt neurological rehabilitation [6].\n\nWe present an interesting case of encephalopathy in a patient diagnosed with COVID-19 pneumonia describing the clinical course and recovery.\n\nWe hope this unique presentation can contribute to the ever-growing evidence and literature on COVID-19 encephalopathy.\n\nCase Report\n\nA 48-year-old female, with a past medical history of hypothyroidism, presented for evaluation of a 3-day history of fever, cough, and breathlessness.\n\nShe was identified as a COVID-19 suspect as per standard COVID-19 protocols and admitted to the ward with an opening saturation of 90% on room air and a respiratory rate of 22 cycles per minute.\n\nPhysical examination was remarkable for reduced air entry on auscultation of bilateral lung fields.\n\nThe diagnosis of COVID-19 was confirmed by the presence of SARS-CoV-2 viral nucleic acid in a nasopharyngeal swab specimen detected by the real-time polymerase chain reaction (RT-PCR) test.\n\nThe patient further underwent a full COVID-19 workup which included chest HRCT thorax, routine serum and hematological investigations, inflammatory markers, and special tests.\n\nThe HRCT thorax showed patchy multifocal areas of ground-glass opacities scattered bilaterally in peripheral and subpleural portions of lung parenchyma.\n\nRoutine serum and hematologic workup were as in Table 1.\n\nLow flow oxygen support and oral Favipiravir was started along with standard supportive care for COVID-19.\n\nThe patient's condition worsened over three days with increased oxygen requirement and was shifted to the intensive care unit in view of tachypnoea.\n\nDuring the course in the intensive care unit, the patient was provided high flow oxygen support for three days and was started on injectable Remdesivir on compassionate grounds for six days.\n\nOwing to the raised interleukin-6 levels and parameters indicating an imminent cytokine storm, a single dose of injectable Tocilizumab in a dose of 400mg was given intravenously on the seventh day of illness (fourth day of admission).\n\nThe patient's oxygen requirement decreased after 6 days of intensive care and was gradually weaned-off oxygen support in two days.\n\nHowever, the patient suddenly had seizures a few hours before she was to be shifted to the wards.\n\nThe initial presentation was that of partial seizures followed by secondary generalization.\n\nAntiepileptic Leviteracetam was started immediately and helped terminate the seizure but on the following day, the patient presented with status epilepticus.\n\nThe patient was intubated in view of altered sensorium and low GCS.\n\nAn infusion of midazolam was started for the status epilepticus, after which her seizures terminated.\n\nExamination of the neurological system was suggestive of sluggishly reacting with preserved motor and sensory reflexes.\n\nA full workup for correctable causes of seizures was unremarkable.\n\nLumbar puncture demonstrated CSF proteins of 46 mg/dl, glucose of 200mg/dl and no cells. CSF culture both bacterial and fungal demonstrated no growth.\n\nA panel for screening out other viral, bacterial and fungal infections in CSF such as Escherichia coli, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, Cytomegalovirus (CMV), Enterovirus (EV), Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), Human herpesvirus 6 (HHV-6), Human parechovirus (HPeV), Varicella zoster virus (VZV), Cryptococcus neoformans/gattii was done and no organisms were detected.\n\nThus, steering our diagnosis towards encephalopathy and making encephalitis less likely.\n\nHowever, the testing facility for CSF-COVID-19 was not available and hence the presence of COVID-19 in CSF could not be ruled out.\n\nFurther workup included an EEG and MRI that were done after appropriate neurological opinion.\n\nThe MRI was suggestive of areas of diffusion restriction with T2, FLAIR hyperintense signal in cortical sulci of bilateral cerebral, cerebellar hemispheres, bilateral thalami and hippocampi which was suggestive of encephalopathy.\n\nThe initial EEG had left temporo-occipital spike and wave discharges of 1Hz with secondary generalization (Figure 1).\n\nThe midazolam infusion was tapered as the patient was not convulsive and the patient's mental status was reassessed.\n\nThe patient moved limbs in response to command but had eye opening on painful stimulus.\n\nPupils were reacting normally with normal motor and sensory reflexes.\n\nA repeat EEG was done to reassess the seizure activity and poor GCS that was suggestive of diffuse slowing.\n\nAfter 3 days of mechanical ventilation, the patient was weaned off the ventilator.\n\nHowever, due to a poor GCS, a tracheostomy was done.\n\nThe patient gradually improved in the following 2 weeks and began responding to verbal commands with an improved GCS of E4M5VT.\n\nThe patient was given a T-piece trial on which she maintained her saturation and tracheostomy tube was removed after 48 days of admission.\n\nThe patient further improved clinically and hemodynamic parameters were stable and was shifted to the wards after 50 days of ICU stay.\n\nDuring the course of admission in the wards, functional endoscopic evaluation of vocal was done to assess swallowing and was suggestive of left vocal cord palsy with minimal pooling in valleculae and pyriform fossa.\n\nThe patient was advised swallowing exercises to be continued.\n\nThe patient's GCS further improved to E4M6V5 and appropriate neurological rehabilitation was provided along with speech, swallowing and physical therapy till day 85 of admission.\n\nOn day 88 from the admission patient was discharged with minimal difficulty in articulation of speech and swallowing.\n\nThe patient was advised to follow up for neurological rehabilitation and physical therapy after 15 days of discharge.\n\nOn follow up, the patients EEG and MRI brain were repeated.\n\nThe EEG was suggestive of inter-ictal EEG suggestive of mild generalized background slowing.\n\nThe follow-up MRI brain reported resolving cortical changes.\n\nA written informed consent was obtained from the patient regarding the publication of these data.\n\nTable 1 Reports of the patient\n\n \n\n\tOn admission\n\n\tOnset of encephalopathy requiring intensive care\n\n(Day 6 of admission)\n\n\tPost-COVID encephalopathy while requiring mechanical ventilation\n\n(Day 8 of admission)\n\n\tOn discharge\n\n\t\nWBC (4-10x10^3/µL)\n\n\t3.4\n\n\t5.7\n\n\t8.3\n\n\t4.1\n\n\t\nPlatelets (150-400 x10^3/µL)\n\n\t165\n\n\t135\n\n\t100\n\n\t196\n\n\t\nN/L ratio\n\n\t2.2/0.9=2.44\n\n\t4.83/0.34=14.2\n\n\t6.6/1.1=6\n\n\t2.98/0.5=5.96\n\n\t\nPF ratio (Normal >300)\n\n\t81\n\n\t-\n\n\t133\n\n\t476\n\n\t\nFerritin (10-291 ng/ml)\n\n\t47.7\n\n\t-\n\n\t-\n\n\t-\n\n\t\nLDH (0-500 U/l)\n\n\t566.3\n\n\t-\n\n\t-\n\n\t-\n\n\t\nD-dimer (ng/ml)\n\n\t150\n\n\t-\n\n\t-\n\n\t-\n\n\t\nCRP (mg/l)\n\n\t60.93\n\n\t-\n\n\t-\n\n\t-\n\n\t\nPCT (0-0.5ng/ml)\n\n\t0.12\n\n\t0.24\n\n\t0.19\n\n\t1.8\n\n\t\nIL-6 (pg/ml)\n\n\t144.8\n\n\t-\n\n\t-\n\n\t-\n\n\t\nRT-PCR\n\n\tpositive\n\n\tPOSITIVE\n\n\tNEGATIVE\n\n\tNegative\n\n\t\nCreatinine (mg/dl)\n\n\t0.5\n\n\t0.5\n\n\t0.6\n\n\t0.4\n\n\t\nSodium (mg/dl)\n\n\t138\n\n\t140\n\n\t146\n\n\t137\n\n\t\n\nFigure 1 EEG suggestive of left temporo-occipital spike and wave discharges of 1 Hz with secondary generalization\n\nDiscussion\n\nVarious presentations have been described for patients diagnosed with COVID-19 infection.\n\nEncephalopathy as one of the sequelae of COVID-19 has been documented and it poses a clinical challenge to differentiate from metabolic causes of encephalopathy and encephalitis.\n\nUsually, the presence of fever, focal neurologic signs, cerebrospinal fluid (CSF) pleocytosis, neuroimaging, and electroencephalogram (EEG) findings along with presence of virus in the CSF suggest encephalitis, however only a few cases have reported a presence of COVID-19 virus in CSF [7].\n\nA definitive diagnosis of encephalopathy and distinguishing it from encephalitis is dependent on virus isolation.\n\nIn COVID-19 this is difficult because SARS-CoV-2 is transient in CSF and its titer in CSF can be extremely low [8].\n\nIn our case there was no testing facility available for CSF for COVID-19.\n\nThe occurrence of encephalopathy and encephalitis has been observed with other viral infections such as Herpes simplex virus, Dengue virus, Japanese B virus, Varicella virus, enterovirus etc. [3,5,9].\n\nVarious mechanisms of encephalopathy/ encephalitis have been studied in other viral infections which include metabolic derangement, cytokine storm, vasogenic brain edema, Reye-like syndrome, hemorrhagic shock and encephalopathy syndrome and acute necrotizing encephalopathy.\n\nIn some cases, with severity, the cases were complicated by multiple organ dysfunction and disseminated intravascular coagulation (DIC).\n\nSome cases were found to have localized edema of the cerebral cortex and have been termed acute encephalopathy with febrile convulsive status epilepticus.\n\nThese include hemi-convulsion and hemiplegia with frontal lobe predominance.\n\nThe pathogenesis is unclear but there is increasing evidence of excitotoxicity and neuronal death [3].\n\nOverall, the presence of fever, seizures and altered sensorium in this patient with COVID-19 with initial hypoxia and ongoing sepsis, with EEG and MRI suggestive of encephalopathy leads us to a near definitive diagnosis.\n\nHowever, because of lack of CSF evidence, the etiology of encephalopathy can be attributed to multiple factors.\n\nVarious mechanisms have been postulated with respect to encephalopathy in COVID-19.\n\nThe key receptor for host intracellular invasion (ACE2) is expressed in neurons and glia.\n\nThis is the site of invasion by SARS-CoV [10].\n\nIt has also been observed that in the absence of SARS-CoV-2 infiltration of CNS, cytokines can elicit neuropsychiatric symptoms.\n\nThis is hypothesized to be a consequence of neuroinflammatory responses and/or blood-brain-interface (BBI) with compromised integrity which leads to migration of peripheral immune cells into the CNS causing a disruption of neurotransmission [11,12].\n\nAnother mechanism for encephalopathy in COVID-19 is hypoxic encephalopathy, in a study by Chen T, 161 patients diagnosed with COVID-19 were evaluated of which 20% showed evidence of hypoxic encephalopathy [13].\n\nVarious drugs have been implicated in worsening encephalitis and encephalopathy in cases with viral infections.\n\nThese include salicylates, other NSAIDs and theophylline [3].\n\nAn additional mechanism implicated in COVID-19 infection is that the virus may have similar antigenic determinants as that in the human neuronal cells.\n\nEspecially with myelin autoantigens which may result in postinfectious encephalomyelitis in patients with COVID-19 infection [14].\n\nIt has also been noted that individuals with comorbidities are predisposed with hypoxic/ metabolic changes which might be responsible for encephalopathy in patients with COVID-19 [15].\n\nEncephalopathies and encephalitis in COVID-19 have been managed by injectable Remdesivir, IVIG, plasma exchange, high doses of dexamethasone along with antibiotics [16].\n\nIn our case we used empirical treatment for management of viral encephalitis by using injectable acyclovir.\n\nOur patient had already received injectable Remdesivir, Tocilizumab and Methylprednisolone.\n\nHigher antibiotics viz. injectable Meropenem and Teicoplanin were administered to our patient.\n\nReports suggest that patients with COVID-19 encephalopathy often required intensive care and mechanical ventilation.\n\nPatients have also been treated with repeated plasmapheresis with some regaining full consciousness following treatment.\n\nIn general, COVID-19 patients with neurological complications in the intensive care setting have poor outcomes but some reports have indicated that the patients improve following ICU management [15].\n\nConclusion\n\nEncephalopathies in the setting of viral infections are associated with neuropsychiatric manifestations and are often seen with poor functional outcomes and greater mortality in hospitalized patients [1,3].\n\nThis emphasizes the need for early diagnosis with better and aggressive management in patients with COVID-19, thus improving the outcomes, as was observed in our patient.\n\nFurther modalities for treatment need to be explored for early recovery of patients with encephalopathy in the setting of COVID-19.\n\nConflict of interests\n\nNone to declare.\n==== Refs\nReferences\n\n1 Kobayashi S Negishi Y Ando N Ito T Nakano M Togari H Wakuda M Taniguchi K Two Patients with Acute Rotavirus Encephalitis Associated with Cerebellar Signs and Symptoms Eur J Pediatr 2010 169 10 1287 1291 20461531\n2 Mehta R Gerardin P de Brito CAA Soares CN Ferreira MLB Solomon T The neurological complications of chikungunya virus: A systematic review Rev Med Virol 2018 28 3 e1978 e1978 29671914\n3 Netland J Meyerholz DK Moore S Cassell M Perlman S Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2 Journal of Virology 2008 82 15 7264 7275 18495771\n4 Pérez CA Looking ahead: The risk of neurologic complications due to COVID-19 Neurol Clin Pract 2020 10 4 371 374 32983618\n5 Liotta EM Batra A Clark JR Shlobin NA Hoffman SC Orban ZS Koralnik IJ Frequent neurologic manifestations and encephalopathy‐associated morbidity in Covid‐19 patients Ann Clin Transl Neurol 2020 7 11 2221 2230 33016619\n6 Jain S Patel B Bhatt GC Enteroviral encephalitis in children: clinical features, pathophysiology, and treatment advances Pathog Glob Health 2014 108 5 216 222 25175874\n7 Garg RK Paliwal VK Gupta A Encephalopathy in patients with COVID‐19: A review J Med Virol 2020 1 17\n8 Thirugnanam U Wei Ming Jason Quek Jia Min Yen Hnin Su Wai Khin Yun Yuan Mah Chee Yee Joel Chan Li Min Ling Wai-Yung Yu Encephalopathy in COVID-19 patients; viral, parainfectious, or both eNeurologicalSci 2020 21 100275 100275 32984561\n9 Ye M Ren Y Lv T Encephalitis as a clinical manifestation of COVID-19 Brain Behav Immun 2020 88 945 946 32283294\n10 Julie H Stéphane K Hamid M Malika S François S Raphaël Clere-Jehl Antoine S Mirjana R Christine K Alexandra M Clotilde B Samira Fafi-Kremer Vincent C Mickaël O Mathieu A Francis S Ferhat M Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients Critical Care 2020 24 1 491 491 32771053\n11 Dantzer R Heuser I Lupien S Covid-19: An Urgent Need For A Psychoneuroendocrine Perspective Psychoneuroendocrinology 2020 116 0 0\n12 Chen T Wu D Chen H Yan W Yang D Chen G Ma K Xu D Yu H Wang H Wang T Guo W Chen J Ding C Zhang X Huang J Han M Li S Luo X Zhao J Ning Q Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study BMJ 2020 368 m1091 m1091 32217556\n13 Troyer EA Kohn JN Hong S Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms Brain Behav Immun 2020 87 34 9 32298803\n14 Mizuguchi M Yamanouchi H Ichiyama T Shiomi M Acute encephalopathy associated with influenza and other viral infections Acta Neurol Scand Suppl 2007 186 45 56 17784537\n15 Moriguchi T Harii N Goto J Harada D Sugawara H Takamino J Ueno M Sakata H Kondo K Myose N Nakao A Takeda M Haro H Inoue O Suzuki-Inoue K Kubokawa K Ogihara S Sasaki T Kinouchi H Kojin H Ito M Onishi H Shimizu T Sasaki Y Enomoto N Ishihara H Furuya S Yamamoto T Shimada S A first case of meningitis/encephalitis associated with SARS-Coronavirus-2 Int J Infect Dis 2020 94 55 58 32251791\n16 Erkkinen MG Berkowitz AL A Clinical Approach to Diagnosing Encephalopathy The American Journal of Medicine 2019 132 10 1142 1147 31330129\n\n",
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"title": "Encephalopathy in the Setting of COVID-19: A Case Report.",
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"abstract": "Cytomegalovirus (CMV) infection following kidney transplantation is associated with increased morbidity and mortality. In this case report we describe a case of a 23-year-old woman with an unusual presentation of diffuse CMV lymphadenitis following kidney transplantation that did not respond to gangiclovir therapy. This case highlights the atypical presentation of CMV disease in a kidney transplant recipient, the importance of CMV hypergammaglobulin in the treatment of CMV infection post kidney transplantation, and the difficulties in transitioning care from pediatric to adult transplant programs.",
"affiliations": "UCLA David Geffen School of Medicine Department of Medicine, Division of Nephrology, Kidney Transplant, Los Angeles, Califonia, USA. Electronic address: [email protected].;UCLA David Geffen School of Medicine Department of Medicine, Infectious Diseases, Los Angeles, Califonia, USA.;UCLA David Geffen School of Medicine Department of Pathology, Los Angeles, Califonia, USA.;UCLA David Geffen School of Medicine Department of Medicine, Division of Nephrology, Kidney Transplant, Los Angeles, Califonia, USA.;UCLA Harbor Department of Medicine, Division of Nephrology, Los Angeles, Califonia, USA.;UCLA David Geffen School of Medicine Department of Pathology, Los Angeles, Califonia, USA.",
"authors": "Lum|E L|EL|;Schaenman|J M|JM|;DeNicola|M|M|;Reddy|U G|UG|;Shen|J I|JI|;Pullarkat|S T|ST|",
"chemical_list": null,
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"issue": "47(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008199:Lymphadenitis",
"nlm_unique_id": "0243532",
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"pubdate": "2015",
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"references": "10544437;15200441;9498461;22483471;15147427;17029132;17605813;12198618;21599818;17640310;2839916;22094954;23896556;22917575;2847293;19715860;20426575;20564615;1331542;1323340",
"title": "A case report of CMV lymphadenitis in an adult kidney transplant recipient.",
"title_normalized": "a case report of cmv lymphadenitis in an adult kidney transplant recipient"
}
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{
"abstract": "The authors present a case of delayed radiation myelopathy in a 12-year-old girl with Hodgkin lymphoma and Artemis mutation. This is the first of such a case presented in the literature.",
"affiliations": "Departments of Pediatric Hematology and Oncology.;Radiology.;Pediatric Immunology and Allergy.;Radiation Oncology, Faculty of Medicine, Selcuk University, Konya, Turkey.;Radiology.;Pediatric Immunology and Allergy.;Department of Pediatric and Adolescent Medicine, Norwegian National Unit for Newborn Screening, Oslo University Hospital, Oslo, Norway.;Departments of Pediatric Hematology and Oncology.",
"authors": "Kara|Buket|B|;Seher|Nusret|N|;Ucaryilmaz|Hulya|H|;Yavas|Guler|G|;Paksoy|Yahya|Y|;Artac|Hasibe|H|;Stray-Pedersen|Asbjørg|A|;Koksal|Yavuz|Y|",
"chemical_list": "D004268:DNA-Binding Proteins; C426344:DCLRE1C protein, human; D004720:Endonucleases",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001815",
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"issue": "43(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D002648:Child; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D009154:Mutation; D011832:Radiation Injuries; D013118:Spinal Cord Diseases; D013131:Spine",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e404-e407",
"pmc": null,
"pmid": "32341262",
"pubdate": "2021-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed Radiation Myelopathy in a Child With Hodgkin Lymphoma and ARTEMIS Mutation.",
"title_normalized": "delayed radiation myelopathy in a child with hodgkin lymphoma and artemis mutation"
}
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{
"abstract": "BACKGROUND\nPelvic irradiation in childhood may result in abnormal uterine function. Poor obstetric outcomes have been reported in these patients.\n\n\nMETHODS\nA 30-year-old woman with a previous midtrimester miscarriage, G2, P0, presented at 234 weeks gestation with acute abdominal pain and signs of hemodynamic instability. The patient was treated in childhood for Ewing sarcoma of the pelvis. Spontaneous uterine rupture was diagnosed. A supracervical hysterectomy with intrauterine fetus was performed.\n\n\nCONCLUSIONS\nA high index of suspicion is needed in primigravidas with risk factors for uterine rupture. Pelvic radiotherapy in childhood may be a risk factor.",
"affiliations": "Department of Obstetrics and Gynaecology, Complejo Hospitalario de Navarra, Pamplona, Spain. Electronic address: [email protected].;Department of Obstetrics and Gynaecology, Complejo Hospitalario de Navarra, Pamplona, Spain.;Department of Obstetrics and Gynaecology, Complejo Hospitalario de Navarra, Pamplona, Spain.;Department of Obstetrics and Gynaecology, Complejo Hospitalario de Navarra, Pamplona, Spain.",
"authors": "Huarte Ciganda|María|M|;Estaún Echavarren|Cecilia|C|;García Jiménez|Ana|A|;Huarte Sala|Isabel|I|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jogc.2019.02.152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1701-2163",
"issue": "42(1)",
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": "Uterine rupture; cancer; cervical cerclage; childhood; hysterectomy; radiotherapy",
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D001859:Bone Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007085:Ilium; D011247:Pregnancy; D011248:Pregnancy Complications; D011262:Pregnancy Trimester, Second; D011296:Prenatal Diagnosis; D011832:Radiation Injuries; D012512:Sarcoma, Ewing; D017741:Survivors; D014597:Uterine Rupture",
"nlm_unique_id": "101126664",
"other_id": null,
"pages": "84-87",
"pmc": null,
"pmid": "31078434",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous Uterine Rupture in the Second Trimester in a Patient With Previous Pelvic Radiotherapy in Childhood: A Case Report.",
"title_normalized": "spontaneous uterine rupture in the second trimester in a patient with previous pelvic radiotherapy in childhood a case report"
}
|
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"abstract": "We describe the prenatal and postnatal course of an infant with a large 19p deletion. Cases such as ours will improve the knowledge of specific gene functions for every medical specialist. The goal is to allow for a more rapid diagnosis, accurate prognosis and to decrease the likelihood of complications.",
"affiliations": "MedStar Georgetown University Hospital Neonatal-Perinatal Medicine Washington DC USA.;Division of Maternal Fetal Medicine Sibley Memorial Hospital Washington DC USA.;Department of Pediatrics MedStar Georgetown University Hospital Washington DC USA.;Division of Maternal Fetal Medicine Sibley Memorial Hospital Washington DC USA.;MedStar Georgetown University Hospital Neonatal-Perinatal Medicine Washington DC USA.;Division of Maternal Fetal Medicine Sibley Memorial Hospital Washington DC USA.",
"authors": "Culjat|Marko|M|0000-0002-9021-1498;Razak|Jennifer|J|;Saadeh-Haddad|Reem|R|;Driggers|Rita|R|;Kamholz|Karen|K|;Timofeev|Julia|J|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1615CCR31615Case ReportCase ReportsPerinatal findings in a patient with a novel large chromosome 19p deletion CULJAT et al.Culjat Marko http://orcid.org/[email protected] \n1\nRazak Jennifer \n2\nSaadeh‐Haddad Reem \n3\nDriggers Rita \n2\n\n4\nKamholz Karen \n1\nTimofeev Julia \n2\n\n4\n\n1 \nMedStar Georgetown University Hospital\nNeonatal‐Perinatal Medicine\nWashington\nDC\nUSA\n\n2 \nDivision of Maternal Fetal Medicine\nSibley Memorial Hospital\nWashington\nDC\nUSA\n\n3 \nDepartment of Pediatrics\nMedStar Georgetown University Hospital\nWashington\nDC\nUSA\n\n4 \nDivision of Maternal Fetal Medicine\nJohns Hopkins School of Medicine\nBaltimore\nMD\nUSA\n* Correspondence\n\nMarko Culjat, MedStar Georgetown University Hospital, Neonatal‐Perinatal Medicine, Washington, DC, USA.\n\nEmail: [email protected]\n21 6 2018 8 2018 6 8 10.1002/ccr3.2018.6.issue-81525 1530 08 8 2017 16 3 2018 08 5 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.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.Key Clinical Message\nWe describe the prenatal and postnatal course of an infant with a large 19p deletion. Cases such as ours will improve the knowledge of specific gene functions for every medical specialist. The goal is to allow for a more rapid diagnosis, accurate prognosis and to decrease the likelihood of complications.\n\n19p deletionhiatal herniahypotoniaintrauterine growth restrictionneonatepyloric stenosissmall for gestational age source-schema-version-number2.0component-idccr31615cover-dateAugust 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:19.08.2018\n\n\nCuljat \nM \n, \nRazak \nJ \n, \nSaadeh‐Haddad \nR \n, \nDriggers \nR \n, \nKamholz \nK \n, \nTimofeev \nJ \n. Perinatal findings in a patient with a novel large chromosome 19p deletion . Clin Case Rep . 2018 ;6 :1525 –1530 . 10.1002/ccr3.1615\n==== Body\n1 INTRODUCTION\nSixteen cases with a deletion in the short arm of chromosome 19 are described in detail in the literature. Patients presented with neonatal hypotonia and developmental delay. Other findings varied significantly. We describe the perinatal course of an infant with a 3.7‐megabase deletion in the short arm of chromosome 19.\n\nDeletions in the short arm of chromosome 19 are exceedingly rare.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11While reported cases of chromosome 19p deletions have varying sizes and breakpoints and a wide range of phenotypes, all have developmental delays. We present the clinical course of a male newborn with a large deletion in the short arm of chromosome 19.\n\n2 CASE REPORT\nTwin B of a spontaneous dichorionic and diamniotic twin pregnancy of a 30‐year‐old multigravida was found to have symmetrical intrauterine growth restriction (IUGR) at 25‐week gestation (estimated fetal weight (EFW) <3rd percentile, intertwin weight discordance 28%), with abnormal Dopplers indicating increased placental resistance and cranial sparing with cephalization of blood flow. Also noted were mild right lateral cerebral ventriculomegaly, small stomach, and enlarged gallbladder. Aneuploidy screening results were low‐risk, with cell‐free DNA negative for trisomy 21, 18, and 13. Amniocentesis was declined. Maternal viral serology for cytomegalovirus, toxoplasmosis, and parvovirus was negative for recent infection. From 27 weeks onward, persistently absent end‐diastolic flow of the umbilical artery was noted. Ventriculomegaly worsened to moderate range at 28 and 33 weeks, with bitemporal skull narrowing and strawberry‐shaped skull appearance noted at 31 weeks (Figure 1). Anhydramnios for Twin B was noted at 36‐week gestation. As diagnosis of aneuploidy would affect postnatal management, bladder aspiration of Twin B was performed, but cell culture was without growth. At 38 weeks, the EFW for Twin B was 1559 g, with twin discordance of 48%.\n\nFigure 1 Select prenatal ultrasound images representative of (A) right lateral ventriculomegaly (12.4 mm), and (B) strawberry‐shaped head\n\nThe patient was born at 38 weeks and 3 days gestation, via scheduled repeat cesarean delivery. Apgar scores were 5, 7, and 8 at 1, 5, and 10 minutes of life, respectively. He was small for gestational age (SGA) with birthweight 1133 g (Z‐score: −5.49), birth length 39.4 cm (Z‐score: −4.43), and head circumference 29.5 cm (Z‐score: −3.23). Physical examination was significant for small facies with underdeveloped chin, relative macrocephaly, overlapping cranial sutures, mild crumpling of the ears, wide‐spaced nipples, second and fifth fingers of the right hand overlapping the third and fourth fingers, and a small sacral hemangioma (Figure 2). The patient developed hypoglycemia and hypophosphatemia, likely secondary to his IUGR/SGA status, which responded to modifications in intravenous fluids. He tolerated full enteral feeds by the second week of life, but due to poor oromotor skills, he was fully nasogastric tube‐dependent. Patient developed self‐resolving leukopenia. Thrombocytopenia, reaching a nadir on day of life (DOL) 2, responded to 1 platelet transfusion. Mild self‐resolving anemia was noted with a high reticulocyte count. Second anemia nadir at fourth week of life was treated with epoetin alfa, with normalization of erythrocyte indices. From DOL 5 onward, patient had a prolonged need for respiratory support, attributed to chronic microaspirations, with a waxing‐and‐waning degree of respiratory distress, which was subsequently attributed to a hiatal hernia. Gastrointestinal contrast study showed approximately half the stomach within the thoracic cavity, along with an incidental finding of inguinal hernia.\n\nFigure 2 Photograph of the patient. Note the relative macrocephaly, downslanting palpebral fissures, low‐set ears, and mild micrognathia. The second finger overlaps the third finger, and the fifth overlaps the fourth finger. The nipples are wide‐spaced (left not visible)\n\nDuring the patient's hospital course, extensive workup was completed as part of evaluation for the chromosome 19p deletion (see Section 3). Initial head ultrasound showed a small hyperechogenic focus inferior to the third ventricle. Noncontrast brain MRI performed on DOL 23 showed normal findings. Follow‐up head ultrasound performed on DOL 50 showed resolution of the previously described echogenic focus, with a new finding of mild dilation of frontal horns of lateral ventricles. Spinal ultrasound was significant for a low lying conus and a tethered spinal cord. Whole spine MRI confirmed this finding, additionally showing 6 lumbar vertebrae. Abdominal and focused renal ultrasounds were normal. Echocardiogram was significant for suspected interrupted inferior vena cava with hemiazygos continuation to the left superior vena cava draining to the coronary sinus; no right superior vena cava was noted. Suspected cervical aortic arch was present with mild tortuosity of transverse arch without evidence of coarctation. Normal pulmonary venous drainage and a patent foramen ovale with left‐to‐right shunt were also seen. Ophthalmologic examination performed on DOL 13 showed a thin iris with rugged pupils. Mild stippling of the left retina with irregularly shaped optic disk was also noted.\n\nOn DOL 53, laparoscopy was performed to repair the hiatal hernia. Intraoperative diagnoses were: type I paraesophageal hernia with almost the entire stomach located within the chest, and a significant pyloric stenosis. The infant underwent paraesophageal hernia repair, Nissen fundoplication, G‐tube placement, and pyloromyotomy. On postoperative day four, the patient developed a firm abdomen and respiratory compromise. Abdominal X‐ray revealed intestinal pneumatosis and presence of portal vein gas. Emergent laparotomy found a 3 mm gastric perforation and necrotic small bowel. Unfortunately, the patient passed away intraoperatively. Cause of death was shock secondary to gastric perforation, peritonitis, and bowel necrosis.\n\n3 METHODS AND RESULTS\nPrenatal screening included First Trimester Screen (Eurofins NTD, NY) and cell‐free DNA screen (MaterniT21, Sequenom, CA). Maternal viral serologies were performed at Quest Diagnostics, VA. Prenatal fluorescent in situ hybridization (FISH) was performed by Integrated Genetics, LabCorp, NC (probes: nuc ish Xcen (DXZ1x1), Ycen (DYZ3x1), 13q14 (IRB1x1), 18cent (D18Z1x2), 21q22.13‐q22.2 (D2S342/D211S341/D21S259)x2). All prenatal imaging performed by a registered diagnostic medical sonographer with Voluson E8 (GE Healthcare, WI) and reviewed by a board certified maternal fetal medicine specialist. Neonatal FISH screen showed a normal male chromosome complement, suggesting no numerical abnormality of chromosome 13, 18, 21 or sex chromosomes. Subsequent karyotype analysis showed a normal male karyotype (46, XY). High‐resolution chromosomal microarray showed a 3.7 Mb interstitial deletion of the short arm of chromosome 19, bands p13.2 p13.12 (11 836 342‐15 505 009)x1 (Quest Diagnostics Nichols Institute, Chantilly, VA).\n\n4 DISCUSSION\nWe present a newborn with multiple anomalies (Table 1) and a large 3.7‐Mb interstitial deletion of the short arm of chromosome 19, bands p13.2 p13.12 (11 836 342‐15 505 009)x1, which accounts for approximately 5.8% of the total length of chromosome 19 and contains at least 111 genes, including 60 OMIM‐annotated genes. There have been a total of thirteen patients with a deletion in the short arm of chromosome 19, that partially or fully overlapped with the deletion seen in our patient (Figure 3), reported in the literature with a detailed prenatal and neonatal course. Additionally, DECIPHER database provides a list of lifetime phenotypic changes for up to 41 patients with an overlapping deletion, 10 of which were classified as having “definitive or likely pathogenic deletions”.\n\nTable 1 Clinical, laboratory and imaging findings seen in our patient\n\nPrenatal findings\t\nSevere intrauterine growth restriction with abnormal umbilical artery and middle cerebral artery Dopplers\t\nDilated gallbladder\t\nSmall stomach\t\nBitemporal narrowing/strawberry‐shaped skull\t\nUnilateral moderate ventriculomegaly\t\nAnhydramnios in the third trimester\t\nNewborn physical examination\t\nSmall for gestational age\t\nSmall facies with micrognathia\t\nRelative macrocephaly\t\nOverlapping cranial sutures\t\nDownslanting palpebral fissures\t\nLow set ears\t\nMild crumpling of the ears bilaterally\t\nWide‐spaced nipples\t\nSecond and fifth fingers of the right hand overlapped the third and fourth fingers, respectively\t\nHypoglycemia, hypophosphatemia\t\nHematologic anomalies\t\nThrombocytopenia, transitory (25 000 per microliter)\t\nLeukopenia, transitory (3660 per microliter)\t\nAnemia\t\nNeurologic anomalies\t\nHyperechogenic focus inferior to the third ventricle, resolved by 2 months of age\t\nMild dilatation of frontal horns of lateral ventricles, noted at 2 months of age\t\nLow lying conus medullaris, tethered spinal cord\t\nThin iris with rugged pupils, with mild left retinal stippling and irregularly shaped optic disk\t\nMusculoskeletal anomalies\t\nSix lumbar vertebrae\t\nCardiovascular anomalies\t\nInterrupted inferior vena cava\t\nHemiazygos continuation to left superior vena cava, draining into the coronary sinus\t\nAbsent right superior vena cava\t\nSuspected cervical aortic arch\t\nGastrointestinal anomalies\t\nParaesophageal hernia, type I\t\nPyloric stenosis\t\nInguinal hernia, bilateral\t\nJohn Wiley & Sons, LtdFigure 3 Graphic representation of sites of 19p deletion in our patient, and previously reported patients by distance in megabases (Mb) from the centromere. The shaded area corresponds to the extent of the deletion seen in our patient. OMIM‐annotated genes, pertinent to the findings seen in our patient, and their positions relative to the deletion are shown in the bottom part of the graph. The width of the bar next to the gene corresponds with the size of the gene. Hg19 positions of the genes: CALR (19:12,938,599‐12,944,489), NFIX (19:12,995,511‐13,098,795), LYL1 (19:13,099,027‐13,103,159), MIR genes (19:13,836,286‐ 13,874,807), PRKACA (19:14,091,687‐14,117,746), PTGER1 (19:14,472,465‐14,475,361), GIPC1 (19:14,477,758‐14,496,148), EMR3 (19:14,600,174‐14,674,917), EMR2 (19:14,732,696‐14,778,540), NOTCH (19:15,159,632‐15,200,980), BRD4 (19:15,236,835‐15,332,542). IER2 (GenBank accession no. NM_004907)\n\nThe patients described in detailed case reports all had varying degree of neonatal hypotonia. In addition, 2 patients4, 10 had IUGR with head sparing, one10 had neonatal seizures, one4 had severe microcephaly, while two4, 6 presented with facial dysmorphism. Lysy et al and Lyon et al described patients with large 19p deletions and craniosynostosis. The authors raised the possibility that DAND5 and CALR genes might be involved in the pathogenesis of the neurocranial abnormality. As the same 2 genes were affected in our patient, it is unlikely that they alone would be responsible for the craniosynostosis. Additionally, the patient with a 1 Mb‐deletion in Lyon et al's report had several phenotypic features similar to our patient: antenatal onset of ventriculomegaly, postnatally noted dysmorphisms (low‐set ears and micrognathia), and bilateral optic dysplasia. The authors also raised a potential role of CACNA1A and CC2D1A genes in epilepsy and developmental delay, respectively. It is possible our patient would have developed these features, but given his early demise the full phenotype was not able to develop. Malan et al described 2 patients with a deletion of NFIX gene, who presented with drastically different phenotypes. One patient presented with Sotos‐like overgrowth syndrome, while the other presented with Marshall‐Smith syndrome (MSS). The difference was postulated to be a result of differing effects of nonsense‐mediated mRNA decay of the NFIX gene product. Many physical findings of our patient overlap with those seen in MSS: underdeveloped/small face, retrognathia, failure to thrive, respiratory distress, and pyloric stenosis. It is interesting to note that our patient's deletion affected the microRNA genes (MIR24‐2, MIR27A, MIR23A, MIR181C, MIR181D, and MIR639), potentially contributing to the MSS‐like phenotype. NFIX mutations have also been associated with pathologic thinning of the intestinal wall and diminished blood supply.12 Olley et al showed that haploinsufficiency of BRD4, either as part of a larger deletion or as a single gene mutation, is the likely genetic mechanism of Cornelia de Lange (CdL)‐like syndrome. Our patient had several features that would fall under either major or secondary characteristics of CdL syndrome, including: small for gestational age, microcephaly, low‐set ears, clinodactyly of the fifth finger and gastrointestinal abnormalities. It is interesting to note that of the patients described in the DECIPHER database, ones with deletions overlapping with the telomeric side of our patient's deletion had macrocephaly and optic nerve hypoplasia, while the ones overlapping with the centromeric side tended to have microcephaly and low‐set ears.\n\nLYL1 and IER2 gene products are involved in angiogenesis, capillary formation, and vessel stabilization.13, 14 We speculate that the gastrointestinal tract in a patient with deletions of these genes would be more prone to tissue injury in a setting of peritonitis or surgery, as seen in our patient. Other potentially clinically significant genes were affected (Figure 3). CALR codes for calreticulin, which acts as a general recognition signal on apoptotic cells, thus having a crucial role in resolution of inflammation.15 EMR2 and EMR3 genes are involved in potentiating inflammatory responses.16 Deletion of these 3 genes could have led to poor healing and increased risk of gastric perforation in a setting of surgical manipulation. Steroid production is increased with increase in activity level of PRKACA‐coded protein kinase17 and modulated at the hypothalamic level through prostaglandin E2 receptor, coded by PTGER1.18 Our patient did not exhibit any hemodynamic instability that would prompt us to consider initiation of steroid replacement therapy. Nonetheless, we would recommend that with future patients who have a deletion of one or both of these genes, measurement of cortisol level be considered. It is interesting to note that despite chronic microaspiration and a remarkable number of desaturation episodes, our patient never developed any signs of pulmonary hypertension. Animal models showed that NOTCH3‐null mice did not develop pulmonary hypertension in a setting of hypoxic stimulation.19 It is possible that the deletion of NOTCH3 gene might have protected our patient from developing clinically significant pulmonary hypertension. GIPC1 codes for synectin, a protein crucial for cell surface receptor expression.20 Synectin‐null mice have abnormal pattern of arterial formation and branching, with hypoplastic dorsal aorta and stunted intersomitic vessels.21 Our patient's echocardiogram showed a cervical aortic arch with transverse arch tortuosity, a finding consistent with the animal models. Major vascular anomalies noted in our patient affected the large systemic veins. None of the genes deleted in our patient have previously been related to such phenotypes.\n\nIn this report, we describe the prenatal and postnatal courses of an infant with a large 19p13 deletion and address possible clinical correlation to the deletion of specific genes. Cases such as our will further improve our knowledge of specific gene functions.\n\nCONFLICT OF INTERESTS\nAuthors have no conflict of interests to declare.\n\nAUTHORSHIP\nMC: involved in postnatal management of the patient, literature review of the 19p deletions, preclinical and clinical studies of genes involved by the deletion, writing the manuscript. JR: provided prenatal genetic counseling to the patient and coordinated prenatal aneuploidy screening and testing during the pregnancy. RSH: aided in the interpretation of the genetic anomaly, review of microarray, genes and gene location involved, and revisions of the manuscript. RD: involved in prenatal management of the mother, providing the antenatal course, and interpretation of the ultrasound findings. KK: involved in postnatal management of the patient, providing the postnatal clinical course. JT: involved in prenatal management of the mother, providing the antenatal course and interpretation of the ultrasound findings, edits, and revisions of the manuscript.\n==== Refs\nREFERENCES\n1 \n\nArcher \nHL \n, \nGupta \nS \n, \nEnoch \nS \n, et al. Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13.3‐pter . Am J Med Genet A . 2005 ;136 :38 ‐44 .15937949 \n2 \n\nAten \nE \n, \nden Hollander \nN \n, \nRuivenkamp \nC \n, et al. Split hand‐foot malformation, tetralogy of Fallot, mental retardation and a 1 Mb 19p deletion‐evidence for further heterogeneity? \nAm J Med Genet A . 2009 ;149A :975 ‐981 .19353584 \n3 \n\nAuvin \nS \n, \nHolder‐Espinasse \nM \n, \nLamblin \nMD \n, \nAndrieux \nJ \n. Array‐CGH detection of a de novo 0.7‐Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms . Epilepsia . 2009 ;50 :2501 ‐2503 .19874387 \n4 \n\nBonaglia \nMC \n, \nMarelli \nS \n, \nNovara \nF \n, et al. Genotype‐phenotype relationship in three cases with overlapping 19p13.12 microdeletions . Eur J Hum Genet . 2010 ;18 :1302 ‐1309 .20648052 \n5 \n\nHurgoiu \nV \n, \nSuciu \nS \n. Occurrence of 19p‐ in an infant with multiple dysmorphic features . Ann Genet . 1984 ;27 :56 ‐57 .6609675 \n6 \n\nJensen \nDR \n, \nMartin \nDM \n, \nGebarski \nS \n, et al. A novel chromosome 19p13.12 deletion in a child with multiple congenital anomalies . Am J Med Genet A . 2009 ;149A :396 ‐402 .19215039 \n7 \n\nLyon \nSM \n, \nWaggoner \nD \n, \nHalbach \nS \n, \nThorland \nEC \n, \nKhorasani \nL \n, \nReid \nRR \n. Syndromic craniosynostosis associated with microdeletion of chromosome 19p13.12‐19p13.2 . Genes Dis . 2015 ;2 :347 ‐352 .26966713 \n8 \n\nLysy \nPA \n, \nRavoet \nM \n, \nWustefeld \nS \n, et al. A new case of syndromic craniosynostosis with cryptic 19p13.2‐p13.13 deletion . Am J Med Genet A . 2009 ;149A :2564 ‐2568 .19842200 \n9 \n\nMalan \nV \n, \nRajan \nD \n, \nThomas \nS \n, et al. Distinct effects of allelic NFIX mutations on nonsense‐mediated mRNA decay engender either a Sotos‐like or a Marshall‐Smith syndrome . Am J Hum Genet . 2010 ;87 :189 ‐198 .20673863 \n10 \n\nNatiq \nA \n, \nElalaoui \nSC \n, \nMiesch \nS \n, et al. A new case of de novo 19p13.2p13.12 deletion in a girl with overgrowth and severe developmental delay . Mol Cytogenet . 2014 ;7 :40 .24963350 \n11 \n\nOlley \nG \n, \nAnsari \nM \n, \nBengani \nH \n, et al. BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange‐like syndrome . Nat Genet . 2018 ;50 :329 ‐332 .29379197 \n12 \n\nDriller \nK \n, \nPagenstecher \nA \n, \nUhl \nM \n, et al. Nuclear factor I X deficiency causes brain malformation and severe skeletal defects . Mol Cell Biol . 2007 ;27 :3855 ‐3867 .17353270 \n13 \n\nGiroux \nS \n, \nKaushik \nAL \n, \nCapron \nC \n, et al. lyl‐1 and tal‐1/scl, two genes encoding closely related bHLH transcription factors, display highly overlapping expression patterns during cardiovascular and hematopoietic ontogeny . Gene Expr Patterns . 2007 ;7 :215 ‐226 .17112790 \n14 \n\nWu \nW \n, \nZhang \nX \n, \nLv \nH \n, et al. Identification of immediate early response protein 2 as a regulator of angiogenesis through the modulation of endothelial cell motility and adhesion . Int J Mol Med . 2015 ;36 :1104 ‐1110 .26260137 \n15 \n\nGardai \nSJ \n, \nMcPhillips \nKA \n, \nFrasch \nSC \n, et al. Cell‐surface calreticulin initiates clearance of viable or apoptotic cells through trans‐activation of LRP on the phagocyte . Cell . 2005 ;123 :321 ‐334 .16239148 \n16 \n\nYona \nS \n, \nLin \nHH \n, \nDri \nP \n, et al. Ligation of the adhesion‐GPCR EMR2 regulates human neutrophil function . FASEB J . 2008 ;22 :741 ‐751 .17928360 \n17 \n\nBeuschlein \nF \n, \nFassnacht \nM \n, \nAssié \nG \n, et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome . N Engl J Med . 2014 ;370 :1019 ‐1028 .24571724 \n18 \n\nMatsuoka \nY \n, \nFuruyashiki \nT \n, \nBito \nH \n, et al. Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes . Proc Natl Acad Sci USA . 2003 ;100 :4132 ‐4137 .12642666 \n19 \n\nLi \nX \n, \nZhang \nX \n, \nLeathers \nR \n, et al. Notch 3 signaling promotes the development of pulmonary arterial hypertension . Nat Med . 2009 ;15 :1289 ‐1297 .19855400 \n20 \n\nLee \nNY \n, \nRay \nB \n, \nHow \nT \n, \nBlobe \nGC \n. Endoglin promotes transforming growth factor beta‐mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC . J Biol Chem . 2008 ;283 :32527 ‐33233 .18775991 \n21 \n\nChittenden \nTW \n, \nClaes \nF \n, \nLanahan \nAA \n, et al. Selective regulation of arterial branching morphogenesis by synectin . Dev Cell . 2006 ;10 :783 ‐795 .16740480\n\n",
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"keywords": "19p deletion; hiatal hernia; hypotonia; intrauterine growth restriction; neonate; pyloric stenosis; small for gestational age",
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"title": "Perinatal findings in a patient with a novel large chromosome 19p deletion.",
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"abstract": "We experienced a favorable outcome in an adult case of atypical hemolytic uremic syndrome (aHUS) after long-term eculizumab treatment. A 38-year-old Japanese man with a history of central retinal vein occlusion was admitted to our hospital with progressive dyspnea. He was found to have non-immune hemolytic anemia, thrombocytopenia, and acute renal failure two weeks after an episode of the common cold. Plasma exchange was ineffective; therefore, we initiated eculizumab after we excluded other thrombotic microangiopathies. Although long-term peritoneal dialysis was required, we successfully discontinued dialysis 18 months after the onset of aHUS with eculizumab.",
"affiliations": "Department of Medicine, Kawasaki Municipal Kawasaki Hospital, Japan.;Department of Medicine, Kawasaki Municipal Kawasaki Hospital, Japan.;Department of Medicine, Kawasaki Municipal Kawasaki Hospital, Japan.;Department of Medicine, Kawasaki Municipal Kawasaki Hospital, Japan.",
"authors": "Yamada|Yuji|Y|;Abe|Ryohei|R|;Okano|Yutaka|Y|;Miyakawa|Yoshitaka|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2845831710.2169/internalmedicine.56.7862Case ReportLong-term Eculizumab Treatment Contributes to Recovery from End-stage Renal Disease Caused by Atypical Hemolytic Uremic Syndrome Yamada Yuji 12Abe Ryohei 13Okano Yutaka 1Miyakawa Yoshitaka 141 Department of Medicine, Kawasaki Municipal Kawasaki Hospital, Japan2 Department of Medicine, Mount Sinai Beth Israel, USA3 Division of Hematology, Keio University School of Medicine, Japan4 Department of General Internal Medicine, Saitama Medical University Hospital, JapanCorrespondence to Dr. Yoshitaka Miyakawa, [email protected]\n\n1 5 2017 56 9 1085 1088 15 6 2016 31 8 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The 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/).We experienced a favorable outcome in an adult case of atypical hemolytic uremic syndrome (aHUS) after long-term eculizumab treatment. A 38-year-old Japanese man with a history of central retinal vein occlusion was admitted to our hospital with progressive dyspnea. He was found to have non-immune hemolytic anemia, thrombocytopenia, and acute renal failure two weeks after an episode of the common cold. Plasma exchange was ineffective; therefore, we initiated eculizumab after we excluded other thrombotic microangiopathies. Although long-term peritoneal dialysis was required, we successfully discontinued dialysis 18 months after the onset of aHUS with eculizumab. \n\natypical hemolytic uremic syndromeeculizumabperitoneal dialysisthrombotic microangiopathy\n==== Body\nIntroduction\nAtypical hemolytic uremic syndrome (aHUS) is characterized by three major components: microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. This syndrome is known to be caused by the abnormal activation of the compliment cascade (1). In Japan, the number of new patients with aHUS is estimated to be around 100 cases per year. aHUS was certified as an intractable disease by a new law in January 2015, and its medical expenses are covered by the Japanese government. This syndrome was treated previously with plasma exchange, which is a standard treatment for thromboembolic thrombocytopenic purpura (TTP), but its prognosis was poor (2). When patients with aHUS are treated with plasma exchange, a reported approximately 10% die and approximately 50% progress to end-stage renal disease 1 year after the onset of aHUS (2). Anti-complement factor 5 antibody, eculizumab, which has been used for the treatment of paroxysmal nocturnal hemoglobinuria, was recently reported effective for aHUS (3). Following that trial and US Food and Drug Administration approval, eculizumab was approved for the treatment of aHUS in Japan in 2013.\n\nWe herein report a case of aHUS, for which we successfully discontinued dialysis 18 months after initiation of eculizumab. Our case suggests that long-term treatment with eculizumab may gradually recover kidney damage and ultimately lead to discontinuation of dialysis.\n\nCase Report\nThe patient was a 38-year-old man who presented with a 1-week history of dyspnea. Two weeks prior to presentation, the patient developed a cough and a fever, which resolved quickly. One week later, the patient started experiencing progressive dyspnea while walking and decided to visit our hospital. He denied having any episodes of bloody diarrhea. His medical history revealed central retinal vein occlusion at the age of 36 years. He had no family history of thrombosis or chronic renal failure. On the day of presentation, he was alert and oriented. He was afebrile, his pulse rate was 108 beats/min, and his blood pressure was 172/90 mmHg. On a physical examination, his conjunctiva was pale and icteric. There were no other significant findings upon our examination. The laboratory data on presentation are shown in Table. Normocytic anemia, increased reticulocyte count, significant presence of schistocytes, and elevation of lactate dehydrogenase (LDH) and indirect bilirubin levels suggested MAHA.\n\nTable. Laboratory Findings on Admission.\n\nCBC\t\t\tChemistry\t\t\tSerology\t\t\t\nWBC\t9.53×103\n\t/μL\tAlb\t4.2 \tg/dL\tDirect Coomb’s\t(-)\t\t\nNeu\t81.0 \t%\tLDH\t2,470 \tIU/L\tIndirect Coomb’s\t(-)\t\t\nEo\t0.0 \t%\tT-bil\t2.7 \tmg/dL\tADAMTS13\t\t\t\nBaso\t0.0 \t%\tD-bil\t0.6 \tmg/dL\tactivity\t72.9 \t%\t\nMono\t4.0 \t%\tBUN\t58 \tmg/dL\tinhibitor\t<0.5 \tBU/mL\t\nLym\t14.0 \t%\tCre\t6.8 \tmg/dL\t\t\t\t\nRBC\t268×104\n\t/μL\tCRP\t0.25 \tmg/dL\tUrinalysis\t\t\t\nHb\t7.4 \tg/dL\tHaptoglobin\t11 \tmg/dL\tProtein\t(3+)\t\t\nHt\t21.6 \t%\t\t\t\tOccult blood\t(3+)\t\t\nMCV\t80.6 \tfl\tCoagulation\t\t\t\t\t\t\nMCH\t27.6 \tpg\tPT-INR\t1.07\t\tStool\t\t\t\nMCHC\t34.3 \t%\taPTT\t27.3 \tsec\tOccult blood\t(-)\t\t\nPlt\t7.6×104\n\t/μL\tFibrinogen\t131.0 \tmg/dL\tSTEC\t(-)\t\t\nRet\t81.1 \t‰\tFDP\t194.0 \tμg/mL\t\t\t\t\nSchistocytes (+)\t\t\t\t\t\t\t\t\nFDP: fibrin degradation product, Plt: platelet, RBC: red blood cell, Ret: reticulocyte, STEC: Shiga toxin-producing Escherichiacoli, WBC: white blood cell\n\nBased on the presence of MAHA, thrombocytopenia, and renal insufficiency, thrombotic microangiopathy (TMA) was suspected. Emergency plasma exchange and steroid pulse treatment were initiated. Although we repeated plasma exchange 20 times, the patient did not respond well to the treatment, with a worsening of his renal function, persistent severe thrombocytopenia, and continuous elevation of LDH. We later found that his ADAMTS13 activity was normal while that of its inhibitor was negative, which excluded the possibility of TTP. A stool culture obtained on the day of admission was negative for Shiga-toxin-producing Escherichia coli (STEC); therefore, STEC-HUS was ruled out. We also excluded other diseases such as collagen disease, cancer, drug reaction, and severe infection, any of which might cause secondary TMA. Based on these results, aHUS was the working diagnosis, and eculizumab was considered as the treatment of choice. However, at that time in 2013, eculizumab had not yet been approved in Japan for the treatment of aHUS. Therefore, the validity of using eculizumab for this case was discussed by the ethics committee at our hospital. After that discussion and obtaining informed consent from the patient, we decided to import eculizumab personally from Alexion Pharma in the United States, and treatment was started on Day 29 post-admission.\n\nTo confirm activation of the complement cascade, we sent the patient's plasma to the Department of Transfusion, Nara Prefectural University, for a quantitative hemolysis assay using sheep blood cells (4). The patient's plasma revealed severe hemolysis that was 1.6 times that of the positive control, and addition of recombinant complement factor H (CFH) suppressed the hemolysis, indicating the presence of CFH-related complement amplification (data not shown). However, anti-CFH antibody in the patient's plasma was negative by Western blotting. In addition, genetic testing conducted at the National Cerebral and Cardiovascular Center in Osaka, Japan, did not reveal any abnormalities, including levels of CFH, component 3 (C3), membrane cofactor protein (MCP), complement factor I (CFI), complement factor B (CFB), and thrombomodulin. Around half of cases of aHUS do not have mutations in the complement regulatory proteins (5); therefore, we clinically diagnosed this case as aHUS.\n\nThe clinical course of our case is shown in Figure. A decrease in the LDH levels and improvement in the hemoglobin and platelet count were observed after eculizumab was initiated. However, the renal function continued to worsen, the creatinine level rose to 10 mg/dL, and hemodialysis was started shortly after the initiation of eculizumab. Hemodialysis was transitioned to peritoneal dialysis around three months after onset, based on the patient's request.\n\nFigure. Clinical course of aHUS. aHUS: atypical hemolytic uremic syndrome, HD: hemodialysis, mPSL: methylprednisolone, PD: peritoneal dialysis, PEx: plasma exchange, PSL: prednisolone, RBC: red blood cell transfusion\n\nWe continued eculizumab, which gradually improved his renal function, and at 18 months after onset of aHUS, we successfully discontinued dialysis. Up to 36 months after onset, the patient has had no signs of recurrence, with continuation of eculizumab.\n\nDiscussion\nTMA is a syndrome of MAHA, thrombocytopenia, and organ dysfunction, which has a variety of causes (6). aHUS is one of those causes (7), and the Japanese guidelines for aHUS were first published in 2016. It is thought that genetic abnormalities of complement regulatory factors or anti-CFH antibody lead to uncontrollable activation of complement, which results in endothelial damage, intravascular microthrombosis, and eventually organ dysfunction (1,8). Approximately 25% of cases of aHUS have resulted in death from thrombosis or acute renal failure (9). Even if death in the acute phase can be avoided by plasmapheresis, around half of the surviving cases eventually develop end-stage renal disease that requires dialysis (9). Kidney transplantation has been performed in such cases, but the recurrence rate was around 50%, and the rate of post-transplant kidney loss was 30% (10). Simultaneous liver and kidney transplantation has also been attempted (11), but the number of applicable cases is limited, and it is still a controversial treatment. About 40% of cases of aHUS are in young patients, including pediatric cases (12); therefore, lifelong dialysis can markedly reduce the quality of life. However, based on previous reports, eculizumab is expected to improve chronic kidney disease by more than 1 stage and meaningfully improve the health-related quality of life in more than half of all aHUS cases (3).\n\nBased on the three major components of TMA―normal activity of ADAMTS13 and exclusion of STEC infection and other clear causes of TMA―our case met the diagnostic criteria of aHUS under the current guidelines (13), and these findings led us to the clinical diagnosis. A hemolytic analysis using sheep blood cells suggested a CFH-related abnormality, which also supported the diagnosis of aHUS. Subsequently, further genetic tests were conducted, but we did not detect any abnormalities of complement genes. To date, genetic abnormalities of C3, CFB, CFH, CFI, MCP, and thrombomodulin are reported to be related to aHUS (14-17). In Japan, several cases of abnormal C3 have also been reported (18). However, previous reports have shown that genetic abnormalities can be detected in around half of cases (5), as with the present case, which suggests that there are still several unknown genetic abnormalities causing aHUS. Considering his history of retinal vein thrombosis, we suspect that our patient might have an underlying genetic abnormality. Other experimental tests, such as measurements of C5a and C5b-9 complex in serum and urine samples by enzyme-linked immunosorbent assay (ELISA) (19), observation of deposits of C5b-9 protein on the endothelial cells in vitro using immunofluorescence microscopy (20), a modified Ham test using a genetically modified complement-sensitive cell line (21), and a skin biopsy (22), have been reported as possible diagnostic tools. However, further investigations are necessary to apply the findings from those tests in a clinical setting.\n\nEculizumab was not approved in Japan in 2013; thus, we initially treated the patient only with plasma exchange, which was insufficient to control disease progression. We started eculizumab 29 days after onset, following thorough discussion regarding the benefits and risks of off-label use of self-imported eculizumab. It has been reported that delayed initiation of eculizumab is associated with a worse outcome of the renal function (3,23). Eventually, our case required long-term dialysis. However, long-term treatment with eculizumab resulted in our patient discontinuing dialysis 18 months after onset. This case suggests that it is worth considering long-term eculizumab, even for cases with delayed admission requiring dialysis, as the renal function can still be recovered and slowly improved by eculizumab.\n\nEculizumab is estimated to cost in the range of US$600,000 per year (24); thus, we need to avoid the overuse of eculizumab by performing careful diagnosis and treatment decision-making. An observational study revealed that around 70% of cases in other countries were able to successfully discontinue eculizumab without recurrence (25). However, there are no prospective studies on the discontinuation of eculizumab in Japan. Therefore, in the present case, we are continuing treatment with eculizumab in the expectation of further, gradual improvement of the renal function.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nYoshitaka Miyakawa: Honoraria, Alexion Phamaceuticals; Research funding, Alexion Pharmaceuticals.\n\nAcknowledgement\nA complement hemolytic assay using sheep red blood cells was conducted by Prof. Yoshihiro Fujimura, Prof. Masanori Matsumoto, and Dr. Yoko Yoshida, Department of Transfusion Medicine, Nara Prefectural Medical University. The genetic testing was conducted by Dr. Toshiyuki Miyata, National Cerebral and Cardiovascular Center, Osaka, Japan. We greatly appreciate all of their kind support.\n==== Refs\n1. Noris M , Mescia F , Remuzzi G \nSTEC-HUS, atypical HUS and TTP are all diseases of complement activation . Nat Rev Nephrol \n8 : 622 -633 , 2012 .22986360 \n2. Kaplan BS , Meyers KE , Schulman SL \nThe pathogenesis and treatment of hemolytic uremic syndrome . J Am Soc Nephrol \n9 : 1126 -1133 , 1998 .9621299 \n3. Legendre CM , Licht C , Muus P , et al \nTerminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome . N Engl J Med \n368 : 2169 -2181 , 2013 .23738544 \n4. Yoshida Y , Miyata T , Matsumoto M , et al \nA novel quantitative hemolytic assay coupled with restriction fragment length polymorphisms analysis enabled early diagnosis of atypical hemolytic uremic syndrome and identified unique predisposing mutations in Japan . PLoS One \n10 : e0124655 , 2015 .25951460 \n5. Sellier-Leclerc AL , Fremeaux-Bacchi V , Dragon-Durey MA , et al \nDifferential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome . J Am Soc Nephrol \n18 : 2392 -2400 , 2007 .17599974 \n6. George JN , Nester CM \nSyndromes of thrombotic microangiopathy . N Engl J Med \n371 : 654 -666 , 2014 .25119611 \n7. Tsai HM \nUntying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome . Am J Med \n126 : 200 -209 , 2013 .23410558 \n8. Noris M , Remuzzi G \nAtypical hemolytic-uremic syndrome . N Engl J Med \n361 : 1676 -1687 , 2009 .19846853 \n9. Kavanagh D , Goodship THJ \nAtypical hemolytic uremic syndrome, genetic basis, and clinical manifestations . Hematology Am Soc Hematol Educ Program \n2011 : 15 -20 , 2011 .22160007 \n10. Taylor CM , Machin S , Wigmore SJ , Goodship THJ \nClinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom . Br J Haematol \n148 : 37 -47 , 2010 .19821824 \n11. Saland J \nLiver-kidney transplantation to cure atypical HUS: still an option post-eculizumab? \nPediatr Nephrol \n29 : 329 -332 , 2014 .24362724 \n12. Fremeaux-Bacchi V , Fakhouri F , Garnier A , et al \nGenetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults . Clin J Am Soc Nephrol \n8 : 554 -562 , 2013 .23307876 \n13. Kato H , Nangaku M , Hataya H , et al \nClinical guides for atypical hemolytic uremic syndrome in Japan . Pediatr Int \n58 : 549 -555 , 2016 .27460397 \n14. Caprioli J , Noris M , Brioschi S , et al \nGenetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome . Blood \n108 : 1267 -1279 , 2006 .16621965 \n15. Richards A , Kemp EJ , Liszewski MK , et al \nMutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome . Proc Natl Acad Sci U S A \n100 : 12966 -12971 , 2003 .14566051 \n16. Delvaeye M , Noris M , De Vriese A , et al \nThrombomodulin mutations in atypical hemolytic-uremic syndrome . N Engl J Med \n361 : 345 -357 , 2009 .19625716 \n17. Fan X , Yoshida Y , Honda S , et al \nAnalysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome . Mol Immunol \n54 : 238 -246 , 2013 .23314101 \n18. Campistol JM , Arias M , Ariceta G , et al \nAn update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document . Nefrologia \n33 : 27 -45 , 2013 .23364625 \n19. Cataland SR , Holers VM , Geyer S , Yang S , Wu HM \nBiomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP . Blood \n123 : 3733 -3738 , 2014 .24695849 \n20. Noris M , Galbusera M , Gastoldi S , et al \nDynamics of complement activation in aHUS and how to monitor eculizumab therapy . Blood \n124 : 1715 -1726 , 2014 .25037630 \n21. Gavriilaki E , Yuan X , Ye Z , et al \nModified Ham test for atypical hemolytic uremic syndrome . Blood \n125 : 3637 -3646 , 2015 .25862562 \n22. Magro CM , Momtahen S , Mulvey JJ , Yassin AH , Kaplan RB , Laurence JC \nRole of the skin biopsy in the diagnosis of atypical hemolytic uremic syndrome . Am J Dermatopathol \n37 : 349 -356-quiz357-359 , 2015 .25893747 \n23. Greenbaum LA , Fila M , Ardissino G , et al \nEculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome . Kidney Int \n89 : 701 -711 , 2016 .26880462 \n24. Parker C \nEculizumab for paroxysmal nocturnal haemoglobinuria . Lancet \n373 : 759 -767 , 2009 .19144399 \n25. Ardissino G , Testa S , Possenti I , et al \nDiscontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases . Am J Kidney Dis \n64 : 633 -637 , 2014 .24656451\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(9)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "atypical hemolytic uremic syndrome; eculizumab; peritoneal dialysis; thrombotic microangiopathy",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D044466:Asians; D065766:Atypical Hemolytic Uremic Syndrome; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D057049:Thrombotic Microangiopathies; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1085-1088",
"pmc": null,
"pmid": "28458317",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23364625;22986360;17599974;19846853;25862562;9621299;23738544;24656451;25037630;27460397;19144399;14566051;16621965;24695849;25893747;19821824;23410558;26880462;24362724;22160007;25951460;25119611;23314101;19625716;23307876",
"title": "Long-term Eculizumab Treatment Contributes to Recovery from End-stage Renal Disease Caused by Atypical Hemolytic Uremic Syndrome.",
"title_normalized": "long term eculizumab treatment contributes to recovery from end stage renal disease caused by atypical hemolytic uremic syndrome"
}
|
[
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"literaturereference": "YAMADA Y, ABE R, OKANO Y, MIYAKAWA Y. LONG-TERM ECULIZUMAB TREATMENT CONTRIBUTES TO RECOVERY FROM END-STAGE RENAL DISEASE CAUSED BY ATYPICAL HEMOLYTIC UREMIC SYNDROME. INTERNAL MEDICINE. 2017;56:1085-1088",
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{
"abstract": "Sofosbuvir and daclatasvir are direct-acting antiviral drugs used to treat chronic hepatitis C virus infection. In 2015, the Food and Drug Administration and European Medical Agency warned that bradycardia could occur when amiodarone was administered in combination with sofosbuvir, but no case reports had been published. We report extreme bradycardia within 2 hrs after intake of sofosbuvir and daclatasvir by 2 patients receiving amiodarone. The first patient had a cardiac asystole 30 min after receiving sofosbuvir and daclatasvir. Amiodarone, sofosbuvir, and daclatasvir treatment were stopped; after 10 days, the cardiac evaluation was normal and patient was discharged. The second patient was taking amiodarone and propranolol; 2 hrs after receiving sofosbuvir and daclatasvir, he had an extreme sinus node dysfunction (heart rate of 27beats/min). Amiodarone and propranolol were stopped, but the patient continued receiving sofosbuvir and daclatasvir for 3 days and sinus bradycardia was recorded each day, 2 hrs after intake of these drugs. When he stopped taking the drugs, no bradycardia was observed. Administration of sofosbuvir and daclatasvir on day 13 induced bradycardia 2 hrs after intake. However, no bradycardia occurred following a rechallenge 8 weeks after the patient stopped taking amiodarone. These observations indicate that patients treated with amiodarone should be continuously monitored within the first 48 hrs following the initiation of sofosbuvir and daclatasvir.",
"affiliations": "AP-HP, Hôpital Antoine Béclère, Service de Pharmacie, DHU TORINO, Clamart, France.;AP-HP, Hôpital Antoine Béclère, Service de Pharmacie, DHU TORINO, Clamart, France; INSERM UMR-S 999, DHU TORINO, LabEx LERMIT, Le Plessis-Robinson, France; Univ. Paris-Sud, France.;Univ. Paris-Sud, France; AP-HP, Hôpital Paul-Brousse, Centre Hépato-Biliaire, DHU Hepatinov, France; INSERM UMR-S 1193, Villejuif, France.;AP-HP, Hôpital Antoine Béclère, Service de Cardiologie, DHU TORINO, Clamart, France.;AP-HP, Centre Régional de Pharmacovigilance, Hôpital Henri Mondor, Créteil, France.;Cardiology department, Charles Nicolle University Hospital, Rouen, France.;Univ. Paris-Sud, France; AP-HP, Hôpital Paul-Brousse, Centre Hépato-Biliaire, DHU Hepatinov, France; INSERM UMR-S 1193, Villejuif, France.;Univ. Paris-Sud, France; AP-HP, Hôpital Paul-Brousse, Centre Hépato-Biliaire, DHU Hepatinov, France; INSERM UMR-S 1193, Villejuif, France.;Univ. Paris-Sud, France; AP-HP, Hôpital Antoine Béclère, Service de Cardiologie, DHU TORINO, Clamart, France; INSERM UMR-S 1180, TORINO, LabEx LERMIT, Chatenay Malabry, France. Electronic address: [email protected].",
"authors": "Renet|Sophie|S|;Chaumais|Marie-Camille|MC|;Antonini|Teresa|T|;Zhao|Alexandre|A|;Thomas|Laure|L|;Savoure|Arnaud|A|;Samuel|Didier|D|;Duclos-Vallée|Jean-Charles|JC|;Algalarrondo|Vincent|V|",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014665:Vasodilator Agents; D014633:Valine; C549273:daclatasvir; D000638:Amiodarone; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "149(6)",
"journal": "Gastroenterology",
"keywords": "Cardiac Arrest; DAA; Drug Interactions; Side Effect",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000638:Amiodarone; D000998:Antiviral Agents; D001919:Bradycardia; D002219:Carbamates; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D000069474:Sofosbuvir; D013997:Time Factors; D014633:Valine; D014665:Vasodilator Agents",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "1378-1380.e1",
"pmc": null,
"pmid": "26253303",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge.",
"title_normalized": "extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone 2 cases including a rechallenge"
}
|
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"literaturereference": "RENET S, CHAUMAIS MC, ANTONINI T, ZHAO A, THOMAS L, SAVOURE A ET AL. EXTREME BRADYCARDIA AFTER FIRST DOSES OF SOFOSBUVIR AND DACLATASVIR IN PATIENTS RECEIVING AMIODARONE: 2 CASES INCLUDING A RECHALLENGE. GASTROENTEROLOGY. 2015?149(6):1378-1380.",
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"abstract": "BACKGROUND\nCombination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period.\n\n\nMETHODS\nThis prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR.\n\n\nRESULTS\nOver a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001).\n\n\nCONCLUSIONS\nIn the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy.",
"affiliations": "Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada; Oak Tree Clinic, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.;Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.;Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada; Oak Tree Clinic, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.;Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.;Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.;Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.;Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada.;Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.",
"authors": "Money|Deborah M|DM|;Wagner|Emily C|EC|;Maan|Evelyn J|EJ|;Chaworth-Musters|Tessa|T|;Gadawski|Izabelle|I|;van Schalkwyk|Julie E|JE|;Forbes|John C|JC|;Burdge|David R|DR|;Albert|Arianne Y K|AY|;Lohn|Zoe|Z|;Côté|Hélène C F|HC|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0135041",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2624721110.1371/journal.pone.0135041PONE-D-15-13256Research ArticleEvidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women mtDNA Alterations in HIV-Infected Pregnant WomenMoney Deborah M. \n1\n\n2\n\n3\n*Wagner Emily C. \n2\nMaan Evelyn J. \n2\n\n3\nChaworth-Musters Tessa \n1\nGadawski Izabelle \n4\nvan Schalkwyk Julie E. \n1\n\n2\nForbes John C. \n5\nBurdge David R. \n1\n\n2\nAlbert Arianne Y. K. \n2\nLohn Zoe \n2\nCôté Hélène C. F. \n2\n\n4\n The Oak Tree Clinic Research Group \n¶\n\n1 \nDepartment of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada\n\n2 \nWomen’s Health Research Institute, BC Women’s Hospital and Health Centre, Vancouver, BC, Canada\n\n3 \nOak Tree Clinic, BC Women’s Hospital and Health Centre, Vancouver, BC, Canada\n\n4 \nDepartment of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada\n\n5 \nDepartment of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada\nMoodley Dhayendre Editor\nUniversity of Kwazulu-Natal, SOUTH AFRICA\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: DMM EJM JVS JCF DB HCFC. Performed the experiments: DMM EJM TCM IG JVS JCF DB HCFC. Analyzed the data: DMM ECW AYKA HCFC. Contributed reagents/materials/analysis tools: DMM HCFC. Wrote the paper: DMM ECW EJM JVS AYKA ZL HCFC.\n\n¶ A full list of the Oak Tree Clinical Research Group members is provided in the Acknowledgments.\n\n* E-mail: [email protected] 8 2015 2015 10 8 e013504126 3 2015 16 7 2015 © 2015 Money et al2015Money 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 properly credited.Introduction\nCombination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period.\n\nMethods\nThis prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30–40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR.\n\nResults\nOver a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001).\n\nConclusions\nIn the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy.\n\nFinancial support for this study was provided by a research grant from the Canadian Foundation for AIDS Research (CANFAR; www.canfar.com) awarded to DMM and HCFC (grant reference #016012). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityData are restricted for ethical reasons by the University of British Columbia Research Ethics Board. Data requests can be sent to the Oak Tree Clinic Research Group, who may be contacted via [email protected]. Researchers requesting data must meet criteria for access to confidential data and data sharing activities must be approved by the UBC Research Ethics Board.Data Availability\nData are restricted for ethical reasons by the University of British Columbia Research Ethics Board. Data requests can be sent to the Oak Tree Clinic Research Group, who may be contacted via [email protected]. Researchers requesting data must meet criteria for access to confidential data and data sharing activities must be approved by the UBC Research Ethics Board.\n==== Body\nIntroduction\nAn estimated 17 million women are infected with HIV (HIV+) worldwide [1]. Without intervention, vertical transmission rates during and after pregnancy range from 14% to 48% [2]. Since 1994, the use of antiretroviral therapy (ART) has contributed substantially to the prevention of vertical transmission [3] and with progression to the use of combination ART (cART), in conjunction with comprehensive obstetrical care, dramatically decreased neonatal infection rates (~0.4%) have been widely reported [4–10]. However, there is limited knowledge or data available on the long term safety of cART exposure in human foetuses during pregnancy [11–16], and how in utero cART exposure may affect HIV exposed uninfected (HEU) infants later in life.\n\ncART continues to be the standard of care for pregnant women living with HIV, but as an increasing number of drugs are introduced and used in HIV treatment regimens, there are numerous examples of clinical cases where, for various reasons, regimens not well studied in pregnancy must be used. Although most individuals taking cART have tolerable and relatively mild side effects, it has also been associated with moderate or severe complications [17], particularly in pregnancy [18]. In addition to other suggested mechanisms [19–21], off-target effects of nucleoside reverse transcriptase inhibitors (NRTI) on the mitochondria and its polymerase-gamma [5, 22–25] are likely playing a role in many cART-induced toxicities. These can result in mtDNA depletion, increased mtDNA mutations, decreased mitochondrial gene expression, increased mitochondrial oxidative stress, and ultimately, mitochondrial dysfunction [19, 20, 26–31].\n\nHIV+ ART-exposed women have higher rates of adverse perinatal outcomes compared to HIV- ART-unexposed women. Specifically, the incidences of preterm birth and being small for gestational age (GA) are significantly increased among infants born to HIV+ women taking ART during pregnancy compared to infants born to HIV- women [13, 16, 32–43], although the contribution of HIV, other cofactors and/or antiviral therapy remains unclear. Signs of mitochondrial dysfunction in infants, such as transient hyperlactatemia, are common [11]. Furthermore, altered blood mtDNA levels [11, 13–15], as well as increased blood mtDNA somatic mutations [29] have been reported in ART-exposed HEU infants. Somatic mtDNA mutations have been associated with aging and age-related diseases [44–46], including mitochondrial aging in the context of HIV and NRTI exposure [30]. Clinical symptoms suggestive of mitochondrial dysfunction in HEU infants born to HIV+ women treated with cART in pregnancy are either not [11,13,14,43], or rarely [47,48] observed. However, subclinical mitochondrial alterations in HIV+ mothers or their HEU infants could impact health later in life.\n\nThere have been conflicting reports regarding the effect of HIV and ART use during pregnancy on mtDNA levels. Observational studies comparing mtDNA levels in tissues from HIV+ ART-exposed pregnant women and their infants to HIV- women and their infants have reported higher, lower, or no significant change in levels of mtDNA [11, 13–15, 49–53]. The disparity between these findings may be related to differences in cART regimen type, cART duration between studies and/or the fact that multiple mechanisms may be at play. For example, exposure to some NRTI may induce mtDNA depletion [25] or increase mtDNA mutations, possibly through replication errors by polymerase gamma or oxidative damage [54] which may in turn induce mitochondrial biogenesis as an adaptive mechanism, favouring clonal expansion of mtDNA mutations [55–56]. Concurrently, other ART agents belonging to other drug class are reported to modulate autophagy [57–58], and can thereby affect mtDNA levels. There clearly is a need for further research using larger samples and rigorous study designs. Indeed, most studies conducted to date are cross-sectional, of small to moderate sample size, with often heterogeneous cART regimens. No previous study has assessed longitudinal mtDNA/nDNA ratio during pregnancy in HIV- or HIV+ cART treated women. Ultimately, understanding the pharmacopathology of cART is important because many ART drugs can cross the placenta, and thus may impact foetal development or long term health.\n\nWe aimed to establish whether subclinical mitochondrial alterations occur during pregnancy in HIV+ cART treated women by investigating peripheral blood mtDNA levels during and after pregnancy in HIV+ cART-exposed women, as well as in HIV- control women. This information is vitally important for ongoing global efforts to determine the safest and most effective application of cART in pregnancy.\n\nMaterials and Methods\nDesign\nThis single-site, prospective longitudinal observational study consisted of two cohorts: (i) HIV+ women (N = 65) using cART during pregnancy (cART started pre-conception or during pregnancy); (ii) HIV- women (N = 45). The Clinical Research Ethics Review Board at the University of British Columbia, Canada approved this study (H04-70540).\n\nRecruitment\nAll women were approached to participate from December 2004 to October 2008. The cohort of HIV+ women (N = 65) was recruited from the Oak Tree Clinic, a provincial referral centre in Vancouver, British Columbia (BC), Canada, which coordinates HIV care for all known HIV+ pregnant women in BC. The cohort of HIV- women (N = 45) were recruited from the same city.\n\nDuring recruitment of controls, a deliberate effort was made to approach potential participants with similar characteristics to the HIV+ group. While this approach worked well toward reducing confounding factors (i.e. maternal age, smoking, alcohol consumption, and illicit drug use during pregnancy) between the groups, we did not achieve similar ethnicity among participants in the two groups due to cultural and ethical barriers encountered when dealing with small communities in which participation in an HIV study is negatively perceived. However, the ethnic distribution in our control sample was more closely comparable to the HIV+ group than the background Canadian population.\n\nData Collection\nAt enrolment, demographic, behavioural and clinical parameters were collected. All participants provided written informed consent. Peripheral blood was collected from HIV+ participants at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30–40 weeks), at delivery, and six weeks postpartum. Blood samples for mtDNA assays were collected in conjunction with clinically indicated blood tests for prenatal care, evaluation of HIV status and toxicity of cART. Clinical data pertaining to the infants born to HIV+ mothers was collected during the first week of life and at six weeks of age. HIV- pregnant women were asked to contribute peripheral blood samples during the same three time points during pregnancy to provide a reflection of physiological mtDNA dynamics in pregnancy. Peripheral blood was not collected from the control group at delivery or six weeks postpartum due to impracticalities in obtaining specimens.\n\nMitochondrial DNA Assay\nPeripheral blood was collected in ACD solution A tubes, transferred to a cryotube, and stored frozen at -80° C until used. Total DNA was extracted from 0.1 ml of whole blood using the QIAGEN DNA isolation kit, according to the manufacturer’s protocol and as previously described [25]. Mitochondrial gene cytochrome c oxidase subunit I and the nuclear gene for the accessory subunit of the polymerase gamma were quantified in duplicate by monochrome real-time quantitative PCR with fluorescent probes, using a Roche LightCycler 480. A standard curve was prepared with serially diluted plasmid DNA containing the two genes of interest. Both genes were quantified separately in duplicate on the same 96 well plate along with two internal controls, for a total of 20 samples per run. Results are expressed as the relative ratio between mtDNA and nDNA, according to the standard curve. Samples were assayed in a blinded and randomized fashion, but all extracts from a given participant were always assayed within a given run to minimize intra-subject variability. The intra- and inter-run coefficients of variation were5% and 10%, respectively.\n\nData Analysis\nDescriptive statistics report one standard deviation (SD) or standard error on the mean (SEM). To explore the effect of cART and HIV infection on the mtDNA ratios in pregnant women, a multivariate linear nested mixed-effects model was applied. In addition to the effect of HIV infection (HIV- vs. HIV+), the effect of the following was analysed: (a) maternal age at birth, (b) ethnicity (c) GA at time of sampling, (d) smoking, (e) alcohol consumption, and (f) use of illicit drugs (e.g. cocaine, heroin, see Table 1 footnote) throughout pregnancy (e.g. women reported active substance use at three or more time points in pregnancy). As platelets contain a small amount of mtDNA, platelet count was included in all models as a covariate. Women with missing data were casewise removed resulting in 265 mtDNA measures in pregnancy from 105 women.\n\n10.1371/journal.pone.0135041.t001Table 1 Demographic, clinical and laboratory characteristics of study participants (n = 105).\nCharacteristic\tMean ± SD or n (%)\t\n\tHIV+\tHIV-\tp-value\nb\n\n\t\n\t(n = 63)\t(n = 42)\t\t\n\nMaternal Age (years)\n\t30 ± 6\t31 ± 5\t0.23\t\n\nMaternal Ethnicity\n\t\t\t0.0004\t\n Aboriginal\t18 (29)\t5 (12)\t\t\n Caucasian\t23 (37)\t27 (64)\t\t\n Black\t12 (19)\t0 (0)\t\t\n Asian/Other\t10 (16)\t10 (24)\t\t\n\nHCV Antibody+\n\t\t\t<0.0001\t\n Positive\t17 (27)\t2 (5)\t\t\n Negative\t40 (63)\t16 (37)\t\t\n Unknown\t6 (10)\t24 (57)\t\t\n\nHCV PCR+\n\t\t\t\t\n Positive\t8 (13)\t1 (2)\t0.0004\t\n Negative\t41 (65)\t18 (43)\t\t\n Cleared\t3 (5)\t1 (2)\t\t\n Unknown\t11 (17)\t22 (52)\t\t\n\nSubstance use throughout pregnancy\n\na\n\n\t\t\t\t\n Smoking\t29 (46)\t17 (40)\t0.72\t\n Alcohol\t2 (3)\t3 (7)\t0.39\t\n Illicit Drugs\t6 (10)\t7 (17)\t0.43\t\n\nPlatelets (10\n9\n/L)\n\t\t\t\t\n 13-<23 weeks\t242 ± 65\t253 ± 83\t0.48\t\n 23-<30 weeks\t257 ± 79\t241 ± 72\t0.27\t\n 30–40 weeks\t257 ± 76\t225 ± 62\t0.03\t\n Delivery\t245 ± 75\t-\t-\t\n Postpartum\t276 ± 108\t-\t-\t\n\na Substance use is defined as self-reported use of substance at ≥3 study visits. Illicit Drugs = heroin, cocaine, opioids, amphetamines, benzodiazepenes and/or MDMA (ecstasy).\n\n\nb P-values are from Fisher’s exact tests for categorical data, and t-tests for continuous data (Platelets\n\nStepwise model selection was used to remove any non-significant variables from the model, resulting in an optimal model containing only variables significantly associated with mtDNA/nDNA ratio. Significance of the variables was assessed using Chi-square tests comparing the log-likelihoods of a model containing the variable versus one with it removed. A significant test (p < 0.05) means that inclusion of the variable significantly increased the fit of the model. Where applicable, post-hoc comparisons between groups were conducted using Tukey tests modified for mixed-effects models as implemented in the multcomp package in R [54]. Adjusted p-values are reported.\n\nTo explore differences between HIV+ women, modelling procedures used were the same as those described above, with the addition of three HIV specific variables: (a) lifetime ART exposure, (b) duration of cART in pregnancy, and (c) CD4 nadir, selected as a proxy to indicate severity of HIV disease. After removal of missing data, there were 253 mtDNA measures distributed amongst 63 women. To further investigate the effects of cART exposure on mtDNA ratio, the percent change in mtDNA/nDNA ratios from delivery to postpartum were compared between women who remained on cART and those who stopped using cART after delivery, using ANOVA.\n\nComparisons of demographic, clinical and laboratory characteristics between HIV+ and HIV- women were made. Continuous variables were tested for differences between the groups using t-tests; Apgar scores were compared using a Wilcoxon rank-sum test; categorical variables were compared using Chi Squared tests or Fisher exact tests where appropriate.\n\nResults\nParticipant Characteristics\nIn total, 105 pregnant women were enrolled in this study: 63 HIV+ pregnant women and 42 HIV- control pregnant women. Of the 115 women who were approached to participate, ten declined, corresponding to an enrolment rate of 91%. Demographic characteristics for both groups are summarized in Table 1, and HIV-specific characteristics of the HIV+ group are summarized in Table 2. Distribution of ethnicities was significantly different between the two groups (p = 0.0004) with more Aboriginal and Black/African women in the HIV+ group and more Caucasian and Asian women in the HIV- control group. The proportion of women reporting substance use (i.e., smoking, alcohol, illicit drugs) during pregnancy did not differ significantly between the two groups.\n\n10.1371/journal.pone.0135041.t002Table 2 HIV-specific clinical characteristics of HIV+ cohort (n = 63).\nCharacteristic\tMedian (range) or n (%)\t\n\nTime since HIV diagnosis (yrs)\n\t4 (0.2–17)\t\n HIV diagnosis during index pregnancy\t15 (21)\t\n\nCD4 Nadir (cells/μL)\n\t250 (20–910)\t\n\nLifetime ART exposure (weeks)\n\t36 (2–800)\t\n\ncART exposure in pregnancy (weeks)\n\t20 (2–42)\t\n\nTiming of cART Initiation\n\t\t\n Pre conception\t17 (27)\t\n 2–23 weeks gestation\t30 (48)\t\n 23-<30 weeks gestation\t12 (19)\t\n 30–37 weeks gestation\t4 (6)\t\n\nImmunovirological parameters at first visit (13–22 weeks)\n\t\t\n CD4 (cells/μL)\t445 (90–1200)\t\n HIV viral load (log10copies/mL)\t1.7 (0–3.8)\t\n\nImmunovirological parameters at delivery (32–40 weeks)\n\t\t\n CD4 (cells/μL)\t450 (100–1300)\t\n HIV viral load (log10copies/mL)\t0 (0–3.9)\t\n\nVertical transmission of HIV\n\t0 (0)\t\ncART Regimens\nHIV+ women treated during pregnancy were on a variety of regimens based on their individual circumstances (Please see Table 3 for detailed information). These included 56 women receiving a regimen containing ZDV and lamivudine (3TC); 59 women receiving a one or more protease inhibitors (PI) [n = 36 on nelfinavir (NFV), n = 28 on ritonavir-boosted lopinavir (LPV/r), n = 4 on ritonavir-boosted atazanavir (ATV)]; and 8 women receiving a non-NRTI (NNRT1)-containing regimen [n = 6 on nevirapine (NVP), n = 2 on efavirenz (EFV)].\n\n10.1371/journal.pone.0135041.t003Table 3 Combination antiretroviral therapy regimens taken during pregnancy by HIV positive study cohort (n = 63).\nNRTI\tN\tNNRTI\tN\tPI\tN\t\n\nZDV/3TC\n\t49\t—-\t42\tNFV\t24\t\n\t\t\tLPV/r\t14\t\n\t\t\tNFV/LPV/r\t4\t\n\t\tNVP\t5\t—-\t2\t\n\t\t\tNFV\t2\t\n\t\t\tLPV/r\t1\t\n\t\tEFV\t2\t—-\t1\t\n\t\t\tLPV/r\t1\t\n\nZDV/3TC/TDF\n\t3\t—-\t3\tNFV\t1\t\n\t\t\tLPV/r\t1\t\n\t\t\tNFV/LPV/r\t1\t\n\nZDV/3TC/TDF/ABC\n\t1\t—-\t1\tATV/LPV/r\t1\t\n\nZDV/3TC/TDF/DDI\n\t1\t—-\t1\tATV/LPV/r\t1\t\n\nZDV/3TC/ABC\n\t2\t—-\t2\t—-\t1\t\n\t\t\tNFV/LPV/r\t1\t\n\nZDV/DDI\n\t1\t—-\t1\tNFV\t1\t\n\n3TC/TDF\n\t1\t—-\t1\tATV/r\t1\t\n\nd4T/3TC\n\t3\t—-\t3\tNFV\t1\t\n\t\t\tLPV/r\t2\t\n\nFTC/TDF\n\t2\t—-\t1\tATV/r\t1\t\n\t\tNVP\t1\tLPV/r\t1\t\n\nTotal N\n\t\n63\n\t\t\n8\n\t\t\n59\n\t\nNRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; ZDV, zidovudine; 3TC, lamivudine; TDF, tenofovir; ABC, abacavir; ddI, didanosine; d4T, stavudine; FTC, emtricitabine; NVP, nevirapine; EFV, efavirenz; NFV, nelfinavir; LPV, lopinavir; NFV, nelfinavir; ATV, atazanavir; r, ritonavir boosted\n\nInfant Outcomes\nInfants born to HIV- and HIV+ women were not significantly different in terms of GA at birth, sex, birth weight, birth length, Apgar score at five minutes, and frequency of congenital anomalies and neonatal morbidities (Table 4). The proportion of preterm births observed in this population (18% for HIV+ women, 17% for HIV- women; Table 4) was higher than the provincial rate for preterm births (~5.3) [59] but not different between the groups. None of the 63 infants born to HIV+ women in this study were infected with HIV.\n\n10.1371/journal.pone.0135041.t004Table 4 Perinatal and neonatal outcomes for HIV+ (n = 63) and HIV- (n = 42) maternal infant pairs.\nCharacteristic\tMean ± SD (range) or n (%)\t\t\n\tHIV+\tHIV-\tp-value\t\n\t(n = 63)\t(n = 42)\t\t\n\nLive birth frequency\n\na\n\n\t63 (100)\t41 (98)\t0.41\t\n Proportion singleton births\t63 (100)\t42 (100)\t-\t\n Proportion male (%)\t32 (51)\t22 (52)\t1\t\n\nGA at birth (weeks)\n\t39 ± 2 (32–42)\t39 ± 2 (34–42)\t0.49\t\n Preterm birth (<37 weeks)\t11 (18)\t7 (17)\t1\t\n\nBirth weight (g)\n\t3078 ± 484 (1800–4075)\t3095 ± 557 (1925–4535)\t0.87\t\n\nBirth length (cm)\n\t50 ± 4 (35–57)\t50 ± 4 (38–57)\t0.53\t\n\nMedian Apgar score at 5 min (range)\n\t9 (7–10)\t9 (8–10)\t0.31\t\n\nCongenital abnormality\n\nc\n\n\t4 (3)\t1 (3)\t0.65\t\n\nNeonatal complications\n\nd\n\n\t6 (9)\t3 (8)\t0.24\t\n\nMild/Moderate neonatal withdrawal symptoms\n\t13 (19)\t7 (18)\t0.8\t\n\nNeonatal ZDV exposure\n\nb\n\n\t62 (100)\t2 (5)\t-\t\n\nNeonatal NVP exposure\n\nb\n\n\t9 (14)\t2 (5)\t-\t\n\na One infant born to an HIV- mother was stillborn.\n\n\nb Two HIV- control women were considered at high risk of contracting HIV due to drug use and unprotected intercourse with partners with unknown HIV status; therefore, infants were treated with zidovudine (ZDV) and nevirapine (NVP) as per standard of care.\n\n\nc Maternal HIV+ group: pulmonary artery stenosis (n = 2), pyloric stenosis (n = 1), hydronephrosis (n = 1); Maternal HIV- group: hydronephrosis (n = 1).\n\n\nd Maternal HIV+ group: mild respiratory distress (n = 1), respiratory syncytial virus (RSV) infection (n = 1), seizures (n = 1), sepsis (n = 1), apnoea of prematurity (n = 1), pneumonia (n = 1); Maternal HIV- group: mild respiratory distress (n = 1), neonatal intensive care unit for >24 hours (n = 1), hyperbilirubinaemia (n = 1).\n\nContinuous variables were tested for differences between the groups using t-tests; Apgar scores were compared using a Wilcoxon rank-sum test; categorical variables were compared using Chi Squared tests or Fisher exact tests where appropriate.\n\nSD, standard deviation\n\nmtDNA/nDNA ratios in HIV+ compared to HIV-\nThe within woman intra-class correlation from the mixed-effects model was estimated at 0.73, thus measurements of mtDNA/nDNA ratio in the same woman at different times were highly correlated. During pregnancy, the mtDNA/nDNA ratios within each woman were relatively stable over time with a slight upward trend. Four variables were significantly associated with mtDNA/nDNA ratio after controlling for repeated measurements on women and platelet count in the multivariable mixed-effects model: HIV infection (p = 0.003), ethnicity (p = 0.024), GA (p = 0.02), and illicit drug use (p = 0.004; Table 5, Fig 1A–1C).\n\n10.1371/journal.pone.0135041.g001Fig 1 Significant associations between mtDNA/nDNA ratio and variables of interest for both HIV- and HIV+ cohorts (N = 105).\n(A) Ethnicity, (B) GA at visit (weeks) and (C) Illicit drug use. In A and C, the horizontal line in the boxplots indicates the median value, boxes represent the interquartile range, whiskers indicate 1.5 times the interquartile range, while points indicate outliers. In B, the best-fit line from the mixed-effects model controlling for platelets and other significant variables is shown. All samples were collected during pregnancy.\n\n10.1371/journal.pone.0135041.t005Table 5 Means, model estimates, and log-likelihood ratio test Chi-squared results for the mixed-effects modelling of mtDNA levels in all HIV+ and HIV- pregnant women (n = 105).\n\tMean (SEM)\na\n\n\tEstimated Model coefficient (±SEM)\nb\n\n\tLRT\nd\n (df)\tp-value\t\n\nIntercept\n\t\t87.2\t\t\t\n\nEthnicity\n\t\t\t9.5 (3)\t0.02\t\n Caucasian\t117 (7)\treference\t\t\t\n Asian/Other\t112 (10)\t-3.0 (7.2)\t\t\t\n Black/African\t129 (10)\t26.8 (9.5)\t\t\t\n Aboriginal\t126 (4)\t1.2 (7.7)\t\t\t\n\nHIV status\n\t\t\t9.1 (1)\t0.003\t\n HIV-\t126 (3)\treference\t\t\t\n HIV+\t115 (3)\t-18.0 (6.1)\t\t\t\n\nGA at visit (weeks)\n\t\t0.5 (0.2)\t5.4 (1)\t0.02\t\n\nIllicit drug use\n\nc\n\n\t\t\t8.1 (1)\t0.004\t\n No\t115 (2)\treference\t\t\t\n Yes\t147 (6)\t24.5 (8.7)\t\t\t\n\na Means (± SEM) are reported for the raw data without correction for covariates.\n\n\nb Estimated effects after taking covariates into account.\n\n\nc The modelling did not differentiate between women using 2 or more illicit drugs during pregnancy and women only taking one illicit drug.\n\n\nd LRT = likelihood-ratio test statistic\n\nSEM, Standard error on the mean\n\ndf, degrees of freedom\n\nGA, gestational age\n\nThe HIV+ group had significantly lower mtDNA/nDNA ratios than the HIV- control group during pregnancy (estimated model coefficients, estimated effect = -18.0 ± 6.1 SE, p = 0.003; Table 5). Black/African women had significantly higher ratios compared to Asian/other (p = 0.02) and Caucasian women (p = 0.02), as shown by post-hoc Tukey-tests. Increasing GA (slope = 0.46 ± 0.20 SE, p = 0.02) and reported illicit drug use (estimated effect = 24.5 ± 8.7 SE, p = 0.004) were associated with an increase in mtDNA/nDNA ratio (Table 5). The distribution of illicit drug users was uneven in respect to ethnicity and HIV status, as women of Black/African ethnicity had no self-reported incidences of illicit drug use during pregnancy, but were more likely to be HIV+. Although Black/African women had higher mtDNA/nDNA ratios on average, and were over-represented in the HIV+ group compared to the other ethnicities, there was still a strong negative effect of HIV status on mtDNA/nDNA ratio after ethnicity and drug use were taken into account. These results may thus be conservative in estimating the difference in mtDNA/nDNA ratio between HIV+ and HIV- pregnant women.\n\nmtDNA/nDNA ratios among HIV+ women\nAmong the HIV+ women, the within woman intra-class correlation from the mixed-effects model was 0.44, indicating that measurements in the same woman were somewhat correlated. While there appeared to be a trend toward lower mtDNA/nDNA ratios among women who started cART therapy pre-conception (n = 17) versus those who started cART during pregnancy (n = 46), after other significant variables were taken into account, there were no significant differences between these two groups in terms of mean mtDNA/nDNA ratios over time (p = 0.67; Fig 2A). Three variables were significantly associated with mtDNA/nDNA ratio after controlling for repeated measurements and platelet count in the multivariable mixed-effects model: timing of sample (pregnancy, delivery and postpartum; p<0.0001), ethnicity (p = 0.03), and CD4 nadir (p<0.0001; Fig 2B–2D).\n\n10.1371/journal.pone.0135041.g002Fig 2 Temporal variation in mtDNA/nDNA ratio during pregnancy, at delivery and postpartum for the HIV+ cohort.\nA) mtDNA/nDNA ratio in HIV- women (n = 42), HIV+ women who initiated cART prior to conception (n = 17) and continued throughout pregnancy, and HIV+ women who initiated cART during pregnancy (n = 46) at each sample time point (13–22 weeks, 23–30 weeks, 31–40 weeks, delivery, 6 weeks postpartum); mtDNA/ nDNA ratio among HIV+ women (n = 63) for the significant variables of (B) time of visit (13–22 weeks, 23–30 weeks, 31–40 weeks, delivery, 6 weeks postpartum), where the horizontal line in the boxplots indicates the median value, boxes represent the interquartile range, whiskers indicate 1.5 times the interquartile range, while points indicate outliers; (C) CD4 nadir, where the best-fit line from the mixed-effects model is shown.\n\nWhen post-hoc comparisons were conducted, only comparisons between samples taken during pregnancy versus postpartum showed significant differences in mean mtDNA/nDNA ratio. Samples taken at 13-<23 weeks, 23-<30 weeks, 30–40 weeks and delivery (p-values = <0.001, <0.001, 0.002, and <0.001 respectively, as shown by post-hoc Tukey tests) had lower mtDNA ratios compared to those taken postpartum. Comparisons among samples collected during pregnancy were not significantly different. HIV+ Black/African women had significantly higher mtDNA ratios than the Asian/other HIV+ women (p = 0.02) as shown by post-hoc Tukey tests. Higher CD4 nadir was positively associated with higher mtDNA/nDNA ratios (model coefficients, slope = 0.06 ± 0.02 SE; Table 6). The estimates and standard errors of the model coefficients, and the Chi-square and p-value for the tests of significance are summarized in Table 6.\n\n10.1371/journal.pone.0135041.t006Table 6 Means, model estimates, and Chi-squared results for the mixed-effects modelling of mtDNA levels within the 63 HIV+ pregnant women.\n\tMean (±SEM)\na\n\n\tEstimated Model coefficient (±SEM)\nb\n\n\tLRT\nd\n (df)\tp-value\t\n\nIntercept\n\t\t58.1\t\t\t\n\nEthnicity\n\t\t\t9.3 (3)\t0.03\t\n Caucasian\t116 (4)\treference\t\t\t\n Asian/Other\t106 (6)\t-8.5 (8.8)\t\t\t\n Black/African\t131 (4)\t19.9 (8.4)\t\t\t\n Aboriginal\t124 (4)\t2.0 (7.5)\t\t\t\n\nTiming of visit\n\t\t\t29.3 (4)\t< 0.0001\t\n 13–22 weeks\t111 (4)\treference\t\t\t\n 23–30 weeks\t114 (5)\t-0.8 (4.5)\t\t\t\n 31–40 weeks\t119 (5)\t3.9 (4.6)\t\t\t\n Delivery\t117 (6)\t-0.03 (4.7)\t\t\t\n 6 weeks postpartum\t139 (6)\t20.5 (4.8)\t\t\t\n\nCD4 Nadir\n\t\t0.06 (0.02)\t17.1 (1)\t< 0.0001\t\n\na Means (± SEM) are reported for the raw data without correction for covariates.\n\n\nb Estimated effects after taking covariates into account.\n\n\nd LRT = likelihood-ratio test statistic\n\nSEM, Standard error on the mean\n\ndf, degrees of freedom\n\nmtDNA/nDNA ratios among HIV+ women postpartum samples\nOf the 63 HIV+ women, 28 remained on cART postpartum, 28 stopped cART postpartum, and postpartum cART information was not available for 7 women. Of these, 44 had data for mtDNA/nDNA ratios at both delivery and postpartum (20 who remained on cART, and 24 who discontinued). There was no significant difference in the percent change in mtDNA/nDNA ratio from delivery to postpartum between HIV+ women who remained on cART postpartum (mean percent change in mtDNA/nDNA ± SD ratio 13 ± 16%) compared to those women who did not (7 ± 18%; ANOVA, F = 0.99, p = 0.33).\n\nDiscussion\nMitochondrial DNA levels through pregnancy have not been previously studied in a longitudinal design and the HIV- control group illustrates stability of levels within women through pregnancy with modest increase prior to delivery. Our study demonstrates the novel finding that compared to HIV- controls, HIV+ cART-exposed women had significantly lower blood mtDNA levels during pregnancy. This finding was remarkable in that the HIV+ group consisted of participants of ethnicities that, on average, have higher mtDNA ratios. This finding is consistent with other studies that have found significantly decreased mtDNA levels in other tissues such as umbilical cord blood [49,50] and placental tissue [50, 51] of HIV+ women compared to HIV- women. Of note, this is also consistent with another study [43], which reported non-significantly lower mtDNA levels shortly after delivery in HIV+ women treated with ART therapy compared to HIV- women. Higher mtDNA levels in infants born to HIV+ cART-treated mothers compared to HIV- women were previously reported by our group [11] and others [17,22], and may be a compensatory mechanism to overcome HIV/ART associated mitochondrial toxicity in utero [11,14].\n\nIt is critical to be aware of lower mtDNA levels during pregnancy because altered mtDNA may impact metabolism and energy production within the placenta, affecting foetal growth and development. Furthermore, mtDNA depletion during pregnancy may contribute to the neurological symptoms suggestive of mitochondrial dysfunction observed in some children born to HIV+ ART-exposed women [47, 48]. In this study, no infants born to HIV+ mothers showed clinically recognised neurological symptoms suggestive of mitochondrial dysfunction within the study period. There were instances of transient mild to moderate hyperlactatemia but no lactic acidosis. This is consistent with previous studies among similarly exposed infants. Nevertheless, lower mtDNA levels in HIV+ mothers may contribute to their children’s future development, growth and health. Further, there were no significant differences in obstetrical and neonatal outcomes of HIV+ and HIV- pregnancies in this study, which was surprising considering that many studies have shown a significantly increased incidence of preterm birth and low birth weight among infants born to HIV+ ART-exposed women compared to infants born to HIV- women [13,16,32–42]. However, HIV- women in this study were unusually well matched with respect to other risk factors known to be associated with prematurity/low birth weight, including smoking and illicit drug use illustrated by the high rates of preterm birth in both our study and control arms. This matching may also have exerted a negative effect on the HIV- women’s mtDNA/nDNA ratios compared to low risk HIV- women, minimizing any difference between their results and that of our HIV+ cohort.\n\nIn spite of a trend for women who initiated cART during pregnancy to have increased mtDNA levels compared to women who initiated therapy prior to conception, this effect was not statistically significant. While it is possible that timing of initiation and duration of cART could impact mtDNA levels, our study lacked the statistical power for such a sub-analysis and therefore could not adequately ascertain the effect of timing of cART initiation on mtDNA. Furthermore, women who were taking cART prior to conception likely had greater HIV disease duration and severity, as indicated by a lower CD4 nadir, something that could impact mitochondrial function in addition to exposure to cART. Indeed, the observation that lower CD4 nadir was positively associated with lower mtDNA/nDNA ratio among HIV+ women would be consistent with several studies that have found significant mtDNA depletion in the peripheral blood of untreated HIV+ adults compared to uninfected controls [21,60–62]. Whether cART initiation can fully reverse this effect is unknown.\n\nAmong HIV+ women, mtDNA levels were significantly higher postpartum than during pregnancy, both in HIV+ women who continued and those who discontinued cART. This result indicates that pregnancy/delivery itself is associated with a change in blood mtDNA levels. Postpartum peripheral blood samples in HIV- women would be required to tease apart the effects of cART, HIV, and pregnancy itself on mtDNA levels, which were not available in this study, but warrants further investigation. Despite our inability in this study to compare postpartum HIV+ levels to HIV- levels, we hypothesize that the metabolic stress of pregnancy through the high growth and development of the placental/fetal unit likely suppresses mtDNA/nDNA levels which appear to rebound post-partum.\n\nStudy Strengths and Limitations\nThe longitudinal design of this study allowed a more extensive documenting of blood mtDNA levels during pregnancy among HIV+ cART-exposed women relative to cross-sectional studies. Furthermore, the fact that the HIV- and HIV+ groups were well matched with respect to important factors such as substance use allowed consideration of these possible confounders. However, these data have several limitations. Firstly, our analyses included peripheral blood but other tissues may show different mtDNA levels, limiting the interpretation of our results in the context of other studies that utilized different tissue types. Secondly, we could not distinguish between the impacts of HIV infection itself and that of cART on mtDNA levels because not offering cART to HIV+ pregnant women would be unethical. Nevertheless, this adds an important confounding factor to our results as both cART and HIV could independently impact mtDNA. Thirdly, the lack of peripheral blood samples at delivery and six weeks postpartum from HIV- women makes it difficult to interpret the increased mtDNA levels seen postpartum in HIV+ women. Finally, the groups were not balanced with respect to the proportions of ethnicities.\n\nConclusions\nThis is the first study to assess temporal trends of mtDNA/nDNA ratios during pregnancy. In both HIV+ and HIV- women, mtDNA/nDNA was observed to be relatively stable throughout pregnancy; however HIV+ women had lower mtDNA/nDNA ratios compared to HIV- women after controlling for ethnicity and illicit drug use. In HIV+ women, higher CD4 nadir was positively associated with higher mtDNA/nDNA ratio, although this association was not influenced by cART. Though some data exist on this subject, pregnant HIV+ women receiving cART are still understudied and there is much need for research in this population. While cART successfully reduces the vertical transmission rate of HIV in infected pregnant women, further research is critical to improve optimal selection of the safest regimens in pregnancy.\n\nForemost, we would like to express our gratitude to all of the women who participated in this study and to the Canadian Foundation for AIDS Research (CANFAR) for funding this research (grant reference #016012). Thank you to Dr. Aroha Miller for critically reviewing the manuscript and providing editorial assistance. 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Environ Mol Mutagen . 2009 ; 50 : 10 –26 . 10.1002/em.20433 \n19031409 \n29 \nPayne BA , Wilson IJ , Hateley CA , Horvath R , Santibanez-Koref M , Samuels DC , et al\nMitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations . Nat Genet , 2011 ; 43 : 806 –810 . 10.1038/ng.863 \n21706004 \n30 \nJitratkosol MH , Sattha B , Maan EJ , Gadawski I , Harrigan PR , Forbes JC , et al\nBlood mitochondrial DNA mutations in HIV-infected women and their infants exposed to HAART during pregnancy . AIDS . 2012 ; 26 : 675 –683 . 10.1097/QAD.0b013e32835142eb \n22436539 \n31 \nMorén C , Noguera-Julian A , Garrabou G , Rovira N , Catalán M , Bañó M , et al\nMitochondrial disturbances in HIV pregnancies . AIDS . 2015 \n1 \n2 ; 29 (1 ): 5 –12 . 10.1097/QAD.0000000000000486 \n25268887 \n32 \nEuropean Collaborative Study , Swiss Mother and Child HIV Cohort Study . Combination antiretroviral therapy and duration of pregnancy . AIDS . 2000 ; 14 : 2913 –2920 .\n11398741 \n33 \nTuomala RE , Shapiro DE , Mofenson LM , Bryson Y , Culnane M , Hughes MD , et al\nAntiretroviral therapy during pregnancy and the risk of an adverse outcome . N Engl J Med . 2002 ; 346 : 1863 –1870 .\n12063370 \n34 \nTuomala RE , Watts DH , Li D , Vajaranant M , Pitt J , Hammill H , et al\nImproved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy . J Acquir Immune Defic Syndr . 2005 ; 38 : 449 –473 .\n15764963 \n35 \nThorne C , Patel D , Newell ML . Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe . AIDS . 2004 ; 18 : 2337 –2339 .\n15577551 \n36 \nCotter AM , Garcia AG , Duthely ML , Luke B , O'Sullivan MJ . Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? \nJ Infect Dis . 2006 ; 193 : 1195 –1201 .\n16586354 \n37 \nBoer K , Nellen JF , Patel D , Timmermans S , Tempelman C , Wibaut M , et al\nThe AmRo study: pregnancy outcome in HIV-1-infected women under effective highly active antiretroviral therapy and a policy of vaginal delivery . BJOG . 2007 ; 114 : 148 –155 .\n17305888 \n38 \nSzyld EG , Warley EM , Freimanis L , Gonin R , Cahn PE , Calvet GA , et al\nMaternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth . AIDS . 2006 ; 20 : 2345 –2353 .\n17117021 \n39 \nPatel K , Shapiro DE , Brogly SB , Livingston EG , Stek AM , Bardeguez AD , et al\nPrenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy . J Infect Dis . 2010 ; 201 : 1035 –1044 . 10.1086/651232 \n20196654 \n40 \nPowis KM , Kitch D , Ogwu A , Hughes MD , Lockman S , Leidner J , et al\nIncreased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy . J Infect Dis . 2011 ; 204 : 506 –514 . 10.1093/infdis/jir307 \n21791651 \n41 \nAebi-Popp K , Lapaire O , Glass TR , Vilen L , Rudin C , Elzi L , et al\nPregnancy and delivery outcomes of HIV infected women in Switzerland 2003–2008 . J Perinat Med . 2010 ; 38 : 353 –358 . 10.1515/JPM.2010.052 \n20184398 \n42 \nLopez M , Figueras F , Hernandez S , Lonca M , Garcia R , Palacio M , et al\nAssociation of HIV infection with spontaneous and iatrogenic preterm delivery: effect of HAART . AIDS . 2012 ; 26 : 37 –43 . 10.1097/QAD.0b013e32834db300 \n22008651 \n43 \nHernandez S , Moren C , Lopez M , Coll O , Cardellach F , Gratacós E , et al\nPerinatal outcomes, mitochondrial toxicity and apoptosis in HIV-treated pregnant women and in-utero-exposed newborn . AIDS . 2012 ; 26 : 419 –428 . 10.1097/QAD.0b013e32834f3232 \n22156962 \n44 \nTaylor R , Turnbull D . Mitochondrial DNA mutations in human disease . Nat Rev Genet . 2005 ; 6 : 389 –402 .\n15861210 \n45 \nPark C , Larsson N . Mitochondrial DNA mutations in disease and aging . J Cell Biol . 2011 ; 193 : 809 –818 . 10.1083/jcb.201010024 \n21606204 \n46 \nGreaves L , Reeve A , Taylor R , Turnbull R . Mitochondrial DNA and disease . J Pathol . 2012 ; 226 : 274 –286 . 10.1002/path.3028 \n21989606 \n47 \nBlanche S , Tardieu M , Rustin P , Slama A , Barret B , Firtion G , et al\nPersistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues . Lancet . 1999 ; 354 : 1084 –1089 .\n10509500 \n48 \nBarret B , Tardieu M , Rustin P , Lacroix C , Chabrol B , Desguerre I , et al\nPersistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort . AIDS . 2003 ; 17 : 1769 –1785 .\n12891063 \n49 \nDivi RL , Walker VE , Wade NA , Nagashima K , Seilkop SK , Adams ME ,et al\nMitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir . AIDS . 2004 ; 18 : 1013 –1021 .\n15096804 \n50 \nShiramizu B , Shikuma KM , Kamemoto L , Gerschenson M , Erdem G , Pinti M , et al\nPlacenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy . J Acquir Immune Defic Syndr . 2003 ; 33 : 370 –374 .\n51 \nGingelmaier A , Grubert TA , Kost BP , Setzer B , Lebrecht D , Mylonas I , et al\nMitochondrial toxicity in HIV type-1-exposed pregnancies in the era of highly active antiretroviral therapy . Antivir Ther . 2009 ; 14 : 331 –338 .\n19474467 \n52 \nPoirier MC , Divi RL , Al-Harthi L , Olivero OA , Nguyen V , Walker B , et al\nLong-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers . J Acquir Immune Defic Syndr . 2003 ; 33 : 175 –183 .\n12794551 \n53 \nKunz A , von Wurmb-Schwark N , Sewangi J , Ziske J , Lau I , Mbezi P , et al\nZidovudine Exposure in HIV-1 Infected Tanzanian Women Increases Mitochondrial DNA Levels in Placenta and Umbilical Cords . PLoS One . 2012 ; 7 : e41637 \n10.1371/journal.pone.0041637 \n22848552 \n54 \nHothorn T , Bretz F , Westfall P . Simultaneous inference in general parametric models . Biom J . 2008 ; 50 : 346 –363 . 10.1002/bimj.200810425 \n18481363 \n55 \nLagouge M , Larsson NG . The role of mitochondrial DNA mutations and free radicals in disease and ageing . J Intern Med . 2013 ; 273 : 529 –43 . 10.1111/joim.12055 \n23432181 \n56 \nPayne BA , Wilson IJ , Yu-Wai-Man P , Coxhead J , Deehan D , Horvath R , et al\nUniversal heteroplasmy of human mitochondrial DNA .Hum Mol Genet . 2013 ; 22 : 384 –90 . 10.1093/hmg/dds435 \n23077218 \n57 \nZha BS , Wan X , Zhang X , Zha W , Zhou J , Wabitsch M , et al\nHIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes . PLoS One . 2013 ; 8 : e59514 \n10.1371/journal.pone.0059514 \n23533630 \n58 \nApostolova N , Gomez-Sucerquia LJ , Gortat A , Blas-Garcia A , Esplugues JV . Compromising mitochondrial function with the antiretroviral drug efavirenz induces cell survival-promoting autophagy . Hepatology . 2011 ; 54 : 1009 –19 . 10.1002/hep.24459 \n21626526 \n59 Perinatal Services BC. BC Perinatal Surveillance 2003/2004 to 2012/2013. 2014; Available: http://www.perinatalservicesbc.ca/NR/rdonlyres/EB1AC307-689C-4E20-A551-86568CBE9FFF/0/AnnualIndicators_Residents_BC_2013_14.pdf.\n60 \nCasula M , Bosboom-Dobbelaer I , Smolders K , Otto S , Bakker M , de Baar MP , et al\nInfection with HIV-1 induces a decrease in mtDNA . J Infect Dis . 2005 ; 191 : 1468 –1471 .\n15809905 \n61 \nMaagaard A , Holberg-Petersen M , Kvittingen EA , Sandvik L , Bruun JN . Depletion of mitochondrial DNA copies/cell in peripheral blood mononuclear cells in HIV-1-infected treatment-naive patients . HIV Med . 2006 ; 7 : 53 –58 .\n16313293 \n62 \nMiro O , Lopez S , Martinez E , Pedrol E , Milinkovic A , Deig E , et al\nMitochondrial effects of HIV infection on the peripheral blood mononuclear cells of HIV-infected patients who were never treated with antiretrovirals . Clin Infect Dis . 2004 ; 39 : 710 –716 .\n15356787\n\n",
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"issn_linking": "1932-6203",
"issue": "10(8)",
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"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D004272:DNA, Mitochondrial; D005260:Female; D005865:Gestational Age; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008928:Mitochondria; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011446:Prospective Studies",
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"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
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"title": "Evidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women.",
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"abstract": "A 73-year-old Japanese woman with untreated Graves' hyperthyroidism developed glucocorticoid-induced adrenal insufficiency (AI) after a supraphysiological dose of prednisolone therapy for bronchial asthma. Days later, she had high plasma adrenocorticotropic hormone (ACTH) levels and was expected to recover from glucocorticoid-induced AI. Her plasma ACTH levels remained high over 3 months during a physiological dose of hydrocortisone replacement. However, she suffered a further decrease in her serum cortisol level and was diagnosed with isolated adrenocorticotropin deficiency (IAD), in which bioinactive ACTH likely caused the high ACTH value. IAD should be considered as an unusual disorder associated with Graves' disease, especially in older patients.",
"affiliations": "Department of Endocrinology and Metabolism, Nagaoka Red Cross Hospital, Japan.",
"authors": "Ohara|Nobumasa|N|;Kaneko|Masanori|M|;Kuriyama|Hideyuki|H|;Sato|Kazuhiro|K|;Katakami|Hideki|H|;Oki|Yutaka|Y|;Kaneko|Kenzo|K|;Kamoi|Kyuzi|K|",
"chemical_list": "D013956:Antithyroid Agents; D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D011239:Prednisolone; D006854:Hydrocortisone",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6599",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(18)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000309:Adrenal Insufficiency; D000324:Adrenocorticotropic Hormone; D000368:Aged; D000855:Anorexia; D013956:Antithyroid Agents; D001249:Asthma; D004700:Endocrine System Diseases; D005221:Fatigue; D005260:Female; D030342:Genetic Diseases, Inborn; D005938:Glucocorticoids; D006111:Graves Disease; D006801:Humans; D006854:Hydrocortisone; D007003:Hypoglycemia; D011239:Prednisolone; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2649-58",
"pmc": null,
"pmid": "27629962",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Isolated Adrenocorticotropin Deficiency Concomitant with Graves' Disease: A Case Report and Literature Review.",
"title_normalized": "isolated adrenocorticotropin deficiency concomitant with graves disease a case report and literature review"
}
|
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] |
{
"abstract": "We report a case of complete atrioventricular block (CAVB) with ventricular asystole and recurrent AVBs due to all-trans retinoic acid (ATRA). A 57-year-old man with acute promyelocytic leukemia was undergoing induction therapy with ATRA and developed episodic seizures with altered consciousness on the 14(th) day and then CAVB followed by cardiac arrest on the 15(th) day. Although he initially recovered after resuscitation, he suffered from recurrent CAVB, which persisted for 3 days despite immediate ATRA discontinuation. He then received ATRA retreatment with reduction of dosage, but a high-degree AVB recurred on the 5(th) day. After discontinuation of ATRA therapy, the patient recovered 3 days later without any cardiovascular event during follow-up. The serial electrocardiogram changes suggested an infra-Hisian block with possible ATRA dose-response relationship. To our knowledge, this is the first established case of ATRA-induced CAVB in the literature. We suggest clinical alertness for this life-threatening complication.",
"affiliations": "Division of Cardiology, Department of Medicine, Edah Hospital, Kaohsiung, Taiwan, ROC.;Division of Hematology Oncology, Department of Medicine, Taipei City Hospital, Renai Branch, Taipei, Taiwan, ROC. Electronic address: [email protected].",
"authors": "Shih|Chen-Hsiang|CH|;Wu|Hung-Bo|HB|",
"chemical_list": "D014212:Tretinoin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1726-4901",
"issue": "78(5)",
"journal": "Journal of the Chinese Medical Association : JCMA",
"keywords": "acute promyelocytic leukemia; all-trans retinoic acid; arrhythmia; complete atrioventricular block",
"medline_ta": "J Chin Med Assoc",
"mesh_terms": "D054537:Atrioventricular Block; D004562:Electrocardiography; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D014212:Tretinoin",
"nlm_unique_id": "101174817",
"other_id": null,
"pages": "316-9",
"pmc": null,
"pmid": "25726499",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "All-trans retinoic acid-induced, life-threatening complete atrioventricular block.",
"title_normalized": "all trans retinoic acid induced life threatening complete atrioventricular block"
}
|
[
{
"companynumb": "TW-MYLANLABS-2015M1020314",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "020404",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "45 MG/M2/DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ACUTE PROMYELOCYTIC LEUKAEMIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRETINOIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Bradycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Delirium",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mucosal inflammation",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Atrioventricular block complete",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Paresis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aphasia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bone pain",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHIH C-H, WU H-B. ALL-TRANS RETINOIC ACID-INDUCED, LIFE-THREATENING COMPLETE ATRIOVENTRICULAR BLOCK. J-CHIN-MED-ASSOC 2015; 78(5):316-319.",
"literaturereference_normalized": "all trans retinoic acid induced life threatening complete atrioventricular block",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20150623",
"receivedate": "20150623",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11211882,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Evaluation of adverse events (AEs) in pivotal registration trials and ongoing postmarketing surveillance is important for all biologics, including biosimilars. A combined analysis of two pivotal registration studies was performed to strengthen evidence on safety for biosimilar filgrastim EP2006 in patients with breast cancer receiving myelosuppressive chemotherapy, a sensitive clinical setting to confirm biosimilarity of filgrastim.\n\n\n\nData were combined from two phase III studies of biosimilar filgrastim EP2006. The U.S. registration study was a randomized, double-blind comparison of biosimilar and reference filgrastim in women aged ≥18 years with breast cancer, receiving (neo)adjuvant treatment with TAC (docetaxel + doxorubicin + cyclophosphamide). The European Union registration study was a single-arm, open-label study of biosimilar filgrastim in women aged ≥18 years with breast cancer receiving doxorubicin + docetaxel. Patients received filgrastim as a subcutaneous injection on day 2 of each cycle for <14 days or until the absolute neutrophil count reached 10 × 109/L after the expected nadir. Results were combined for cycles 1-4.\n\n\n\nA total of 277 patients received biosimilar filgrastim EP2006. Patients had a mean (± standard deviation) age of 51.1 (± 10.8) years, and 78.7% of patients had stage II or III breast cancer. A total of 46 (20.6%) patients receiving biosimilar filgrastim had AEs considered filgrastim-related. The most frequently reported filgrastim-related AEs were musculoskeletal or connective tissue disorders (15.2%), including bone pain (7.2%). One death (due to pulmonary embolism) occurred of a patient receiving biosimilar filgrastim (not considered filgrastim-related). No patient developed antidrug antibodies during the study.\n\n\n\nBiosimilar filgrastim has a safety profile consistent with previous filgrastim studies and is effective in preventing febrile neutropenia in patients with breast cancer.\n\n\n\nThe biosimilar filgrastim EP2006 (Zarzio, Zarxio, biosimilar filgrastim-sndz) has been approved in Europe since 2009 and in the U.S. since 2015. This combined analysis of two phase III studies provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of reference filgrastim and supports large postmarketing studies of EP2006 in Europe. Strengthening the evidence for biosimilar filgrastim can help improve acceptance of biosimilars and increase patient access to biologics.",
"affiliations": "Brustzentrum der Universität München (LMU), Munich, Germany [email protected].;Fundacio Clinic, Barcelona, Spain.;Hexal AG, Holzkirchen, Germany.;Hexal AG, Holzkirchen, Germany.;Hexal AG, Holzkirchen, Germany.;Duke Cancer Institute, Durham, North Carolina, USA.",
"authors": "Harbeck|Nadia|N|;Gascón|Pere|P|;Krendyukov|Andriy|A|;Hoebel|Nadja|N|;Gattu|Sreekanth|S|;Blackwell|Kimberly|K|",
"chemical_list": "D059451:Biosimilar Pharmaceuticals; D006401:Hematologic Agents; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2017-0348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "23(4)",
"journal": "The oncologist",
"keywords": "Biosimilar; EP2006; Filgrastim; Granulocyte colony‐stimulating factor",
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D059451:Biosimilar Pharmaceuticals; D001943:Breast Neoplasms; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D005260:Female; D000069585:Filgrastim; D006401:Hematologic Agents; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009503:Neutropenia; D012449:Safety; D016896:Treatment Outcome",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "403-409",
"pmc": null,
"pmid": "29317553",
"pubdate": "2018-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12123336;16682719;11821454;27793849;23903799;28848668;15930421;22258705;20926897;26622996;15226326;27829539;27633122;24041627;28111718;27020170;12488289;21610020;23945072;21095116;26314782;12637459;22123557;11208821;25298038;20019087;26306517;23677653;21812668;26122726;27091420;25877937",
"title": "Safety Profile of Biosimilar Filgrastim (Zarzio/Zarxio): A Combined Analysis of Phase III Studies.",
"title_normalized": "safety profile of biosimilar filgrastim zarzio zarxio a combined analysis of phase iii studies"
}
|
[
{
"companynumb": "DE-TEVA-2018-DE-898413",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "63097",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BREAST CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"medicinalproduct": "DOXORUBICIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "75 MG/M2",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BREAST CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DOCETAXEL."
},
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": "058",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "BOLUS; ADMINISTERED FROM DAY 2 OF EACH CYCLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "EP2006"
}
],
"patientagegroup": "5",
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"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HARBECK N, GASCON P, KRENDYUKOV A, HOEBEL N, GATTU S, BLACKWELL K. SAFETY PROFILE OF BIOSIMILAR FILGRASTIM (ZARZIO/ZARXIO): A COMBINED ANALYSIS OF PHASE III STUDIES. ONCOLOGIST 2018?23(4):403-409.",
"literaturereference_normalized": "safety profile of biosimilar filgrastim zarzio zarxio a combined analysis of phase iii studies",
"qualification": "1",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20180530",
"receivedate": "20180530",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14951982,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
},
{
"companynumb": "DE-TEVA-2018-DE-898414",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "75 MG/M2",
"drugenddate": null,
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"drugindication": "BREAST CANCER",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DOCETAXEL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "63097",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
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"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "BREAST CANCER",
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXORUBICIN"
},
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": "058",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "BOLUS; ADMINISTERED FROM DAY 2 OF EACH CYCLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "EP2006"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HARBECK N, GASCON P, KRENDYUKOV A, HOEBEL N, GATTU S, BLACKWELL K. SAFETY PROFILE OF BIOSIMILAR FILGRASTIM (ZARZIO/ZARXIO): A COMBINED ANALYSIS OF PHASE III STUDIES. ONCOLOGIST 2018?23(4):403-409.",
"literaturereference_normalized": "safety profile of biosimilar filgrastim zarzio zarxio a combined analysis of phase iii studies",
"qualification": "1",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20180530",
"receivedate": "20180530",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14952050,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
},
{
"companynumb": "DE-TEVA-2018-DE-898412",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "63097",
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"drugcharacterization": "1",
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"drugindication": "BREAST CANCER",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXORUBICIN"
},
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": "058",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "BOLUS; ADMINISTERED FROM DAY 2 OF EACH CYCLE",
"drugenddate": null,
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"drugindication": "PROPHYLAXIS",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "EP2006"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "75 MG/M2",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BREAST CANCER",
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOCETAXEL."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HARBECK N, GASCON P, KRENDYUKOV A, HOEBEL N, GATTU S, BLACKWELL K. SAFETY PROFILE OF BIOSIMILAR FILGRASTIM (ZARZIO/ZARXIO): A COMBINED ANALYSIS OF PHASE III STUDIES. ONCOLOGIST 2018?23(4):403-409.",
"literaturereference_normalized": "safety profile of biosimilar filgrastim zarzio zarxio a combined analysis of phase iii studies",
"qualification": "1",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20180530",
"receivedate": "20180530",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14952093,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Although spontaneous and simultaneous bilateral hip fractures without trauma are seen rarely, epileptic seizures may lead to these fractures. We present an 82-year-old female patient with poor bone quality and a 20-year history of epilepsy. She had been using anticonvulsant drugs for almost 20 years. Following a convulsive epileptic attack, bilateral intertrochanteric femur fractures occurred (causing bilateral hip pain), which was diagnosed on the 12th day. An earlier pelvic anteroposterior roentgenogram would be helpful for early diagnosis. It should not be forgotten that bone fractures may be observed without trauma in epilepsy patients.",
"affiliations": "Department of Orthopaedics and Traumatology, Trakya University, Edirne, Turkey. [email protected]",
"authors": "Copuroğlu|Cem|C|;Ozcan|Mert|M|;Dülger|Hakan|H|;Yalnız|Erol|E|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5505/tjtes.2011.76402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "18(1)",
"journal": "Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery : TJTES",
"keywords": null,
"medline_ta": "Ulus Travma Acil Cerrahi Derg",
"mesh_terms": "D000369:Aged, 80 and over; D004827:Epilepsy; D005260:Female; D005265:Femoral Neck Fractures; D006801:Humans; D015601:Injury Severity Score; D009104:Multiple Trauma; D011859:Radiography",
"nlm_unique_id": "101274231",
"other_id": null,
"pages": "92-4",
"pmc": null,
"pmid": "22290060",
"pubdate": "2012-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late-diagnosed bilateral intertrochanteric femur fracture during an epileptic seizure.",
"title_normalized": "late diagnosed bilateral intertrochanteric femur fracture during an epileptic seizure"
}
|
[
{
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{
"abstract": "Middle meningeal artery (MMA) embolization has emerged as a promising treatment for chronic subdural hematoma (cSDH).\n\n\n\nTo determine the safety and efficacy of MMA embolization.\n\n\n\nConsecutive patients who underwent MMA embolization for cSDH (primary treatment or recurrence after conventional surgery) at 15 centers were included. Clinical details and follow-up were collected prospectively. Primary clinical and radiographic outcomes were the proportion of patients requiring additional surgical treatment within 90 d after index treatment and proportion with > 50% cSDH thickness reduction on follow-up computed tomography imaging within 90 d. National Institute of Health Stroke Scale and modified Rankin Scale were also clinical outcomes.\n\n\n\nA total of 138 patients were included (mean age: 69.8, 29% female). A total of 15 patients underwent bilateral interventions for 154 total embolizations (66.7% primary treatment). At presentation, 30.4% and 23.9% of patients were on antiplatelet and anticoagulation therapy, respectively. Median admission cSDH thickness was 14 mm. A total of 46.1% of embolizations were performed under general anesthesia, and 97.4% of procedures were successfully completed. A total of 70.2% of embolizations used particles, and 25.3% used liquid embolics with no significant outcome difference between embolization materials (P > .05). On last follow-up (mean 94.9 d), median cSDH thickness was 4 mm (71% median thickness reduction). A total of 70.8% of patients had >50% improvement on imaging (31.9% improved clinically), and 9 patients (6.5%) required further cSDH treatment. There were 16 complications with 9 (6.5%) because of continued hematoma expansion. Mortality rate was 4.4%, mostly unrelated to the index procedure but because of underlying comorbidities.\n\n\n\nMMA embolization may provide a safe and efficacious minimally invasive alternative to conventional surgical techniques.",
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"authors": "Kan|Peter|P|;Maragkos|Georgios A|GA|;Srivatsan|Aditya|A|;Srinivasan|Visish|V|;Johnson|Jeremiah|J|;Burkhardt|Jan-Karl|JK|;Robinson|Timothy M|TM|;Salem|Mohamed M|MM|;Chen|Stephen|S|;Riina|Howard A|HA|;Tanweer|Omar|O|;Levy|Elad I|EI|;Spiotta|Alejandro M|AM|;Kasab|Sami Al|SA|;Lena|Jonathan|J|;Gross|Bradley A|BA|;Cherian|Jacob|J|;Cawley|C Michael|CM|;Howard|Brian M|BM|;Khalessi|Alexander A|AA|;Pandey|Aditya S|AS|;Ringer|Andrew J|AJ|;Hanel|Ricardo|R|;Ortiz|Rafael A|RA|;Langer|David|D|;Kelly|Cory M|CM|;Jankowitz|Brian T|BT|;Ogilvy|Christopher S|CS|;Moore|Justin M|JM|;Levitt|Michael R|MR|;Binning|Mandy|M|;Grandhi|Ramesh|R|;Siddiq|Farhan|F|;Thomas|Ajith J|AJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/neuros/nyaa379",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "88(2)",
"journal": "Neurosurgery",
"keywords": "Chronic subdural hematoma; Chronic subdural hemorrhage; Middle meningeal artery embolization; Refractory subdural hematoma; Refractory subdural hemorrhage",
"medline_ta": "Neurosurgery",
"mesh_terms": "D000368:Aged; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D020200:Hematoma, Subdural, Chronic; D006801:Humans; D008297:Male; D008576:Meningeal Arteries; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "268-277",
"pmc": null,
"pmid": "33026434",
"pubdate": "2021-01-13",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: A Multi-Center Experience of 154 Consecutive Embolizations.",
"title_normalized": "middle meningeal artery embolization for chronic subdural hematoma a multi center experience of 154 consecutive embolizations"
}
|
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"abstract": "Autoimmune haemolytic anaemia (AIHA) and paroxysmal nocturnal haemoglobinuria (PNH) are two distinct causes of haemolytic anaemia. They have different mechanisms that underpin their pathogenesis and, therefore, require different treatment strategies. The direct antiglobulin test (DAT) or Coombs test is positive in cases of immune-mediated haemolytic anaemia and, thus, is positive in AIHA but negative in PNH. We report a case of a woman presenting with a haemolytic anaemia who was found to have concomitant evidence of AIHA and PNH. The case highlights the importance of carrying out a comprehensive haemolysis work-up in patients who present with haemolytic anaemia.",
"affiliations": "Department of Neurology, Charing Cross Hospital, London, W6 8RF, UK.;Department of Nephrology, Royal Free Hospital, London NW3 2QG, UK.;Department of Haematology, Royal Free Hospital, London NW3 2QG, UK.;Department of Haematology, King's College Hospital, London SE5 9RS, UK.;Department of Endocrinology, University College London Hospital, London NW1 2BU, UK.",
"authors": "Kalam|Sabrina|S|;Beale|Rupert|R|;Hughes|Derralynn|D|;Kulasekararaj|Austin|A|;Srirangalingam|Umasuthan|U|",
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"doi": "10.1093/omcr/omz125",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855 Oxford University Press \n\n10.1093/omcr/omz125\nomz125\nCase Report\nCoombs-positive Paroxysmal Nocturnal Haemoglobinuria\nKalam Sabrina 1 Beale Rupert 2 Hughes Derralynn 3 Kulasekararaj Austin 4 Srirangalingam Umasuthan 5 1 \nDepartment of Neurology, Charing Cross Hospital, London, W6 8RF, UK\n2 \nDepartment of Nephrology, Royal Free Hospital, London NW3 2QG, UK\n3 \nDepartment of Haematology, Royal Free Hospital, London NW3 2QG, UK\n4 \nDepartment of Haematology, King’s College Hospital, London SE5 9RS, UK\n5 \nDepartment of Endocrinology, University College London Hospital, London NW1 2BU, UK\nCorrespondence address. Charing Cross Hospital, London W6 8RF, UK. Tel: 07460118283; Email: [email protected]\n3 2020 \n30 3 2020 \n30 3 2020 \n2020 3 omz12524 8 2017 22 4 2018 27 10 2019 © The Author(s) 2020. Published by Oxford University Press.2020This 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 [email protected]\nAutoimmune haemolytic anaemia (AIHA) and paroxysmal nocturnal haemoglobinuria (PNH) are two distinct causes of haemolytic anaemia. They have different mechanisms that underpin their pathogenesis and, therefore, require different treatment strategies. The direct antiglobulin test (DAT) or Coombs test is positive in cases of immune-mediated haemolytic anaemia and, thus, is positive in AIHA but negative in PNH. We report a case of a woman presenting with a haemolytic anaemia who was found to have concomitant evidence of AIHA and PNH. The case highlights the importance of carrying out a comprehensive haemolysis work-up in patients who present with haemolytic anaemia.\n\nAutoimmune haemolytic anaemiaParoxysmal Nocturnal HaemoglobinuriaGlycosylphosphatidylinositolEculizumabDirect antiglobulin testPIGA\n==== Body\nINTRODUCTION\nHaemolytic anaemia is defined as anaemia due to haemolysis of red blood cells (RBC) and its causes are subdivided into intracorpuscular or extracorpuscular aetiologies. The hallmark of the autoimmune haemolytic anaemia (AIHA) and paroxysmal nocturnal haemoglobinuria (PNH) is shortened red blood cell survival. Despite this, their pathophysiological mechanisms are distinct. AIHA results from an extracorpuscular defect in which the generation of autoantibodies against antigens on the surface of red blood cells leads to their premature destruction. PNH is a rare, acquired genetic condition caused by the non-malignant clonal expansion of haemopoietic stem cells with somatic mutation of phosphatidylinositol glycan class A (PIGA), which results in red cells being extremely sensitive to complement mediated lysis [1]. This results in a syndrome characterized by intravascular haemolysis, haemoglobinuria, thromboembolic episodes and bone marrow failure. A spectrum of forms has been identified from haemolytic-type PNH through to an aplastic anaemia-PNH form (AA-PNH) [2]. We report the case of a woman who initially presented with an intravascular haemolytic anaemia and was subsequently found to have concomitant AIHA and PNH.\n\nCASE REPORT\nA 65-year-old Caucasian female presented to the emergency department with a 3-day history of haematuria, exertional dyspnoea, abdominal pain, myalgia and profound fatigue. She reported profuse non-bloody diarrhoea the day before onset of symptoms, having eaten at a seafood restaurant. Her past medical and drug history are shown in Table 1. Upon clinical examination, she had marked conjunctival pallor, scleral icterus and marked tachypnoea with a respiratory rate of 24 breaths per minute and oxygen saturation of 95% on room air. Left iliac fossa tenderness and voluntary guarding were noted on abdominal palpation and rectal examination was unremarkable.\n\nTable 1 Past medical history, drug history and blood results\n\nPast medical history\tMedications\t\nChronic obstructive pulmonary disease\tLevothyroxine\t\nOvarian carcinoma (bilateral oophorectomy)\tBumetanide\t\nEpilepsy\tAspirin\t\nAortic valve replacement (porcine valve)\tPhenytoin\t\nHypothyroidism\tPhenobarbital\t\nFatty liver disease\t\t\nBlood results\t\n\tUnits\tDay 1\tDay 2\tDay 3\tPost-eculizumab\t\nHb\t(g/l)\t115\t95\t67\t111\t\nWCC\t(× 109/l)\t10.88\t13.05\t10.16\t7.24\t\nPlatelets\t(× 109/l)\t339\t408\t315\t312\t\nMCV\t(fl)\t88\t84\t84.9\t100\t\nReticulocyte count\t%\t6.2\t\t7.3%\t3.1\t\nUrea\t(mmol/l)\t8.7\t20.0\t24.2\t6.0\t\nCreatinine\t(μmol/l)\t124\t307\t352\t79\t\neGFR\t(ml/min/1.73 m2)\t39\t<15\t<15\t63\t\nLDH (<240)\t(IU/l)\t989\t1100\t-\t209\t\nCK\t(IU/l)\t611\t\t\t\t\nInitial blood tests (Table 1) revealed a normocytic anaemia, raised reticulocyte counts and hyperbilirubinaemia, raising the possibility of a haemolytic process. Urinalysis demonstrated 3+ of both protein and blood, with microscopy (Table 2) demonstrating renal tubular cells and red cell casts. At presentation, she had an acute kidney injury (AKI) which subsequently worsened throughout the admission. ECG was normal and her chest x-ray showed small bilateral pleural effusions.\n\nTable 2 Autoimmune haemolytic anaemia\n\nAutoimmune haemolytic anaemia\t\nAutoimmune haemolytic anaemia\t\nGroup\tA Rh D positive\nC + c + E + e + K\t\nAntibody report\tNo atypical antibodies detected\t\nDAT (short profile)\tPositive\t\nProbable due to auto D and Auto E.\t\nAnti-IgG\t3\t\nAnti C3b-C3d\t0\t\nDAT control\t0\t\n\t\nFlow cytometry\t\nAcidified serum lysis\tPositive\t\nAcidified serum lysis—%lysis\t\nCD55 (DAF)\t83%\t\nCD59 (MIRL)\t83%\t\nFLAER/CD24\t22% positive\t\nPNH screen Interpretation\t\n78% doubly negative FLAER/CD24 granulocytes detected. 17% RBC showing double negativity for CD55/59. Consistent with patient having PNH in both granulocyte and RBC populations\n\nThe differential diagnoses considered at this stage were gastrointestinal blood loss, haemolytic anaemia secondary to sepsis, haemolytic uraemic syndrome (HUS), infective endocarditis and malignancy. Initial management included IV fluids and fluid balance monitoring in the context of the AKI.\n\nSubsequent blood tests were noted to haemolyse and her haemoglobin rapidly fell to 6 g/dl. No clotting samples could be processed. The peripheral blood smear revealed a few spherocytes, mild polychromasia, no fragments and toxic looking neutrophils (Fig. 1). The lack of red cell fragments and normal platelet count made HUS an unlikely differential. Transthoracic ECHO revealed a functioning porcine aortic valve without evidence of infective endocarditis and renal ultrasound showed normal kidneys.\n\nFigure 1 Blood film appearances showing polychromasia (large bluish red cells) and spherocytes (small round red cells with no central pallor).\n\nA haemolysis screen noted a raised LDH, undetectable haptoglobin levels and a positive direct antiglobulin test (DAT) (3+ IgG), suggesting an autoimmune haemolytic anaemia (AIHA) (Table 2). Cold agglutinins and a viral screen were negative. A paroxysmal nocturnal haemoglobinuria (PNH) screen was requested given the possibility of haemoglobinuria (urinalysis positive for blood but absence of red cells on microscopy) and an intravascular source of the haemolysis. This identified marked clonal expansion of GPI-anchor deficient blood cells by flow cytometry, with 17% red cell clone and 78% monocyte and granulocyte clones. A bone marrow aspiration and trephine (BMAT) showed no evidence of an underlying myelodysplastic syndrome or aplastic anaemia.\n\nA diagnosis of concurrent AIHA and PNH, precipitated by a presumed acute gastrointestinal infection was formulated. The patient received packed red cell transfusions and was commenced on oral prednisolone (at a dose of 1 mg/kg) for AIHA. The patient was transferred to PNH National Service centre and subsequently commenced on eculizumab. She was also treated with thromboembolic prophylaxis (following resolution of the AKI) and was vaccinated against meningitis, due to increased risk conferred with eculizumab treatment.\n\nShe made a good recovery with eculizumab therapy and was under surveillance. At 3 years following her initial presentation, the PNH clone had persisted. Despite her good recovery and haematological stability, our patient died unexpectedly at 3 years following complications of her underlying (bio-prosthetic) valvular heart disease.\n\nDISCUSSION\nWe report a rare case of concomitant AIHA and PNH. The patient presented with haemolysis and a positive DAT test, suggesting a diagnosis of AIHA. However the presence of persistent haemoglobinuria also raised the possibility of intravascular haemolysis and prompted a comprehensive haemolysis screen which included flow cytometric analysis, which confirmed an additional diagnosis of PNH.\n\nIn PNH, the complement regulatory proteins CD59 and CD55 are unable to attach to the cell membrane via GPI, rendering haemopoietic cells susceptible to complement mediated intravascular haemolysis and reduced bone-marrow production of white cells and platelets. The cell surface GPI deficiency in PNH is responsible for both the clonal expansion of these PIGA mutant cells, by allowing them to evade immune/apoptotic regulation, but is also the cause of the associated haemolysis [3]. Flow cytometry using antibodies against GPI to detect percentages of GPI deficient cells is the gold standard for diagnosis.\n\nThe flow cytometry in our patient identified the marked clonal expansion of GPI anchor deficient blood cells. The red cell clone was noted to be smaller (17%) than the granulocyte clone (78%). This is a result of a portion of the red cells being lost to haemolysis and highlights the importance of granulocytes, as they are not lysed like red cells and therefore provide a more accurate reflection of the true PNH clone size.\n\nPNH is linked to aplastic anaemia (AA) and myelodysplastic syndrome (MDS) where cellular autoimmunity is directed against hematopoietic cells. CD55 and/or CD59 deficient cells are not specific to PNH and can be found in other autoimmune mediated haematological conditions including AA, MDS and AIHA [4]. PNH and AIHA occasionally occur concomitantly and it has been suggested that the inflammatory/thrombotic process in PNH may cause a conformational change on the erythrocyte surface, which triggers an immune antibody response. Alternatively, autoantibodies in AIHA may facilitate clonal expansion of the GPI deficient cell [5]. AIHA is characterized by extravascular haemolysis in contrast to the intravascular haemolysis of PNH. Additionally the presence of a positive DAT could have been incidental and not the primary reason for the patient’s haemolysis, as our patient had a persistent PNH clone 3 years after diagnosis but her DAT became negative\n\nThere has only been one other case report of possible coexisting AIHA and PNH reported in the literature [6]. This patient had presented with recurrent deep vein thrombosis and was diagnosed with AIHA. However, on flow cytometric red cell analysis, the authors found that they possessed PNH-like defects. Their patient was treated with steroids, antibiotics and an anti-thrombotic agent and made a good clinical recovery. Interestingly, they noted that the clinical recovery corresponded with improvement in the flow cytometry anomalies [6].\n\nPNH has been historically managed with blood transfusions and iron and folate supplementation. Anticoagulation needs to be considered due to the thromboembolic risk, which is the principal cause of death in patients with PNH. If the diagnosis of PNH had been missed in our patient, it could have resulted In serious and even life threatening consequences from thromboembolic complications. Eculizumab, a humanized monoclonal antibody against terminal protein C5, inhibits complement activation and thus intravascular haemolysis. It has been shown to reduce intravascular haemolysis, stabilize haemoglobin, reduce transfusion dependence and improve quality of life in patients with PNH [5]. In the UK patients diagnosed with PNH are managed via the PNH National service. Poor outcomes are linked with the AA-PNH, older age and poor performance status [2].\n\nThis case highlights the possibility of a dual pathology in cases of haemolytic anaemia and the need to broaden investigations where clinical signs and symptoms diverge from a unifying diagnosis.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nCONSENT\nWritten consent not required as patient is deceased.\n\nFUNDING\nNil (not required).\n\nETHICS\nVerbal consent from family. Formal ethical approval not required.\n\nGUARANTOR\nDr U. Srilangalingam ([email protected]).\n\nACKNOWLEDGEMENTS\nWe thank the patient for allowing us to write and publish this report.\n==== Refs\nREFERENCES\n1. \nTakeda J , Miyata T , Kawagoe K , Iida Y , Endo Y , Fujita T et al. \nDeficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria\n. Cell. 1993 ;73 :703 –11\n.8500164 \n2. \nSocie G , Schrezenmeier H , Muus P , Lisukov I , Roth A , Kulasekararaj A et al. \nChanging prognosis in Paroxysmal Nocturnal Haemoglobinuria disease subcategories; an analysis of International PNH Registry\n. Intern Med J. 2016 .\n3. \nChen G , Zeng W , Maciejewski JP , Kcyvanfar K , Billings EM , Young NS \nDifferential gene expression in hematopoietic progenitors from paroxysmal nocturnal hemoglobinuria patients reveals an apoptosis/immune response in ‘normal’ phenotype cells\n. Leukemia. 2005 ;19 :862 –8\n.15759038 \n4. \nRuiz-Delgado GJ , Vazquez-Garza E , Mendez-Ramirez N , Gomez-Almaguer D \nAbnormalities in the expression of CD55 and CD59 surface molecules on peripheral blood cells are not specific to paroxysmal nocturnal hemoglobinuria\n. Hematology. 2009 ;14 :33 –7\n.19154662 \n5. \nHillmen P , Young NS , Schubert J , Brodsky RA , Socie G , Muus P et al. \nThe complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria\n. The New England journal of medicine. 2006 ;355 :1233 –43\n.16990386 \n6. \nżupańska B , Bogdanik I , Fabijanska-Mitek J , Pyl H \nAutoimmune haemolytic anaemia with a paroxysmal nocturnal haemoglobinuria-like defect\n. European Journal of Haematology 2009 ;62 :346 –9\n.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2020(3)",
"journal": "Oxford medical case reports",
"keywords": "Autoimmune haemolytic anaemia; Direct antiglobulin test; Eculizumab; Glycosylphosphatidylinositol; PIGA; Paroxysmal Nocturnal Haemoglobinuria",
"medline_ta": "Oxf Med Case Reports",
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"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "15759038;16990386;8500164;27305361;19154662;10359065",
"title": "Coombs-positive Paroxysmal Nocturnal Haemoglobinuria.",
"title_normalized": "coombs positive paroxysmal nocturnal haemoglobinuria"
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"medicinalproduct": "SOLIRIS"
}
],
"patientagegroup": null,
"patientonsetage": "65",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cardiac valve disease",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KALAM S, BEALE R, HUGHES D, KULASEKARARAJ A, SRIRANGALINGAM U. COOMBS-POSITIVE PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA. OXFORD MEDICAL CASE REPORTS. 2020?3:79-82",
"literaturereference_normalized": "coombs positive paroxysmal nocturnal haemoglobinuria",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20200417",
"receivedate": "20200417",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 17679593,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200714"
}
] |
{
"abstract": "Enterococcus hirae is a gram-positive coccus that is rarely implicated in human disease and has not been reported in pediatric patients. We report a case of catheter-associated bloodstream infection and prolonged bacteremia in a 7-month-old infant dependent on total parenteral nutrition. The species was identified by the VITEK2 system and confirmed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. The organisms was susceptible to ampicillin, vancomycin, and high-level gentamicin. The patient was treated with vancomycin and gentamicin with adjunctive vancomycin lock therapy but had persistent bacteremia. Therapy was changed to dual β-lactam therapy of ampicillin and ceftriaxone with synergistic gentamicin, which led to clearance of the enterococcal bacteremia. E hirae is an unusual species that may be difficult for the microbiology laboratory to identify. This is the first pediatric case and the second case of invasive E hirae in the United States.",
"affiliations": "University of Pittsburgh School of Medicine, Pennsylvania.;University of Pittsburgh School of Medicine, Pennsylvania.;Departments of Medicine, University of Pittsburgh School of Medicine, Pennsylvania.;Departments of Pediatrics, University of Pittsburgh School of Medicine, Pennsylvania.;Departments of Pathology, University of Pittsburgh School of Medicine, Pennsylvania.;Departments of Pediatrics, University of Pittsburgh School of Medicine, Pennsylvania.",
"authors": "Brayer|Samuel|S|;Linn|Alexandra|A|;Holt|Stephanie|S|;Ellery|Kate|K|;Mitchell|Stephanie|S|;Williams|John|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins; D014640:Vancomycin; D002443:Ceftriaxone; D000667:Ampicillin",
"country": "England",
"delete": false,
"doi": "10.1093/jpids/piz028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-7193",
"issue": "8(6)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": "CLABSI; bacteremia; enterococcus",
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D000667:Ampicillin; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002443:Ceftriaxone; D000070076:Enterococcus hirae; D005839:Gentamicins; D006801:Humans; D007223:Infant; D008297:Male; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014481:United States; D014640:Vancomycin",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "571-573",
"pmc": null,
"pmid": "31209486",
"pubdate": "2019-12-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Enterococcus hirae Bacteremia in an Infant: Case Report and Review of the Literature.",
"title_normalized": "enterococcus hirae bacteremia in an infant case report and review of the literature"
}
|
[
{
"companynumb": "US-SLATE RUN PHARMACEUTICALS-SLTR-AE-19-84",
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"medicinalproduct": "CEFTRIAXONE."
},
{
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},
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"medicinalproduct": "GENTAMICIN."
},
{
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"medicinalproduct": "AMPICILLAN"
},
{
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"medicinalproduct": "PIPERACILLIN-TAZABACTAM"
}
],
"patientagegroup": null,
"patientonsetage": "7",
"patientonsetageunit": "802",
"patientsex": "1",
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"reaction": [
{
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BRAYER S, LINN A, HOLT S, ELLERY K, MITCHELL S, ET AL. ENTEROCOCCUS HIRAE BACTEREMIA IN AN INFANT: CASE REPORT AND REVIEW OF THE LITERATURE. JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY. 2019?1-3.",
"literaturereference_normalized": "enterococcus hirae bacteremia in an infant case report and review of the literature",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "US",
"receiptdate": "20191211",
"receivedate": "20191211",
"receiver": {
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"receivertype": "6"
},
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},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200122"
}
] |
{
"abstract": "IMTs belong to the group of soft tissue tumor and could occur at any anatomical site; however, the causes and growth feature remain unclear. This case report documents a 10-yr-old male suffering from slowly developing dyspnea on exertion and cough around seven months post-HCT. He was diagnosed with an endobronchial tumor based on imaging, and histology confirmed ALK-positive submucosal spindle-shaped cells with infiltrative cells, compatible with IMT. We should be aware that IMT is a potential complication of pediatric allogeneic HCT and can cause sudden airway obstruction.",
"affiliations": "Department of Pediatrics, Osaka Red Cross Hospital, Osaka, Japan.",
"authors": "Fujino|Hisanori|H|;Park|Young-Dong|YD|;Uemura|Suguru|S|;Tanaka|Shinzo|S|;Kawabe|Masakazu|M|;Maeda|Sayaka|S|;Kato|Itaru|I|;Watanabe|Ken-Ichiro|K|;Umeda|Katsutsugu|K|;Hiramatsu|Hidefumi|H|;Adachi|Souichi|S|;Sato|Toshihiko|T|;Date|Hiroshi|H|;Haga|Hironori|H|;Sumimoto|Shinichi|S|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12275",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "18(5)",
"journal": "Pediatric transplantation",
"keywords": "bone marrow transplantation; lung diseases",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D016026:Bone Marrow Transplantation; D001980:Bronchi; D001984:Bronchial Neoplasms; D002648:Child; D003371:Cough; D004724:Endoscopy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007249:Inflammation; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012983:Soft Tissue Neoplasms; D014057:Tomography, X-Ray Computed; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E165-8",
"pmc": null,
"pmid": "24814936",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An endobronchial inflammatory myofibroblastic tumor in a 10-yr-old child after allogeneic hematopoietic cell transplantation.",
"title_normalized": "an endobronchial inflammatory myofibroblastic tumor in a 10 yr old child after allogeneic hematopoietic cell transplantation"
}
|
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{
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{
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"abstract": "BACKGROUND\nWe conducted a randomized clinical trial to determine whether adjunctive lidocaine diminishes the incidence of adverse effects in pediatric patients sedated with ketamine.\n\n\nMETHODS\nThis case-control study involved 586 consecutive pediatric patients necessitating anesthesia. Then systolic blood pressure, heart rate, respiratory rate, and blood oxygen saturation were observed. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), and creatinine (Cr) levels were tested. General dose of ketamine, the time of onset and duration of anesthesia and postoperative recovery, anesthesia effect, and adverse reaction were subsequently compared. High-performance liquid chromatography was employed to detect ketamine concentration at different time points after administration, and the postoperative cognition function was further evaluated.\n\n\nRESULTS\nIntra- and post-operation, the rising degree of ALT, AST, BUN, and Cr in patients treated with ketamine was higher than those in patients treated with the ketamine-lidocaine complex. General dose of ketamine, the time of onset and duration of anesthesia, postoperative recovery time, and the incidence rate of adverse reaction in patients treated with ketamine-lidocaine complex were lower, but the concentration of ketamine was higher compared to the patients treated with ketamine. In patients treated with the ketamine-lidocaine complex, elimination half-life of ketamine was prolonged, the area under curve was increased, and the plasma clearance rate was decreased relative to those with ketamine alone.\n\n\nCONCLUSIONS\nKetamine combined with lidocaine may be beneficial in shortening the onset of anesthesia, promoting postoperative awake, prolonging elimination half-life, increasing area under curve, and decreasing plasma clearance rate and incidence of adverse reactions.",
"affiliations": "Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.;Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.;Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.;Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.;Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.;Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.;Guizhou University Research Center for Analysis of Drugs and Metabolites, Guizhou University, Guiyang, China.;Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.",
"authors": "Fang|Hua|H|;Li|Hua-Feng|HF|;Yang|Miao|M|;Zhang|Fang-Xiang|FX|;Liao|Ren|R|;Wang|Ru-Rong|RR|;Wang|Quan-Yun|QY|;Zheng|Peng-Cheng|PC|;Zhang|Jian-Ping|JP|https://orcid.org/0000-0002-3324-7793",
"chemical_list": "D000778:Anesthetics, Dissociative; D000779:Anesthetics, Local; D007649:Ketamine; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1002/jcla.23115",
"fulltext": "\n==== Front\nJ Clin Lab Anal\nJ. Clin. Lab. Anal\n10.1002/(ISSN)1098-2825\nJCLA\nJournal of Clinical Laboratory Analysis\n0887-8013 1098-2825 John Wiley and Sons Inc. Hoboken \n\n10.1002/jcla.23115\nJCLA23115\nResearch Article\nResearch Articles\nEffect of ketamine combined with lidocaine in pediatric anesthesia\nFANG et al.Fang Hua \n1\n\n2\n Li Hua‐Feng \n3\n Yang Miao \n1\n\n2\n Zhang Fang‐Xiang \n1\n\n2\n Liao Ren \n4\n Wang Ru‐Rong \n4\n Wang Quan‐Yun \n4\n Zheng Peng‐Cheng \n5\n Zhang Jian‐Ping https://orcid.org/0000-0002-3324-7793\n1\n\n2\[email protected] \n1 \nDepartment of Anesthesiology\nGuizhou Provincial People's Hospital\nGuiyang\nChina\n\n\n2 \nDepartment of Anesthesiology\nGuizhou University People's Hospital\nGuiyang\nChina\n\n\n3 \nDepartment of Anesthesiology\nWest China Second University Hospital\nSichuan University\nChengdu\nChina\n\n\n4 \nDepartment of Anesthesiology\nWest China Hospital\nSichuan University\nChengdu\nChina\n\n\n5 \nGuizhou University Research Center for Analysis of Drugs and Metabolites\nGuizhou University\nGuiyang\nChina\n\n* Correspondence\n\nJian‐Ping Zhang, Department of Anesthesiology, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang 550002, Guizhou Province, China and Department of Anesthesiology, Guizhou University People's Hospital, No. 83, Zhongshan East Road, Guiyang 550002, Guizhou Province, China.\n\nEmail [email protected]\n\n15 11 2019 \n4 2020 \n34 4 10.1002/jcla.v34.4e2311530 7 2019 21 10 2019 22 10 2019 © 2019 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals, Inc.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.Abstract\nBackground\nWe conducted a randomized clinical trial to determine whether adjunctive lidocaine diminishes the incidence of adverse effects in pediatric patients sedated with ketamine.\n\nMethods\nThis case‐control study involved 586 consecutive pediatric patients necessitating anesthesia. Then systolic blood pressure, heart rate, respiratory rate, and blood oxygen saturation were observed. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), and creatinine (Cr) levels were tested. General dose of ketamine, the time of onset and duration of anesthesia and postoperative recovery, anesthesia effect, and adverse reaction were subsequently compared. High‐performance liquid chromatography was employed to detect ketamine concentration at different time points after administration, and the postoperative cognition function was further evaluated.\n\nResults\nIntra‐ and post‐operation, the rising degree of ALT, AST, BUN, and Cr in patients treated with ketamine was higher than those in patients treated with the ketamine‐lidocaine complex. General dose of ketamine, the time of onset and duration of anesthesia, postoperative recovery time, and the incidence rate of adverse reaction in patients treated with ketamine‐lidocaine complex were lower, but the concentration of ketamine was higher compared to the patients treated with ketamine. In patients treated with the ketamine‐lidocaine complex, elimination half‐life of ketamine was prolonged, the area under curve was increased, and the plasma clearance rate was decreased relative to those with ketamine alone.\n\nConclusions\nKetamine combined with lidocaine may be beneficial in shortening the onset of anesthesia, promoting postoperative awake, prolonging elimination half‐life, increasing area under curve, and decreasing plasma clearance rate and incidence of adverse reactions.\n\ninjectable anesthesiaketaminelidocainepediatric anesthesiathe Foundation of Science and Technology Department of Sichuan ProvinceChuanrenshebanfa(2017) 919‐26the Foundation of Science and Technology Department of Guizhou ProvinceQiankehe SY zi[2012]001the National Key Technology R&D Program2014BAI05B05Foundation of Science and Technology Department of Guizhou Province 10.13039/501100004001Qiankehe SY zi[2012]3090 source-schema-version-number2.0cover-dateApril 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:21.04.2020\n\n\nFang \nH \n, \nLi \nH‐F \n, \nYang \nM \n, et al. Effect of ketamine combined with lidocaine in pediatric anesthesia\n. J Clin Lab Anal . 2020 ;34 :e23115\n10.1002/jcla.23115 \n\n\n\nFang and Li are regarded as co‐first authors.\n\n\nFunding information\n\n\nThis work was supported by the Foundation of Science and Technology Department of Guizhou Province (Qiankehe SY zi[2012]001), the National Key Technology R&D Program (2014BAI05B05), the Foundation of Science and Technology Department of Guizhou Province (Qiankehe SY zi[2012]3090) and the Foundation of Science and Technology Department of Sichuan Province (Chuanrenshebanfa(2017) 919‐26).\n==== Body\n1 INTRODUCTION\nAdequate pain control plays an important role in patients undergoing operation and painful procedures, which is particularly essential for pediatric patients undergoing operation. During operation process, inadequate pain control may lead to incomplete procedure and adverse complications.1 To facilitate a higher success rate, a majority of procedures are performed under anesthetic effect, especially for uncooperative circumstances among children.2, 3 Therefore, administering an appropriate degree of anesthesia to cope with the procedural demands remains a challenge for the anesthesiologist. Recently, administering a combination of two or more agents has become a readily adopted solution to meet the procedural requirements.4\n\n\nKetamine is acknowledged among the oldest hypnotic agents for anesthesia due to its analgesic properties and minimal suppressive effects on respiration.5 Based on its effective bronchodilating respiratory properties and stable hemodynamics, ketamine use has been reported in patients with brain injury, resulting in increased clinical use.6 Moreover, the administration of ketamine as an anesthetic has branched for extraperitoneal procedures, cardiac catheterization, orthopedics, and skin grafting, as well as otolaryngology and optical procedures.7 Lidocaine, firstly synthesized by the Swedish chemist Lofgren, has been used extensively, such as for pain management, clinical anesthesia, nervous system diseases, arrhythmia, treatment of respiratory diseases, and gastrointestinal diseases.8 The administration of a high concentration of lidocaine led to the illustration of adverse reactions such as skeletal muscle twitching, slurred speech, and drowsiness.9 As an amide local anesthetic, the analgesic, prokinetic, and antiarrhythmic properties of lidocaine are evident upon systemic administration in humans.10 A previous study conducted by Kvarnström et al11 revealed the analgesic effects of lidocaine on peripheral neuropathic pain. Besides, intravenous lidocaine before operation exhibited its preventive effect on propofol‐induced injection pain and hyperalgesia, and subsequently protected against bronchial reactivity due to bronchotracheal relaxation during the operation, consequently resulting in the increase in depth of general anesthesia.12 A double‐blind and randomized study performed by Jendoubi et al13 flagged the use of intravenous lidocaine and ketamine as safe and effective adjuvants to decrease opioid consumption and for early pain management after open nephrectomy procedure. Moreover, pretreatment with lidocaine (20 mg) and ketamine (5 mg) with venous occlusion for 1 minute is the most effective in attenuating the pain on propofol injection vs pretreatment with the lidocaine combined with metoclopramide or plain lidocaine.14 However, currently, there is an inadequacy in clinical trials to provide evidence about the efficacy and safety of ketamine and lidocaine in combination on pediatric anesthesia. Hence, we hypothesized that a combination of lidocaine and ketamine would produce a clinically relevant decrease in the adverse effects in pediatric patients.\n\n2 METHODS\n2.1 Ethics statement\nThe present study was conducted under the approval of the medical ethics committee of the Guizhou Provincial People's Hospital and Guizhou University People's Hospital. The participants and patient guardians included in the current study signed written informed consents.\n\n2.2 Study subjects\nThe study recruited children (n = 586) who were operated upon in the Guizhou Provincial People's Hospital and Guizhou University People's Hospital from a period between March 2013 and December 2015, including 338 cases undergoing surgical intervention for hernia, 140 cases undergoing cleft lip and palate repair, and 108 cases undergoing appendectomy. The operation time period ranged between 15 and 100 minutes with a mean time of 55.26 ± 4.45 minutes. Among the participants, there were 478 males and 108 females aged 2‐12 years (mean age of 6.35 ± 2.32 years) and weighing 9.13‐55.42 kg (mean weight of 22.03 ± 6.28 kg). Prior to operation, the pediatric patients underwent physical examination with liver and kidney function testing as well as blood and urine testing to ensure the parameters were all within the normal range. The pediatric patients were then randomly divided into the observation group and the control group (n = 293, respectively). The observation group was comprised of 170 pediatric patients undergoing hernia repair, 71 undergoing cleft lip and palate repair, and 52 undergoing appendectomy; 237 males and 56 females, aging between 1 and 12 years (mean age of 6.91 ± 2.23 years) and weighing 8.11‐45.17 kg (mean weight of 25.93 ± 6.92 kg), respectively. The control group consisted of 168 cases undergoing hernia repair, 69 cases undergoing cleft lip and palate repair, and 56 cases undergoing appendectomy. Among them, there were 241 males and 52 females, aging between 1 and 13 years (mean age of 6.63 ± 2.17 years) and weighing 8.04‐42.48 kg (mean weight of 25.25 ± 6.15 kg). No statistical difference was observed between the two groups for parameters such as gender, age, weight, and operation type (P > .05). The screening of the participants and subsequent grouping are shown in Figure S1.\n\n2.3 Anesthesia methods\nAll pediatric patients were fasted for 6 hours and prohibited to drink 4 hours prior to the operation. They were treated in a conventional manner with an intramuscular injection with 0.2 mg/kg midazolam (H10980025, Nhwa Pharma Co., Ltd., Nhwa Pharmaceutical Factory, Jiangsu, China) and 0.02 mg/kg atropine (H50020044, Xinan Pharmaceutical Chemical Co., Ltd.). The patients were transferred to the operating theaters upon sleeping, after which they received an intravenous infusion and routine nasal oxygen. The patients in the observation group were administered with an intravenous injection of 2 mg/kg ketamine (H14022824, Shanxi Taiyuan Pharmaceutical Chemical Co., Ltd.) and 2 mg/kg lidocaine (H20133209, Hubei Tianyao Pharmaceutical Chemical Co., Ltd.) at the ratio of 1:1. The patients in the control group only underwent an intravenous administration with 2 mg/kg ketamine. When tracheal intubation was required during the operation, it was conducted 3 minutes after administering the anesthetic injection, followed by a mechanical ventilation by connecting the machine, with the respective respiratory parameters: tidal volume of 10‐15 mL/kg, respiratory frequency of 16‐24 times/min, inspiration‐expiration ratio of 1:1.5, and partial pressure of end‐tidal carbon dioxide maintained at 35‐45 mm Hg. On the basis of the limb movements of pediatric patients and the length of operation time, anesthesia requirement was maintained by a fractional intravenous injection. During the operation, the anesthetic dose could be adjusted according to the anesthetic effect.\n\n2.4 Observation of indices\nChanges of systolic blood pressure (SBP), heart rate (HR), respiratory rate (RR) and blood oxygen saturation (SpO2) pre‐anesthesia, intra‐ and post‐operation were observed using a multifunctional monitor in a continuous manner. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), and creatinine (Cr) were also detected using an immunoturbidimetric assay (ITA) in the Au2700 automatic biochemical analyzer (Olympus Corporation). Following the operation, some secretions in the oropharynx were extracted. Then, the tracheal tube was removed after ensuring effortless breathing of the patients; the pharynx and larynx reflex recovered and could be further awakened. When the SpO2 concentration during spontaneous breathing reached above 0.98, the patients were sent to the care unit, to monitor the vital signs and oxygen inhalation for more than 1 hour by mask. Subsequently, the onset time and the duration time of anesthesia, ketamine dose, the recovery time, and the occurrence of various postoperative adverse reactions such as nausea and vomiting, suctioning, shiver, dysphoria and lethargy were documented. The patients with unobstructed breathe under the condition of no oxygen inhalation, SpO2 > 95%, conscious movement, and crying were regarded as the standard to determine whether there was substantial recovery or not in pediatric patients. The onset time of anesthesia was defined as follows: patients changed from a waking state to a sleeping state after an anesthetic injection, with simultaneous loss of consciousness and relaxation of the body muscles. The duration time of anesthesia was calculated from the onset of anesthesia to the reinjection of anesthetics. The time of recovery was defined as follows: after the operation, the concentration of anesthetics gradually decreased as the excretion of anesthetics from the patients’ body until patients could breathe freely and were conscious.\n\n2.5 Anesthetic effect criteria\nThrough the course of the operation, no body movement was judged as excellent anesthetic effect; body movement having no influence on the operative procedure and no need for further anesthetic administration was assessed as good anesthetic effect; strong body movement interfering with the operation so as to increase the anesthetic dose was regarded as poor anesthetic effect.\n\n2.6 Drug concentration monitoring and measurement\nWith drug induced pre‐anesthesia as a baseline, venous blood was collected for the patients prior to drug administration. Next, repeated venous blood collection was conducted for the pediatric patients after administration at 5, 15, 30, 60, 120, 240, and 480 minutes, respectively. The venous blood was allowed to stand for 30 minutes, and then centrifuged at 1610 g for 10 minutes, after which the serum was collected. High‐performance liquid chromatography (HPLC; Spectra‐Physics Analytical) was used to measure the ratio of ketamine/internal standard peak height, in which the detection wavelength was set at 215 nm, the injection volume was 60 μL at 1 mL/min, and the mobile phase was the mixture of acetonitrile, methanol, and monometallic sodium orthophosphate at a ratio of 32:51: 16. Standard curve Y = 1.0862X − 0.0072 was employed to calculate the value with ketamine/internal standard peak height ratio as Y‐axis and ketamine concentration as X‐axis; and the correlation coefficient “r” was .9995; the lowest limit of detection was 10 ng/L; and the recovery rates were 96% (0.5 g/mL, n = 2) and 92.3% (0.2 g/mL, n = 2). According to the changes of ketamine concentration, two groups of compartment models were fitted to two‐compartment model (Model 7) with the Winnolin software, and pharmacokinetic parameters were detected using a computer, and further assessed by the combination with Akaike information criterion.\n\n2.7 Maze and decoding test\nIn the experiment, the pediatric patients were treated with maze and decoding test before and after the operation for evaluating cognition function. At first, a demonstration on a sample paper with a pencil was given to patients as an illustration; next, the patients were facilitated to depict the maze path on the test paper, followed by calculation of the correct numbers of the maze in quantitative time, which served as the value of maze. The patients underwent observation of a set of simple graphs and symbols (each graph had its symbol) and were asked to draw the corresponding symbol in response to the given graph. Right answer was credited as one score to the patient. The correct numbers of graphic matching by pediatric patients within 2 minutes were defined as the decoding value.\n\n2.8 Statistical analysis\nAll statistical data analyses were conducted using the SPSS 20.0 software (IBM Corp.). The measurement data were expressed as mean ± standard deviations. Initially, normal distribution and homogeneity of variance were tested for all the data. If data conformed to normal distribution and homogeneity of variance, comparison between groups was analyzed by unpaired t test, data in different group were analyzed by one‐way analysis of variance (ANOVA), and pairwise comparisons were conducted using Tukey's post hoc test. The data with skew distribution or unequal variances were compared by the rank sum test. Categorical data were measured using a Chi‐square test, and rank data were compared with rank sum test. A value of P < .05 indicated statistical significance. As for one‐way ANOVA, the power observed was determined to be 80.53%, and for repeated measurement ANOVA, the power was determined to be 90.75%. This was based on the effect value of 0.8165 obtained by calculating the concentration of ketamine in serum at 5 minutes (peak value) and 240 minutes after administration. Power calculation was analyzed using the G* Power Software.\n\n3 RESULTS\n3.1 Baseline characteristics of patients\nThe observation group was comprised of 170 pediatric patients with hernia repair, 71 with cleft lip and palate repair, and 52 with appendectomy; 237 males and 56 females, aged between 1 and 12 years (mean age of 6.91 ± 2.23 years) and weighing 8.11‐45.17 kg (mean weight of 25.93 ± 6.92 kg), respectively. While the control group consisted of 168 cases with hernia repair, 69 cases with cleft lip and palate repair, and 56 cases with appendectomy. Among them, there were 241 males and 52 females, aged between 1 and 13 years (mean age of 6.63 ± 2.17 years) and weighing 8.04‐42.48 kg (mean weight of 25.25 ± 6.15 kg). No statistical difference was observed between the two groups for parameters such as gender, age, weight, and operation type (P > .05; Table 1).\n\nTable 1 The baseline characteristics of patients administered with ketamine alone or with lidocaine\n\nCharacteristics\tObservation\tControl\t\nt/χ\n2\n\t\nP\n\t\nGender (male/female)\t237/56\t241/52\t0.182\t.670\t\nAge\t6.91 ± 2.23\t6.63 ± 2.17\t1.54\t.124\t\nWeight\t25.93 ± 6.92\t25.25 ± 6.15\t1.257\t.209\t\nType of operation\t \t \t \t \t\nHernia repair\t170\t168\t0.189\t.910\t\nCleft lip and palate repair\t71\t69\t\nAppendectomy\t52\t56\t\nJohn Wiley & Sons, Ltd3.2 Pediatric patients receiving intravenous injections of ketamine/lidocaine combination show stable vital signs during operation\nAs shown in Table 2, insignificant differences were evident in SBP, HR, and RR between the observation and control groups before anesthesia (P > .05). SBP, HR, and RR in the observation group were lower intra‐ and post‐operation compared with the control group (P < .05). SBP, HR, and RR of the control group were increased intra‐ and post‐operation compared with the values before administration (all P < .05), while the observation group exhibited no statistical differences (all P > .05), which indicated that the vital signs of pediatric patients in the observation group were stable. Between the two groups, SpO2 was maintained between 97% and 100% pre‐anesthesia, intra‐ and post‐operation (P > .05).\n\nTable 2 SBP, HR, RR, and SpO2 levels of patients administered with ketamine alone or with lidocaine during and after operation\n\nIndex\tGroup\tPre‐anesthesia\t\nP\n\tIntra‐operation\t\nP\n\tPost‐operation\t\nP\n\t\nSBP (mmHg)\tObservation\t92.2 ± 17.0\t.142\t(−0.0081) ± 0.0008\t<.001\t(−0.0208) ± 0.0011\t<.001\t\nControl\t94.2 ± 16.9\t0.3383 ± 0.0006*\n\t0.2128 ± 0.0012*e\t\nHR (T/min)\tObservation\t91.3 ± 21.1\t.763\t(−0.0264) ± 0.0007\t<.001\t(−0.0237) ± 0.0008\t<.001\t\nControl\t91.8 ± 19.7\t0.3313 ± 0.0009*\n\t0.2367 ± 0.0008*\n\t\nRR (T/min)\tObservation\t20.9 ± 3.6\t.06\t(−0.0294) ± 0.0012\t<.001\t(−0.0128) ± 0.0007\t<.001\t\nControl\t22.8 ± 5.1\t0.2581 ± 0.0013*\n\t0.1512 ± 0.0009*\n\t\nSpO2 (%)\tObservation\t98.7 ± 0.9\t.072\t(−0.0061) ± 0.0011\t.097\t(−0.003) ± 0.0039\t.07\t\nControl\t98.9 ± 0.7\t(−0.0059) ± 0.009\t(−0.0036) ± 0.0041\t\nNote\nThe statistical values of the data obeying the normal distribution between the observation group and the control group were >0.05.\n\nAbbreviations: HR, heart rate; RR, respiratory rate; SBP, systolic blood pressure; SpO2, blood oxygen saturation.\n\n* Compared with pre‐anesthesia, P < .05.\n\nJohn Wiley & Sons, Ltd3.3 The safety is the same whether ketamine is administered alone or with lidocaine\nIn our findings, only the control group demonstrated a case with ALT changes of clinical significance (reached 152 μ/L), while the remaining cases were well within the normal range. No significant differences were evident in ALT, AST, BUN, and Cr before administration, as well as intra‐ and post‐operation between the observation group and the control group (all P > .05). Intra‐ and post‐operation, ALT, AST, BUN, and Cr were higher in both the observation group and the control group (all P < .05), while the rising degree of ALT, AST, BUN, and Cr in the control group was higher than those in the observation group without any statistical differences (all P > .05) (Table 3).\n\nTable 3 ALT, AST, BUN, and Cr levels when ketamine is administered alone or with lidocaine at pre‐anesthesia, intra‐operation, and post‐operation\n\nIndex\tGroup\tPre‐anesthesia\t\nP\n\tIntra‐operation\t\nP\n\tPost‐operation\t\nP\n\t\nALT (U/L)\tObservation\t17.1 ± 6.0\t.782\t0.29 ± 0.18*\n\t.064\t0.16 ± 0.09*\n\t.254\t\nControl\t17.3 ± 5.3\t0.32 ± 0.21*\n\t0.17 ± 0.12*\n\t\nAST (U/L)\tObservation\t23.1 ± 6.1\t.56\t0.25 ± 0.09*\n\t.229\t0.13 ± 0.07*\n\t.108\t\nControl\t22.8 ± 7.1\t0.26 ± 0.11*\n\t0.12 ± 0.08*\n\t\nBUN (mmol/L)\tObservation\t4.3 ± 1.5\t.437\t0.11 ± 0.08*\n\t.07\t0.09 ± 0.06*\n\t.064\t\nControl\t4.4 ± 1.3\t0.12 ± 0.05*\n\t0.10 ± 0.07*\n\t\nCr (umol/L)\tObservation\t62.6 ± 16.8\t.095\t0.16 ± 0.07*\n\t.134\t0.10 ± 0.06*\n\t.064\t\nControl\t64.7 ± 14.5\t0.17 ± 0.09*\n\t0.09 ± 0.07*\n\t\nNote\nThe statistical values of the data obeying the normal distribution between the observation group and the control group were >0.05.\n\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, urea nitrogen; Cr, creatinine.\n\n* Compared with pre‐anesthesia, P < .05.\n\nJohn Wiley & Sons, Ltd3.4 Ketamine/lidocaine combination reduces recovery agitation in pediatric patients\nAs shown in Table 4, a general dose of ketamine in the observation group was lower than that in the control group; the time of onset and duration of anesthesia, and postoperative recovery time were shorter in the observation group compared with the control group (all P < .05).\n\nTable 4 General doses of ketamine, the time of onset and duration of anesthesia, and postoperative recovery time when ketamine is administered with lidocaine in pediatric patients during the operation\n\nGroup\tObservation (n = 293)\tControl (n = 293)\t\nP\n\t\nGeneral ketamine dose (mg)\t53.9 ± 11.8\t80.7 ± 2.0\t<.001\t\nOnset time (min)\t2.9 ± 0.5\t4.3 ± 0.9\t<.001\t\nDuration time (min)\t48.6 ± 7.2\t61.3 ± 9.0\t<.001\t\nRecovery time (min)\t6.8 ± 1.2\t15.8 ± 4.9\t<.001\t\nJohn Wiley & Sons, Ltd3.5 Ketamine/lidocaine combination reduces the incidence of adverse reactions\nAs shown in Table 5, the excellent rate of anesthesia in the observation group was higher than the rate in the control group (P < .05). The incidence rate of various adverse reactions like nausea and vomiting, suctioning, shiver, dysphoria, and lethargy of anesthesia was lower in the observation group compared with the control group, with a lower number of overall adverse reactions in the observation group than the control group (all P < .05).\n\nTable 5 Anesthesia effects and adverse reactions when ketamine is administered alone or with lidocaine during the operation\n\nGroup\tObservation (n = 293)\tControl (n = 293)\t\nx\n2\n\t\nP\n\t\nAnesthesia effects\t\nExcellent\t187 (63.8%)\t99 (33.8%)\t18.38\t<.001\t\nGood\t70 (23.9%)\t63 (21.5%)\t0.30\t.584\t\nPoor\t36 (12.3%)\t131 (44.7%)\t42.74\t<.001\t\nAdverse reactions\t57\t194\t53.79\t<.001\t\nNausea and vomiting\t24 (8.2%)\t59 (20.1%)\t12.96\t<.001\t\nSuctioning\t8 (2.7%)\t35 (12.0%)\t15.82\t<.001\t\nShiver\t5 (1.7%)\t28 (9.6%)\t15.20e\t<.001\t\nDysphoria\t9 (3.1%)\t38 (13.0%)\t16.60\t<.001\t\nLethargy\t11 (3.8%)\t34 (11.6%)\t10.93\t<.001\t\nJohn Wiley & Sons, Ltd3.6 Ketamine/lidocaine combination maintains plasma concentrations of ketamine, reduces ketamine clearance, and prolongs its half‐life\nKetamine concentrations of pediatric patients at each time point in the observation and the control groups are shown in Figure 1 (Blood drug concentration = [values detected at different time points ‐ baseline values]/baseline values). In comparison with the control group, before and after administration at 5, 15, and 480 minutes, no statistical differences were evident in the concentration of ketamine in the observation group (P > .05), but it was higher than the value in the control group at 30, 60, 120, and 240 minutes (P < .05). As shown in Table 6, compared with the control group, the elimination half‐life of ketamine in the observation group was prolonged, the AUC was increased, and the plasma clearance rate was decreased (all P < .05).\n\nFigure 1 The HPLC results suggest that ketamine combined with lidocaine could maintain plasma concentrations of ketamine, reduce ketamine clearance, and prolong its half‐life. *Compared with the control group, P < .05 (data were presented in median [95% confidence interval])\n\nTable 6 Comparison of pharmacokinetic parameters when ketamine is administered alone or with lidocaine at 30, 60, 120, and 240 min after administration in pediatric patients\n\nGroup\tObservation (n = 293)\tControl (n = 293)\t\nP\n\t\nDistribution half‐life (min)\t13.7 ± 1.4\t13.5 ± 1.1\t.092\t\nElimination half‐life (min)\t262.9 ± 15.1\t164.2 ± 10.0\t<.001\t\nVDSS (L/kg)\t1.9 ± 0.6\t2.0 ± 0.5\t.071\t\nAUC [mg/(min*mL)]\t278.0 ± 26.1\t163.9 ± 14.0\t<.001\t\nPlasma clearance rate [mg/(kg*min)]\t7.3 ± 0.6\t13.9 ± 0.9\t<.001\t\nAbbreviations: AUC, area under the curve; VDSS, volume of distribution at stead state.\n\nJohn Wiley & Sons, Ltd3.7 Ketamine/lidocaine combination favors postoperative cognition function\nThe scores of maze and decoding test among the observation and control groups are shown in Table 7, which exhibited no significant differences between the two groups before administration (both P > .05). In the observation group, the scores of maze and decoding test post‐operation were lower than that during pre‐anesthesia, with no significant differences (both P > .05); however, those in the control group were decreased compared with the same pre‐anesthesia (both P < .05). The scores in the observation group were higher than the scores observed in the control group (both P < .05).\n\nTable 7 Comparison of cognition function before and after anesthesia when ketamine is administered alone or with lidocaine\n\nGroup\tTime\tMaze test (score)\t\nP\n\tDecoding (score)\t\nP\n\t\nObservation\tPre‐anesthesia\t6.1 ± 2.0\t.055\t41.0 ± 7.0\t0.068\t\nPost‐operation\t5.8 ± 1.4\t39.7 ± 10.1\t\nControl\tPre‐anesthesia\t6.1 ± 0.8\t<.001\t41.3 ± 3.5\t<0.001\t\nPost‐operation\t4.1 ± 0.8*\n\t30.0 ± 5.5*\n\t\n* Compared with the observation group post‐operation, P < .05.\n\nJohn Wiley & Sons, Ltd4 DISCUSSION\nSurgical care of all patients relies on proper anesthesia.15 Anesthetic exposure may work as a specific marker of ascended risk,16 irrespective of risk association with patient characteristics.2 Principally in young children, the administration of general anesthesia should be performed if it emerges as a necessity and the general anesthesia duration should be as shorter as well.16 With an effort to improve the current anesthetic practice, this study was performed to explore the efficacy and safety of ketamine use combined with lidocaine on pediatric anesthesia.\n\nKetamine has been extensively used in the emergency department for various emergencies including conscious sedation and rapid sequence induction.17 Ketamine inhibits morphine metabolism to increase the duration of analgesia, thereby exercising its intrinsic anti‐inflammatory effects.18, 19 A report by Hwang et al20 revealed that ketamine could potentially induce sympathetic stimulation, accompanied by an increase in BP and HR. Moreover, as a local anesthetic, lidocaine is a member of the amide group.21 Existing literature has signified its systemic use for analgesic effects in various human experimental studies and animal pain models.22, 23 Lidocaine confers cerebral protection and could improve the cognitive performance of elderly patients who underwent spine surgery.24\n\n\nIn our study, the findings exhibited the combination of ketamine and lidocaine to be more effective and safer for pediatric anesthesia, which was evidenced by more stable vital signs (reduced SBP, HR, and RR) of pediatric patients in response to the combination treatment with ketamine and lidocaine than ketamine treatment alone. It has been suggested that IV lidocaine could potentiate changes in HR by interacting with sodium channels and repressing cellular calcium influx, thus inducing changes in depolarization and conduction velocity in myocardial Purkinje fibers.25 SBP change may be observed on an arterial pressure waveform induced by changes in intrathoracic pressure resulting from controlled ventilation.26 Consistent with our study, Kaka et al27 reported that the combination of ketamine with lidocaine potentially enhances the anesthetic effects, reduces drug‐related side effects, and decreases the opioid requirement and postoperative adverse reactions. As previously reported, combination of lidocaine and ketamine was predominantly effective in 73% of patients with acute neuropathic pain.28 A combination of ketamine with promethazine is effective in the sedation of pediatric dental patients by eliminating the incidence of vomiting and enhancing the sedative efficacy.29\n\n\nAdditionally, a lower dose of general ketamine was evident in the observation group than the control group; the time of onset and duration of anesthesia, and postoperative recovery time were shorter than those in the control group. A conjoint administration of lidocaine with ketamine shortens the onset of anesthesia in mice and improves the anesthetic efficacy without prolonging the recovery time.30, 31 Besides, the addition of ketamine to epidural lidocaine or bupivacaine as an additive anesthetic has been identified to increase the duration of regional anesthesia and postoperative analgesia, and peri‐incisional use of 0.3%‐0.5% ketamine combined with local anesthetic in surgical wounds could enhance analgesia.32 Pretreatment with a combination of intravenous lidocaine 40 mg and ketamine 25 mg is a more effective anesthetic than lidocaine 40 mg or ketamine 25 mg alone in preventing subsequent pain.20 Reports have illustrated that there is no interaction between ketamine and intravenous lidocaine when administered at antihyperalgesic/low doses.33 Lidocaine is a kind of amides commonly used in clinical local anesthesia, which has good analgesic and local anesthetic effects. The specific analgesic effect increases with the increase of dose of lidocaine, but there are more toxic and side effects when lidocaine is excessively applied. Ketamine mainly plays an anesthetic effect by inhibiting excitatory neurotransmitters and interacting with N‐methyl‐d aspartate and improves the comfort of patients during and after operation. Since ketamine has obvious excitatory effect on cardiovascular system, while lidocaine has a slight inhibitory effect on circulation, the combination of the two can make the hemodynamics more stable during operation.11, 33, 34\n\n\nAdditionally, the incidence rate of adverse reactions after anesthesia in the observation group was lower than the rate in the control group. Existing reports have documented the appearance of less adverse reactions with ketamine used in children compared to those treated with midazolam and have ascertained lidocaine infusion to be safe with no severe side effects.9, 35 Patients receiving conjoint administration with ketamine and lidocaine exhibited significant clinical improvement in aneurysmal subarachnoid hemorrhage without any adverse reactions.36 Pharmacological agents have been demonstrated to attenuate the hemodynamic (orthosympathetic/stress) response to tracheal intubation in pediatric patients undergoing elective surgery, thus preventing a wide array of side effects.37 Besides, decreased general anesthesia can induce adverse laryngeal effects after operation, such as hoarseness and vocal cord injuries.38 After intravenous injection, lidocaine could not only reduce the adverse effects such as the increase of BP, HR, and myocardial oxygen consumption caused by the increase of catecholamine level induced by ketamine, but also diminish the increase of intracranial pressure and brain oxygen consumption induced by ketamine, thus effectively protect the brain tissue.11, 33, 34\n\n\nIn conclusion, the gathered evidence in our study provided information supporting the use of the combination of ketamine and lidocaine contributed to more stable vital signs, shorter onset and recovery time, prolonged elimination half‐life, increased area under curve, decreased plasma clearance rate, and less general dosage and adverse reactions. In this study, however, only two kinds of regimens were administered: ketamine and ketamine combined with lidocaine. Further studies are warranted in the future to determine the efficacy of multiple anesthetic agents such as morphine or fentanyl in comparison.\n\nAUTHOR CONTRIBUTIONS\nHF involved in conception and design of research; HFL and PL performed the experiments; HFL, MY, and FXZ analyzed the data; RL and PCZ interpreted the results of experiments; RRW and QYW prepared the figures; HF and PCZ drafted the manuscript; HF and JPZ edited and revised the manuscript; HF, HFL, MY, FXZ, RL, RRW, QYW, PCZ, and JPZ approved final version of the manuscript.\n\nETHICAL APPROVAL\nThe present study was conducted under the approval of the medical ethics committee of the Guizhou Provincial People's Hospital and Guizhou University People's Hospital. The participants and patient guardians included in the current study signed written informed consents.\n\nSupporting information\n \n\nClick here for additional data file.\n\n ACKNOWLEDGMENT\nWe would like to acknowledge the helpful comments on this paper received from our reviewers.\n==== Refs\nREFERENCES\n1 \n\nSchwartz \nKR \n, \nFredricks \nK \n, \nAl Tawil \nZ \n, et al. An innovative safe anesthesia and analgesia package for emergency pediatric procedures and surgeries when no anesthetist is available\n. Int J Emerg Med . 2016 ;9 (1 ):16 .27286891 \n2 \n\nGoudra \nBG \n, \nSingh \nPM \n, \nBorle \nA \n, \nFarid \nN \n, \nHarris \nK \n. Anesthesia for advanced bronchoscopic procedures: state‐of‐the‐art review\n. Lung . 2015 ;193 (4 ):453 ‐465\n.25921014 \n3 \n\nJose \nRJ \n, \nShaefi \nS \n, \nNavani \nN \n. Anesthesia for bronchoscopy\n. Curr Opin Anaesthesiol . 2014 ;27 (4 ):453 ‐457\n.24785119 \n4 \n\nLi \nX \n, \nWang \nX \n, \nJin \nS \n, \nZhang \nD \n, \nLi \nY \n. 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"fulltext_license": "CC BY",
"issn_linking": "0887-8013",
"issue": "34(4)",
"journal": "Journal of clinical laboratory analysis",
"keywords": "injectable anesthesia; ketamine; lidocaine; pediatric anesthesia",
"medline_ta": "J Clin Lab Anal",
"mesh_terms": "D000758:Anesthesia; D000778:Anesthetics, Dissociative; D000779:Anesthetics, Local; D001062:Appendectomy; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip; D002972:Cleft Palate; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D059685:Herniorrhaphy; D006801:Humans; D007275:Injections, Intravenous; D007649:Ketamine; D008012:Lidocaine; D008297:Male; D061646:Operative Time; D011184:Postoperative Period; D055986:Vital Signs",
"nlm_unique_id": "8801384",
"other_id": null,
"pages": "e23115",
"pmc": null,
"pmid": "31733006",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "25695060;22833771;24785119;21612145;19522888;19727934;21057611;20124399;28910423;20594878;28442956;27787355;25921014;12779109;28321251;28257514;28158165;27832553;15041597;28296782;23178900;27459996;27368000;30117019;12859309;25538918;20927263;22431870;15779623;23438032;25627273;23041484;8895046;27286891;31733006;23233136;20588151;23011561;25975969",
"title": "Effect of ketamine combined with lidocaine in pediatric anesthesia.",
"title_normalized": "effect of ketamine combined with lidocaine in pediatric anesthesia"
}
|
[
{
"companynumb": "US-DENTSPLY PHARMACEUTICAL-2019SCDP000657",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
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},
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"medicinalproduct": "KETAMINE"
},
{
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},
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"medicinalproduct": "LIDOCAINE."
}
],
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"reaction": [
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic product effect prolonged",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug clearance decreased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FANG H, LI H?F, YANG M, ZHANG F?X, LIAO R, WANG R?R ET.AL. EFFECT OF KETAMINE COMBINED WITH LIDOCAINE IN PEDIATRIC ANESTHESIA. J. CLIN. LAB. ANAL. 2019?E23115",
"literaturereference_normalized": "effect of ketamine combined with lidocaine in pediatric anesthesia",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200730",
"receivedate": "20200730",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18094469,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
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"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20201103"
}
] |
{
"abstract": "The prognosis of relapsed/refractory classical Hodgkin lymphoma companied with Human immunodeficiency virus (R/R HIV-cHL) is poor due to insufficient effective treatments. Nowadays, immune checkpoint blockade is an important new treatment option for patients with relapsed/refractory classical Hodgkin lymphoma (cHL), but rare cases have been reported in R/R HIV-cHL. We present a case of R/R HIV-cHL young patient, who has been successfully treated with sintilimab without significant side effects. In May 2018, we received an Hodgkin lymphoma companied with Human immunodeficiency virus (HIVcHL) patient. At first, we gave him ABVD regime chemotherapy. In April 2019, after 6 cycles of ABVD and radiation, we evaluated the effect of treatment and found that the disease actually progressed. The patient refused auto stem cell transplant, so the second line GDP regime chemotherapy was administrated. After five cycles of the treatment, in September 2019, a PET-CT examination found a new emerging enlargement lymph node in the retroperitoneum and with an elevated SUV. In October 2019, after obtaining the patient's consent, we gave him PD-1 immune checkpoint treatment. And 9 cycles later, PET-CT showed that the enlargement lymph node found last time in the retroperitoneum had disappeared completely, with no other lesions were found. All the courses of treatment went through smoothly, and no severe toxicity happened. Immune checkpoint blockade is successful in R/R HIV-cHL, the toxicities are mild and accepted.",
"affiliations": "Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China.;Department of Hemo-oncolgy, Chongqing University Cancer Hospital, Chongqing, China. [email protected].",
"authors": "Shi|Yang|Y|;Li|Qiying|Q|;Zhang|Wenjun|W|;Nan|Yingyu|Y|;Yang|Tao|T|;Liang|Xiping|X|;Xiao|Chunyan|C|;Guo|Bingling|B|;Xiang|Ying|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin; C000632826:sintilimab",
"country": "China",
"delete": false,
"doi": "10.21037/apm-20-1333",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "9(4)",
"journal": "Annals of palliative medicine",
"keywords": "Hodgkin lymphoma (HL); Immune checkpoint inhibitor; human immunodeficiency virus",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D015658:HIV Infections; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D016879:Salvage Therapy; D014747:Vinblastine",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "2414-2419",
"pmc": null,
"pmid": "32692239",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sintilimab as salvage treatment in an HIV patient with relapsed/refractory Hodgkin: a case report.",
"title_normalized": "sintilimab as salvage treatment in an hiv patient with relapsed refractory hodgkin a case report"
}
|
[
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-256040",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HODGKIN^S DISEASE",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
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"medicinalproduct": "DEXAMETHASONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
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"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "HODGKIN^S DISEASE",
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"medicinalproduct": "CISPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "78433",
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"drugcharacterization": "1",
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"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "HODGKIN^S DISEASE",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GEMCITABINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201909"
}
},
"primarysource": {
"literaturereference": "SHI Y, LI Q, ZHANG W, NAN Y, YANG T, LIANG X, ET AL. SINTILIMAB AS SALVAGE TREATMENT IN AN HIV PATIENT WITH RELAPSED/ REFRACTORY HODGKIN: A CASE REPORT. ANN PALLIAT MED. 2020?JUL 20",
"literaturereference_normalized": "sintilimab as salvage treatment in an hiv patient with relapsed refractory hodgkin a case report",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20200806",
"receivedate": "20200806",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18119949,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20201103"
}
] |
{
"abstract": "Despite limited options for rate control of atrial fibrillation and for low-output heart failure seen in cardiac amyloidosis (CA), digoxin use is discouraged due to a reported increased risk of sensitivity and toxicity. We present our experience with digoxin use in patients with CA and report the event rate of suspected digoxin-related arrhythmias and toxicity. This is a retrospective study of patients with CA seen at our institution between November 1995 and October 2018. Patients were screened for a history of ≥7 days of continuous digoxin use and stratified based on amyloid precursor protein-transthyretin (ATTR) and immunoglobulin light chain (AL). Medical records were used to identify suspected digoxin-related arrhythmias and toxicity events. Digoxin was used in 69 patients (42 ATTR, 27 AL) for a median duration of 6 months (IQR, 1 to 16). Indication for use was rate control in 64% of patients and symptomatic heart failure management in 36%. Suspected digoxin-related arrhythmias and toxicity events occurred in 12% of patients. No deaths were attributed to digoxin use or toxicity, but 11 patients died while on digoxin-most due to progressive heart failure in the setting of CA. In conclusion, digoxin may be a therapeutic option for rate and symptom control for some patients with AL-CA and ATTR-CA. Rigorous patient selection is recommended, and patients should be closely monitored during digoxin administration.",
"affiliations": "Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Chemistry, The Scripps Research Institute, La Jolla, California.;Saint Luke's Mid America Heart Institute, Kansas City, Missouri.;Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio.;Department of Neurology, The University of New Mexico Health Sciences Center, Albuquerque, New Mexico.;Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio.;Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio.;Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address: [email protected].",
"authors": "Donnelly|Joseph P|JP|;Sperry|Brett W|BW|;Gabrovsek|Andrej|A|;Ikram|Asad|A|;Tang|W H Wilson|WHW|;Estep|Jerry|J|;Hanna|Mazen|M|",
"chemical_list": "D002316:Cardiotonic Agents; D004077:Digoxin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjcard.2020.07.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "133()",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D028227:Amyloid Neuropathies, Familial; D001281:Atrial Fibrillation; D002316:Cardiotonic Agents; D004077:Digoxin; D005260:Female; D006333:Heart Failure; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "134-138",
"pmc": null,
"pmid": "32800294",
"pubdate": "2020-10-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Digoxin Use in Cardiac Amyloidosis.",
"title_normalized": "digoxin use in cardiac amyloidosis"
}
|
[
{
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"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "40481",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
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"drugindication": "CARDIAC AMYLOIDOSIS",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "DIGOXIN."
}
],
"patientagegroup": null,
"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Ventricular tachycardia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DONNELLY JP, GABROVSEK A, SPERRY BW, YOUNG L, ESTEP J, TANG WHW ET AL.. DIGOXIN USE IN CARDIAC AMYLOIDOSIS. JOURNAL OF CARDIAC FAILURE. 2019?25 (85):S25-6",
"literaturereference_normalized": "digoxin use in cardiac amyloidosis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190828",
"receivedate": "20190828",
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"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191005"
},
{
"companynumb": "NL-IMPAX LABORATORIES, LLC-2019-IPXL-01687",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "078556",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
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"drugindication": "CARDIAC AMYLOIDOSIS",
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"medicinalproduct": "DIGOXIN."
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DONNELLY J.P, GABROVSEK A, SPERRY B.W ET.AL. DIGOXIN USE IN CARDIAC AMYLOIDOSIS. J. CARD. FAIL.. 2019?25(8):S25-6",
"literaturereference_normalized": "digoxin use in cardiac amyloidosis",
"qualification": "3",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
"receiptdate": "20190822",
"receivedate": "20190822",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16730697,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191005"
},
{
"companynumb": "PHHY2019US197257",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "40481",
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "CARDIAC AMYLOIDOSIS",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DIGOXIN."
}
],
"patientagegroup": null,
"patientonsetage": "76",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nodal rhythm",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DONNELLY JP, SPERRY BW, GABROVSEK A, IKRAM A, TANG WHW, ESTEP J ET AL.. DIGOXIN USE IN CARDIAC AMYLOIDOSIS. AMERICAN JOURNAL OF CARDIOLOGY. 2020?1?5",
"literaturereference_normalized": "digoxin use in cardiac amyloidosis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200819",
"receivedate": "20200819",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18170587,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20201103"
},
{
"companynumb": "PHHY2019US197255",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "40481",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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{
"abstract": "Aspirin desensitization (AD) has been the only available modifying treatment in aspirin-exacerbated respiratory disease (AERD). The mechanisms of AD are nonetheless poorly understood. Though very effective, AD is limited by its risks and side-effects.\n\n\n\nMoving forward to the targeted biologicals era, the aim of this study was to characterize the airway inflammatory response to long-term AD, including TSLP dynamics, in order to assess potential new targets in AERD.\n\n\n\nAdult patients with aspirin challenge-confirmed AERD underwent an oral AD followed by daily ingestion of aspirin for at least 6 months. Clinical data and inflammatory biomarkers were measured and compared, before and after AD. Induced sputum analyses were performed at baseline, one and six months after AD (differential cell count and levels of sputum supernatant leukotriene C4, prostaglandin D2 and E2, and TSLP).\n\n\n\nAD was followed by significant clinical improvement, as quantified by all monitored parameters. The good clinical outcomes of AD in our study are supported by overall changes observed in the arachidonic acid metabolites (decreased PGD2 over a constant LTC4/PGE2). TSLP increased (mean baseline 0.1 ± 0.03; 1 month 3.68 ± 7; 6 months 212.2 ± 44 pg/ml; p < 0.01).\n\n\n\nOur findings suggest that new biologicals blocking TSLP might have a clinical benefit in AERD, by cutting down the TSLP-induced PGD2 generation.",
"affiliations": "Department of Pulmonology and Allergy, Hospital Clinic Barcelona- Institute for Health Research (IdiBAPS), Spain. Electronic address: [email protected].;Department of Immunology, IIS-Fundación Jiménez Díaz, Madrid, Spain; Spanish Network of Centers for Biomedical Research on Respiratory Diseases (CIBERES), Spain.;Department of Immunology, IIS-Fundación Jiménez Díaz, Madrid, Spain; Spanish Network of Centers for Biomedical Research on Respiratory Diseases (CIBERES), Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.;Department of Otorhinolaryngology, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.;Spanish Network of Centers for Biomedical Research on Respiratory Diseases (CIBERES), Spain; Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.",
"authors": "Bobolea|Irina|I|;Del Pozo|Victoria|V|;Sanz|Veronica|V|;Cabañas|Rosario|R|;Fiandor|Ana|A|;Alfonso-Carrillo|Carolina|C|;Salcedo|María Ángeles|MÁ|;Heredia Revuelto|Rocío|R|;Quirce|Santiago|S|",
"chemical_list": "D016207:Cytokines; C116914:thymic stromal lymphopoietin; D001241:Aspirin; D015230:Prostaglandin D2",
"country": "England",
"delete": false,
"doi": "10.1016/j.rmed.2018.08.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "143()",
"journal": "Respiratory medicine",
"keywords": "Aspirin desensitization; Aspirin desensitization mechanism; Aspirin-exacerbated respiratory disease; Asthma; Nasal polyps; TSLP",
"medline_ta": "Respir Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D001241:Aspirin; D055963:Asthma, Aspirin-Induced; D016207:Cytokines; D003888:Desensitization, Immunologic; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015230:Prostaglandin D2; D055815:Young Adult",
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"pmid": "30261990",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Aspirin desensitization in aspirin-exacerbated respiratory disease: New insights into the molecular mechanisms.",
"title_normalized": "aspirin desensitization in aspirin exacerbated respiratory disease new insights into the molecular mechanisms"
}
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"abstract": "BACKGROUND\nPatients with head and neck carcinoma are considered to be at high risk of developing tuberculosis, since the risk of morbidity due to tuberculosis in these patients is 2.86 to 16 times the risk in the general population.\n\n\nMETHODS\nThis case series describes an 83-year-old Japanese man, a 60-year-old Japanese man, and a 69-year-old Japanese man who developed active pulmonary tuberculosis while being treated for head and neck carcinoma. Two had previously developed tuberculosis and were treated for more than 50 years, but no symptoms or imaging findings suggested tuberculosis onset in the patients at initiation of treatment for head and neck carcinoma. Initially, local radiotherapy was performed for all three patients. Chemotherapy was continued for two patients who had pulmonary metastasis since initial consultation. For the other patient, surgery was performed for recurrence. In all three cases, active tuberculosis infection was observed during maintenance chemotherapy or immediately following surgery.\n\n\nCONCLUSIONS\nDue to the high risk of developing tuberculosis, the possibility of prophylactic administration of anti-tuberculosis agents to patients with head and neck carcinoma should be investigated, although prophylactic administration is not a cost-effective option for all patients with head and neck carcinoma. However, if tuberculosis onset occurs, it leads to various problems; it has a major impact on not only patients with cancer but also various people in the social environment. In the future, it is essential to consider prophylactic administration in patients requiring long-term maintenance drug therapy, especially in those who are treated at out-patient chemotherapy clinics, where there are several patients with cancer with low disease resistance.",
"affiliations": "Department of Head and Neck Surgery, Japan Community Health Care Organization Kyushu Hospital, 1-8-1 Kishinoura, Yahatanishi-ku, Kitakyushu City, Fukuoka, 806-8501, Japan. [email protected].",
"authors": "Matsuo|Mioko|M|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2055-2",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 205510.1186/s13256-019-2055-2Case ReportDevelopment of active tuberculosis during treatment of head and neck carcinoma: a case series Matsuo Mioko (093) [email protected] grid.460253.6Department of Head and Neck Surgery, Japan Community Health Care Organization Kyushu Hospital, 1-8-1 Kishinoura, Yahatanishi-ku, Kitakyushu City, Fukuoka 806-8501 Japan 24 5 2019 24 5 2019 2019 13 1626 3 2018 15 3 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPatients with head and neck carcinoma are considered to be at high risk of developing tuberculosis, since the risk of morbidity due to tuberculosis in these patients is 2.86 to 16 times the risk in the general population.\n\nCase presentation\nThis case series describes an 83-year-old Japanese man, a 60-year-old Japanese man, and a 69-year-old Japanese man who developed active pulmonary tuberculosis while being treated for head and neck carcinoma. Two had previously developed tuberculosis and were treated for more than 50 years, but no symptoms or imaging findings suggested tuberculosis onset in the patients at initiation of treatment for head and neck carcinoma. Initially, local radiotherapy was performed for all three patients. Chemotherapy was continued for two patients who had pulmonary metastasis since initial consultation. For the other patient, surgery was performed for recurrence. In all three cases, active tuberculosis infection was observed during maintenance chemotherapy or immediately following surgery.\n\nConclusions\nDue to the high risk of developing tuberculosis, the possibility of prophylactic administration of anti-tuberculosis agents to patients with head and neck carcinoma should be investigated, although prophylactic administration is not a cost-effective option for all patients with head and neck carcinoma. However, if tuberculosis onset occurs, it leads to various problems; it has a major impact on not only patients with cancer but also various people in the social environment. In the future, it is essential to consider prophylactic administration in patients requiring long-term maintenance drug therapy, especially in those who are treated at out-patient chemotherapy clinics, where there are several patients with cancer with low disease resistance.\n\nKeywords\nHead and neck carcinomaActive tuberculosisProphylactic administrationissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe global incidence of tuberculosis (TB) is declining every year [1]. However, even in 2017, TB was only second to human immunodeficiency virus (HIV) in the number of deaths caused [1]. Furthermore, even in countries with low TB incidence, there has recently been an increase in the number of patients in the high-risk group for TB, which includes those who have HIV infection, have undergone organ transplantation, or are undergoing hemodialysis because of chronic renal failure; therefore, there are new issues in relation to the measures for treating TB [2, 3]. In addition to the high-risk group for TB, patients with malignant neoplasms are considered to have an increased risk of developing TB; among the different types of malignancies, head and neck carcinoma is associated with the second highest risk group for TB after hematological malignancies [3–5]. However, there is no consensus on the approach to the treatment of head and neck carcinoma and/or TB in patients who develop active pulmonary TB during treatment for head and neck cancer [6, 7]; as a countermeasure, the treatment is stagnated.\n\nI report the cases of three patients who developed active TB during treatment for head and neck carcinoma; they were selected from patients with head and neck cancer who received treatment during the 3 years from January 2015 to December 2017. The frequency at which active pulmonary TB develops during treatment of head and neck carcinoma is reported to be approximately 0.5% [5]; therefore, these three rare cases are believed to be useful for future reference.\n\nCase presentation\nThese reports were approved by the Community Health Care Organization Kyushu Hospital, Japan.\n\nCase 1\nAn 83-year-old Japanese man was diagnosed as having laryngeal squamous cell carcinoma (T2N0M0) at the Department of Head and Neck Surgery, Kyushu Hospital, in November 2016. He had been treated for pulmonary TB at the age of 18, but on examination, thoracic computed tomography (CT) and positron emission tomography (PET) showed no thoracic abnormalities. Radiotherapy for laryngeal cancer at 70 Gy (35 fr) was performed and the tumor disappeared. However, in April 2017, primary lesion recurrence with laryngeal edema and cervical lymph node metastasis were observed. While waiting for surgery, steroid (prednisolone) was administered for 1 month, with the dose starting at 60 mg and being reduced gradually, with the aim of alleviating the edema. In May 2017, a total laryngectomy and bilateral cervical lymph node dissection were conducted.\n\nNo thoracic abnormalities were observed on initial examination in November 2016, but a thoracic X-ray 2 weeks before surgery in May 2017 revealed a small amount of pleural effusion. The amount of pleural effusion increased immediately after surgery, and by the following day he had developed fever (39 °C). At first, the condition was considered to be pleural effusion associated with pneumonia due to general bacteria, and sulbactam/ampicillin and meropenem were administered, but alleviation of symptoms was not achieved. Pleural fluid analysis showed that lymphocytes were present, abating the concern for bacterial infection. The possibility of TB was considered; therefore, sputum smear tests, including rapid molecular diagnostic testing for TB using real-time polymerase chain reaction (PCR), were conducted five times, but the results were negative. Mycobacterium tuberculosis was detected in a solid medium (“Ogawa” medium) culture test after 3 weeks; our patient was considered to have TB pleural effusion, and TB treatment was initiated. He continued to receive anti-TB drugs, which were rifampicin (RFP), isoniazid (INH), and ethambutol (EB), but died 2 months later because his general condition subsequently deteriorated. Because he had a history of TB infection, the possibility of TB was considered unlikely; therefore, an interferon-γ release assay (IGRA) test was not performed.\n\nCase 2\nA 60-year-old Japanese man was diagnosed as having mesopharyngeal squamous cell carcinoma (T1N2bM1 – lung) at the Department of Head and Neck Surgery, Kyushu Hospital, in April 2017. He had been treated for pulmonary TB as an elementary school student, but on examination, thoracic CT and PET revealed no signs suggestive of inflammation, despite multiple pulmonary metastases (Fig. 1a). The first treatment attempted was a combination of cisplatin chemotherapy and local radiotherapy at 60 Gy (30 fr). The pulmonary metastases increased in size; therefore, weekly administration of paclitaxel + cetuximab combination therapy was initiated in August 2017 and a steroid (dexamethasone 10 mg) was simultaneously administered weekly. In October 2017, CT revealed consolidation, suggesting inflammation at loci other than the pulmonary metastases (Fig. 1b). Although our patient reported no subjective symptoms such as cough or fever, sputum was collected. A sputum smear test and real-time PCR yielded negative results, but M. tuberculosis was detected in a solid medium (“Ogawa” medium) culture test after 7 weeks. He was admitted to our hospital for TB treatment, and treatment of head and neck carcinoma was discontinued. He underwent treatment with anti-TB drugs, which were RFP, INH, EB, and pyrazinamide (PZA), but the cancer progressed and he died 2 months later. Because he had a history of TB infection, an IGRA test was not performed.Fig. 1 Chronological changes in the lungs for Case 1 as shown usingcontrast-enhanced computed tomography. a Multiple pulmonarymetastases in both lungs. b Consolidation suggesting inflammationapart from pulmonary metastasis. The arrow is pointing to the part of the tuberculosis infection\n\n\n\nCase 3\nA 69-year-old Japanese man was diagnosed as having maxillary squamous cell carcinoma (T4aN0M1 – lung) at the Department of Head and Neck Surgery, Kyushu Hospital, in August 2016. He had no history of treatment for TB, and on examination, CT and PET revealed nodules, suspected to be pulmonary metastases, with mixed infiltrative opacity in the surrounding areas (Fig. 2a). He was treated with a combination of cisplatin chemotherapy and radiotherapy at 60 Gy (30 fr). However, locoregional control was not possible, and the pulmonary metastases increased in size; therefore, weekly paclitaxel + cetuximab combination therapy was initiated in May 2017 and a steroid (dexamethasone 10 mg) was simultaneously administered weekly. In November 2017, CT revealed partial expansion of the original consolidation (Fig. 2b). Although he reported no subjective symptoms such as cough or fever, sputum was collected. A sputum smear test and real-time PCR yielded negative results, but M. tuberculosis was detected in a solid medium (“Ogawa” medium) culture test after 4 weeks. Because TB was considered unlikely, an IGRA test was not performed. Treatment of head and neck carcinoma and treatment of TB was continued. He is currently alive 2 months after starting anti-TB drugs (RFP, INH, EB, and PZA).Fig. 2 Chronological changes in the lungs for Case 2 as shown usingcontrast-enhanced computed tomography. a Multiple pulmonary metastases suspected in right lung. b Consolidation which appeared in a part of the pulmonary metastases. The arrow is pointing to the part of the tuberculosis infection\n\n\n\nDiscussion and conclusions\nIn 2000, the American Thoracic Society and the US Centers for Disease Control and Prevention presented the concept of latent TB infection (LTBI) [3]. LTBI refers to a condition in which the patient has M. tuberculosis infection that is indicated solely by a positive tuberculin reaction or a positive result in an IGRA test, with none of the following being observed: (i) clinical symptoms, (ii) bacteriological signs, and (iii) X-ray image findings suggesting TB. Vigorous treatment of LTBI is important for patients who are at high risk of developing TB. At present, this approach is an important part of the strategy for eradicating TB [2, 3].\n\nAlthough TB is gradually decreasing in prevalence, the existence of patients in the high-risk group for TB presents new problems. The patients in this group are those with HIV infection or silicosis, those who have undergone organ transplantation, or those who are undergoing hemodialysis because of chronic renal failure [2, 3]. A group with an increased TB risk is also suggested to exist, in which the risk is increased but is less than that in the high-risk group for TB. This group also includes patients who are undergoing treatment with steroids or biological agents or have poorly controlled diabetes [2, 3]. In addition to this group, patients with malignant neoplasms are also at an increased risk of developing TB; the risk of this is highest with hematological malignancies, followed by head and neck carcinoma (Table 1) [3–5].Table 1 Relative risk for developing active tuberculosis\n\nRisk factor\tEstimated risk of tuberculosisa\tReferences\t\nHigh-risk group\t\n 1) HIV infection\t35–170\t[2, 3]\t\n 2) Chronic renal failure and/or hemodialysis\t10–25\t[2, 3]\t\n 3) Solid organ transplantation\t20–74\t[2, 3]\t\n 4) Silicosis\t30\t[2, 3]\t\nIncreased risk group\t\n 1) Treatment with glucocorticosteroids\t2–4\t[2, 3]\t\n 2) TNF-α inhibitors\t1.5–4\t[2]\t\n 3) Diabetes mellitus\t2–4\t[2, 3]\t\nHead and neck carcinoma\t16\t[4]\t\n2.86\t[5]\t\nHIV human immunodeficiency virus, TNF tumor necrosis factor\n\naRelative to persons with no known risk factors\n\n\n\nHowever, there have been few reports on the onset of active TB during head and neck carcinoma treatment when active pulmonary TB was not observed at initiation of the treatment. There is no consensus on the approach for the treatment of head and neck carcinoma and/or TB in patients discharging M. tuberculosis [6, 7]. In practice, once a patient has developed TB, TB treatment is prioritized, although this does depend on bacterial discharge and infection severity. Therefore, the situation is one in which difficult choices have to be made, such as whether to suspend treatment of head and neck carcinoma, which may lead to progression of the cancer, or whether use of out-patient chemotherapy facilities must be restricted, due to the presence of other patients with cancer with low disease resistance.\n\nFurther, it is now possible to markedly extend the life expectancy of patients with head and neck carcinoma using novel maintenance drug therapies [8, 9]. This introduces the potential for an increase in the number of patients who readily develop TB due to regular steroid use and/or reduced immunity due to long-term maintenance chemotherapy.\n\nCurrently, patients with LTBI in the high-risk group for TB are prophylactically administered INH (an anti-TB agent) monotherapy. Although this treatment is strongly recommended, there are limited guidelines for patients with head and neck carcinoma [2, 3, 10, 11]. In the 1980s, the Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center stated that patients with head and neck carcinoma must be added to the guidelines, in addition to patients with a hematological tumor, as requiring prophylactic administration [10]. In addition, since then, there have been marked changes in the treatment of patients with cancer as well as in TB diagnostic methods. As a result, there are reports on the importance of reassessment of TB onset risks in patients with cancer and optimal management methods [11].\n\nIt is generally considered impractical and/or inefficient to conduct IGRA tests, sputum tests, and/or prophylactic administration of anti-TB agents in all patients with head and neck carcinoma. However, to avoid TB onset during cancer treatment, establishing a strategy for preventing TB onset before treatment is considered important from the viewpoints of the patient and the physician. Therefore, based on the experience with the three patients in this case series, it is suggested that it is efficient to investigate the need for prophylactic treatment, to initially focus on patients in whom TB onset would have a major impact on their social environment as well as the patients themselves, such as those who require long-term maintenance drug therapy. These are mainly patients treated in out-patient chemotherapy facilities where there are numerous patients with cancer with impaired disease resistance.\n\nIn addition, if lung field infiltrative opacity develops during treatment of head and neck carcinoma, particularly in asymptomatic patients, it is important to determine TB onset using TB tests with detection sensitivity before the spread of the contagious infection.\n\nThere have been no previous reports on active pulmonary TB onset during treatment of head and neck carcinoma; therefore, it is believed that this report will be useful for future studies.\n\nAbbreviations\nCTComputed tomography\n\nEBEthambutol\n\nHIVHuman immunodeficiency virus\n\nIGRAInterferon-γ release assay\n\nINHIsoniazid\n\nLTBILatent tuberculosis infection\n\nPCRPolymerase chain reaction\n\nPETPositron emission tomography\n\nPZAPyrazinamide\n\nRFPRifampicin\n\nTBTuberculosis\n\nAcknowledgements\nI would like to thank Editage for English language editing.\n\nFunding\nNo funding was received for this study.\n\nAvailability of data and materials\nAll data are listed in the medical records of the Kyushu Hospital. One cannot read the data of patients on the website of the hospital. Medical record disclosure request is necessary.\n\nAuthors’ contributions\nThe author read and approved the final manuscript.\n\nEthics approval and consent to participate\nApproval from Ethical Review Board was not required considering that this was a case report.\n\nConsent for publication\nWritten informed consent was obtained from all three patients for the 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.\n\nCompeting interests\nThe author declares that she has no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. World Health Organization. Global tuberculosis report 2018. http://www.who.int/tb/publications/global_report/en/. Accessed 13 Dec 2018.\n2. Landry J Menzies D Preventive chemotherapy. Where has it got us? Where to go next? Int J Tuberc Lung Dis 2008 12 1352 1364 19017442 \n3. American Thoracic Society & Centers for Disease Control and Prevention Targeted tuberculin testing and treatment of latent tuberculosis infection MMWR Recomm 2000 49 1 51 \n4. Cheng MP Abou Chakra CN Yansouni CP Cnossen S Shrier I Menzies D Risk of active tuberculosis in patients with cancer: a systematic review and meta-analysis Clin Infect Dis 2017 64 635 644 10.1093/cid/cix209 27986665 \n5. Lai SW Lin CL Liao KF Head and neck carcinoma associated with increased rate of pulmonary tuberculosis in a population-based cohort study Medicine (Baltimore) 2017 96 e8366 10.1097/MD.0000000000008366 29069025 \n6. Libshitz HI Pannu HK Elting LS Cooksley CD Tuberculosis in cancer patients: an update J Thorac Imaging 1997 12 41 46 10.1097/00005382-199701000-00006 8989758 \n7. Nishiike S Osaki Y Uno M Irifune M Aihara T Harada T Active pulmonary tuberculosis accompanying head and neck carcinomas: clinical aspects of 9 cases Jibirinsho 2008 101 549 553 \n8. Vermorken JB Mesia R Rivera F Remenar E Kawecki A Rottey S Platinum-based chemotherapy plus cetuximab in head and neck carcinoma N Engl J Med 2008 359 1116 1127 10.1056/NEJMoa0802656 18784101 \n9. Ferris RL Blumenschein G Fayette J Guigay J Colevas AD Licitra L Nivolumab for recurrent squamous-cell carcinoma of the head and neck N Engl J Med 2016 375 1856 1867 10.1056/NEJMoa1602252 27718784 \n10. Bailey WC Albert RK Davidson PT Farer LS Glassroth J Kendig E Jr Treatment of tuberculosis and other mycobacterial diseases Am Rev Respir Dis 1983 127 790 796 6859666 \n11. Kamboj M Sepkowitz KA The risk of tuberculosis in patients with cancer Clin Infect Dis 2006 42 1592 1595 10.1086/503917 16652317\n\n",
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"abstract": "With the following report we want to present an unusual case of a patient suffering from acute respiratory distress syndrome with early discovery of bacterial pathogens in bronchoalveolar liquid samples that developed a fatal undiscovered disseminated fungal infection.\n\n\n\nA 67-year-old man was admitted to our university hospital with dyspnea. Progressive respiratory failure developed leading to admission to the intensive care unit, intubation and prone positioning was necessary. To ensure adequate oxygenation and lung protective ventilation veno-venous extracorporeal membrane oxygenation was established. Despite maximal therapy and adequate antiinfective therapy of all discovered pathogens the condition of the patient declined further and he deceased. Postmortem autopsy revealed Mucor and Aspergillus mycelium in multiple organs such as lung, heart and pancreas as the underlying cause of his deterioration and death.\n\n\n\nRoutine screening re-evaluation of every infection is essential for adequate initiation and discontinuation of every antiinfective therapy. In cases with unexplained deterioration and unsuccessful sampling the possibility for diagnostic biopsies should be considered.",
"affiliations": "Department of Anesthesiology and Intensive Care Medicine, Intensivstation 39, Tübingen University Hospital, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. [email protected].;Department of Anesthesiology and Intensive Care Medicine, Intensivstation 39, Tübingen University Hospital, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.;Department of Pathology, Tübingen University Hospital, Eberhard-Karls-University, Tübingen, Germany.;Department of Pathology, Tübingen University Hospital, Eberhard-Karls-University, Tübingen, Germany.;Department of Anesthesiology and Intensive Care Medicine, Intensivstation 39, Tübingen University Hospital, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.;Department of Anesthesiology and Intensive Care Medicine, Intensivstation 39, Tübingen University Hospital, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.",
"authors": "Prohaska|Stefanie|S|0000-0002-7563-7730;Henn|Philipp|P|;Wenz|Svetlana|S|;Frauenfeld|Leonie|L|;Rosenberger|Peter|P|;Haeberle|Helene A|HA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12871-020-01031-9",
"fulltext": "\n==== Front\nBMC Anesthesiol\nBMC Anesthesiol\nBMC Anesthesiology\n1471-2253\nBioMed Central London\n\n1031\n10.1186/s12871-020-01031-9\nCase Report\nA case report of fatal disseminated fungal sepsis in a patient with ARDS and extracorporeal membrane oxygenation\nhttp://orcid.org/0000-0002-7563-7730\nProhaska Stefanie [email protected]\n\n1\nHenn Philipp 1\nWenz Svetlana 2\nFrauenfeld Leonie 2\nRosenberger Peter 1\nHaeberle Helene A. 1\n1 Department of Anesthesiology and Intensive Care Medicine, Intensivstation 39, Tübingen University Hospital, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany\n2 Department of Pathology, Tübingen University Hospital, Eberhard-Karls-University, Tübingen, Germany\n7 5 2020\n7 5 2020\n2020\n20 10710 9 2019\n3 5 2020\n© The Author(s) 2020\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nWith the following report we want to present an unusual case of a patient suffering from acute respiratory distress syndrome with early discovery of bacterial pathogens in bronchoalveolar liquid samples that developed a fatal undiscovered disseminated fungal infection.\n\nCase presentation\n\nA 67-year-old man was admitted to our university hospital with dyspnea. Progressive respiratory failure developed leading to admission to the intensive care unit, intubation and prone positioning was necessary. To ensure adequate oxygenation and lung protective ventilation veno-venous extracorporeal membrane oxygenation was established. Despite maximal therapy and adequate antiinfective therapy of all discovered pathogens the condition of the patient declined further and he deceased. Postmortem autopsy revealed Mucor and Aspergillus mycelium in multiple organs such as lung, heart and pancreas as the underlying cause of his deterioration and death.\n\nConclusion\n\nRoutine screening re-evaluation of every infection is essential for adequate initiation and discontinuation of every antiinfective therapy. In cases with unexplained deterioration and unsuccessful sampling the possibility for diagnostic biopsies should be considered.\n\nKeywords\n\nMucormycosis\nARDS\nECMO\nissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\n\nARDS may be caused by a variety of conditions but in immunocompromised patients it is mainly due to infection. In this patient the pattern of infection by Pneumocystis jiroveci, Staphylococcus aureus/MSSA, Candida dubliniensis, Cytomegalovirus and Legionella pneumophila reflecst the compromised immune function. The mortality of immunosuppressed patients suffering ARDS is increased [1] regardless of the severity of the disease. Polimicrobial infections are seen regularly in immunocompromised critically ill patients. Fungal coinfections were described in children [2] and adults suffering ARDS [3, 4] due to viral infections. Pneumocystis jiroveci is often found in immunocompromised patients [5], as is the reactivation of Cytomegalovirus [6].\n\nThe differentiation of fungal contamination or infection in non-hematological patients may be challenging. Risk factors for fungal infections or coinfections in non-hematological ICU-patients are numerous, but not suitable as a distinguishing factor between infection and contamination. Diagnostics and first line treatment of the most common invasive fungal infections are listed in Table 1. Table 1 most common invasive fungal infections [7] with additional diagnostics and first line treatment [8–11]\n\n\tDiagnostics\tTreatment\t\nCandida spp.\tDirect microscopy and histopathology, cultur\tBlood cultures\n\nB-D-Glucan\n\nSerum-Mannan/ anti-Mannan (in Candidaemia)\n\n\tEchinocandins\t\nAspergillus spp.\tCT (chest)\n\nGalactomannan (Serum, BAL)\n\n\tIsacuconazol\n\nVoriconazol\n\n\t\nMucorales\tCT (chest)\tSurgical debridement\n\nLipos. Amphotericin B\n\nPosaconazol (salvage treatment)\n\n\t\n\nThe reported single cases about mucormycosis increased lately. Most cases were described in patients with malignancies, organ transplantation, HIV or DM (recently reviewed in [12]). Recently Jiang and coworkers suggested the liquid-based cytopathology to identify mucorales promptly in samples obtained by bronchial brushes [13]. Much like with conventional cultures, the result may be difficult to interpret due to overgrowth.\n\nCase presentation\n\nA 67-year-old man with progressive dyspnea over 2 days was presented to the emergency department. Due to respiratory insufficiency he required intubation and initiation of mechanical ventilation and was therefore directly admitted to the ICU. The patient had a history of high-dose steroid therapy (dexamethasone 24 mg/day) for 5 weeks prior because of a spinal (suspected ependymoma presenting with spinal bleeding and paraplegia). His body temperature peaked at 40.4 °C approximately 2 h after admittance to the ICU. Leukocyte counts were normal but C-reactive protein (CRP) and Procalcitonin (PCT) levels were elevated (CRP 45.05 mg/ml, PCT 5.59 ng/ml). Several blood and BAL samples were taken for microbiological diagnosis. Anti-infective therapy was started with Piperacillin/Tazobactam and Clarithromycin in accordance with the local standard. On the following day CT scan showed bipulmonary infiltrates and no signs of pulmonary embolism (Fig. 1). At this point adequate ventilation required high driving pressures (paO2/FiO2 77, pressure control ventilation, Pmax 32 mbar). Tidal volume goals were calculated with 6 ml/kg body weight. Prone positioning for about 19 h significantly improved the patient’s oxygenation and ventilation settings (paO2/FiO2 207, pressure control ventilation, Pmax 24 mbar). On the second day we received the first results from the bronchoalveolar lavage. PCR for Pneumocystis jiroveci, Legionella species and Cytomegalovirus was positive. PCT levels peaked at 63.02 ng/ml and CRP levels at 56.18 mg/ml while leukocyte counts were remaining within normal range. Anti-infective therapy was changed to Primaquine, Clindamycin, Ganciclovir and Levofloxacin. Results from PCR and cultures 2 days later showed Pneumocystis jiroveci, Staphylococcus aureus/MSSA, Candida dubliniensis, Cytomegalovirus and Legionella pneumophila. Blood tests showed signs of a disseminated Cytomegalovirus infection with 13.800 copies per ml CMV DNA. Renal replacement therapy was started. On day 5 after admission to the ICU, the patient’s condition was rapidly deteriorating (FiO2/paO2 50–60, pressure control ventilation, PEEP 14 mbar, Pmax 31, paCO2 66, pH 7.12, BE − 7.8). Due to continuing severe septic shock (Lactat 8.3 mmol/l, Norepinephrine 1.5 μg/kg/min) and persistent risk of hypoxemia after interdisciplinary discussion extracorporal veno-venous oxygenation was established. In cases of septic shock extracorporal veno-arterial oxygenation is often limited due to higher heart time volumes in sepsis and developing harlequin phenomenon with insufficient systemic oxygenation. In these cases a veno-veno-arterial ECMO might be an option if the cardiac function is sufficient. After the start of veno-venous ECMO therapy, the patient stabilized slowly and the lactate levels decreased. There was no need for an additional arterial cannulation. Fig. 1 CT scan of the lung on day 1 after admission\n\nAnti-infective therapy was expanded to cover the detected and suspected pathogen spectrum: Legionella pneumophila (Azithromycin, Levofloxacin), Staphylococcus aureus/MSSA (Linezolid), Pneumocystis jirovecii (Trimethoprim/Sulfamethoxazole), Candida dubliniensis (Anidulafungin), Cytomegalovirus (Ganciclovir). In addition an antibody deficiency syndrome was treated with intravenous IgM-enriched immunoglobulin (Pentaglobin®) substitution. FACS analysis showed a decreased subset of T-suppressor cells (CD3 + CD8+/CD45+) and NK Lymphocytes (CD16 + 56+/CD45+) (Fig. 2). On day 6, signs of hepatic failure and disseminated intravascular coagulation were developing with rapidly declining platelet count and coagulation parameters, in spite of repeated transfusion and substitution. Lactate levels were rising and CT scan now showed massive bipulmonary infiltration with multiple pulmonary embolism and signs of kidney and cerebral ischemia due to disseminated embolism. This was primarily interpreted as a sign of disseminated intravascular coagulation but echocardiography was scheduled for the following day to rule out endocarditis and anticoagulation was switched from Heparin to Argatroban. Blood samples were sent to an extern laboratory to rule out HIT. Based on the impaired hemeostasis with severe thrombopenia (14.000/μl), biopsie on ECMO was abandoned and echocardiography postponed. Fig. 2 T-cell distribution on day 3 after admission\n\nOn day 7 after the initiation of anti-infective therapy Candida glabrata, Pneumocystis jiroveci, Cytomegalovirus and Legionella pneumophila were still present in BAL cultures. Even though MSSA was not detected anymore, Flucloxacillin was added to cover all bases and Anidulafungin was changed to Voriconazol.\n\nStill, there were no signs of improvement. The signs of pulmonary, renal and hepatic failure and clinical signs of disseminated intravascular coagulation were still progressing. D-Dimers rose up to 42 μg/ml FEU. When the patient failed to awake after discontinuation of sedation we again performed CT scan on day 12. The massive bipulmonary infiltration was again progressing with signs of possible pulmonary hemorrhage (Fig. 3). The CT scan of the brain showed diffuse intracerebral hemorrhages with signs of increased intracranial pressure. Without further options and no achievable therapeutic goal extracorporeal membrane oxygenation was stopped. The patient died within minutes. Fig. 3 CT scan of the lung on day 12 after admission\n\nThe autopsy revealed the following findings: Extensive intracerebral hemorrhage of both hemispheres, with emphasis of the left side, with cerebral edema and signs of hypoxic encephalopathy, as well as upper and lower herniation. No signs of fungal infiltration inside the brain.\n\nIntramedullary malignant melanoma at the height of thoracic vertebra 1.\n\nMassive infarct pneumonia on both sides. Lung parenchyma with evidence of Mucor and Aspergillus mycelium with angio-invasive/−destructive and focal bronchi-destructive growth. Focal parenchymatous hemorrhage on both sides. (Fig. 4)\n\nNumerous infarctions (max. 0.5 cm) with focal Aspergillus and Mucor colonization in the myocardium. Accompanied by a very pronounced phlegmonous purulent myocarditis. (Fig. 5, right)\n\nKidneys: On both sides numerous infarctions (max. 1.5 cm) with Aspergillus and Mucor colonization with angio-invasive and glomeruli-destructing growth. Acute renal failure.\n\nMultiple sharply delineated ulcer with raised margins and focal Aspergillus and Mucor colonization, predominantly in the corpus and antrum of the stomach, as well as in the whole colon.\n\nChronic recurrent pancreatitis with fatty necrosis. Several stray herds with Mucor and Aspergillus mycelium detection. (Fig. 5, left)\n\nNo fungus detection in paraaortal lymph nodes but aspergillus and Mucor colonization in the adjoining tissue.\n\nFig. 4 lung tissue, macroscopy (left) and Grocott-Gomori methenamine silver stain (right)\n\nFig. 5 Pancreas tissue (left) and Myocard tissue (right)\n\nDiscussion and conclusions\n\nARDS may be caused by a variety of conditions and mortality remains high. Even more so if the patient is immunocompromised due to medical therapy or infection. Fungal infections are hardly ever the first pathogens thought of, but fungal coinfections were described in children suffering ARDS due to viral infection [2]. Risk factors for fungal infections in ICU-patients are numerous, including immunosuppressive drugs and the differentiation of contamination or infection in non-hematological patients is challenging.\n\nIn this case the decision to deescalate and stop the therapy was based on the CT scan of the brain. The scan showed diffuse intracerebral hemorrhages with signs of increased intracranial pressure. The situation was evaluated and deemed to be infaust. With the knowledge of the autopsy findings, the overall situation of the mucor infection must now also be regarded as hopeless. Our initial discussion and decision to establish ECMO therapy was based upon the facts known at the time.\n\nAlthough the reported single cases about mucormycosis increased lately, they are rare. Most cases were described in patients with malignancies, organ transplantation, HIV or DM (recently reviewed in [12]). Our patient was affected by none of these diseases but had received corticoid therapy and was therefore immunocrompromised.\n\nThere is some evidence, that mucormycosis and aspergillosis may be linked to previous antifungal therapy [14] although mainly in patients with hematological disorders. Therefore the onset of antifungal therapy is an important issue. Based on the expert opinion of the European Society of Anesthesia Intensive Care Scientific Subcommittee [15] the decision pathway in this case was correct. Initially the colonization index was < 0.5; candida score < 3. PCR- and Serum-tests were negative for fungal infection. 1,3-Beta-D-Glucan was not applied. However, the interpretation of this marker in patients infected by pneumocystis may be challenging [16]. The serological test (Platelia®; Bio Rad; München) did not prove positive Aspergillus-Galaktomannan-Antigen until 2 days before the patient’s death. In addition diagnosis of pulmonary mucormycosis by conventional culture may be difficult due to overgrowth. Microscopical examination of BAL may lead to misinterpretation due to contamination. Histopathological examination may be a valid option, although it is of risk in patients with anticoagulation and/or disseminated intravascular coagulation [8, 17]. Recently Jiang and coworkers suggested the liquid-based cytopathology to identify mucorales promptly in samples obtained by bronchial brushes, which could be a less invasive method to detect this infection promptly [13].\n\nConsidering and even re-considering frequent risk factors of fungal infections, e.g. mucormycosis and aspergillus, might be more fruitful than pursuing the question of how to provide evidence of the pathogen. There is no evidence but according to data obtained in the few hundred known cases of mucormycosis, history of poorly controlled diabetes in combination with impaired cell-mediated immune function including neutropenia are mainly the issue. Recent data suggests that T cells may play an important role in host defense to fungal disease [18, 19]. Like in our patient, lymphopenia may be an important indicator for the application of frequent fungal screening and fungal prophylaxis.\n\nRoutine screening before starting an antifungal prophylaxis and frequent re-evaluation of every infection are essential for adequate initiation and discontinuation of every fungal therapy especially with patients at high risk for fungal infections. All patients receiving immunosuppressive therapy, for whatever reason, must be included in this group. In case of assumed mucor infection the decision for biopsy should be taken into account for ARDS patients with progressive lung inflammation of unknown origin when all standard samples fail to provide an edaquate explanation for the patients status, since the risk to die due to mucor may outweigh the risk of fatal bleeding due to the biopsy. But this decision needs to be based on a detailed risk/benefit analysis for each patient.\n\nAbbreviations\n\nARDS Acute respiratory distress syndrome\n\nBAL Bronchoalveolar lavage\n\nCMV Cytomegalovirus\n\nDNA Desoryribonucleic acid\n\nCRP C-reactive protein\n\nCT Computed tomography\n\nDIC Disseminated intravascular coagulation\n\nDM Diabetes mellitus\n\nECMO Extracorporeal membrane oxygenation\n\nFACS Fluorescence activated cell sorting\n\nFiO2 Fraction of inspired oxygen\n\npaO2 Arterial partial pressure of oxygen\n\nHIT Heparin induced thrombocytopenia\n\nHIV Human immunodeficiency virus\n\nICU Intensive care unit\n\nIgM Immunoglobulin M\n\nINR International normalized ratio\n\nMSSA Methicillin sensitive Staphylococcus aureus\n\nPCR Polymerase chain reaction\n\nPCT Procalcitonin\n\nPmax Peak pressure\n\nAcknowledgements\n\nThe authors would like to thank all their colleges for their support and help. In addition we would like to thank the Department of Radiology for the access to the CT scan and their help to create those special figures.\n\nAuthors’ contributions\n\nPS: Preparation of the manuscript, preparation of Figs. HP: Collection of data, review of manuscript. WS: Preparation of figures, review of manuscript. FL: Preparation of figures, review of manuscript. RP: review of manuscript. HHA: review of manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nWe acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of University of Tübingen to cover article-processing charges.\n\nAvailability of data and materials\n\nAdditional clinical data is available on request. Please contact the corresponding author for any additional clinical data. This case report contains five figures.\n\nAll figures have been uploaded with the manuscript.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nSince the Patient died, written consent to publish was obtained from his wife and legal representative. Consent was given on August 23rd 2019.\n\nCompeting interests\n\nThe authors are not aware of any competing interests concerning this publication.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Cortegiani A Madotto F Gregoretti C Bellani G Laffey JG Pham T Van Haren F Giarratano A Antonelli M Pesenti A Grasselli G Investigators LS, the ETG. Immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the LUNG SAFE database Crit Care 2018 22 157 10.1186/s13054-018-2079-9 29895331\n2. Phung TTB Suzuki T Phan PH Kawachi S Furuya H Do HT Kageyama T Ta TA Dao NH Nunoi H Tran DM Le HT Nakajima N Pathogen screening and prognostic factors in children with severe ARDS of pulmonary origin Pediatr Pulmonol 2017 52 1469 1477 10.1002/ppul.23694 28703486\n3. Alobaid K Alfoudri H Jeragh A Influenza-associated pulmonary aspergillosis in a patient on ECMO Med Mycol Case Rep 2020 27 36 38 10.1016/j.mmcr.2019.12.010 31908911\n4. Vanderbeke L Spriet I Breynaert C Rijnders BJA Verweij PE Wauters J Invasive pulmonary aspergillosis complicating severe influenza: epidemiology, diagnosis and treatment Curr Opin Infect Dis 2018 31 471 480 10.1097/QCO.0000000000000504 30299367\n5. Avino LJ Naylor SM Roecker AM Pneumocystis jirovecii Pneumonia in the Non-HIV-Infected Population. Ann Pharmacother 2016\n6. Kotton CN Kumar D Caliendo AM Huprikar S Chou S Danziger-Isakov L Humar A Group TTSICC The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation Transplantation 2018 102 6 900 931 10.1097/TP.0000000000002191 29596116\n7. Bongomin F Gago S Oladele RO Denning DW Global and multi-National Prevalence of fungal diseases—estimate precision J Fungi (Basel) 2017 3 4 57 10.3390/jof3040057\n8. Cornely OA Cuenca-Estrella M Meis JF Ullmann AJ European Society of Clinical Microbiology and Infectious Diseases (ESCMID) fungal infection study group (EFISG) and European Confederation of Medical Mycology (ECMM) 2013 joint guidelines on diagnosis and management of rare and emerging fungal diseases Clin Microbiol Infect 2014 20 Suppl 3 1 4 10.1111/1469-0691.12569\n9. Cornely OA Bassetti M Calandra T Garbino J Kullberg BJ Lortholary O Meersseman W Akova M Arendrup MC Arikan-Akdagli S Bille J Castagnola E Cuenca-Estrella M Donnelly JP Groll AH Herbrecht R Hope WW Jensen HE Lass-Floerl C Petrikkos G Richardson MD Roilides E Verweij PE Viscoli C Ullmann AJ Group EFIS ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients Clin Microbiol Infect 2012 18 19 37 10.1111/1469-0691.12039 23137135\n10. Pappas PG Kauffmann CA Andes DR Clancy CJ Marr KA Ostrosky-Zeichner L Reboli AC Schuster MG Vazques JA Walsh TJ Zaoutis TE Sobel JD Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America Clin Infect Dis 2016 62 e1 50 10.1093/cid/civ1194 26679628\n11. Ullmann AJ Aquado JM Arikan-Akdagli S Denning DW Groll AH Lagrou K Lass-Floerl C Lewis RE Munoz P Verweij P Warris A Ader F Akova M Arendrup MC Barnes RA Beigelman-Aubry C Blot S Bouza E Brüggemann RJM Buchheidt D Cadranel J Castagnola E Chakrabarti A Cuenca-Estrella M Dimopoulos G Fortun J Gangneux JP Garbino J Heinz WJ Herbrecht R Heussel CP Kibbler CC Klimko N Kullberg BJ Lange C Lehrnbecher T Löffler J Lortholary O Maertens J Marchetti O Meis JF Pagano L Ribaud P Richardson M Roilides E Ruhnke M Sanguinetti M Sheppard DC Sinko J Skiada A Vehreschild MJGT Viscoli C Cornely OA Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline Clin Microbiol Infect 2018 24 e1 e38 10.1016/j.cmi.2018.01.002 29544767\n12. Yamin HS Alastal AY Bakri I Pulmonary Mucormycosis over 130 years: a case report and literature review Turk Thorac J 2017 18 1 5 10.5152/TurkThoracJ.2017.16033 29404149\n13. Jiang X Yang T Li Q Zhu X Su X Li J Jiang Y Liquid-based cytopathology test: a novel method for diagnosing pulmonary Mucormycosis in bronchial brushing samples Front Microbiol 2018 9 2923 10.3389/fmicb.2018.02923 30542339\n14. Guinea J Escribano P Vena A Munoz P Martinez-Jimenez MDC Padilla B Bouza E Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: epidemiology and microbiological characterization of the isolates PLoS One 2017 12 e0179136 10.1371/journal.pone.0179136 28591186\n15. O'Leary RA Einav S Leone M Madach K Martin C Martin-Loeches I Management of invasive candidiasis and candidaemia in critically ill adults: expert opinion of the European Society of Anaesthesia Intensive Care Scientific Subcommittee J Hosp Infect 2018 98 382 390 10.1016/j.jhin.2017.11.020 29222034\n16. Lahmer T da Costa CP Held J Rasch S Ehmer U Schmid RM Huber W Usefulness of 1,3 Beta-D-Glucan detection in non-HIV Immunocompromised mechanical ventilated critically ill patients with ARDS and suspected Pneumocystis jirovecii pneumonia Mycopathologia 2017 182 701 708 10.1007/s11046-017-0132-x 28378239\n17. Combes A Hajage D Capellier G Demoule A Lavoue S Guervilly C Da Silva D Zafrani L Tirot P Veber B Maury E Levy B Cohen Y Richard C Kalfon P Bouadma L Mehdaoui H Beduneau G Lebreton G Brochard L Ferguson ND Fan E Slutsky AS Brodie D Mercat A Eolia Trial Group R, Ecmonet Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome N Engl J Med 2018 378 1965 1975 10.1056/NEJMoa1800385 29791822\n18. Arens C, Kramm T, Decker S, Spannenberger J, Brenner T, Richter DC, Weigand MA, Uhle F, Lichtenstern C. Association of Immune Cell Subtypes and Phenotype with Subsequent Invasive Candidiasis in Patients with Abdominal Sepsis. Shock. 2019;52(2):191–97.\n19. Zhang J Cui N Long Y Wang H Han W Li Y Xiao M Prospective evaluation of lymphocyte subtyping for the diagnosis of invasive candidiasis in non-neutropenic critically ill patients Int J Infect Dis 2019 78 140 147 10.1016/j.ijid.2018.10.028 30399447\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2253",
"issue": "20(1)",
"journal": "BMC anesthesiology",
"keywords": "ARDS; ECMO; Mucormycosis",
"medline_ta": "BMC Anesthesiol",
"mesh_terms": "D000368:Aged; D001228:Aspergillosis; D015199:Extracorporeal Membrane Oxygenation; D017809:Fatal Outcome; D016469:Fungemia; D006801:Humans; D008297:Male; D009091:Mucormycosis; D012128:Respiratory Distress Syndrome",
"nlm_unique_id": "100968535",
"other_id": null,
"pages": "107",
"pmc": null,
"pmid": "32381041",
"pubdate": "2020-05-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29791822;30399447;31908911;29404149;29222034;29596116;29371573;30542339;30138297;28378239;29895331;29544767;28591186;26679628;27242349;28703486;30299367;23137135;24606200",
"title": "A case report of fatal disseminated fungal sepsis in a patient with ARDS and extracorporeal membrane oxygenation.",
"title_normalized": "a case report of fatal disseminated fungal sepsis in a patient with ards and extracorporeal membrane oxygenation"
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"reactionmeddrapt": "Brain herniation",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Septic shock",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal ischaemia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Gastric ulcer",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Aspergillus infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Myocarditis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pancreatitis necrotising",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Intracranial pressure increased",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumocystis jirovecii infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cytomegalovirus infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Legionella infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Candida infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute respiratory distress syndrome",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disseminated intravascular coagulation",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pulmonary embolism",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cerebral ischaemia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fungal sepsis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PROHASKA S, HENN P, WENZ S, FRAUENFELD L, ROSENBERGER P, HAEBERLE HA. A CASE REPORT OF FATAL DISSEMINATED FUNGAL SEPSIS IN A PATIENT WITH ARDS AND EXTRACORPOREAL MEMBRANE OXYGENATION. BMC?ANESTHESIOL 2020?20:107.",
"literaturereference_normalized": "a case report of fatal disseminated fungal sepsis in a patient with ards and extracorporeal membrane oxygenation",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20210628",
"receivedate": "20200702",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17971833,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210717"
}
] |
{
"abstract": "Maternal morbidity and mortality in the United States continues to be high. Understanding parturient complications and causes of death is critical to determine corrective actions. Analysis of closed malpractice claims evaluates patient care, identifies preventable morbidity and mortality, and offers recommendations for improvement. A review of obstetric anesthesia malpractice claims filed against nurse anesthetists (N = 21), extracted from the American Association of Nurse Anesthetists Foundation Closed Claims database, was completed. The malpractice claims included 18 maternal claims and 3 neonatal claims. The most common adverse maternal outcomes were maternal death (8/18) and nerve injury (4/18). Hemorrhage accounted for the greatest number of maternal deaths (3/8) followed by cardiovascular failure, emboli, and neuraxial opioid overdose. All neonatal claims (3/3) involved hypoxic encephalopathy resulting in 1 neonatal death and 2 cases of neonatal permanent brain injury. The majority of maternal cases were identified as nonemergent (15/18) and involved relatively healthy patients (15 identified as ASA physical status 2). Qualitative analysis of closed claims provides the opportunity to identify patterns of injuries, precipitating events, and interventions to improve care. Themes related to poor outcomes in this study include care delays, failed communication, incomplete documentation, maternal hemorrhage, and lack of provider vigilance.",
"affiliations": "is a Certified Registered Nurse Anesthetist and educator at the University of Cincinnati, Cincinnati, Ohio.;is a Certified Registered Nurse Anesthetist and educator at the University of Southern Mississippi, Hattiesburg, Mississippi.;is a Certified Registered Nurse Anesthetist and educator at the University of Alabama at Birmingham, Birmingham, Alabama.",
"authors": "Clayton|Beth Ann|BA|;Geisz-Everson|Marjorie A|MA|;Wilbanks|Bryan|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0094-6354",
"issue": "86(6)",
"journal": "AANA journal",
"keywords": "Errors; maternal; morbidity; mortality; preventable errors",
"medline_ta": "AANA J",
"mesh_terms": "D000773:Anesthesia, Obstetrical; D036861:Delivery, Obstetric; D005260:Female; D006801:Humans; D007345:Insurance Claim Review; D008318:Malpractice; D008508:Medication Errors; D009719:Nurse Anesthetists; D011247:Pregnancy; D014481:United States",
"nlm_unique_id": "0431420",
"other_id": null,
"pages": "464-470",
"pmc": null,
"pmid": "31584420",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thematic Analysis of Obstetric Anesthesia Cases From the AANA Foundation Closed Claims Database.",
"title_normalized": "thematic analysis of obstetric anesthesia cases from the aana foundation closed claims database"
}
|
[
{
"companynumb": "US-FRESENIUS KABI-FK201901037",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": "3",
"drugadministrationroute": "008",
"drugauthorizationnumb": "019316",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MAGNESIUM SULFATE (MANUFACTURER UNKNOWN)"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Incorrect route of product administration",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Medication error",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Neuralgia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CLAYTON B, GEISZ-EVERSON M, WILBANKS B. THEMATIC ANALYSIS OF OBSTETRIC ANESTHESIA CASES FROM THE AANA FOUNDATION CLOSED CLAIMS DATABASE. AANA. 2018 DEC?VOL. 86:464-470.",
"literaturereference_normalized": "thematic analysis of obstetric anesthesia cases from the aana foundation closed claims database",
"qualification": null,
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190130",
"receivedate": "20190130",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15891989,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": 1,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190417"
},
{
"companynumb": "US-PFIZER INC-2019029620",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": null,
"drugadministrationroute": "008",
"drugauthorizationnumb": "020309",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK, SINGLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANAESTHESIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MAGNESIUM SULFATE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ROPIVACAINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "090194",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ROPIVACAINE HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Wrong product administered",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuralgia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CLAYTON, B.. THEMATIC ANALYSIS OF OBSTETRIC ANESTHESIA CASES FROM THE AANA FOUNDATION CLOSED CLAIMS DATABASE. AANA JOURNAL. 2018?86 (6):464-470",
"literaturereference_normalized": "thematic analysis of obstetric anesthesia cases from the aana foundation closed claims database",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190125",
"receivedate": "20190125",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 15867871,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "High dose of vitamin C intake could increase urine oxalate excretion and hence the risk of calcium stone formation. We report a case of left ureteral stone in a 9-year-old boy with an extremely high urine oxalate excretion. Besides, he had a habit of taking high-dose supplementation of vitamin C since the age of 3 years. After vitamin C intake prohibited without other therapy and change of dietary intake, the urine oxalate excretion was decreased to normal level and no recurrence of urolithiasis was present during the 3-year follow-up. Thus, high-dose supplementation with vitamin C for years in a child could induce the urinary stones.",
"affiliations": "Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China.;Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China.;Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China. Electronic address: [email protected].;Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China.;Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China.;Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China.;Department of Urology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, P.R. China.",
"authors": "Chen|Xuehua|X|;Shen|Luming|L|;Gu|Xiaojian|X|;Dai|Xinjuan|X|;Zhang|Li|L|;Xu|Yan|Y|;Zhou|Ping|P|",
"chemical_list": "D014815:Vitamins; D001205:Ascorbic Acid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "84(4)",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D001205:Ascorbic Acid; D002648:Child; D019587:Dietary Supplements; D006801:Humans; D008297:Male; D014514:Ureteral Calculi; D014815:Vitamins",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "922-4",
"pmc": null,
"pmid": "25260453",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "High-dose supplementation with vitamin C--induced pediatric urolithiasis: the first case report in a child and literature review.",
"title_normalized": "high dose supplementation with vitamin c induced pediatric urolithiasis the first case report in a child and literature review"
}
|
[
{
"companynumb": "PHHY2015CN018752",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASCORBIC ACID"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "EFFERVESCENT TABLET",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INFLUENZA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ASCORBIC ACID."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASCORBIC ACID"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "EFFERVESCENT TABLET",
"drugdosagetext": "3 G, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NASOPHARYNGITIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "3",
"drugstructuredosageunit": "002",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ASCORBIC ACID."
}
],
"patientagegroup": null,
"patientonsetage": "9",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hyperoxaluria",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Calculus urinary",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Renal pain",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Haematuria",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201104"
}
},
"primarysource": {
"literaturereference": "CHEN X, SHEN L, GU X, DAI X, ZHANG L, XU Y, ET AL.. HIGH-DOSE SUPPLEMENTATION WITH VITAMIN C-INDUCED PEDIATRIC UROLITHIASIS: THE FIRST CASE REPORT IN A CHILD AND LITERATURE REVIEW.. UROLOGY. 2014;84(4):922-4",
"literaturereference_normalized": "high dose supplementation with vitamin c induced pediatric urolithiasis the first case report in a child and literature review",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20150225",
"receivedate": "20150225",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10869052,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150721"
}
] |
{
"abstract": "OBJECTIVE\nThe purpose of this article is to present a case of metastatic malignant melanoma of the ovary, a review of the current literature, and current recommendations for preventative and consultative management.\n\n\nMETHODS\nThis is a case report and literature review. A 34-year-old woman had symptoms of pelvic abscess 1 month after clomiphene citrate stimulation for infertility. After a failed course of antibiotic therapy, an exploratory laparotomy was performed. Bilateral malignant melanomas of the ovary were discovered. The patient died 4 weeks later of disseminated metastases. Retrospectively, a history of a \"mole\" with unknown histopathologic characteristics had been removed from her arm 15 years earlier. A review of the literature was performed to provide current findings regarding malignant melanomas of the ovary, as well as to evaluate the potential relationship between the use of ovarian stimulating drugs and the development of melanomas.\n\n\nRESULTS\nMelanomas account for 3% of cancers, but the incidence of melanoma is rising. Genital melanomas are uncommon; the primary site is the vulva. Primary malignant melanoma of the ovary is rare; however, delayed recurrence from a primary skin site with metastasis to the ovary is documented. The literature suggests a possible relationship between the use of clomiphene citrate and an increase in melanomas of the skin.\n\n\nCONCLUSIONS\nThe gynecologist, as a primary provider, must be aware of the increasing incidence of malignant melanoma, as well as the recommendations for prevention. The gynecologist, as a consultant, must be aware of the risk of delayed recurrence of malignant melanoma. The potential for development of melanomas associated with the use of ovarian stimulation for infertility needs further monitoring and analysis.",
"affiliations": "Kaiser Permanente Medical Center, Riverside, CA, 92505, USA.",
"authors": "Fuller|P N|PN|",
"chemical_list": "D005300:Fertility Agents, Female; D002996:Clomiphene",
"country": "United States",
"delete": false,
"doi": "10.1016/s0002-9378(99)70045-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "180(6 Pt 1)",
"journal": "American journal of obstetrics and gynecology",
"keywords": null,
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D001932:Brain Neoplasms; D002996:Clomiphene; D017809:Fatal Outcome; D005260:Female; D005300:Fertility Agents, Female; D006801:Humans; D008545:Melanoma; D010051:Ovarian Neoplasms; D012008:Recurrence; D012878:Skin Neoplasms",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "1499-503",
"pmc": null,
"pmid": "10368497",
"pubdate": "1999-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Malignant melanoma of the ovary and exposure to clomiphene citrate: a case report and review of the literature.",
"title_normalized": "malignant melanoma of the ovary and exposure to clomiphene citrate a case report and review of the literature"
}
|
[
{
"companynumb": "US-SA-2018SA123770",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOMIPHENE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "016131",
"drugbatchnumb": "UNK",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INFERTILITY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CLOMIFENE CITRATE"
}
],
"patientagegroup": "5",
"patientonsetage": "34",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pelvic abscess",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Metastasis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Ovarian cancer",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FULLER PN, HENDERSON SR, MARSHALL LA, DECASTRO RM, STEINKE R, SCHLESINGER RE, ET AL. MALIGNANT MELANOMA OF THE OVARY AND EXPOSURE TO CLOMIPHENE CITRATE: A CASE REPORT AND REVIEW OF THE LITERATURE. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY 1999?180(6)I:1499-503.",
"literaturereference_normalized": "malignant melanoma of the ovary and exposure to clomiphene citrate a case report and review of the literature",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180511",
"receivedate": "20180511",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14880738,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Severe immune thrombocytopenia complicating pregnancy may require treatment beyond first-line medications (intravenous immunoglobulins or corticosteroids), but there is a paucity of literature on the use of such second-line agents in pregnancy.\n\n\n\nThe patient is a 29-year-old woman with early-onset severe immune thrombocytopenia at 13 weeks of gestation. Maternal platelet counts reached a nadir of less than 5×10/L. The thrombocytopenia persisted despite first-line medications. Romiplostim, rituximab, and azathioprine were added to the therapeutic regimen. Platelet counts eventually stabilized at greater than 150×10/L before delivery. After delivery at term, the neonate had transient B-cell suppression, which was presumed to be secondary to rituximab, but was otherwise doing well and meeting all milestones at 7 months of age.\n\n\n\nThe addition of second-line agents was associated with sustained elevation in maternal platelet counts and may have obviated the need for splenectomy.",
"affiliations": "Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, and the Division of Pediatric Hematology/Oncology and the Division of Allergy-Immunology, Department of Pediatrics, LAC+USC Medical Center, the Division of Neonatal Medicine, LAC+USC, and the Jane Anne Nohl Division of Hematology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.",
"authors": "Chon|Andrew H|AH|;Chan|Randall|R|;Lee|Richard H|RH|;Kwong|Kenny|K|;Wertheimer|Fiona B|FB|;Weitz|Ilene C|IC|",
"chemical_list": "D007166:Immunosuppressive Agents; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; D013926:Thrombopoietin; C488777:romiplostim; D001379:Azathioprine",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000003699",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "135(3)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D011247:Pregnancy; D011248:Pregnancy Complications; D016553:Purpura, Thrombocytopenic, Idiopathic; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; D013926:Thrombopoietin",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "723-727",
"pmc": null,
"pmid": "32028499",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multidrug Therapy for Refractory Immune Thrombocytopenia in Pregnancy.",
"title_normalized": "multidrug therapy for refractory immune thrombocytopenia in pregnancy"
}
|
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},
{
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},
{
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},
{
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}
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},
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "B-lymphocyte abnormalities",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHON AH, CHAN R, LEE RH, KWONG K, WERTHEIMER FB, WEITZ IC. MULTIDRUG THERAPY FOR REFRACTORY IMMUNE THROMBOCYTOPENIA IN PREGNANCY. OBSTETRICS AND GYNECOLOGY. 2020?1-2",
"literaturereference_normalized": "multidrug therapy for refractory immune thrombocytopenia in pregnancy",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200401",
"receivedate": "20200218",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17430893,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200713"
}
] |
{
"abstract": "Concerning the risk of antidepressant induced liver injury, it is not clear whether psychiatrists perform a liver function test (LFT) and whether an increase in aminotransferase levels should contraindicate antidepressant treatment.\n\n\n\nTo evaluate LFT availability, the prevalence of LFT abnormalities and the probable cause of an altered LFT in patients with a major depressive episode (MDE) requiring an antidepressant drug.\n\n\n\nWe studied LFT evaluation in a real world psychiatric setting, in a sample of 321 consecutive patients with a current major depressive episode (MDE) requiring an antidepressant drug treatment, but without current alcohol or drug dependence or unstable medical disease.\n\n\n\nAn LFT is performed in 36.1% (116/321) of depressed patients. One fifth of antidepressant-treated patients who had an LFT evaluation had abnormal results. The most frequent causes of LFT abnormalities were: NAFLD (nonalcoholic fatty liver disease) (7/321; 2.1%), acute alcohol consumption (4/321; 1.2%), antidepressant-induced liver injury (3/321; 0.9%), hepatitis C virus infection (2/321; 0.6%) and heart failure (1/321; 0.3%). The cause of LFT abnormalities was unknown in 32% of patients (8/25) due to the absence of etiological investigations.\n\n\n\nThese results demonstrate that an LFT is infrequently performed by psychiatrists in depressed patients requiring an antidepressant drug. Baseline LFT assessment and observations during the first six months of antidepressant treatment may be useful for detection of patients with pre-existing liver disease such as NAFLD, and early identification of cases of antidepressant-induced liver injury. An increase in aminotransferase levels may be related to an underlying liver disease, but does not contraindicate antidepressant treatment.",
"affiliations": "Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.;Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.;Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.;Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.;Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.;Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.",
"authors": "Voican|Cosmin Sebastian|CS|;Martin|Severine|S|;Verstuyft|Céline|C|;Corruble|Emmanuelle|E|;Perlemuter|Gabriel|G|;Colle|Romain|R|",
"chemical_list": "D000928:Antidepressive Agents; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0155234",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2717156110.1371/journal.pone.0155234PONE-D-16-07605Research ArticleMedicine and Health SciencesPharmacologyDrugsAntidepressantsMedicine and Health SciencesMental Health and PsychiatryMood DisordersDepressionMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesFatty LiverBiology and Life SciencesNutritionDietAlcohol ConsumptionMedicine and Health SciencesNutritionDietAlcohol ConsumptionMedicine and Health SciencesMetabolic DisordersBiology and Life SciencesGeneticsGenetic LociAllelesMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesMedicine and Health SciencesPharmacologyPharmacokineticsDrug MetabolismLiver Function Test Abnormalities in Depressed Patients Treated with Antidepressants: A Real-World Systematic Observational Study in Psychiatric Settings Liver Function Test Abnormalities and Antidepressant UseVoican Cosmin Sebastian 123Martin Severine 145Verstuyft Céline 167Corruble Emmanuelle 145‡*Perlemuter Gabriel 123‡*Colle Romain 1451 \nFaculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France2 \nINSERM U996, DHU Hepatinov, Labex LERMIT, Clamart, France3 \nService d’hépato-gastroentérologie, Hôpital Antoine-Béclère, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Clamart, France4 \nEquipe «Depression et Antidépresseurs», INSERM UMR-1178, Le Kremlin Bicêtre, France5 \nService de Psychiatrie, Hôpital de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France6 \nINSERM U1184, Le Kremlin Bicêtre, France7 \nService de Génétique moléculaire, Pharmacogénétique et Hormonologie, Hôpital de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, FranceWong Vincent EditorThe Chinese University of Hong Kong, HONG KONGCompeting Interests: The authors have read the journal's policy and have the following competing interests: CV has received travel funds from Janssen, Abbvie and Gilead; GP has received travel funds from Abbvie and Gilead, consulting fees from Gilead, Pileje and Servier, and royalties from Elsevier-Masson, John Libbey Eurotext and Solar; EC has consulted for and received lecture fees from Astra-Zeneca, Eisai, Lundbeck, Otsuka, Sanofi-Aventis and Servier. SM, RC and CV declare that they have no conflict of interest. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: EC GP. Performed the experiments: CSV SM CV. Analyzed the data: CSV SM RC CV GP EC. Contributed reagents/materials/analysis tools: RC CV. Wrote the paper: CSV SM GP EC. Critical revision of the article: RC CV GP EC.\n\n‡ These authors also contributed equally to this work.\n\n* E-mail: [email protected] (EC); [email protected] (GP)12 5 2016 2016 11 5 e015523422 2 2016 26 4 2016 © 2016 Voican et al2016Voican 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.Background\nConcerning the risk of antidepressant induced liver injury, it is not clear whether psychiatrists perform a liver function test (LFT) and whether an increase in aminotransferase levels should contraindicate antidepressant treatment.\n\nAim\nTo evaluate LFT availability, the prevalence of LFT abnormalities and the probable cause of an altered LFT in patients with a major depressive episode (MDE) requiring an antidepressant drug.\n\nMethods\nWe studied LFT evaluation in a real world psychiatric setting, in a sample of 321 consecutive patients with a current major depressive episode (MDE) requiring an antidepressant drug treatment, but without current alcohol or drug dependence or unstable medical disease.\n\nResults\nAn LFT is performed in 36.1% (116/321) of depressed patients. One fifth of antidepressant-treated patients who had an LFT evaluation had abnormal results. The most frequent causes of LFT abnormalities were: NAFLD (nonalcoholic fatty liver disease) (7/321; 2.1%), acute alcohol consumption (4/321; 1.2%), antidepressant-induced liver injury (3/321; 0.9%), hepatitis C virus infection (2/321; 0.6%) and heart failure (1/321; 0.3%). The cause of LFT abnormalities was unknown in 32% of patients (8/25) due to the absence of etiological investigations.\n\nConclusion\nThese results demonstrate that an LFT is infrequently performed by psychiatrists in depressed patients requiring an antidepressant drug. Baseline LFT assessment and observations during the first six months of antidepressant treatment may be useful for detection of patients with pre-existing liver disease such as NAFLD, and early identification of cases of antidepressant-induced liver injury. An increase in aminotransferase levels may be related to an underlying liver disease, but does not contraindicate antidepressant treatment.\n\nThe authors have no support or funding to report. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nDrug-induced liver injury (DILI) is the fourth leading cause of liver damage in western industrialized countries (1.28–29 cases per 100,000 patient-years) and a matter of concern in the current context of increasing drug availability and medical prescription [1]. No specific markers are available and DILI is a diagnosis of exclusion. The first accepted sign for a DILI diagnosis is an increase of ALT (alanine aminotransferase) and AP (alkaline phosphatase) values temporally associated with the administration of the drug. In order to avoid unnecessary drug withdrawal, ALT>5x upper limit of normal (ULN) and/or AP>2xULN have been proposed as threshold values indicating a potential DILI [2, 3]. Once DILI is suspected, other causes of liver injury have to be excluded and several clinical scores have been developed to assess drug imputability [4–7].\n\nAntidepressant-induced liver injury is a rare event but may be severe and irreversible[8]. Liver function is assessed in some clinical trials evaluating newer antidepressant (AD) agents. But patients included in clinical trials do not reflect patients treated with AD in real life settings. Therefore, the incidence of abnormal liver function tests (LFTs) or DILI during AD treatment in real life settings is difficult to estimate [8]. In clinical practice, an LFT is not routinely performed before or during AD treatment and recommendations exist only for recently commercialized AD such as agomelatine [9].\n\nAsymptomatic mild abnormal LFTs are detected in 0.5–3% of patients with major depressive disorder (MDD) treated with AD [8]. The nonalcoholic fatty liver disease (NAFLD) associated with metabolic syndrome is a leading cause of transaminase increase and liver injury [10]. Several studies have shown an association between major depression and metabolic syndrome [11, 12, 13]. NAFLD may therefore be a cause of LFT abnormalities in patients treated with AD, but there are no studies addressing this issue. Patients with alcohol abuse or chronic viral hepatitis may also have increased ALT levels and need antidepressants. Therefore, an increase of transaminase levels in MDD may not be related to AD themselves in a DILI process, but to several other causes, which are not mutually exclusive. Nevertheless, studies evaluating the reasons for LFT abnormalities in MDD patients are insufficient.\n\nIn this observational study of depressed patients, we aimed to evaluate LFT availability, the prevalence of LFT abnormalities and the most probable cause of an altered LFT with a particular focus on DILI due to AD treatment in MDD.\n\nPatients and Methods\nPatients\nWe retrospectively assessed the clinical records of 321 consecutive patients (90% Caucasians); however, they were initially prospectively included in the METADAP cohort study between 2011 and 2014 [13]. The METADAP study aimed to assess the incidence of metabolic syndrome in patients with Major Depressive Episode (MDE) treated with antidepressants. Patients were eligible for inclusion if they were between 18 and 65 years-old, had a current MDE in a context of MDD [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IVTR) diagnostic criteria] with a Hamilton Depression Rating Scale (HDRS) score > 18, requiring an index prescription of AD. They were admitted to the hospital in the psychiatry department or followed up by a psychiatrist in the hospital outpatient service. The exclusion criteria were bipolar disorder, psychotic disorder, eating disorders (DSM-IVTR diagnostic criteria), psychiatric symptoms of a somatic disorder, unstable somatic disorder, pregnancy, treatment with a mood stabilizer, long-term antipsychotic treatment (prescribed for more than 4 months during the last year), legal protection, current alcohol (daily alcohol consumption ≥30 g for men and ≥20 g for women) or drug dependence, and participation in another research protocol in the last two months. Written informed consent was obtained from all participants. The study was conducted in accordance with the French law concerning medical investigations (Huriet Law) and the Helsinki declaration. The protocol was approved by the ethics committee of Bicêtre Hospital.\n\nAntidepressant treatment\nPatients were initiated with a monotherapy of AD treatment, all marketed AD on France being considered. The AD treatment included a drug from one of the four AD drug classes: selective serotonin reuptake inhibitor(s) (SSRI) (citalopram, escitalopram, paroxetine, fluoxetine, sertraline), serotonin-norepinephrine reuptake inhibitor(s) (SNRI) (venlafaxine, duloxetine, minalcipran), imipraminic medications (clomipramine, amitriptyline, maprotiline), or other AD medications (mianserine, mirtazapine, agomelatine). Other medications were allowed except mood stabilizers and antipsychotics. None of the hospitalised patients were admitted for suicide/self-harm attempt by drug overdose.\n\nDefinition of LFT abnormalities and DILI\nThe METADAP cohort was not intended to assess liver function and the decision to perform an LFT was not influenced by inclusion in the study.\n\nIn most cases, DILI related to AD use occurs during the first six months of treatment [8]. Therefore, we retrospectively collected the LFT [ALT, AST (aspartate aminotransferase), AP, gamma-glutamyl transferase and bilirubin] available at baseline (includes the six months before study inclusion) and during the first six months of AD treatment. Abnormal LFTs were defined by the presence of at least one of the following variables above the ULN provided by the local laboratory: ALT>45 IU/l, AST>40 IU/l, AP>130 IU/l and total bilirubin > 17 μmol/l. For patients with an abnormal LFT, the available etiologic data were collected: alcohol consumption (quantified as self-reported drinking habits; patients' families were also interviewed, when possible; no blood markers for alcohol consumption such as carbohydrate-deficient transferrin were performed), presence of NAFLD, viral hepatitis [immunoglobulin M antibodies (IgM) to hepatitis A, IgM to hepatitis B core antigen, antibodies to hepatitis C and hepatitis C viral load, IgM to hepatitis E and hepatitis E viral load, IgM to cytomegalovirus, IgM to Epstein-Barr virus, IgM to herpes viruses], ongoing medications, hemochromatosis (serum ferritin level and transferrin saturation), Wilson disease (serum ceruloplasmin level and urinary copper excretion), autoimmune hepatitis (diagnosis based on previously validated criteria)[14], bile duct obstruction (abdominal ultrasound), liver ischemia (clinical context and transthoracic echocardiography), hepatic arterial or venous obstruction (abdominal ultrasound examination with Doppler). Patients without available etiologic exploration were classified as LFT abnormalities of unknown etiology. Alcohol consumption was evaluated at inclusion as a daily alcohol intake ≥30 g for men and ≥20 g for women was one of the exclusion criteria. A new evaluation of daily alcohol consumption was done when LFT abnormalities were detected. Acute alcohol consumption was defined as a relapse from alcohol during the study period. The diagnosis of NAFLD was based on the following criteria: evidence of steatosis on liver ultrasound, daily alcohol consumption <30 g for men and <20 g for women, abnormal LFT, presence of metabolic syndrome components and no other cause of liver steatosis [15, 16]. DILI was suspected in patients with ALT values > 5xULN or AP values > 2xULN [3] which were temporally associated with the administration of the antidepressant drug. Drug imputability was assessed by Roussel Uclaf Causality Assessment Method (RUCAM) scale [4, 17], a widely used method to quantify the strength of association between liver injury and implicated medication. The RUCAM scale is composed of several different criteria including: temporal relationship between the drug intake and development of an abnormal LFT, evolution of LFTs following drug withdrawal, alcohol consumption, age, previous case reports of DILI, concomitant medication, exclusion of all potential causes of liver damage, drug rechallenge. A semi-quantitative score was calculated and an association between AD drug use and liver injury was defined as follows: highly probable (score>8); probable (score = 6–8); possible (score = 3–5); unlikely (score = 1–2); excluded (score<0). Data collection was carried out independently by two investigators (CSV and SM) under the supervision of GP and EC. The investigators were blind from the results of the METADAP cohort.\n\nDefinition of metabolic syndrome\nMetabolic syndrome was evaluated using clinical and biologic criteria: waist circumference, blood pressure, fasting blood glucose, lipid profile, use of antihypertensive, lipid-lowering medications or glucose lowering drugs. We used the definition from the National Cholesterol Education Program, 3 of the following criteria had to be met: waist circumference >102 cm in men and >88 cm in women, triglycerides ≥1.7 mmol/l, HDL (high density lipoprotein) cholesterol <1.03 mmol/l in men and <1.29 mmol/l in women, systolic pressure ≥130 mmHg or diastolic pressure ≥85 mmHg, fasting plasma glucose ≥6.2 mmol/l) [18].\n\nEvaluation of CYP450 and glutathione S-transferase polymorphisms\nFor patients with an available LFT, we assessed the polymorphisms of main cytochrome P450 (CYP) and glutathione S-transferase (GST) isoenzyme involved in AD metabolism. Genomic DNA was extracted from circulating leukocytes using the Puregene Kit (Gentra systems, MN, USA). CYP2D6 polymorphisms referred to the CYP Allele Nomenclature Committee (http://www.cypalleles.ki.se). CYP2D6 pharmacogenetic analysis used defined genotype-phenotype relationships based on known biochemical and pharmacological effects and included major CYP2D6 alleles within a population of European descendants [19]. We referred to the following phenotypes: poor metabolizers (PM)—lacking active enzyme function, homozygous or compound heterozygous for CYP2D6*3, *4, or *5alleles; intermediate metabolizers (IM)—reduced enzyme activity, carrying *10 and *41 alleles either homozygous or in combination with a PM allele. Patients were genotyped for the genetic polymorphisms: CYP2D6*3 (rs35742686), CYP2D6*4 (rs3892097), CYP2D6*6 (rs5030655), CYP2D6*10 (rs1065852), CYP2D6*41 (rs28371725), CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), CYP3A4*22 (rs35599367), CYP3A5*3 (rs776746), CYP1A2*1F (rs762551), blind from clinical data. The described genetic polymorphisms referred to the international list described by the CYP Allele Nomenclature Committee (http://www.cypalleles.ki.se). Single nucleotide polymorphisms (SNPs) detection and deletion were performed using Taqman® allelic discrimination assay (ABI prism 7900HT, Applied Biosystem, Courtaboeuf, France), as previously described [20]. The CYP2D6 duplication and deletion (CYP2D6*5) were determined using the real time PCR TaqMAn 7900HT Applied Biosystems Instrument [21]. GSTT1, GSTP1, GSTM1 genotyping was performed by genomic-level polymerase chain reaction (PCR) with restriction fragment length polymorphism analysis. All patients were treated in duplicate. The informed consent for DNA tests was obtained from all patients. Approval by ethics committee of Bicêtre Hospital was also obtained.\n\nStatistical analysis\nQuantitative variables are expressed as mean and standard deviation. Qualitative variables are expressed as percentages. Chi-squared tests were used to compare qualitative variables. Student’s t-tests were used to compare normally distributed quantitative variables and the Mann–Whitney test was used to compare quantitative variables that were not normally distributed. GraphPad Prism software was used for statistical analyses.\n\nResults\nPatients who were prescribed a LFT\nIn this real life cohort of 321 patients with a MDE treated by psychiatrists, LFTs were not systematically performed in patients treated with AD drugs. Overall, 116 patients (36.1%) had at least one LFT before or during the first 6 months of treatment. Baseline LFTs were available in 84.4% (98/116) of patients with LFT evaluation while 16.6% (18/116) had a LFT evaluation only after AD treatment initiation. At least two LFT determinations were available in 9% of patients (29/321). Table 1 summarizes the differences between patients who benefited or not from an LFT as prescribed by their psychiatrist. As compared to those who did not, those who benefited from an LFT evaluation before or during AD treatment were more likely to be inpatients and had significantly higher serum triglyceride levels. The frequency of metabolic syndrome was also higher, but the difference was not statistically significant. However, they did not differ in terms of age, gender, history of MDD and previous AD treatments, current MDE severity as rated by the HDRS score, and current AD treatment.\n\n10.1371/journal.pone.0155234.t001Table 1 Characteristics of patients who were prescribed a LFT by their psychiatrist.\n\tAll (n = 321)\tLFT prescribed (n = 116)\tNo LFT prescribed (n = 205)\tp\t\nAge, years (SD)\t46 (12.8)\t46.7 (12.7)\t45.6 (12.9)\tNS\t\nSex (M/F)\t99/222\t37/79\t62/143\tNS\t\nCaucasians\t90%\t93%\t90.2%\tNS\t\nHospitalized *\t82.5%\t89.5%\t78.6%\t0.01\t\nRecurrent MDD\t73.8%\t76.5%\t73.3%\tNS\t\nAge at onset of MDD, years (SD)\t33.3 (13.8)\t32.9 (12.8)\t33.5 (14.4)\tNS\t\nHistory of AD use\t81.9%\t83.4%\t81%\tNS\t\nHDRS (SD)\t23.9 (4.6)\t24 (4.2)\t23.8 (4.9)\tNS\t\nQIDSC (SD)\t22.4 (5.5)\t22.9 (5.2)\t22.2 (5.7)\tNS\t\nQIDSSR (SD)\t21.3 (7)\t21.6 (6.7)\t21.2 (7.2)\tNS\t\nSSRI\t37.4%\t38.3%\t36.8%\tNS\t\nSNRI\t43.1%\t43.7%\t42.7%\tNS\t\nIMI\t11%\t10.7%\t11.2%\tNS\t\nOther antidepressants\t8.5%\t7.3%\t9.3%\tNS\t\nTobacco\t36.4%\t40.8%\t33.9%\tNS\t\nBMI, kg/m2\n(SD)\t24.2 (4.7)\t24.4 (4.5)\t24 (4.9)\tNS\t\nWC, cm (SD)\t90.7 (13.7)\t92.2 (12.4)\t89.8 (14.3)\tNS\t\nDyslipidemia\t19%\t19.8%\t18.5%\tNS\t\nHypertension\t21.8%\t23.2%\t20.9%\tNS\t\nDiabetes\t4.3%\t4.3%\t4.3%\tNS\t\nTriglycerides, mmol/l (SD)\t1.1 (0.7)\t1.3 (0.9)\t1.1 (0.5)\t<0.01\t\nLDL cholesterol, mmol/l (SD)\t1.2 (0.3)\t1.2 (0.4)\t1.2 (0.3)\tNS\t\nHDL cholesterol, mmol/l (SD)\t0.5 (0.1)\t0.5 (0.1)\t0.5 (0.1)\tNS\t\nFPG, mmol/l (SD)\t0.9 (0.2)\t0.9 (0.1)\t0.9 (0.2)\tNS\t\nMetabolic syndrome\t24.5%\t27.8%\t22.7%\tNS\t\nAbbreviations: LFT, liver function tests; SD, standard deviation; NS, non significant; AD, antidepressant; MDD, major depressive disorder; HDRS, Hamilton depression rating scale; QIDSC, quick inventory of depressive symptomatology clinician rated; QIDSSR, quick inventory of depressive symptomatology self-report; SNRI, Serotonin–norepinephrine reuptake inhibitors; SSRI, Selective serotonin re-uptake inhibitors; IMI, imipraminic antidepressants; BMI, body mass index; WC, waist circumference; LDL, low density lipoprotein; HDL, high density lipoprotein; FPG, fasting plasma glucose.\n\nPrevalence of LFT abnormalities in patients who benefited from an LFT\nLFT abnormalities were found in 21.5% of patients with available LFTs (25/116). Thus the frequency of LFT abnormalities is at least 7.8% (25/321) in this sample of MDD patients with a current MDE treated in psychiatric settings. In most cases (18/25 patients, 72%), LFT abnormalities were detected before AD treatment initiation, thus excluding antidepressant-induced injury.\n\nEtiology of LFT abnormalities\nWe evaluated the available etiological data in order to establish the cause of LFT abnormalities. NAFLD was the most probable cause in 28% of cases (7/25). Other causes of LFT abnormalities were: acute alcohol consumption 16% (4/25), hepatitis C virus infection 8% (2/25), and heart failure 4% (1/25). The four patients with LFT abnormalities attributed to alcohol consumption, relapsed from alcohol (>50 g/day) during the study and no other cause of liver enzyme elevation was found. In patients with LFT abnormalities attributed to heart failure, transthoracic echocardiography showed global ventricular failure and other causes of mild liver enzyme elevations (2.5xupper limit of normal) were excluded. LFT improved with treatment of heart failure. Of note, etiological investigations were not carried out in one third of patients (8/25), all of these patients having mild LFT abnormalities (<3xULN). None of these patients had liver biopsy examination.\n\nThe prevalence of NAFLD with an abnormal LFT was 2.1% (7/321) in the overall cohort and 6% (7/116) in patients who were prescribed an LFT. The prevalence of AD-induced liver injury was at least 0.9% (3/321) in the overall cohort. In patients who were prescribed an LFT (n = 116), the prevalence of AD-induced liver injury was 2.5% (3/116). DILI represented 12% (3/25) of all causes of abnormal LFTs.\n\nSince NAFLD is strongly associated with metabolic syndrome, we assessed the differences in terms of metabolic syndrome and metabolic syndrome components (Table 2). We showed that the prevalence of metabolic syndrome was significantly higher in antidepressant-treated patients with an abnormal LFT than in those with a normal LFT (44% vs. 23.3%, p = 0.04), with higher triglycerides serum levels (p = 0.03) (Table 2).\n\n10.1371/journal.pone.0155234.t002Table 2 Characteristics of patients with normal and abnormal LFT.\n\tAbnormal LFT (n = 25)\tNormal LFT (n = 91)\tp\t\nAge, years (SD)\t48.4 (10.9)\t46.3 (13.2)\tNS\t\nSex (M/F)\t11/14\t26/65\tNS\t\nBMI, kg/m2\n(SD)\t25 (4.3)\t24.3 (4.5)\tNS\t\nWC, cm (SD)\t95.7 (11.9)\t91.2 (12.5)\t0.06\t\nDyslipidemia\t16%\t20.8%\tNS\t\nHypertension\t36%\t19.7%\t0.08\t\nDiabetes\t8%\t3.2%\tNS\t\nTriglycerides, mmol/l (SD)\t1.6 (1.2)\t1.2 (0.8)\t0.03\t\nTotal cholesterol, mmol/l (SD)\t2 (0.4)\t1.9 (0.4)\tNS\t\nHDL, mmol/l (SD)\t0.5 (0.1)\t0.5 (0.1)\tNS\t\nFPG, mmol/l (SD)\t0.9 (0.2)\t0.9 (0.1)\tNS\t\nMetabolic syndrome\t44%\t23.3%\t0.04\t\nAbbreviations: LFT, liver function tests; BMI, body mass index; WC, waist circumference; HDL, high density lipoprotein; FPG, fasting plasma glucose; NS, non significant.\n\nThe diagnosis of DILI due to antidepressant drug was suspected in 3 patients with an increase of ALT>5xULN upon initiating antidepressant drug treatment. The three cases of probable DILI are presented in Tables 3 and 4.\n\n10.1371/journal.pone.0155234.t003Table 3 Description of the 3 cases of antidepressant-induced liver injury.\n\tCase 1 (55-year-old woman)\tCase 2 (40-year-old man)\tCase 3 (47-year-old man)\t\nAntidepressant\tEscitalopram\tVenlafaxine\tAmitriptyline\t\nDaily dose\t10 mg\t150 mg\t50 mg\t\nConcomitant medication\tChlorpromazine\tZopiclone\tCyamemazine, Alimemazine\t\nType of lesion\tHepatocellular\tMixed\tMixed\t\nLatency\t4 days\t11 days\t10 weeks\t\nClinical context\tFlu-like syndrome, hypereosinophilia\tAsymptomatic\tAsymptomatic\t\nMedical history\tUnremarkable\tSleep disorders\tUnremarkable\t\nAntidepressant withdrawal\tYes\tYes\tYes\t\nOutcome\tComplete recovery\tComplete recovery\tComplete recovery\t\nRUCAM causality score\t8 (probable)\t7 (probable)\t5 (possible)\t\nCYP450 polymorphism\tGST M1 deletion (loss of function)\tHomozygous: CYP2D6*10 allele (reduced enzymatic activity)GST M1 deletion (loss of function)\tHeterozygous: CYP2D6*4 (inactivating allele); CYP2C19*17 (ultra fast metabolizer allele)Homozygous: CYP1A2*1C (slow metabolizer allele)\t\nAbbreviations: RUCAM, Roussel Uclaf Causality Assessment Method; CYP, cytochrome P450.\n\n10.1371/journal.pone.0155234.t004Table 4 Evolution of liver function tests in the 3 cases of antidepressant-induced liver injury.\n\tCase 1 (escitalopram-induced liver injury)\tCase 2 (venlafaxine-induced liver injury)\tCase 3 (amitriptyline-induced liver injury)\t\n\tIndex\tDay 8\tDay 12\tDay 31\tIndex\tDay 20\tDay 59\tIndex\tD37\tDay 72\tDay 133\t\nALT (IU/l)\t17\t797\t319\t36\t46\t232\t147\t39\t320\t100\t55\t\nAST (IU/l)\t19\t804\t71\t25\t25\t129\t59\t26\t105\t33\t34\t\nALP (IU/l)\t77\t143\t235\t155\t71\t180\t91\t56\t221\t65\t56\t\nTotal bilirubin (μmol/l)\t17\t19\t13\t9\t\t\t5\t17\t7\t\t\t\nINR\t1.1\t1\t\t\t1\t1\t\t1.1\t1\t1\t\t\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; INR, international normalized ratio.\n\nCYP450 and glutathione S-transferase polymorphisms in antidepressant treated patients\nCYP2D6 genotype frequencies in the group of patients with an available LFT were as follows: CYP2D6*3–0% homozygous, 2.6% heterozygous; CYP2D6*4–0% homozygous, 28.4% heterozygous; CYP2D6*5–7.8% duplication or deletion; CYP2D6*6–0% homozygous, 1.7% heterozygous; CYP2D6*10–7.8% homozygous, 23.3% heterozygous; CYP2D6*41–0% homozygous, 14.7% heterozygous. CYP2D6*10 allele was present in a homozygous state in the patient with venlafaxine-related DILI. CYP2D6*10 homozygosity was found in 33.3% (1/3) of patients with antidepressant-induced liver injury, but only in 7.8% (9/116) of patients with an available LFT. CYP2D6*4 and CYP2C19*17 were present in a heterozygous state in the patient with amitriptyline-related DILI. This genotype association was found in 33.3% (1/3) of patients with DILI, but only in 9.5% (11/116) of patients with an available LFT. GST M1 deletion was present in 2 of the 3 patients with antidepressant-related DILI. However, the frequency of this deletion was similar in DILI patients and patients with available LFT (66.6% and 52%, respectively).\n\nDiscussion\nIn this observational cohort study, we showed that evaluation of an LFT is infrequently performed in depressed patients without current alcohol dependence, drug abuse or unstable medical conditions, which require starting an antidepressant treatment, by a psychiatrist. This suggests that psychiatrists are not aware of antidepressant induced DILI. We were not able to identify clear criteria for assessment of LFTs except that they were more often conducted with inpatients, and had higher triglyceride serum levels. Nevertheless, the prevalence of LFT abnormalities was high reaching at least 7.8% of the overall cohort. Recommendations are therefore needed for assessment of LFT in depressed patients treated with antidepressants beyond those with current alcohol dependence, drug abuse or unstable medical conditions.\n\nThere are no recommendations regarding liver function testing in patients taking antidepressant medication. Furthermore, clinical trials evaluating LFTs exist only for newer drugs. Therefore, DILI related to antidepressant use is probably underdiagnosed in clinical practice [8]. In our cohort, only 36.1% of antidepressant-treated patients had at least one liver function testing available at baseline and/or during the first 6 months of treatment. Interestingly, 21.5% of these patients had LFT abnormalities. Most patients showed an altered LFT at baseline arguing against a drug-induced hepatic toxicity. Metabolic syndrome and metabolic syndrome components (waist circumference, hypertension and serum triglycerides) were more frequent in antidepressant-treated patients with LFT abnormalities. Moreover, NAFLD was the major cause of abnormal LFT in this group of patients. Acute alcohol consumption and chronic hepatitis C virus infection were also involved. Alcohol dependence is present in up 20% of patients with depression and may negatively affect the course of depressive disorders [22]. The METADAP cohort included patients without ongoing alcohol consumption. Nevertheless, alcohol relapse was the second most common cause of LFT abnormalities and should be considered in antidepressant-treated patients. These data suggest that an increase in aminotransferase levels (before any antidepressant treatment or during treatment) may be related to an underlying liver disease, not necessarily severe, that does not contraindicate antidepressant treatment. Therefore, assessment of baseline LFTs may be useful as they help to interpret the abnormal LFT results during antidepressant treatment. Abnormal results may be a manifestation of either underlying liver disease or antidepressant-induced hepatotoxicity.\n\nIn 32% of cases, LFT abnormalities were of unknown etiology. These patients did not meet the criteria for metabolic syndrome. Moreover, etiological data such as viral hepatitis status, autoimmune hepatitis markers, ultrasound exploration or liver biopsy were not available. The accepted thresholds for initiating causality evaluation in suspected DILI are ALT/AST > 5XULN, ALP > 2XULN or bilirubin > 2XULN [3]. The mild LFT abnormalities (<3xULN) in this group of patients may therefore explain the dearth of etiological evaluations. On the other hand, mild elevations in levels of the liver enzymes (<3xULN) are found in 1–5% of the general population [23]. Furthermore, physiological variations of aminotransferase (between 1xULN to 3xULN) levels can occur in up to 20% of normal subjects treated with placebo and followed up for a period of 2 weeks [24]. An increase of carbohydrate or fat intake may also lead to an increase of baseline aminotransferase levels in only three days [25]. In our cohort, patients with an abnormal LFT of unknown etiology had no further LFT surveillance. For this reason, we cannot exclude that these LFT abnormalities were related to physiological variations, the concomitant medication or the previous exposure to antidepressants. Surveillance of the LFT once abnormalities are detected may therefore be useful in patients receiving antidepressant medication to discriminate between physiological variations and possible drug-related toxicity.\n\nA French prospective community study showed a global crude annual incidence of DILI of 13.9 cases per 100,000 inhabitants, 16 times higher than spontaneous case reporting rate to national regulatory authorities [26]. A more recent study conducted in medical inpatients reported a DILI incidence of 1.4% [27]. Carvajal Garcia-Pando and colleagues [28] reported an incidence of DILI associated with antidepressants requiring hospitalization of 1,28–29 cases per 100,000 patient-years. This estimation was based on cases of hepatic damage collected via spontaneous reporting and included in the Spanish Pharmacovigilance database, suggesting a possible underestimation of the disease. In our study, we report one case of symptomatic DILI associated to escitalopram and two cases of asymptomatic LFT abnormalities which fulfilled the criteria of DILI attributable to venlafaxine and amitriptyline use. The three patients developed increased ALT serum levels > 5xULN following antidepressant initiation that normalized upon treatment withdrawal and liver biopsy was unnecessary. LFT normalized despite continuation of concomitant medication (Table 3). However, drug-drug interactions involving CYP450 pathway cannot be excluded in these cases of DILI. In our cohort of depressed patients, the frequency of DILI associated with antidepressant use was 0.9% during the first six months of treatment. Considering that LFT were assessed in a minority of antidepressant-treated patients, undiagnosed cases of asymptomatic DILI may exist. Treatment continuation despite hepatotoxicity development could lead to severe hepatic failure or chronic hepatocellular dysfunction [8, 29–31]. All these data suggest that DILI related to antidepressant use is probably underestimated and surveillance of LFT in the first six months of treatment could improve detection of asymptomatic cases. However, routine LFT testing in antidepressant-treated patients may have major cost implications. Our study was not intended to evaluate the cost implications of performing LFT in depressed patients starting antidepressant treatment. Further studies are necessary to evaluate cost-effectiveness of LFT surveillance.\n\nGeneration of toxic metabolites is considered one of the mechanisms of drug-related hepatotoxicity. The metabolic pathway of antidepressant drugs includes CYP450 enzyme complex and GST. Genetic polymorphisms of CYP450 and GST isoenzymes including SNPs, duplications, deletions and gene conversions can cause either increased or reduced enzymatic activity levels [32, 33] with potential implication in DILI pathogenesis. Amitriptyline is demethylated mainly by CYP2C19 and CYP3A4 to form the active metabolite nortriptyline which is further metabolized by hydroxylation through the CYP2D6 pathway [34]. It was shown that nortriptyline but not amitriptyline serum levels correlated with adverse events [35]. Furthermore, increased CYP2C19 activity in combination with diminished CYP2D6 enzymatic activity was associated with high nortriptyline serum levels and high risk of adverse events [35], but the relationship with DILI is unknown for this drug. In this study, we showed that the patient who developed DILI associated with amitriptyline was heterozygous for ultra fast metabolizing allele CYP2C19*17 and inactivating allele CYP2D6*4. This genotype association was present in only in 9.5% of patients with an available LFT. Venlafaxine is metabolized primarily by CYP2D6, CYP3A4 and CYP2C19 [34]. Pharmacokinetics of venlafaxine is affected by CYP2D6*10 polymorphism which is a poor metabolizing allele [36]. The CYP2D6*10 allele was found in a homozygous status in a patient with DILI related to venlafaxine use. The patient was a homozygous carrier for the deletion GST M1 which leads to complete absence of enzymatic activity and potentially higher susceptibility to toxic liver injury. CYP450 and GST polymorphisms may therefore play a role in the pathogenesis of hepatic toxicity related to antidepressant use, but further studies are needed.\n\nOur study has several limitations. First, it is a retrospective review of a prospectively acquired database. Nevertheless, a primary goal was to assess frequency of LFT availability in depressed patients requiring antidepressants in psychiatric clinical practices. Second, the number of patients was relatively low to evaluate DILI associated with antidepressant drug use which is a rare condition.\n\nIn conclusion, this study demonstrates that LFTs are infrequently performed in depressed patients requiring AD and treated by psychiatrists. Baseline LFT assessments and follow-up during the first six months of treatment with AD may be useful for detection of patients with pre-existing liver disease such as NAFLD, and early identification of cases of antidepressant-induced liver injury. Asymptomatic cases of DILI associated with antidepressant use may be relatively frequent and much effort should be done to avoid irreversible liver damage. Our results also suggest that an increase in aminotransferase levels may be related to an underlying liver disease, not necessarily severe, but does not contraindicate antidepressant treatment. Recommendations are needed for assessment of LFTs in depressed patients treated with antidepressants.\n\nWe are grateful to Professor Laurent Becquemont for critical reading of the manuscript.\n==== Refs\nReferences\n1 Schuster D , Laggner C , Langer T . Why drugs fail—a study on side effects in new chemical entities . Curr Pharm Des . 2005 ;11 :3545 –3559 . 16248807 \n2 Verma S , Kaplowitz N . Diagnosis, management and prevention of drug-induced liver injury . Gut . 2009 ;58 :1555 –1564 . 10.1136/gut.2008.163675 \n19834119 \n3 Aithal GP , Watkins PB , Andrade RJ , Larrey D , Molokhia M , Takikawa H , et al\nCase definition and phenotype standardization in drug-induced liver injury . Clin Pharmacol Ther . 2011 ;89 :806 –815 . 10.1038/clpt.2011.58 \n21544079 \n4 Benichou C , Danan G , Flahault A . Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge . J Clin Epidemiol . 1993 ;46 :1331 –1336 . 8229111 \n5 Rockey DC , Seeff LB , Rochon J , Freston J , Chalasani N , Bonacini M , et al\nCausality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method . Hepatology . 2010 ;51 :2117 –2126 . 10.1002/hep.23577 \n20512999 \n6 Maria VA , Victorino RM . Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis . Hepatology . 1997 ;26 :664 –669 . 9303497 \n7 Naranjo CA , Busto U , Sellers EM , Sandor P , Ruiz I , Roberts EA , et al\nA method for estimating the probability of adverse drug reactions . Clin Pharmacol Ther . 1981 ;30 :239 –245 . 7249508 \n8 Voican CS , Corruble E , Naveau S , Perlemuter G . Antidepressant-induced liver injury: a review for clinicians . Am J Psychiatry . 2014 ;171 :404 –415 . 10.1176/appi.ajp.2013.13050709 \n24362450 \n9 produit. VRdcd. Available: http://www.servier.fr/download/VALDOXAN/RCP_VALDOXAN.pdf. 2011.\n10 Perlemuter G , Bigorgne A , Cassard-Doulcier AM , Naveau S . Nonalcoholic fatty liver disease: from pathogenesis to patient care . Nat Clin Pract Endocrinol Metab . 2007 ;3 :458 –469 . 17515890 \n11 McIntyre RS , Park KY , Law CW , Sultan F , Adams A , Lourenco MT , et al\nThe association between conventional antidepressants and the metabolic syndrome: a review of the evidence and clinical implications . CNS Drugs . 2010 ;24 :741 –753 . 10.2165/11533280-000000000-00000 \n20806987 \n12 Akbaraly TN , Ancelin ML , Jaussent I , Ritchie C , Barberger-Gateau P , Dufouil C , et al\nMetabolic syndrome and onset of depressive symptoms in the elderly: findings from the three-city study . Diabetes Care . 2011 ;34 :904 –909 . 10.2337/dc10-1644 \n21346185 \n13 Corruble E , El Asmar K , Trabado S , Verstuyft C , Falissard B , Colle R , et al\nTreating major depressive episodes with antidepressants can induce or worsen metabolic syndrome: results of the METADAP cohort . World Psychiatry . 2015 ;14 :366 –367 . 10.1002/wps.20260 \n26407797 \n14 Alvarez F , Berg PA , Bianchi FB , Bianchi L , Burroughs AK , Cancado EL , et al\nInternational Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis . J Hepatol . 1999 ;31 :929 –938 . 10580593 \n15 Ratziu V , Bellentani S , Cortez-Pinto H , Day C , Marchesini G . A position statement on NAFLD/NASH based on the EASL 2009 special conference . J Hepatol . 2010 ;53 :372 –384 . 10.1016/j.jhep.2010.04.008 \n20494470 \n16 Marchesini G , Brizi M , Bianchi G , Tomassetti S , Bugianesi E , Lenzi M , et al\nNonalcoholic fatty liver disease: a feature of the metabolic syndrome . Diabetes . 2001 ;50 :1844 –1850 . 11473047 \n17 Rochon J , Protiva P , Seeff LB , Fontana RJ , Liangpunsakul S , Watkins PB , et al\nReliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury . Hepatology . 2008 ;48 :1175 –1183 . 10.1002/hep.22442 \n18798340 \n18 Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report . Circulation . 2002 ;106 :3143 –3421 . 12485966 \n19 Zanger UM , Raimundo S , Eichelbaum M . Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry . Naunyn Schmiedebergs Arch Pharmacol . 2004 ;369 :23 –37 . 14618296 \n20 Gressier F , Verstuyft C , Hardy P , Becquemont L , Corruble E . Response to CYP2D6 substrate antidepressants is predicted by a CYP2D6 composite phenotype based on genotype and comedications with CYP2D6 inhibitors . J Neural Transm . 2015 ;122 :35 –42 . 10.1007/s00702-014-1273-4 \n25047911 \n21 Schaeffeler E , Schwab M , Eichelbaum M , Zanger UM . CYP2D6 genotyping strategy based on gene copy number determination by TaqMan real-time PCR . Hum Mutat . 2003 ;22 :476 –485 . 14635107 \n22 Boschloo L , Vogelzangs N , Smit JH , van den Brink W , Veltman DJ , Beekman AT , et al\nComorbidity and risk indicators for alcohol use disorders among persons with anxiety and/or depressive disorders: findings from the Netherlands Study of Depression and Anxiety (NESDA) . J Affect Disord . 2011 ;131 :233 –242 . 10.1016/j.jad.2010.12.014 \n21247636 \n23 Neuschwander-Tetri BA , Caldwell SH . Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference . Hepatology . 2003 ;37 :1202 –1219 . 12717402 \n24 Rosenzweig P , Miget N , Brohier S . Transaminase elevation on placebo during phase I trials: prevalence and significance . Br J Clin Pharmacol . 1999 ;48 :19 –23 . 10383555 \n25 Purkins L , Love ER , Eve MD , Wooldridge CL , Cowan C , Smart TS , et al\nThe influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit . Br J Clin Pharmacol . 2004 ;57 :199 –208 . 14748819 \n26 Sgro C , Clinard F , Ouazir K , Chanay H , Allard C , Guilleminet C , et al\nIncidence of drug-induced hepatic injuries: a French population-based study . Hepatology . 2002 ;36 :451 –455 . 12143055 \n27 Meier Y , Cavallaro M , Roos M , Pauli-Magnus C , Folkers G , Meier PJ , et al\nIncidence of drug-induced liver injury in medical inpatients . Eur J Clin Pharmacol . 2005 ;61 :135 –143 . 15726344 \n28 Carvajal Garcia-Pando A , Garcia del Pozo J , Sanchez AS , Velasco MA , Rueda de Castro AM , Lucena MI . Hepatotoxicity associated with the new antidepressants . J Clin Psychiatry . 2002 ;63 :135 –137 . 11874214 \n29 Larrey D , Amouyal G , Pessayre D , Degott C , Danne O , Machayekhi JP , et al\nAmitriptyline-induced prolonged cholestasis . Gastroenterology . 1988 ;94 :200 –203 . 3335290 \n30 Johnston DE , Wheeler DE . Chronic hepatitis related to use of fluoxetine . Am J Gastroenterol . 1997 ;92 :1225 –1226 . 9219808 \n31 Beck PL , Bridges RJ , Demetrick DJ , Kelly JK , Lee SS . Chronic active hepatitis associated with trazodone therapy . Ann Intern Med . 1993 ;118 :791 –792 . 8470853 \n32 Teh LK , Bertilsson L . Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance . Drug Metab Pharmacokinet . 2012 ;27 :55 –67 . 22185816 \n33 Mejin M , Tiong WN , Lai LY , Tiong LL , Bujang AM , Hwang SS , et al\nCYP2C19 genotypes and their impact on clopidogrel responsiveness in percutaneous coronary intervention . Int J Clin Pharm . 2013 ;35 :621 –628 . 10.1007/s11096-013-9783-y \n23661171 \n34 Wille SM , Cooreman SG , Neels HM , Lambert WE . Relevant issues in the monitoring and the toxicology of antidepressants . Crit Rev Clin Lab Sci . 2008 ;45 :25 –89 . 10.1080/10408360701713112 \n18293180 \n35 Steimer W , Zopf K , von Amelunxen S , Pfeiffer H , Bachofer J , Popp J , et al\nAmitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy . Clin Chem . 2005 ;51 :376 –385 . 15590749 \n36 Fukuda T , Yamamoto I , Nishida Y , Zhou Q , Ohno M , Takada K , et al\nEffect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers . Br J Clin Pharmacol . 1999 ;47 :450 –453 . 10233212\n\n",
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"mesh_terms": "D000928:Antidepressive Agents; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System; D003865:Depressive Disorder, Major; D005260:Female; D005982:Glutathione Transferase; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D015995:Prevalence; D011570:Psychiatry",
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"title": "Liver Function Test Abnormalities in Depressed Patients Treated with Antidepressants: A Real-World Systematic Observational Study in Psychiatric Settings.",
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{
"abstract": "Primary immunodeficiency diseases (PID), encompass a heterogeneous group of diseases, with increased susceptibility to recurrent, severe infections. Invasive fungal infections raise a serious concern related to their morbidity and mortality. Herein, we describe various fungal infections among different PID patients. Twenty-eight PID patients diagnosed with fungal infections were included; fourteen patients with chronic granulomatous disease, two with Hyper Immunoglobulin E syndrome, one with LRBA deficiency and one with MHC class II defect, one with unclassified immune dysregulation, one with CD4 lymphopenia and one patient with Immune dysregulation Polyendocrinopathy Enteropathy X-linked syndrome. Aspergillus species were the most common isolated causative organisms in 78% of patients, Candida species were the causative organisms in 32%, Pneumocystis jirovecii caused infections in 7% followed by Malassezia furfur, Fusarium spp., Mucormycosis, and Penicillium chrysogenium 3.5% for each. The mortality rate among our patients was 10/28 (35.7%). PID patients are at high risk of developing fungal infections.",
"affiliations": "Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Electronic address: [email protected].;Botany and Microbiology Department, Faculty of Science, Cairo University, Cairo, Egypt.;Clinical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.;Clinical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.;Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt.;Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt.;Botany and Microbiology Department, Faculty of Science, Cairo University, Cairo, Egypt.;Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt.",
"authors": "Abd Elaziz|Dalia|D|;Abd El-Ghany|Mohamed|M|;Meshaal|Safa|S|;El Hawary|Rabab|R|;Lotfy|Sohilla|S|;Galal|Nermeen|N|;Ouf|Salama A|SA|;Elmarsafy|Aisha|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clim.2020.108553",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1521-6616",
"issue": "219()",
"journal": "Clinical immunology (Orlando, Fla.)",
"keywords": "Aspergillus infections; Candida infections; Fungal infections; Immunodeficiency diseases",
"medline_ta": "Clin Immunol",
"mesh_terms": "D001419:Bacteria; D001424:Bacterial Infections; D002648:Child; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D005658:Fungi; D006801:Humans; D007223:Infant; D008297:Male; D009181:Mycoses; D000081207:Primary Immunodeficiency Diseases",
"nlm_unique_id": "100883537",
"other_id": null,
"pages": "108553",
"pmc": null,
"pmid": "32738296",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fungal infections in primary immunodeficiency diseases.",
"title_normalized": "fungal infections in primary immunodeficiency diseases"
}
|
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{
"abstract": "Evaluation of the safety of taking lamotrigine (LTG) during lactation in breastfed infants varies according to the information sources. As it is possible that prescribers may avoid prescribing LTG despite of it being one of the essential drugs, more information needs to be accumulated to facilitate its use. We retrospectively compared the safety of LTG during the lactation period in 20 pairs of mothers and infants with 20 pairs as the control group. The mean dose of LTG in 20 mothers was 161.1 mg/day (range: 50-400 mg/day). None of the infants showed a neonatal withdrawal syndrome score of 2 or more up to 1 month after delivery. Although drowsiness (n = 3), skin rash (n = 11), jaundice (n = 8), heart murmur (n = 1), poor suckling (n = 1), and retractive breathing (n = 1) were observed in infants, none of these adverse events were serious and the infants recovered. Nineteen of 20 pairs could continue lactation until 1 month after delivery. One pair discontinued breastfeeding because of pain in the mother's nipples. All pairs could continue maternal medication. We then compared the results with those of the control group. There were no significant differences in the presence of adverse events between the LTG and control groups. These data suggest that taking low to moderate doses of LTG during the lactation period might be relatively safe, at least for a period of 1 month after delivery.",
"affiliations": "Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.;Department of Psychiatry, Tohoku University Hospital, Sendai, Japan.;Department of Obstetrics and Gynecology and Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Obstetrics and Gynecology and Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.",
"authors": "Yashima|Kazushi|K|;Obara|Taku|T|;Matsuzaki|Fumiko|F|;Suzuki|Chihiro|C|;Saeki|Mika|M|;Koyama|Mina|M|;Hosono|Moeko|M|;Noda|Aoi|A|;Kikuchi|Saya|S|;Hoshiai|Tetsuro|T|;Sato|Shinichi|S|;Saito|Masatoshi|M|;Hanita|Takushi|T|;Mano|Nariyasu|N|",
"chemical_list": "D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1089/bfm.2020.0210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-8253",
"issue": "16(5)",
"journal": "Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine",
"keywords": "infant; lactation; lamotrigine; neonatal withdrawal syndrome",
"medline_ta": "Breastfeed Med",
"mesh_terms": "D001942:Breast Feeding; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007774:Lactation; D000077213:Lamotrigine; D012189:Retrospective Studies; D014227:Triazines",
"nlm_unique_id": "101260777",
"other_id": null,
"pages": "432-438",
"pmc": null,
"pmid": "33819427",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Evaluation of the Safety of Taking Lamotrigine During Lactation Period.",
"title_normalized": "evaluation of the safety of taking lamotrigine during lactation period"
}
|
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{
"abstract": "OBJECTIVE\nSome recent reports have indicated that local infection causes osteonecrosis of the jaw and described that tooth extraction may not be a direct cause of developing medication-related osteonecrosis of the jaw (MRONJ) in patients receiving antiresorptive medications. Tooth extraction and elimination of the source of infection are expected to reduce the risk of developing MRONJ. However, there is no data regarding prevention for developing osteonecrosis of the jaw in patients receiving denosumab. Therefore, the aim of this study was to investigate the outcome of tooth extractions with proper wound closure in patients receiving denosumab.\n\n\nMETHODS\nForty teeth in 19 patients treated with denosumab therapy were extracted under preoperative intravenous antibiotics. Patients who had already developed MRONJ in the extraction sites or who had a history of radiation therapy were excluded. During surgery, bone edges were smoothed and all wounds were closed using the double-layered technique.\n\n\nRESULTS\nThirty-seven extraction sites (92.5 %) in 17 out of 19 patients (89.5 %) were healed. However, three extraction sites in two patients had complications; one patient had exposed bone and developed MRONJ (stage 1) and the other developed a mucosa fistula. Additional surgical procedures were performed and all wounds were completely healed.\n\n\nCONCLUSIONS\nTooth extractions in patients receiving denosumab can be performed in an appropriate manner and result in good outcomes.\n\n\nCONCLUSIONS\nThis study indicated that tooth extraction with proper wound closure to avoid secondary infection may be effective for the prevention of MRONJ even in high-risk patients.",
"affiliations": "Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. [email protected].;Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Oral and Maxillofacial Surgery, University Hospital Freiburg, Hugstetter St. 55, 79106, Freiburg im Breisgau, Germany.;Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Oral and Maxillofacial Surgery, University Hospital Freiburg, Hugstetter St. 55, 79106, Freiburg im Breisgau, Germany.",
"authors": "Matsumoto|Akihiko|A|;Sasaki|Masanori|M|;Schmelzeisen|Rainer|R|;Oyama|Yukiko|Y|;Mori|Yoshihide|Y|;Voss|Pit Jacob|PJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00784-016-1762-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1432-6981",
"issue": "21(1)",
"journal": "Clinical oral investigations",
"keywords": "Denosumab; MRONJ; Osteonecrosis of the jaw; Prevention; Tooth extraction",
"medline_ta": "Clin Oral Investig",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013530:Surgical Wound Infection; D014081:Tooth Extraction; D016896:Treatment Outcome; D058106:Wound Closure Techniques",
"nlm_unique_id": "9707115",
"other_id": null,
"pages": "127-134",
"pmc": null,
"pmid": "26924135",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": "18647964;19375001;23426919;20307765;17143310;21818568;21798645;21986094;25234529;22483860;17683649;16626523;20971371;19961450;18528958;12359855;22623376;20149510;21427065;23582590;22113597;22129778;23830772;18927312;15122554;17457784;22336489;23434159;21060033;22840716;25958767;19805682;19671655;20580566;18574158;19495814;16243172;23288026;20006163;21741741;22767993;22977302;18234504;23182374;12966493",
"title": "Primary wound closure after tooth extraction for prevention of medication-related osteonecrosis of the jaw in patients under denosumab.",
"title_normalized": "primary wound closure after tooth extraction for prevention of medication related osteonecrosis of the jaw in patients under denosumab"
}
|
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},
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"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Mother-to-child transmission of hepatitis B virus can occur during the intrauterine, antenatal and postnatal periods, with an increased risk of perinatal transmission. Appropriate management of patients who are hepatitis B surface antigen positive during pregnancy can substantially reduce the rates of perinatal transmission. Herein, two pregnant women with chronic hepatitis B are presented; one became pregnant while receiving tenofovir disoproxil fumarate and continued the treatment during pregnancy, the other discontinued tenofovir disoproxil fumarate treatment on her own due to conception, but restarted at 26 weeks of pregnancy. At birth the newborns of both women were vaccinated and immunoglobulin was given, with no perinatal transmission. Whether pregnant women should receive antiviral therapy or immunoprophylaxis still remains controversial. In order to keep the mother's liver stable and to prevent perinatal transmission, it is of paramount importance to manage pregnant women in line with the current information and guidelines.",
"affiliations": "Department of Infectious Diseases, Medeniyet University Göztepe Training and Research Hospital, Istanbul, Turkey.;Department of Infectious Diseases, Medeniyet University Göztepe Training and Research Hospital, Istanbul, Turkey.",
"authors": "Ergen|Pınar|P|https://orcid.org/0000-0003-3990-7956;Yilmaz Karadağ|Fatma|F|",
"chemical_list": "D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D000068698:Tenofovir",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "46(5)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "hepatitis B; mother-to-child transmission; nucleos(t)ide analogues; pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D005260:Female; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D011247:Pregnancy; D000068698:Tenofovir",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "779-783",
"pmc": null,
"pmid": "32128941",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Approach to women who become pregnant while on tenofovir disoproxil fumarate for chronic B hepatitis: A report of two cases.",
"title_normalized": "approach to women who become pregnant while on tenofovir disoproxil fumarate for chronic b hepatitis a report of two cases"
}
|
[
{
"companynumb": "TR-VIIV HEALTHCARE LIMITED-TR2020GSK048050",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "021003",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "100 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHRONIC HEPATITIS B",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "2010",
"drugstartdateformat": "602",
"drugstructuredosagenumb": "100",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LAMIVUDINE."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ERGEN P AND KARADAG FY. APPROACH TO WOMEN WHO BECOME PREGNANT WHILE ON TENOFOVIR DISOPROXIL FUMARATE FOR CHRONIC B HEPATITIS: A REPORT OF TWO CASES. THE JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH. 2020?DOI:10.1111/JOG.14224",
"literaturereference_normalized": "approach to women who become pregnant while on tenofovir disoproxil fumarate for chronic b hepatitis a report of two cases",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20200319",
"receivedate": "20200319",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17562689,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
},
{
"companynumb": "TR-GLAXOSMITHKLINE-TR2020GSK048050",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "021003",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "100 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHRONIC HEPATITIS B",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "2010",
"drugstartdateformat": "602",
"drugstructuredosagenumb": "100",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LAMIVUDINE."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ERGEN P AND KARADAG FY. APPROACH TO WOMEN WHO BECOME PREGNANT WHILE ON TENOFOVIR DISOPROXIL FUMARATE FOR CHRONIC B HEPATITIS: A REPORT OF TWO CASES. THE JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH. 2020?DOI:10.1111/JOG.14224",
"literaturereference_normalized": "approach to women who become pregnant while on tenofovir disoproxil fumarate for chronic b hepatitis a report of two cases",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20200319",
"receivedate": "20200319",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17562690,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "OBJECTIVE\nInfliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response.\n\n\nMETHODS\nA total of 139 Korean patients with IBD who received infliximab were classified according to infliximab response as follows: (i) primary response vs nonresponse and (ii) sustained response vs loss of response. We performed an association study using whole-exome sequencing data to identify genetic variants associated with infliximab response. Candidate variants were validated in 77 German patients with IBD. Stepwise multivariate logistic regression was performed to identify predictors.\n\n\nRESULTS\nWe found five candidate variants that were associated with primary nonresponse to infliximab (P < 5 × 10-6 ). Of the five variants, rs2228273 in ZNF133 was validated in German (combined P = 6.49 × 10-7 ). We also identified the best genetic variant (rs9144, P = 4.60 × 10-6 ) associated with the loss of infliximab response. In multivariate regression analysis, rs2228273 (P = 2.10 × 10-5 ), concurrent azathioprine/6-mercaptopurine use, and bodyweight at the first infliximab use (< 50 kg) were associated with primary nonresponse. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 (P = 0.001) were independently associated with the loss of response in patients with Crohn's disease.\n\n\nCONCLUSIONS\nWe identified clinical and genetic markers associated with infliximab response in IBD patients. Our findings could provide insights to maximize the efficacy of infliximab therapy in IBD patients.",
"affiliations": "Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.;Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea.;Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.;Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.;Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.;Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.;Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea.;Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.;Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.;Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.;Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea.;Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.",
"authors": "Jung|Eun Suk|ES|;Choi|Ko-Woon|KW|;Kim|Seung Won|SW|;Hübenthal|Matthias|M|;Mucha|Sören|S|;Park|Jihye|J|;Park|Zewon|Z|;Ellinghaus|David|D|;Schreiber|Stefan|S|;Franke|Andre|A|;Oh|Woo Yong|WY|;Cheon|Jae Hee|JH|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D012097:Repressor Proteins; C095224:ZNF133 protein, human; D000069285:Infliximab",
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.14652",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "34(10)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "inflammatory bowel disease; infliximab response; whole-exome sequencing",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D005260:Female; D005765:Gastrointestinal Agents; D005838:Genotype; D005858:Germany; D006801:Humans; D000069285:Infliximab; D008297:Male; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D012074:Remission Induction; D012097:Repressor Proteins; D012307:Risk Factors; D066106:Seoul; D013997:Time Factors; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "1727-1735",
"pmc": null,
"pmid": "30851117",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D023361:Validation Study",
"references": null,
"title": "ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases.",
"title_normalized": "znf133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases"
}
|
[
{
"companynumb": "DE-JNJFOC-20191234123",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INFLAMMATORY BOWEL DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "REMICADE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Neoplasm malignant",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JUNG E, CHOI K, KIM S, HUBENTHAL M, MUCHA S, PARK J, PARK Z, ELLINGHAUS D, SCHREIBER S, FRANKE A, OH W, CHEON J. ZNF133 IS ASSOCIATED WITH INFLIXIMAB RESPONSIVENESS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES. JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY. 2019?34:1727-1735.",
"literaturereference_normalized": "znf133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20191220",
"receivedate": "20191220",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 17186791,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "Chinese patients largely experience acute ischemic stroke (AIS) because of large artery atherosclerosis rather than cardioembolism, and whether tirofiban is safe and effective in these patients treated with endovascular thrombectomy (ET) is unknown. This study evaluated the safety and efficacy of tirofiban in Chinese patients with AIS treated with ET.\n\n\n\nThis observational study is based on a single-center prospective registry study. Patients with AIS undergoing ET with second-generation stent retrievers from January 2013 to February 2017 were treated with ET alone or ET plus low dose of tirofiban. The primary outcome was symptomatic intracerebral hemorrhage (sICH). The secondary outcomes included rate of early reocclusion, any ICH, fatal ICH, and 3-month and long-term functional outcomes.\n\n\n\nOne hundred eighty AIS subjects were included in the analysis, including 90 subjects treated with tirofiban and 90 subjects without tirofiban. Sixty-three subjects (35%) had any ICH, 19 of them (11%) were sICH, and 9 of them (5%) were fatal ICH. Ten subjects (11%) treated with tirofiban experienced sICH and 9 subjects (10%) not given tirofiban experienced sICH, not a significant difference (P=0.808). Early reocclusion happened in 4 of 90 subjects (4.4%) treated with tirofiban and 8 of 90 subjects (8.9%) not treated with tirofiban (P=0.370). One hundred sixty-one subjects (89%) completed long-term follow-up, subjects treated tirofiban were associated with lower odds of death (23% versus 44%, P=0.005) when compared with those who were not treated. Additionally, tirofiban was associated with better odds of long-term functional independence (adjusted odds ratio, 4.37; 95% confidence interval, 1.13-16.97; P=0.033).\n\n\n\nIn patients with AIS undergoing ET, tirofiban is not associated with higher sICH, it seems to lead to lower odds of deaths and better odds of long-term functional independence. Further investigations are needed to determine the efficacy of tirofiban in preventing early reocclusion, the underlying mechanisms, and its optimal treatment protocol.",
"affiliations": "From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.).;From the Department of Neurology (W.Z., R.C., S.S., C.W., L.W., J.D., H.S., Y.W.) and Department of Neurosurgery (C.L., J.C., H.Z., F.L., X.J.), Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA (D.L.); and Department of Neurology, Medical University of South Carolina, Charleston (W.F.). [email protected].",
"authors": "Zhao|Wenbo|W|;Che|Ruiwen|R|;Shang|Shuyi|S|;Wu|Chuanjie|C|;Li|Chuanhui|C|;Wu|Longfei|L|;Chen|Jian|J|;Duan|Jiangang|J|;Song|Haiqing|H|;Zhang|Hongqi|H|;Ling|Feng|F|;Wang|Yuping|Y|;Liebeskind|David|D|;Feng|Wuwei|W|;Ji|Xunming|X|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D014443:Tyrosine; D000077466:Tirofiban",
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.117.019193",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "48(12)",
"journal": "Stroke",
"keywords": "atherosclerosis; cerebral hemorrhage; platelet aggregation; thrombectomy; tirofiban",
"medline_ta": "Stroke",
"mesh_terms": "D000369:Aged, 80 and over; D002545:Brain Ischemia; D002543:Cerebral Hemorrhage; D003131:Combined Modality Therapy; D023381:Endpoint Determination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012008:Recurrence; D012042:Registries; D012307:Risk Factors; D020521:Stroke; D017131:Thrombectomy; D000077466:Tirofiban; D016896:Treatment Outcome; D014443:Tyrosine",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "3289-3294",
"pmc": null,
"pmid": "29127270",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Low-Dose Tirofiban Improves Functional Outcome in Acute Ischemic Stroke Patients Treated With Endovascular Thrombectomy.",
"title_normalized": "low dose tirofiban improves functional outcome in acute ischemic stroke patients treated with endovascular thrombectomy"
}
|
[
{
"companynumb": "CN-AGG-11-2017-1499",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TIROFIBAN HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "013",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "0.2 TO 0.25 MG AT A RATE OF 1 ML/MIN",
"drugenddate": null,
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{
"abstract": "OBJECTIVE\nPostpartum depression can have devastating consequences on the mother and child. Prompt treatment is challenging. Whereas electroconvulsive therapy (ECT) is considered to be an effective treatment modality in severe depression and brings about rapid clinical improvement, little is known about ECT during the postpartum period.\n\n\nMETHODS\nWe systematically reviewed the literature on the use of ECT during the postpartum period using PubMed, Institute for Scientific Information Web of Knowledge and PsycINFO databases until September 2014, using the search terms \"electroconvulsive therapy\" or \"ECT\" and \"postpartum\". Then, we described the successful treatment with ECT and the joint mother-baby hospitalization of a woman with severe depression.\n\n\nRESULTS\nEight case reports and 8 studies were identified. All of the studies reported that ECT is effective in the postpartum period. It is well tolerated, provides a fast response and allows for breastfeeding. In addition, our case report showed the benefits of the hospitalization of the mother-baby unit.\n\n\nCONCLUSIONS\nCombined ECT and joint mother-baby hospitalization could be a valuable treatment by targeting both the mother-infant relationship and the maternal depressive symptoms.",
"affiliations": "Inserm UMR 1178 Team \"Depression and Antidepressants\", Univ Paris Sud, Bicêtre University Hospital, Le Kremlin Bicêtre, France; Department of Psychiatry, Bicêtre University Hospital, Le Kremlin Bicêtre, France. Electronic address: [email protected].;Inserm UMR 1178 Team \"Depression and Antidepressants\", Univ Paris Sud, Bicêtre University Hospital, Le Kremlin Bicêtre, France; Department of Psychiatry, Bicêtre University Hospital, Le Kremlin Bicêtre, France.;Department of Psychiatry, Bicêtre University Hospital, Le Kremlin Bicêtre, France.;Inserm UMR 1178 Team \"Depression and Antidepressants\", Univ Paris Sud, Bicêtre University Hospital, Le Kremlin Bicêtre, France; Department of Psychiatry, Bicêtre University Hospital, Le Kremlin Bicêtre, France.",
"authors": "Gressier|Florence|F|;Rotenberg|Samuel|S|;Cazas|Odile|O|;Hardy|Patrick|P|",
"chemical_list": "D000928:Antidepressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "37(4)",
"journal": "General hospital psychiatry",
"keywords": "Electroconvulsive therapy; Mother–baby unit; Mother–infant relationship; Postpartum; Postpartum depression",
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D019052:Depression, Postpartum; D003865:Depressive Disorder, Major; D004565:Electroconvulsive Therapy; D005260:Female; D006760:Hospitalization; D006801:Humans; D007231:Infant, Newborn; D009034:Mother-Child Relations; D011247:Pregnancy; D012720:Severity of Illness Index",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "310-4",
"pmc": null,
"pmid": "25929986",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Postpartum electroconvulsive therapy: a systematic review and case report.",
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|
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"abstract": "The 42-year-old woman who had been taking 300 mg phenytoin and 2,000 mg levetiracetam daily took 28.6 g of phenytoin and was transferred to our critical care center. The blood phenytoin concentration was 67.9 μg/mL on admission and decreased to 53.4 μg/mL on hospital day 2. Tonic seizures occurred several times on hospital day 2; thus, we resumed levetiracetam via a nasogastric tube. Thereafter, no further seizures were observed. We thought the seizure to have been caused by temporary withdrawal of levetiracetam because it did not occur on the day when the blood phenytoin concentration peaked and stopped altogether after resumption of levetiracetam. We considered that to treat the convulsion attack resulting from an overdose of the other antiepileptic drug with a different action mechanism, it was necessary to promptly restart the administration of the antiepileptic drug, which the patient was usually administered.",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000927:Anticonvulsants; D004338:Drug Combinations; D062787:Drug Overdose; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D010672:Phenytoin; D012640:Seizures",
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"pages": "360-362",
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"pmid": "30461233",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute onset of a tonic seizure in a phenytoin-overdosed patient who had taken phenytoin and levetiracetam daily.",
"title_normalized": "acute onset of a tonic seizure in a phenytoin overdosed patient who had taken phenytoin and levetiracetam daily"
}
|
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{
"abstract": "A 61-year-old man was diagnosed with severe chest trauma after a car accident and had had difficulty in weaning from a ventilator because of flail chest and dilated cardiomyopathy. On the 17th day in the intensive care unit, he received i.v. acetazolamide to increase urine output. One hour after the injection, he suddenly developed severe hypoxia. Chest radiography revealed a butterfly shadow. He received other diuretics and a vasodilator, which seemed slowly to resolve the respiratory failure. Five days later, acetazolamide was again given and he experienced the same deterioration.\n\n\n\nWe concluded that the episodes were attributed to pulmonary edema provoked by acetazolamide.\n\n\n\nAcute non-cardiogenic pulmonary edema is an uncommon and lethal adverse effect of acetazolamide. Careful attention may be warranted when administering acetazolamide to critically ill patients.",
"affiliations": "Hyogo Prefectural Kakogawa Medical Center Kakogawa Hyogo Japan.;Hyogo Prefectural Kakogawa Medical Center Kakogawa Hyogo Japan.;Hyogo Prefectural Kakogawa Medical Center Kakogawa Hyogo Japan.;Hyogo Prefectural Kakogawa Medical Center Kakogawa Hyogo Japan.;Hyogo Prefectural Kakogawa Medical Center Kakogawa Hyogo Japan.",
"authors": "Ono|Yuichiro|Y|0000-0002-8844-7565;Morifusa|Makiko|M|;Ikeda|Satoru|S|;Kunishige|Chika|C|;Tohma|Yoshiki|Y|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1002/ams2.279",
"fulltext": "\n==== Front\nAcute Med SurgAcute Med Surg10.1002/(ISSN)2052-8817AMS2Acute Medicine & Surgery2052-8817John Wiley and Sons Inc. Hoboken 10.1002/ams2.279AMS2279Case ReportCase ReportsA case of non‐cardiogenic pulmonary edema provoked by intravenous acetazolamide Y. Ono et al.Ono Yuichiro http://orcid.org/[email protected] \n1\nMorifusa Makiko \n1\nIkeda Satoru \n1\nKunishige Chika \n1\nTohma Yoshiki \n1\n\n1 \nHyogo Prefectural Kakogawa Medical Center\nKakogawa\nHyogo\nJapan\n* Corresponding: Yuichiro Ono, MD, Hyogo Prefectural Kakogawa Medical Center, 203 Kan‐no, Kan‐no Cho, Kakogawa, Hyogo, 675‐8555, Japan. E‐mail: [email protected] 4 2017 7 2017 4 3 10.1002/ams2.2017.4.issue-3349 352 28 1 2017 12 3 2017 © 2017 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Case\nA 61‐year‐old man was diagnosed with severe chest trauma after a car accident and had had difficulty in weaning from a ventilator because of flail chest and dilated cardiomyopathy. On the 17th day in the intensive care unit, he received i.v. acetazolamide to increase urine output. One hour after the injection, he suddenly developed severe hypoxia. Chest radiography revealed a butterfly shadow. He received other diuretics and a vasodilator, which seemed slowly to resolve the respiratory failure. Five days later, acetazolamide was again given and he experienced the same deterioration.\n\nOutcome\nWe concluded that the episodes were attributed to pulmonary edema provoked by acetazolamide.\n\nConclusion\nAcute non‐cardiogenic pulmonary edema is an uncommon and lethal adverse effect of acetazolamide. Careful attention may be warranted when administering acetazolamide to critically ill patients.\n\nacetazolamideanaphylaxisdrug side‐effectspulmonary edemarespiratory insufficiency source-schema-version-number2.0component-idams2279cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:07.11.2017\nFunding Information\n\n\nNo funding information provided.\n==== Body\nBackground\nAcetazolamide is a carbonic anhydrase inhibitor (CAI) that is widely applied in various clinical settings. This drug inhibits the conversion of carbon dioxide and water into carbonic acid, and has been used to treat high intraocular pressure and high altitude disease, to increase urine volume, and correct metabolic alkalosis. Although CAIs are frequently used, acute non‐cardiogenic pulmonary edema has not been well‐recognized as one of its cryptogenic and fatal adverse effects. We report our experience with a patient who encountered two episodes of pulmonary edema after receiving acetazolamide.\n\nCase\nA 61‐year‐old man had been admitted to an intensive care unit due to severe blunt chest wall trauma from a motor vehicle accident. His injuries were right massive hemopneumothorax, a flail chest and intrahepatic hematoma. Two thoracic catheters were inserted into his right thorax, and computed tomography revealed active bleeding from three vessels, which was controlled by transcatheter arterial embolization. The patient had required prolonged ventilator support owing to his chest wall instability and idiopathic dilated cardiomyopathy with an ejection fraction of approximately 30%, which had been previously evaluated. We had trouble liberating him from a ventilator and carried out tracheostomy on the 10th day of hospitalization.\n\nOn the 17th day, the patient was still receiving ventilator support. Thus, in order to increase urine output and correct metabolic alkalosis, 500 mg acetazolamide was given i.v. One hour after the injection, he suddenly developed hypertension, tachycardia (Fig. 1), and hypoxemia (PaO2/FiO2 ratio was less than 100 mmHg). Wheezing sounds were heard on chest auscultation and much pinkish foamy secretion was suctioned through his tracheal tube. He showed choking‐like signs and his ventilator monitor showed an extremely high airway pressure and significantly decreased tidal volume, which limited its function, and he was transitioned to manual ventilation. Chest radiography (Fig. 2) revealed a bilateral butterfly shadow. We assumed that he developed acute pulmonary edema caused by acute exacerbation of congestive heart failure. Therefore, the respiratory failure was treated using diuretics, nitric acid, and an inhaled β2 stimulant to help relieve the airway pressure. As the event resolved after approximately 8 h, we did not advance a detailed evaluation.\n\nFigure 1 Five‐minute trends of heart rate and blood pressure in a 61‐year‐old man with severe chest trauma treated with i.v. acetazolamide. Approximately 1 h after acetazolamide infusion, both heart rate and blood pressure increased remarkably. The condition continued for approximately 8 h then gradually resolved. Cardiac indexes (bottom line) measured with a radial arterial catheter suggested the patient's hyperdynamic state.\n\nFigure 2 Chest X‐rays of a 61‐year‐old man with severe chest trauma treated with i.v. acetazolamide. A, Chest X‐ray routinely taken on the morning of the first event day. It shows pleural effusion, a vanishing tumor, multiple costal fractures, and subcutaneous emphysema on the right chest. B, Chest X‐ray taken during the attack. Additional findings, such as a bilateral butterfly shadow and air bronchograms, are present.\n\nHowever, 5 days following the previous episode, the same dose of acetazolamide was again given for the same purpose, and the patient experienced an abrupt episode of respiratory failure that was identical to the first. Over the period of the second episode, we managed to carry out additional evaluations, other than chest radiography. A ventilator recorded extremely poor lung compliance, which was less than 10 mL/cmH2O, and slightly increased airway resistance. These suggested the extremely high airway pressure was not derived from bronchospasm, but from pulmonary parenchymal edema. Moreover, echocardiography revealed a hypercontractile left ventricle compared to the usual state, although there were no signs or evidence of significant fluid overload. Only β‐blocker infusion was selected to suppress catecholamine surge‐like symptoms, such as hypertension and tachycardia, and the second episode spontaneously resolved as well.\n\nIn the two episodes, the symptoms were provoked just 1 h after the acetazolamide shot, but there were no apparent signs or evidence of anaphylaxis, such as bronchospasm, cutaneous and mucosal lesions, or shock. Although dilated cardiomyopathy might affect respiratory failure, the patient's left ventricular contraction observed by echocardiogram relatively improved during the episodes. In addition, the cardiac indexes measured by a radial arterial catheter, as described in Figure 1, suggested that the patient cardiac output had increased rather than decreased during the attack. Therefore, it was difficult to attribute the pathophysiology as purely cardiogenic. Finally, we concluded that the pulmonary edema was provoked by acetazolamide. We subsequently avoided the use of acetazolamide and the patient did not experience any further episodes of severe respiratory deterioration, which suggested that the episodes could be associated to the drug.\n\nDiscussion\nNon‐cardiogenic pulmonary edema triggered by a carbonic anhydrase inhibitor is a very rare adverse effect. There are few case reports regarding this topic;1, 2, 3, 4, 5 interestingly, all of them relate to the drug's ophthalmological purpose. Furthermore, no formal case reports have described this adverse effect in critically ill patients, despite its frequent appearance in intensive care units as well as Japan. However, clinical guidelines for the appropriate use of CAIs6 published in 2015 by four Japanese medical societies clearly warn the risk of respiratory failure and death in some cases. The guidelines briefly cover several critical cases that were identical to ours.\n\nAlthough the mechanism for this complication has been idiosyncratic and unexplained, some consideration is given. Acetazolamide is classified into a sulfonamide group for its structure. It has been known that the group, for example, hydrochlorothiazide and sulfamethoxazole, causes non‐cardiogenic pulmonary edema.7 Hence, the pathophysiology is thought to be associated with both sulfonamide cross‐sensitivity and its immunomediated mechanism,1, 3 which could increase the capillary endothelium permeability leading protein and fluid to enter the lung parenchyma and alveolar spaces.8 Bernal et al.9 found that one patient suffering from hydrochlorothiazide‐induced non‐cardiogenic pulmonary edema had decreased serum immunoglobulin G and suggested that drug‐induced immunoglobulin G deposition in lungs might play a role in the development of this reaction. Our patient might already be sensitized to other sulfonamides.\n\nThere are several possible explanations for the lack of clarity regarding the risk of respiratory failure among critically ill patients. First, this adverse effect is very rare, and many doctors may not consider the involvement of acetazolamide at the first episode. Although two case reports4, 5 have identified episodes of anaphylaxis and pulmonary edema, they did not present anaphylaxis‐specific symptoms like skin erythema. Moreover, Zimmermann et al.2 suggested that this mechanism was not connected to an allergic reaction, as they could not identify a specific antigen or allergic reaction to acetazolamide during the skin prick test. Second, pulmonary edema is fairly common in intensive care units, and it might be missed or attributed to another pathophysiology. For example, we considered that the first episode in our patient was a different problem because of the clinical course. In contrast, the reported cases have involved stable patients preparing for scheduled procedures. Thus, the emergence of pulmonary edema might be considered strange and worthy of investigation. Finally, although acetazolamide is frequently chosen as a respiratory stimulant and diuretic, We chose the drug twice before noticing the connection between acetazolamide treatment and respiratory deterioration.\n\nConclusion\nIn the present case, we encountered rare and potentially fatal episodes of pulmonary edema that was provoked by treatment with acetazolamide. Based on both our experience with this adverse event and the fatal outcomes in some reported cases, we believe that careful attention should be paid when treating critically ill patients with acetazolamide.\n\nConflict of interest\nNone declared.\n==== Refs\nReferences\n1 \n\nYilmaz \nSG \n, \nPalamar \nM \n, \nGurgun \nC \n. Acute pulmonary oedema due to single dose acetazolamide taken after cataract surgery . BMJ Case Rep. \n2016 ; doi:10.1136/bcr‐2016‐214829.\n2 \n\nZimmermann \nS \n, \nAchenbach \nS \n, \nWolf \nM \n, et al\nRecurrent shock and pulmonary edema due to acetazolamide medication after cataract surgery . Heart Lung \n2014 ; 43 : 124 –6 .24388201 \n3 \n\nVogiatzis \nI \n, \nKoulouris \nE \n, \nSidiropoulos \nA \n, et al\nAcute pulmonary edema after a single oral dose of acetazolamide . Hippokratia \n2013 ; 17 : 177 –9 .24376328 \n4 \n\nGallerani \nM \n, \nManzoli \nN \n, \nFellin \nR \n, et al\nAnaphylactic shock and acute pulmonary edema after a single oral dose of acetazolamide . Am. J. Emerg. Med. \n2002 ; 20 : 371 –2 .12098191 \n5 \n\nTzanakis \nN \n, \nMetzidaki \nG \n, \nThermos \nK \n, et al\nAnaphylactic shock after a single oral intake of acetazolamide . Br. J. Ophthalmol. \n1998 ; 82 : 588 .9713074 \n6 \nJapan Stroke Society \n, Japan Neurosurgery Society \n, Japanese Society of Neurology \n, and Japanese Society of Nuclear Medicine \n. Clinical guidelines for the appropriate use of carbonic anhydrase inhibitors (Japanese) . 2015 ; Available from www.jsts.gr.jp/img/acetazolamide.pdf [cited 05 Dec 2016].\n7 \n\nReed \nCR \n, \nGlauser \nFL \n. Drug‐induced noncardiogenic pulmonary edema . Chest \n1991 ; 100 : 1120 –4 .1914570 \n8 \n\nPrasad \nR \n, \nGupta \nP \n, \nSingh \nA \n, et al\nDrug induced pulmonary parenchymal disease . Drug Discov. Ther. \n2014 ; 8 : 232 –7 .25639301 \n9 \n\nBernal \nC \n, \nPatarca \nR \n. Hydrochlorothiazide‐induced pulmonary edema and associated immunologic changes . Ann. Pharmacother. \n1999 ; 33 : 172 –4 .10084412\n\n",
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"title": "A case of non-cardiogenic pulmonary edema provoked by intravenous acetazolamide.",
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{
"abstract": "OBJECTIVE\nTo report a case of Urrets-Zavalia syndrome (UZS) after Descemet membrane endothelial keratoplasty (DMEK).\n\n\nMETHODS\nA 74-year-old woman with Fuchs endothelial dystrophy and inconspicuous ocular history developed UZS after DMEK surgery. The intraoperative and postoperative course is presented.\n\n\nRESULTS\nAfter uneventful DMEK surgery, intraocular pressure was elevated up to 40 mm Hg on the first postoperative day. A small bleed from the peripheral wide-open iridectomy in the 12 o'clock position in the otherwise deep anterior chamber was observed. On the sixth postoperative day, a 4-mm-wide pupil, nonreactive to light, was noted. One year after surgery, the fixed medium mydriasis (4 mm) persisted and best-corrected vision was 0.1 logMAR. No pupillary reaction was noted after application of 0.2% or 2% pilocarpine.\n\n\nCONCLUSIONS\nFilling the anterior chamber with air to secure fixation of a grafted Descemet membrane carries the risk of early acute postoperative ocular hypertension. This can lead to iris sphincter defects resulting in a fixed dilated pupil after DMEK surgery. Large patent iridectomy in the 12 o'clock position is insufficient to prevent this. Patients undergoing DMEK surgery should be informed about this potential complication.",
"affiliations": "University Eye Hospital Düsseldorf, Düsseldorf NRW - Germany.",
"authors": "Holtmann|Christoph|C|;Spaniol|Kristina|K|;Geerling|Gerd|G|",
"chemical_list": "D005938:Glucocorticoids; D000086:Acetazolamide",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1120-6721",
"issue": "25(5)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000086:Acetazolamide; D000368:Aged; D002387:Cataract Extraction; D003131:Combined Modality Therapy; D057111:Descemet Stripping Endothelial Keratoplasty; D004359:Drug Therapy, Combination; D005260:Female; D005642:Fuchs' Endothelial Dystrophy; D005938:Glucocorticoids; D006801:Humans; D007429:Intraocular Pressure; D032801:Iridectomy; D007498:Iris; D015878:Mydriasis; D009798:Ocular Hypertension; D064727:Posterior Capsulotomy; D011184:Postoperative Period; D014792:Visual Acuity",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "e75-7",
"pmc": null,
"pmid": "25768696",
"pubdate": "2015-07-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Urrets-Zavalia syndrome after Descemet membrane endothelial keratoplasty.",
"title_normalized": "urrets zavalia syndrome after descemet membrane endothelial keratoplasty"
}
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{
"abstract": "Herein, we report on a patient with known Lynch syndrome and periampullary adenocarcinoma that exhibited a pathological complete response to neoadjuvant nivolumab plus ipilimumab. Two MSH2 mutations, high microsatellite instability, high tumor mutational burden, and elevated PD-L1 expression were identified by next-generation sequencing and immunohistochemistry. Following FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) administration and disease progression, nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for four total cycles. The patient responded well with minimal adverse effects and significant improvement in epigastric pain, appetite, and body weight. She then underwent resection consisting of pancreaticoduodenectomy, which demonstrated pathological complete response. Complete genomic profiling of periampullary carcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles. This case provides an example of a patient who may have further benefited from first-line nivolumab plus ipilimumab to avoid the reduced efficacy and significant side effects associated with chemotherapy. KEY POINTS: A patient with known Lynch syndrome and ampullary adenocarcinoma harboring two MSH2 mutations, high microsatellite instability (MSI-high), high tumor mutational burden (TMB), and elevated PD-L1 expression achieved pathological complete response with neoadjuvant nivolumab plus ipilimumab. The combination of nivolumab plus ipilimumab may be a better first-line option for patients with ampullary adenocarcinomas harboring deficient mismatch repair, MSI-high, and high TMB. Complete genomic profiling of periampullary adenocarcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have different genetic profiles. The presence of either MSI-high or high TMB could be an appropriate predictive biomarker for response to nivolumab plus ipilimumab in the context of Lynch syndrome.",
"affiliations": "Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri, USA.;Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri, USA.;Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri, USA.;Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri, USA.;Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri, USA.",
"authors": "Pothuri|Vikram|V|0000-0003-4725-8706;Herndon|John|J|;Ballentine|Samuel J|SJ|;Lim|Kian-Huat|KH|;Fields|Ryan C|RC|",
"chemical_list": "D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1002/onco.13821",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "26(9)",
"journal": "The oncologist",
"keywords": "Adenocarcinoma; Genomics; Ipilimumab; Microsatellite instability; Mismatch repair; Nivolumab",
"medline_ta": "Oncologist",
"mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D020360:Neoadjuvant Therapy; D000077594:Nivolumab; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "722-726",
"pmc": null,
"pmid": "33982365",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30258276;24142049;24857067;30487949;19861671;29355075;19440799;26001389;30294272;24146684;30755690;31256008;32350089;26804919;32185710;23439753;11266517;26047524;28636851;20395525;33172722;29165669",
"title": "A Case of a Pathological Complete Response to Neoadjuvant Nivolumab plus Ipilimumab in Periampullary Adenocarcinoma.",
"title_normalized": "a case of a pathological complete response to neoadjuvant nivolumab plus ipilimumab in periampullary adenocarcinoma"
}
|
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"drugdosageform": null,
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "SMALL INTESTINE CARCINOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"drugrecurrence": null,
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"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "NIVOLUMAB"
}
],
"patientagegroup": "5",
"patientonsetage": "59",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": "69.6",
"reaction": [
{
"reactionmeddrapt": "Uveitis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "POTHURI V, HERNDON J, BALLENTINE SJ, LIM K?H, FIELDS RC. A CASE OF A PATHOLOGICAL COMPLETE RESPONSE TO NEOADJUVANT NIVOLUMAB PLUS IPILIMUMAB IN PERIAMPULLARY ADENOCARCINOMA. ONCOLOGIST 2021?:NO PAGINATION.",
"literaturereference_normalized": "a case of a pathological complete response to neoadjuvant nivolumab plus ipilimumab in periampullary adenocarcinoma",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210916",
"receivedate": "20210624",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19459722,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
},
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-050993",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "125554",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "1 MILLIGRAM/KILOGRAM, Q3WK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Small intestine carcinoma",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"medicinalproduct": "NIVOLUMAB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "3 MILLIGRAM/KILOGRAM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Small intestine carcinoma",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "3",
"drugstructuredosageunit": "007",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "IPILIMUMAB"
}
],
"patientagegroup": null,
"patientonsetage": "59",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Uveitis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional product use issue",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Pothuri V, Herndon J, Ballentine SJ, Lim K-H, Fields RC. A case of a pathological complete response to neoadjuvant nivolumab plus ipilimumab in periampullary adenocarcinoma. The Oncologist. 2021;1-6",
"literaturereference_normalized": "a case of a pathological complete response to neoadjuvant nivolumab plus ipilimumab in periampullary adenocarcinoma",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211012",
"receivedate": "20210602",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19367071,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "BACKGROUND\nOccasional complete responses have been reported in patients with squamous-cell carcinoma of the esophagus treated with carboplatin, and the inferior outcomes seen in early studies might have been the result of underdosing using BSA calculations. Docetaxel was reported to have single-agent activity in squamous-cell carcinoma of the esophagus, with a 50% response rate in a pilot study performed in South Africa. Thus, ECOG investigated the potential role of combination carboplatin using AUC-based dosing and docetaxel in patients with squamous-cell carcinoma of the esophagus.\n\n\nMETHODS\nECOG 2298 was a multicenter, international, phase II clinical study of docetaxel and carboplatin in patients with histologically confirmed, measurable squamous-cell carcinoma of the esophagus. Docetaxel 75 mg/m(2) was infused over 1 hour on day 1 of each cycle. The carboplatin dose was calculated to an AUC of 6 and infused over 15-30 minutes immediately after the docetaxel. The regimen was repeated every 3 weeks for a total of 6 cycles or until disease progression occurred or unacceptable toxicity developed.\n\n\nRESULTS\nA total of 32 patients were accrued, mostly men (78%) with a median age of 64 (range, 41-86). Half the patients were black and half were white. Five patients were not evaluable due to protocol violations. Of the remaining 27 patients, one (3%) achieved a complete clinical response. Four others (13%) achieved partial responses. Thirteen (41%) had stable disease and 9 (28%) had progression of disease. Overall objective response rate was 15.6% (95% CI 5.9% to 36%). The most common grade 3 and 4 toxicities were leukopenia (25/32=78%) and neutropenia (27/32=84%). Most nonhematologic toxicities were infrequent and ≤ grade 3; however, two patients experienced grade 5 toxicities; one died of bowel obstruction and another died of infection with grade 4 neutropenia.\n\n\nCONCLUSIONS\nThe high toxicity and poor efficacy shown in this study suggest that the combination of carboplatin and docetaxel in squamous-cell carcinoma of the esophagus should not be investigated further. Newer agents need to be investigated in this malignancy.",
"affiliations": null,
"authors": "Rossman|Joanne F|JF|;Falkson|Carla I|CI|;Xu|Ronghui|R|;Slabber|Coenraad F|CF|;Mason|Bernard A|BA|;Mulcahy|Mary F|MF|;Benson|Al B|AB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1934-7820",
"issue": "4(1)",
"journal": "Gastrointestinal cancer research : GCR",
"keywords": null,
"medline_ta": "Gastrointest Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "101300691",
"other_id": null,
"pages": "9-14",
"pmc": null,
"pmid": "21464865",
"pubdate": "2011-01",
"publication_types": "D016428:Journal Article",
"references": "15151955;8042045;4075322;1518165;3912041;10506629;7083245;18287387;9586897;5118689;18376224;6683591;8483558;7191780;8548526;11459997;6540144;4040800;7912736;2672377",
"title": "Phase II Trial of Docetaxel and Carboplatin in Patients With Advanced Squamous Carcinoma of the Esophagus (E2298): A Trial of the Eastern Cooperative Oncology Group.",
"title_normalized": "phase ii trial of docetaxel and carboplatin in patients with advanced squamous carcinoma of the esophagus e2298 a trial of the eastern cooperative oncology group"
}
|
[
{
"companynumb": "US-PFIZER INC-2016500875",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "076517",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "AUC6, INFUSED OVER 15-30 MIN AFTER DOCETAXEL EVERY 3 WEEKS FOR A TOTAL OF 6 CYCLES",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugstartdate": null,
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"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CARBOPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "202356",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "75 MG/M2, OVER 1 HOUR ON DAY 1 OF EACH CYCLE, EVERY 3 WEEKS FOR A TOTAL OF 6 CYCLES",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"drugrecurrence": null,
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"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "75",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOCETAXEL."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "8 MG EVERY 12 HOURS FOR 5 DOSES STARTING 24 HOURS PRIOR TO DOCETAXEL",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PREMEDICATION",
"drugintervaldosagedefinition": "804",
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"drugrecurrence": null,
"drugseparatedosagenumb": "2",
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"drugstartdateformat": null,
"drugstructuredosagenumb": "8",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DEXAMETHASONE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Intestinal obstruction",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ROSSMAN, J.. PHASE II TRIAL OF DOCETAXEL AND CARBOPLATIN IN PATIENTS WITH ADVANCED SQUAMOUS CARCINOMA OF THE ESOPHAGUS (E2298): A TRIAL OF THE EASTERN COOPERATIVE ONCOLOGY GROUP.. GASTROINTESTINAL CANCER RESEARCH.. 2011;4 (1):9-14",
"literaturereference_normalized": "phase ii trial of docetaxel and carboplatin in patients with advanced squamous carcinoma of the esophagus e2298 a trial of the eastern cooperative oncology group",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20161028",
"receivedate": "20161028",
"receiver": {
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"receivertype": "6"
},
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"safetyreportid": 12893237,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170207"
},
{
"companynumb": "US-PFIZER INC-2016500911",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
"drugadministrationroute": "042",
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"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "75 MG/M2, OVER 1 HOUR ON DAY 1 OF EACH CYCLE, EVERY 3 WEEKS FOR A TOTAL OF 6 CYCLES",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DOCETAXEL."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
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"drugcharacterization": "2",
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"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "8 MG EVERY 12 HOURS FOR 5 DOSES STARTING 24 HOURS PRIOR TO DOCETAXEL",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PREMEDICATION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
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"drugseparatedosagenumb": "2",
"drugstartdate": null,
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"drugstructuredosagenumb": "8",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DEXAMETHASONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "076517",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "AUC6, INFUSED OVER 15-30 MIN AFTER DOCETAXEL EVERY 3 WEEKS FOR A TOTAL OF 6 CYCLES",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CARBOPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Neutropenic infection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ROSSMAN, J.. PHASE II TRIAL OF DOCETAXEL AND CARBOPLATIN IN PATIENTS WITH ADVANCED SQUAMOUS CARCINOMA OF THE ESOPHAGUS (E2298): A TRIAL OF THE EASTERN COOPERATIVE ONCOLOGY GROUP.. GASTROINTESTINAL CANCER RESEARCH.. 2011;4 (1):9-14",
"literaturereference_normalized": "phase ii trial of docetaxel and carboplatin in patients with advanced squamous carcinoma of the esophagus e2298 a trial of the eastern cooperative oncology group",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20161028",
"receivedate": "20161028",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 12893713,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170207"
}
] |
{
"abstract": "Central serous chorioretinopathy (CSCR) is of unknown etiology and is the most common cause of retinopathy after age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion. Vision loss results from fluid leakage and serous detachment in the macula. Five percent of patients develop chronic CSCR. It is predominantly found in middle-aged men (age-adjusted rates per 100,000: 9.9 for men and 1.7 for women) and is usually unilateral and reversible. Three-quarters of CSCR patients resolve within 3 months but 45% have recurrences, usually with only minor visual acuity changes. Risk factors include type A personality, emotional stress, elevated catecholamines, hypertension, pregnancy, organ transplantation, increased levels of endogenous cortisol, psychopharmacologic medication, use of phosphodiesterase 5 inhibitors, obstructive sleep apnea, Helicobacter pylori infection, or treatment with corticosteroids. Five percent of patients develop chronic disease as a result of subretinal fibrin formation within the blister. CSCR is often bilateral, multifocal, and recurrent, and may be associated with subretinal fibrin formation within the blister. Permanent loss of vision may result from subretinal fibrin-fibrosis with scarring of the macula. Corticosteroid-associated CSCR occurs bilaterally in 20% of patients. Steroid-associated therapy may begin days to years after therapy with any form of drug delivery. We present three atopic patients who presented at various times after oral, inhaled, intranasal, and topical corticosteroid therapy. One patient developed CSCR after three separate types of administration of corticosteroids, which, to our knowledge, has not been observed in the literature.",
"affiliations": "Department of Internal Medicine, Rutgers University, New Jersey Medical School, Newark, New Jersey, USA.",
"authors": "Ricketti|Peter A|PA|;Unkle|David W|DW|;Cleri|Dennis J|DJ|;Prenner|Jonathan L|JL|;Coluccielo|Michael|M|;Ricketti|Anthony J|AJ|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.2500/aap.2015.36.3827",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1088-5412",
"issue": "36(2)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D001249:Asthma; D056833:Central Serous Chorioretinopathy; D003888:Desensitization, Immunologic; D018572:Disease-Free Survival; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011247:Pregnancy; D012008:Recurrence; D006255:Rhinitis, Allergic, Seasonal; D012307:Risk Factors; D013315:Stress, Psychological; D014434:Type A Personality; D028761:Withholding Treatment",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "123-9",
"pmc": null,
"pmid": "25715240",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Central serous chorioretinopathy secondary to corticosteroids in patients with atopic disease.",
"title_normalized": "central serous chorioretinopathy secondary to corticosteroids in patients with atopic disease"
}
|
[
{
"companynumb": "US-GLAXOSMITHKLINE-US2015GSK125636",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BECLOMETHASONE DIPROPIONATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "019389",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "80 UG, BID (2 PUFFS)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SEASONAL ALLERGY",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "1",
"drugrecurrence": [
{
"drugrecuraction": "Chorioretinopathy"
}
],
"drugseparatedosagenumb": "2",
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"drugstartdateformat": null,
"drugstructuredosagenumb": "80",
"drugstructuredosageunit": "004",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "BECLOMETASONE DIPROPIONATE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BECLOMETHASONE DIPROPIONATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "40 UG, BID",
"drugenddate": null,
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"drugindication": "SINUSITIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "1",
"drugrecurrence": [
{
"drugrecuraction": "Chorioretinopathy"
}
],
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"drugstructuredosagenumb": "40",
"drugstructuredosageunit": "004",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "BECLOMETASONE DIPROPIONATE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
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"abstract": "OBJECTIVE: To report a fatal outcome from pulmonary hemosiderosis in an infant with scimitar syndrome after prolonged pulmonary vasodilator therapy. DESIGN: Case report. SETTING: A tertiary care pediatric intensive care unit. SUBJECT: An infant with scimitar syndrome. INTERVENTIONS: Treatment included redirection of anomalous right pulmonary venous drainage and closure of atrial septal defect, assisted ventilation via tracheostomy, and protracted nitric oxide and prostacyclin therapy until his death at 1 yr of age. RESULTS: Inhaled nitric oxide (iNO) and/or prostacyclin (PGI(2)) were administered for 6.5 months. Numerous echocardiograms demonstrated good control of pulmonary pressures and no evidence of pulmonary venous obstruction. Repeated attempts to slowly wean from the pulmonary vasodilators resulted in return of pulmonary pressures to systemic levels. Although there was no clinically apparent hemoptysis, pulmonary infiltrates worsened, prompting an open-lung biopsy that revealed pulmonary hemosiderosis. During the last 4 days of the patient's life, the pulmonary hypertensive crises with suprasystemic pressures and pulmonary infiltrates worsened regardless of aggressive vasodilator therapy with iNO, PGI(2), alkalinization, and isoproterenol. Vasodilator therapy was withdrawn and the patient rapidly died. CONCLUSION: We achieved long-term control of pulmonary hypertension with iNO and/or PGI(2) without apparent tachyphylaxis or other major reported side effects. Although pulmonary hypertension was successfully controlled with prolonged iNO and intravenous PGI(2) administration in this patient with scimitar syndrome, the patient died of hypoxemic respiratory failure from pulmonary hemosiderosis. Early evaluation of roentgenographic infiltrates for hemosiderosis and potential lung transplantation in similar patients may be warranted.",
"affiliations": "Department of Anesthesiology, Section on Pediatric Anesthesiology and Critical Care, Wake Forest University School of Medicine, Winston-Salem, NC.",
"authors": "Cannon|M L|ML|;Bauman|L A|LA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/00130478-200107000-00016",
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"issn_linking": "1529-7535",
"issue": "2(3)",
"journal": "Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies",
"keywords": null,
"medline_ta": "Pediatr Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "100954653",
"other_id": null,
"pages": "274-9",
"pmc": null,
"pmid": "12793955",
"pubdate": "2001-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pulmonary hemosiderosis in scimitar syndrome after prolonged management of pulmonary hypertension.",
"title_normalized": "pulmonary hemosiderosis in scimitar syndrome after prolonged management of pulmonary hypertension"
}
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{
"abstract": "To assess and compare the prevalence of persistent hepatic abnormalities, including nonalcoholic fatty liver disease (NAFLD) and/or hepatic fibrosis, among perinatally HIV-monoinfected Asian adolescents with history of abnormal hepatic enzymes to those without, using noninvasive diagnostic tools. A multicenter cohort study was conducted in Thailand and Indonesia. Adolescents aged 10-25 years who were on antiretroviral treatment (ART), had virologic suppression (HIV RNA<400 copies/mL within the past 6 months), and had no history of chronic hepatitis B/C infection were enrolled. Participants were pre-classified into 2 subgroups (1:1 ratio) as participants with history of elevated versus normal aminotransferase enzymes. NAFLD was defined as hepatic steatosis (any severity) evaluated by liver ultrasonography. Significant hepatic fibrosis was defined as liver stiffness ≥7.4 kPa evaluated by transient elastography. Participants who met the criteria for protocol-defined NAFLD and/or hepatic fibrosis were re-assessed to evaluate disease progression (persistent versus transient hepatic abnormalities) at one year later. Of 120 participants, 62 (51.7%) were male, 7 (5.8%) had central obesity, and 19 (15.8%) had insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] >3.16). At enrollment, the median age and duration of ART (IQR) were 17.0 (14.6-19.2) years and 10.5 (7.1-12.0) years, respectively. Persistent hepatic abnormalities were identified in 5/60 participants listed in the group having history of elevated aminotransferases, corresponding to the prevalence of 8.3% (95% CI: 2.8-18.4%), whereas none (0/60) were among the group having history of normal hepatic enzymes. All 5 participants had persistent aminotransferase elevation (≥2 episodes within the past 12 months). Baseline alanine aminotransferase (ALT) >30 U/L (adjusted odds ratio [aOR]: 29.1; 95% CI: 1.7-511.8), and HOMA-IR >3.16 (aOR: 17.9; 95% CI: 1.1-289.7) were independently associated with persistent hepatic abnormalities. Among perinatally HIV-monoinfected Asian adolescents with history of elevated aminotransferase enzymes, persistent hepatic abnormalities are not uncommon. Screening for liver complications by noninvasive diagnostic tools might be considered in at risk individuals, including those with persistent ALT elevation and insulin resistance.",
"affiliations": "Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.;HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.;Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.;Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;Department of Child Health, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia.;HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.;Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.;Department of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.",
"authors": "Sudjaritruk|Tavitiya|T|0000-0002-3686-4623;Bunupuradah|Torsak|T|;Aurpibul|Linda|L|0000-0003-0246-8187;Kosalaraksa|Pope|P|;Kurniati|Nia|N|;Sophonphan|Jiratchaya|J|;Trinavarat|Panruethai|P|;Visrutaratna|Pannee|P|;Srinakarin|Jiraporn|J|;Chaijitraruch|Nataruks|N|;Puthanakit|Thanyawee|T|;|||",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0226375",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0226375PONE-D-19-13123Research ArticleBiology and Life SciencesDevelopmental BiologyFibrosisMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesFatty LiverBiology and Life SciencesBiochemistryEnzymologyEnzymesTransferasesAminotransferasesBiology and Life SciencesBiochemistryProteinsEnzymesTransferasesAminotransferasesMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesLiver FibrosisMedicine and Health SciencesPathology and Laboratory MedicineAnatomical PathologyCytopathologySteatosisMedicine and Health SciencesEndocrinologyEndocrine PhysiologyInsulin ResistanceBiology and Life SciencesPhysiologyEndocrine PhysiologyInsulin ResistanceMedicine and Health SciencesPhysiologyEndocrine PhysiologyInsulin ResistanceMedicine and Health SciencesDiagnostic MedicineDiagnostic RadiologyUltrasound ImagingResearch and Analysis MethodsImaging TechniquesDiagnostic RadiologyUltrasound ImagingMedicine and Health SciencesRadiology and ImagingDiagnostic RadiologyUltrasound ImagingBiology and Life SciencesPhysiologyPhysiological ParametersBody WeightObesityMedicine and Health SciencesPhysiologyPhysiological ParametersBody WeightObesityNonalcoholic fatty liver disease and hepatic fibrosis among perinatally HIV-monoinfected Asian adolescents receiving antiretroviral therapy NAFLD and hepatic fibrosis in perinatally HIV-monoinfected Asian adolescentshttp://orcid.org/0000-0002-3686-4623Sudjaritruk Tavitiya ConceptualizationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationSupervisionValidationWriting – original draftWriting – review & editing12*Bunupuradah Torsak InvestigationWriting – review & editing3http://orcid.org/0000-0003-0246-8187Aurpibul Linda InvestigationWriting – review & editing2Kosalaraksa Pope InvestigationProject administrationWriting – review & editing4Kurniati Nia InvestigationProject administrationWriting – review & editing5Sophonphan Jiratchaya Formal analysisWriting – review & editing3Trinavarat Panruethai InvestigationWriting – review & editing6Visrutaratna Pannee InvestigationWriting – review & editing7Srinakarin Jiraporn InvestigationWriting – review & editing8Chaijitraruch Nataruks ResourcesWriting – review & editing9Puthanakit Thanyawee InvestigationMethodologyProject administrationValidationWriting – review & editing3910on behalf of the NAFLD Study Group ¶1 \nDepartment of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand2 \nResearch Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand3 \nHIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand4 \nDepartment of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand5 \nDepartment of Child Health, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia6 \nDepartment of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand7 \nDepartment of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand8 \nDepartment of Radiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand9 \nDepartment of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand10 \nCenter of Excellence in Pediatric Infectious Diseases and Vaccine, Chulalongkorn University, Bangkok, ThailandSyn Wing-Kin EditorInstitute of Hepatology, Foundation for Liver Research, UNITED KINGDOMCompeting Interests: The authors have declared that no competing interests exist.\n\n¶ Membership of the NAFLD Study Group is provided in the Acknowledgments.\n\n* E-mail: [email protected] 12 2019 2019 14 12 e02263759 5 2019 25 11 2019 © 2019 Sudjaritruk et al2019Sudjaritruk 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.To assess and compare the prevalence of persistent hepatic abnormalities, including nonalcoholic fatty liver disease (NAFLD) and/or hepatic fibrosis, among perinatally HIV-monoinfected Asian adolescents with history of abnormal hepatic enzymes to those without, using noninvasive diagnostic tools. A multicenter cohort study was conducted in Thailand and Indonesia. Adolescents aged 10–25 years who were on antiretroviral treatment (ART), had virologic suppression (HIV RNA<400 copies/mL within the past 6 months), and had no history of chronic hepatitis B/C infection were enrolled. Participants were pre-classified into 2 subgroups (1:1 ratio) as participants with history of elevated versus normal aminotransferase enzymes. NAFLD was defined as hepatic steatosis (any severity) evaluated by liver ultrasonography. Significant hepatic fibrosis was defined as liver stiffness ≥7.4 kPa evaluated by transient elastography. Participants who met the criteria for protocol-defined NAFLD and/or hepatic fibrosis were re-assessed to evaluate disease progression (persistent versus transient hepatic abnormalities) at one year later. Of 120 participants, 62 (51.7%) were male, 7 (5.8%) had central obesity, and 19 (15.8%) had insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] >3.16). At enrollment, the median age and duration of ART (IQR) were 17.0 (14.6–19.2) years and 10.5 (7.1–12.0) years, respectively. Persistent hepatic abnormalities were identified in 5/60 participants listed in the group having history of elevated aminotransferases, corresponding to the prevalence of 8.3% (95% CI: 2.8–18.4%), whereas none (0/60) were among the group having history of normal hepatic enzymes. All 5 participants had persistent aminotransferase elevation (≥2 episodes within the past 12 months). Baseline alanine aminotransferase (ALT) >30 U/L (adjusted odds ratio [aOR]: 29.1; 95% CI: 1.7–511.8), and HOMA-IR >3.16 (aOR: 17.9; 95% CI: 1.1–289.7) were independently associated with persistent hepatic abnormalities. Among perinatally HIV-monoinfected Asian adolescents with history of elevated aminotransferase enzymes, persistent hepatic abnormalities are not uncommon. Screening for liver complications by noninvasive diagnostic tools might be considered in at risk individuals, including those with persistent ALT elevation and insulin resistance.\n\nThe Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) grant from the International AIDS Society, supported by ViiV Healthcarehttp://orcid.org/0000-0002-3686-4623Sudjaritruk Tavitiya This study was funded in full by the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) grant from the International AIDS Society, supported by ViiV Healthcare. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the International AIDS Society or ViiV Healthcare. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nIn the combination of antiretroviral therapy (cART) era, mortality associated with HIV and opportunistic infections have dramatically declined, leading to the significantly improved survival for HIV-infected children and adults [1,2]. However, long-term, non-AIDS-related complications have become increasingly recognized in these survivors. Liver disease has emerged as one of the leading causes of death among HIV-infected persons [2]. The increased burden of liver-related mortality, in both adults and children living with HIV, has drawn a great deal of clinical attention.\n\nOver the last decade, the number of obese adolescents has risen substantially. In 2016, the prevalence of obesity among general adolescents was approximately 6% worldwide, and 2% in Southeast Asia [3]. As a consequence, nonalcoholic fatty liver disease (NAFLD), an important complication of obesity, has been increasingly recognized in this population with a prevalence of 11–17% [4]. NAFLD is a clinical-pathological syndrome characterized by the presence of excessive fat in hepatocytes in individuals without significant alcohol consumption [5]. NAFLD has been identified in 31–65% of HIV-monoinfected adults, and was independently associated with male sex, obesity, dyslipidemia, insulin resistance, and elevated serum alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio [6–9]. Hepatic fibrosis is a consequence of NAFLD which may progress to cirrhosis and eventually hepatocellular carcinoma (HCC) [10]. This condition has been found in 15–42% of HIV-monoinfected individuals, and was linked to diabetes, and increased ALT and gamma-glutamyl transferase (GGT) [8,11]. However, the impact of antiretroviral agents, particularly nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) on NAFLD [6–8] and hepatic fibrosis [8,11] among HIV-monoinfected adults are still controversial.\n\nThe gold standard for diagnosis of NAFLD and hepatic fibrosis is liver biopsy [5]. However, the invasiveness, potential risks, and impracticality of this procedure have prompted the exploration of alternative noninvasive diagnostic approaches, including radiological techniques (e.g., liver ultrasonography, controlled attenuation parameter [CAP], transient elastography [TE], computerized tomography [CT], magnetic resonance imaging [MRI], magnetic resonance elastography [MRE]), and liver biomarkers (e.g., cytokeratin-18 fragments [CK-18], AST-to-platelet ratio index [APRI], fibrosis-4 [FIB-4]) to evaluate hepatic steatosis, fibrosis, and cirrhosis [12–16]. Liver ultrasonography is a commonly used tool for NAFLD assessment because of its wide availability and absence of radiation exposure, but it is not good at detecting hepatic fibrosis. CAP is another measurement for NAFLD which is able to quantify the degree of steatosis and is operator-independent. In a previous study, CAP greater than or equal 249 dB/m demonstrated a good diagnostic accuracy for hepatic steatosis detection in children and adolescents with a sensitivity of 72%, a specificity of 98–100%, and an area under the receiver operating characteristic (AUROC) curve of 0.84 [17]. CT is seldom used for evaluating NAFLD, particularly in children, because of high radiation exposure. TE is a useful technique for detecting hepatic fibrosis since it demonstrates a good correlation with liver histology and liver biomarkers. In a recent meta-analysis, TE showed a highly accurate diagnostic performance for the diagnosis of significant hepatic fibrosis in children and adolescents with a sensitivity, a specificity, and an AUROC curve of 95%, 90%, and 0.96, respectively [18]. MRI/MRE is an advanced technique for the assessment of NAFLD and hepatic fibrosis with the greatest accuracy, but is not widely used because of its high cost [19]. CK-18 is a liver biomarker which is used to distinguish nonalcoholic steatohepatitis (NASH) from hepatic steatosis. A previous study demonstrated that an AUROC curve of CK-18 M30 for predicting NASH was 0.85–0.93 in children and adolescents [20,21]. These noninvasive measurements have been extensively investigated in HIV-infected adults [6–8,11,22,23], with limited studies in HIV-infected youth [24].\n\nElevation of aminotransferase enzymes are commonly observed in HIV-infected populations receiving cART, even in the absence of viral hepatitis coinfection [25,26]. Nevertheless, the association of aminotransferase elevation and significant liver diseases has not been well documented. Previous studies found that HIV-monoinfected adults with raised aminotransferase levels had a high prevalence of NASH (26–53%) and hepatic fibrosis (63%) [9,27], but there are still lack of data among adolescents.\n\nThe quiescent evolution of NAFLD and hepatic fibrosis towards irreversible harmful outcomes, specifically cirrhosis and end-stage liver diseases, highlights the importance of these complications in the management of people living with HIV infection and lifelong treatment. Since hepatic enzymes are inexpensive, widely available, and easily accessible biomarkers which might reflect underlying hepatic comorbidities, this study aimed to assess and compare the prevalence of persistent hepatic abnormalities, including NAFLD and/or hepatic fibrosis, among perinatally HIV-monoinfected adolescents with history of abnormal hepatic enzymes to those without, using noninvasive diagnostic tools.\n\nMethods and measurements\nStudy design and participants\nWe conducted a multicenter cohort study in four clinical research sites: three in Thailand and one in Indonesia. Perinatally HIV-infected adolescents aged 10–25 years who were on ART, had a documentation of virologic suppression (HIV RNA <400 copies/mL within the past 6 months), and had no documented history of chronic hepatitis B or C infection were enrolled. Since we aimed to compare the prevalence of persistent hepatic abnormalities among adolescents who had abnormal hepatic enzymes to those without, eligible participants were pre-classified into 2 subgroups (ratio of 1:1), according to their past results of serum hepatic transaminases as Subgroup 1: participants with history of elevated aminotransferase levels if they had AST >50 U/L and/or ALT >30 U/L at least once within the past 12 months; and Subgroup 2: participants with history of normal aminotransferase levels. Briefly, we consecutively identified participants with history of elevated aminotransferases at each site. Then, participants with history of normal aminotransferase levels who had similar age (+/- 12 months) and sex across all sites were selected. The exclusion criteria were self-report significant alcohol consumption (>21 or >14 drinks on an average per week over a 2-year period prior to enrollment for male and female, respectively), a history of autoimmune hepatitis or inherited liver disease, or receiving any drug or chemical agent demonstrating liver injury. The study was approved by the local Institutional Review Boards at all participating sites, including the Research Ethics Committee, Faculty of Medicine, Chiang Mai University (Approval number: 097/2014), the Human Experimentation Committee, Research Institute for Health Sciences, Chiang Mai University (Approval number: 7/2014), the Institutional Review Board, Faculty of Medicine, Chulalongkorn Univeristy (Approval number: 118/2014), the Khon Kaen University Ethics Committee for Human Research (Approval number: HE571099), and the Health Research Ethics Committee, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital (Approval number: 369/H2.F1/ETIK/2014). All participants and their caregivers provided written informed consent and assent, as appropriate, prior to study enrollment.\n\nClinical assessments and data collection\nDemographic and HIV-related characteristics were abstracted from medical records. Anthropometric assessments, including weight, height and waist circumference (WC), and complete physical examination were performed at study entry. For participants aged <15 years, WC was converted into age- and sex-standardized z-score, using Thai normative reference [28]. Central obesity was defined as WC z-score >2, or WC ≥90 and ≥80 cm for male and female aged ≥15 years [29]. BMI for participants aged <18 years was transformed to BMI percentile based on the US Centers for Disease Control and Prevention reference [30]. Overweight were defined as BMI >85th percentile [31], or >25 kg/m2 for participants aged ≥18 years [32].\n\nLaboratory measurements\nLiver profiles, including AST, ALT, and GGT; lipid profiles, including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride; diabetic profiles, including fasting plasma glucose (FPG) and insulin; and hematologic profiles were performed at enrollment after an overnight fast. The normal levels of AST, ALT, and GGT were ≤50 U/L, ≤30 U/L, and ≤50 U/L, respectively. The homeostasis model assessment of insulin resistance (HOMA-IR; FPG [mg/dL] × fasting plasma insulin [μU/mL] / 405) was calculated, and the cutoff for insulin resistance was 3.16 [33].\n\nNoninvasive diagnostic measurements for NAFLD and hepatic fibrosis\nRadiological techniques\nLiver ultrasonography was performed by pediatric radiologists at each site who were blinded to participants’ clinical and laboratory data. The presence of hepatic steatosis was described as a diffuse increase in echogenicity of liver parenchyma. The severity was classified as mild, moderate and severe steatosis as shown in Table 1. To reduce inter-observer variability, the recorded ultrasound images of each participant were cross-read by all pediatric radiologists at the other participating sites. NAFLD was definitely diagnosed when site’s pediatric radiologist and at least one of the other site’s radiologists concordantly confirmed the presence of steatosis. The severity of hepatic steatosis, if discordant, was relied on the site’s radiologist.\n\n10.1371/journal.pone.0226375.t001Table 1 Severity of hepatic steatosis evaluated by noninvasive radiologic measurements.\nSeverity of hepatic steatosis\tNoninvasive radiologic measurements\t\nLiver ultrasonography [34]\tControlled attenuation parametera [35]\t\nMild\tA slight and diffuse increase in hepatic parenchymal echoes with normal visualization of portal vein borders and diaphragm\t>238 dB/m\t\nModerate\tA moderate and diffuse increase in hepatic parenchymal echoes with slightly impaired visualization of portal vein borders and diaphragm\t>259 dB/m\t\nSevere\tA severe and diffuse increase in hepatic parenchymal echoes with poor or no visualization of portal vein border, diaphragm, and posterior portion of the right lobe\t>292 dB/m\t\na The measurement was performed at the one-year follow-up in only participants with persistent hepatic abnormalities.\n\nTransient elastography (TE; FibroScan®, Echosens, Paris, France) was performed on a fasting participant by a well-trained operator, following the manufacturer’s instructions. In brief, 10 measurements with the standard M probe were performed on each participant. TE results were considered reliable if the success rate was ≥60% and the interquartile range (IQR) was <30% of the median. The median value of successful measurements was reported as a hepatic stiffness level (kPa). For this study, we defined hepatic fibrosis as a TE ≥7.4 kPa because this cutoff has a high diagnostic accuracy (sensitivity 100% and specificity 92%) for the diagnosis of significant hepatic fibrosis (≥ F2 disease) in adolescent population [14].\n\nLiver biomarkers\nAST-to-platelet ratio index (APRI: AST [U/L] / upper limit of normal × 100 / platelet count [109 L]) and fibrosis-4 (FIB-4: age [years] × AST [U/L] / platelet count [109 L] × ALT1/2 [U/L]) scores were calculated. APRI scores >0.5 and FIB-4 scores >1.45 are suggestive of hepatic fibrosis [36,37]. Additionally, cytokeratin 18-apoptosin M30 fragments (CK-18 M30) were performed in a subgroup of participants (all participants with history of elevated aminotransferase enzymes, and participants who met the criteria for protocol-defined NAFLD and/or hepatic fibrosis), using enzyme-linked immunosorbent assay (Vivalavida AB, Nacka, Sweden) on Thermo ScientificTM VarioskanTM Flash (Thermo Fisher Scientific Oy, Vantaa, Finland).\n\nDefinitions of NAFLD, hepatic fibrosis and persistent hepatic abnormalities\nIn this study, NAFLD was defined as evidence of hepatic steatosis (any severity), evaluated by liver ultrasonography. Hepatic fibrosis was defined as significant liver stiffness (TE ≥7.4 kPa), evaluated by TE. Participants who met the criteria for protocol-defined NAFLD and/or hepatic fibrosis were re-assessed for anthropometric parameters, physical statuses, laboratory measurements, and noninvasive liver evaluations at 1 year after their first assessments. Participants were defined as having persistent hepatic abnormalities if they still met the criteria indicating NAFLD and/or hepatic fibrosis by the one-year measurements, or were defined as having transient hepatic abnormalities if they had return-to-normal evaluations by the repeated measurements. Additionally, participants with persistent hepatic abnormalities were further investigated by liver MRI/MRE and CAP (CAPTM, Echosens, Paris, France) at the one-year follow-up. Briefly, CAP was performed simultaneously with TE, and the ultrasound attenuation (dB/m) represents percentage of steatosis. The severity of hepatic steatosis was described in Table 1.\n\nStatistical analysis\nThe prevalence of protocol-defined hepatic abnormalities (NAFLD and/or hepatic fibrosis) among participants with and without history of elevated aminotransferases were calculated. The prevalence, baseline clinical characteristics, laboratory parameters, and noninvasive liver evaluations of participants in each group were compared using chi-square and Wilcoxon rank sum tests for categorical and continuous variables, respectively. Similarly, the comparisons between participants who met the criteria of persistent versus transient hepatic abnormalities were performed. Additionally, laboratory parameters and liver biomarkers between initial and one-year follow-up evaluations were compared using McNemar’s test and Wilcoxon sign rank test for categorical and continuous variables, respectively.\n\nUnivariable logistic regression analyses were conducted to identify factors associated with the protocol-defined persistent hepatic abnormalities. Covariates which demonstrated a significance level of <0.05 were included in a multivariable model. The magnitudes of association were summarized with crude odds ratio (crude OR) and adjusted odds ratio (aOR), together with their 95% confidence intervals (CI), in the univariable and multivariable analyses, respectively. All statistical analyses were carried out using Stata statistical software, version 14. (StataCorp LP, College Station, TX). A two-sided P <0.05 was judged to be statistically significant.\n\nResults\nParticipant characteristics and laboratory results\nBetween August 2014 and June 2015, 120 participants with the median age (IQR) of 17.0 (14.6–19.2) years were enrolled. Half of them (51.7%) were male, and 7 participants (5.8%) had central obesity. At enrollment, 38 participants (31.7%) were currently on PI-based regimens. Sixty-two participants (51.6%) had postnatal exposure to stavudine and 21 (17.5%) to didanosine. The median duration of ART and CD4 T-cell count (IQR) were 10.5 (7.1–12.0) years, and 725 (588–946) cells/mm3, respectively. Sixteen participants (13.5%) were current alcohol drinkers, with a median intake (IQR) of 0.8 (0.5–4.0) drinks/day. Other anthropometric parameters and HIV-related characteristics for participants with history of elevated and normal aminotransferase enzymes are summarized in Table 2. Additionally, among participants with history of elevated aminotransferase enzymes, 33 (55.0%) had persistent elevation (≥2 episodes within the past 12 months).\n\n10.1371/journal.pone.0226375.t002Table 2 Clinical characteristics and laboratory results of perinatally HIV-monoinfected adolescents, stratified by history of serum aminotransferase levels.\nCharacteristicsa,b\tParticipants with history of elevated aminotransferase levels\n(n = 60)\tParticipants with history of normal aminotransferase levels\n(n = 60)\tP\t\nAnthropometric parameters\t\t\t\t\nBody mass index (kg/m2)\t19.5 (17.7–21.3)\t18.7 (16.8–20.0)\t0.07\t\n Overweight\t7 (11.7)\t3 (5.0)\t0.07\t\nWaist circumference (cm)\n Central obesity\t69.0 (63.0–72.0)\n3 (5.0)\t65.0 (61.0–71.0)\n4 (6.7)\t0.05\n0.68\t\nHIV-related characteristics\t\t\t\t\nWHO clinical stage 3–4 prior to ART\t32 (61.5)\t25 (51.0)\t0.29\t\nCD4 T-cell percentage prior to ART (%)\t6.5 (2.0–20.0)\t13.5 (5.0–20.1)\t0.25\t\nPostnatal exposure to ART\n Stavudine\n Didanosine\t\n32 (53.3)\n13 (21.7)\t\n30 (50.0)\n8 (13.3)\t\n0.79\n0.25\t\nCurrent ART regimens\n NNRTI-based\n Boosted PI-based\t\n40 (66.7)\n20 (33.3)\t\n42 (70.0)\n18 (30.0)\t0.59\t\nDuration of ART (years)\t11.0 (7.2–11.9)\t9.4 (7.0–12.0)\t0.63\t\nCurrent CD4 T-cell count (cells/mm3)\t694 (546–979)\t771 (612–928)\t0.33\t\nLiver profiles\t\t\t\t\nFrequency of AST/ALT measurements within 12 months prior to enrollment\t3 (2–4)\n\t2 (2–3)\n\t0.004\n\t\nALT (U/L)\n ALT >30 U/L\t29 (21–39)\n26 (43.3)\t16 (12–21)\n1 (1.7)\t<0.001\n<0.001\t\nAST (U/L)\n AST >50 U/L\t24 (21–33)\n2 (3.3)\t21 (18–24)\n0 (0)\t<0.001\n0.15\t\nGamma GT (U/L)\n Gamma GT >50 U/L\t47 (25–95)\n27 (45.0)\t33 (22–50)\n15 (25.0)\t0.03\n0.02\t\nLiver biomarkers\t\t\t\t\nAPRI\t0.3 (0.2–0.3)\t0.2 (0.1–0.2)\t<0.001\t\nFIB-4\t0.3 (0.2–0.4)\t0.3 (0.2–0.4)\t0.06\t\nMetabolic profiles\t\t\t\t\nTotal cholesterol (mg/dL)\t174 (161–196)\t170 (154–197)\t0.46\t\nHDL-cholesterol (mg/dL)\t45 (39–67)\t55 (44–67)\t0.07\t\nLDL-cholesterol (mg/dL)\t106 (86–125)\t102 (88–116)\t0.75\t\nTriglyceride (mg/dL)\t87 (65–131)\t86 (58–125)\t0.51\t\nFPG (mg/dL)\t83 (79–87)\t81 (77–88)\t0.43\t\nInsulin (mU/L)\t7.7 (4.7–10.6)\t8.2 (5.2–14.3)\t0.23\t\nHOMA-IR\nHOMA-IR >3.16\t1.5 (0.9–2.2)\n8 (13.3)\t1.5 (1.0–2.8)\n11 (18.3)\t0.32\n0.48\t\nAbbreviations: ALT, alanine aminotransferase; APRI, aspartate aminotransferase-to-platelet ratio index; ART, antiretroviral treatment; AST, aspartate aminotransferase; FIB-4, fibrosis-4 score; FPG, fasting plasma glucose; Gamma GT, gamma-glutamyl transferase; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; WHO, World Health Organization.\n\na Data presented as n (%) for categorical data and median (IQR) for continuous data. Chi-square test and Wilcoxon rank sum test were used to compare categorical and continuous data, respectively.\n\nb Data represented the characteristics at enrollment, unless otherwise specified.\n\nFor the laboratory parameters, participants in both groups had similar results, except for the liver profiles as they were the protocol-defined recruitment criteria for this study (Table 2). At enrollment, elevated ALT (ALT >30 U/L) was identified in 26 (43.3%) participants with history of elevated aminotransferase enzymes, and 1 (1.7%) participant with normal hepatic enzymes. Four participants (3.3%) had APRI >0.5; all were among the group with elevated aminotransferase levels, whereas none of the participants had FIB-4 >1.45. Insulin resistance (HOMA-IR >3.16) was observed in 8 (13.3%) and 11 (18.3%) participants among the groups having elevated versus normal aminotransferases, respectively. No participants were currently receiving antidiabetic or lipid-lowering medications in both groups.\n\nPrevalence of persistent hepatic abnormalities\nWith the initial evaluations, 10 participants with history of elevated aminotransferases (16.7%; 5 with NAFLD, 4 with hepatic fibrosis, and 1 with both conditions) and 9 participants with history of normal hepatic enzymes (15.0%; 3 with NAFLD and 6 with hepatic fibrosis) demonstrated the evidences of hepatic abnormalities (P >0.05) (Fig 1). However, with the one-year follow-up measurements, only 5 participants in the group having history of elevated aminotransferase levels met the criteria for persistent hepatic abnormalities (3 with persistent NAFLD, 1 with persistent hepatic fibrosis, and 1 with both persistent NAFLD and hepatic fibrosis) (Fig 1), corresponding to the prevalence of 8.3% (95% CI: 2.8–18.4%). Additionally, all 5 participants had persistent aminotransferase elevation. None of the group of having normal hepatic enzymes demonstrated persistent hepatic abnormalities. Clinical information for each participant is shown in Table 3. Three participants (patient number 1, 2 and 3) had persistent moderate to severe hepatic steatosis by both liver ultrasonography and MRI. All of them had also insulin resistance (HOMA-IR >3.16), and 2 (patient number 1 and 3) had central obesity. Patient number 4 had persistent mild hepatic steatosis by ultrasonography; however, demonstrated normal evaluations by CAP and liver MRI. Patient number 5 had persistent hepatic fibrosis by TE, but did not undergo liver MRE due to patient incorporation. The other 14 participants demonstrated transient hepatic abnormalities, including 5 with history of elevated aminotransferases (2 with mild degree of NAFLD and 3 with hepatic fibrosis at the initial assessments), and 9 with history of normal hepatic enzymes (3 with mild degree of NAFLD and 6 with hepatic fibrosis at the initial evaluation) (Fig 1).\n\n10.1371/journal.pone.0226375.g001Fig 1 Flow chart of participants through the study.\nAbbreviations: CAP, controlled attenuation parameter; MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; NAFLD, nonalcoholic fatty liver disease. a Participants in both groups were matched on age and sex in the ratio 1:1. b Participants were listed as having history of elevated aminotransferase levels if they had AST >50 U/L and/or ALT >30 U/L at least once within the past 12 months. c NAFLD was defined as an evidence of hepatic steatosis (any severity), evaluated by liver ultrasonography. Hepatic fibrosis was defined as significant liver stiffness (≥7.4 kPa), evaluated by transient elastography. d Persistent hepatic abnormalities was defined as an evidence of NAFLD and/or hepatic fibrosis at both initial and one-year follow-up evaluations. e Transient hepatic abnormalities was defined as an evidence of NAFLD and/or hepatic fibrosis at initial evaluation, but having a return-to-normal evaluation by the repeated measurements.\n\n10.1371/journal.pone.0226375.t003Table 3 Clinical information of perinatally HIV-monoinfected adolescents with persistent hepatic abnormalities.\nNo.\tAge at\nenrollment\n(years)\tSex\tBMI (kg/m2)\tWC (cm)\tAlcohol use (drink/day)\tCurrent ART/ duration (years)\tAST/ ALT (U/L)\tHOMA-IR\tInvestigations at enrollment\tInvestigations at one-year follow-up\t\n\t\t\tUS: fatty liver grade\tTE: stiffness (kPa)\tUS: fatty liver grade\tTE: stiffness (kPa)\tCAP (dB/m) / grade\tLiver MRI/ MRE\t\n1\t23.4\tM\t36.2\t114.0\t4\tTDF+3TC+EFV/ 11.4\t87/ 160\t4.8\tSevere\t14.0\tSevere\t12.3\t332/ Severe\tModerate hepatic steatosis, and severe liver fibrosis\t\n2\t17.6\tF\t21.3\t69.0\tN\tTDF+3TC+RPV/ 15.5\t24/ 36\t12.6\tSevere\t5.7\tSevere\t7.4\t255/ Mild\tModerate hepatic steatosis,\nno liver fibrosis\t\n3\t21.6\tM\t31.8\t102.0\tN\tTDF+FTC+EFV/ 11.7\t39/ 67\t3.6\tModerate\t5.9\tSevere\t9.4\t337/ Severe\tSevere hepatic steatosis, no liver fibrosis\t\n4\t11.9\tF\t15.5\t59.0\tN\tZDV+3TC+NVP/ 1.6\t31/ 36\t2.8\tMild\t5.7\tMild\t3.7\t201/ No\tNo evidences of hepatic steatosis\nand liver fibrosis\t\n5\t14.0\tM\t17.7\t62.5\tN\tTDF+3TC+ATV/r/ 11.7\t32/ 23\t1.3\tNo\t7.9\tNo\t8.7\t197/ No\t-\t\nAbbreviations: 3TC, lamivudine; ALT, alanine aminotransferase enzyme; ART, antiretroviral treatment; AST, aspartate aminotransferase enzyme; ATV/r, atazanavir/ritonavir; BMI, body mass index; CAP, controlled attenuation parameter; EFV, efavirenz; F, female; FTC, emtricitabine; HOMA-IR, homeostasis model assessment of insulin resistance; M, male; MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; N, alcohol non-drinker; NVP, nevirapine; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; TE, transient elastography; US, ultrasonography; WC, waist circumference; ZDV, zidovudine.\n\nComparisons of participants with persistent versus transient hepatic abnormalities\nCK-18 M30 and insulin levels were significantly higher in participants with persistent hepatic abnormalities than those with transient abnormalities at enrollment (CK-18 M30: 203 versus 95 U/L; P = 0.01, insulin: 15.9 versus 8.7 mU/L; P = 0.04) and one-year follow-up (CK-18 M30: 336 versus 85 U/L; P = 0.03, insulin: 29.9 versus 10.3 mU/L; P = 0.02), while HOMA-IR was significantly greater at only one-year follow-up (6.0 versus 1.9; P = 0.02). Notably, there were no significant changes in all liver profiles and biomarkers from enrollment to one-year follow-up visit within each group of participants (P >0.05).\n\nAssociated factors of persistent hepatic abnormalities\nIn the univariable model, central obesity (crude OR: 14.5; 95% CI: 2.0–107.5), baseline ALT >30 U/L (crude OR: 15.7; 95% CI: 1.7–146.8), and HOMA-IR >3.16 (crude OR: 9.1; 95% CI: 1.4–58.8) were associated with persistent hepatic abnormalities, whereas HIV-related characteristics, dyslipidemia, and liver biomarkers did not demonstrate any statistically significant associations (P >0.05) (Table 4). Both baseline ALT >30 U/L (aOR: 29.1; 95% CI: 1.7–511.8), and HOMA-IR >3.16 (aOR: 17.9; 95% CI: 1.1–289.7) remained independently associated with persistent abnormalities, while central obesity lost the significant association after adjusting for confounding factors (Table 4).\n\n10.1371/journal.pone.0226375.t004Table 4 Associated factors of persistent hepatic abnormalities among perinatally HIV-monoinfected Asian adolescents.\nParameters\tUnivariable analysisa\tMultivariable analysisa\t\nCruded OR\n(95% CI)\tP\tAdjusted OR\n(95% CI)\tP\t\nAge (per 1 year increase)\t1.23 (0.92–1.63)\t0.17\t\t\t\nMale\t0.61 (0.10–3.80)\t0.60\t\t\t\nOverweight\t8.92 (1.30–61.31)\t0.03\t\t\t\nCentral obesity\t14.53 (1.96–107.52)\t0.01\t3.39 (0.17–69.96)\t0.43\t\nHistory of elevated aminotransferase levels\t4.21 (0.46–38.86)\t0.20\t\t\t\nWHO stage 3–4 prior to ART (vs. stage 1–2)\t0.33 (0.03–3.32)\t0.35\t\t\t\nCD4 T-cell <15% prior to ART\t0.70 (0.09–5.16)\t0.72\t\t\t\nPostnatal exposure to stavudine\t0.22 (0.02–2.00)\t0.18\t\t\t\nPostnatal exposure to didanosine\t1.18 (0.12–11.08)\t0.89\t\t\t\nCurrent PI used (vs. NNRTI used)\t0.52 (0.06–4.31)\t0.54\t\t\t\nDuration ART (per 1 year increase)\t1.03 (0.79–1.34)\t0.83\t\t\t\nCurrent CD4 T-cell ≥500 cells/mm3\t1.14 (0.15–8.41)\t0.90\t\t\t\nBaseline ALT >30 U/L\t15.65 (1.67–146.83)\t0.02\t29.09 (1.65–511.76)\t0.02\t\nBaseline gamma GT >50 U/L\t2.92 (0.47–18.23)\t0.25\t\t\t\nAPRI >0.5\t9.17 (0.77–108.00)\t0.11\t\t\t\nFIB-4\t10.84 (0.07–1,773.00)\t0.36\t\t\t\nHOMA-IR >3.16\t9.09 (1.41–58.75)\t0.02\t17.93 (1.11–289.71)\t0.04\t\nCholesterol ≥200 mg/dL\t0.89 (0.10–8.32)\t0.92\t\t\t\nHDL-cholesterol <40 mg/dL\t2.23 (0.35–14.07)\t0.39\t\t\t\nLDL-cholesterol ≥130 mg/dL\t1.18 (0.12–11.08)\t0.89\t\t\t\nTriglyceride ≥150 mg/dL\t1.79 (0.19–17.14)\t0.62\t\t\t\nAbbreviations: ALT, alanine aminotransferase; APRI, aspartate aminotransferase-to-platelet ratio index; ART, antiretroviral treatment; CI, confidence interval; CK-18 M30, cytokeratin 18-apoptosin M30 fragments; FIB-4, fibrosis-4; Gamma GT, gamma-glutamyl transferase; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein; NNRTI, non-nucleoside reverse transcriptase inhibitor; OR, odds ratio; PI, protease inhibitor; WHO, World Health Organization.\n\na Univariable and multivariable logistic regression analyses were performed to identify factors associated with persistent hepatic abnormalities among perinatally HIV-monoinfected adolescents.\n\nDiscussion\nUsing noninvasive diagnostic tools, including liver ultrasonography and TE, 8.3% of our perinatally HIV-monoinfected Asian adolescents with history of elevated aminotransferase levels met the criteria for protocol-defined persistent NAFLD and/or hepatic fibrosis. HIV-infected adolescents with normal aminotransferase enzymes are less likely to have persistent hepatic abnormalities. Therefore, in the clinical practice with high volume of patients, screening for these hepatic co-morbidities might be considered in adolescents with persistent ALT elevation plus metabolic risk factors, such as insulin resistance, to early detect the abnormalities and prevent the progression to irreversible harmful outcomes.\n\nFrom the initial evaluation, the prevalence of NAFLD among our HIV-infected adolescents was 8% which was lower than that of HIV-uninfected adolescents (11–17%) [4,38]. Additionally, our prevalence was much lower than that demonstrated in a range of 31–55% among HIV-monoinfected US, Italian, Canadian, and Greek adults [6–8,39,40]. A recent systematic review and meta-analysis showed that a pooled prevalence of NAFLD, based on imaging studies, among HIV-monoinfected adults was 35% [41]. Focusing on our adolescents with history of elevated aminotransferases, 10% of them had NAFLD which was similarly much lower than a prevalence of 71% among HIV-monoinfected UK adults with persistent elevated aminotransferases [42]. This might be explained by the lower proportion of obesity and metabolic derangement in our adolescents, as well as the variation in definitions and the heterogeneity of diagnostic tools adopted for NAFLD.\n\nHepatic fibrosis is a critical consequence of NAFLD which is associated with liver-related mortality. In this study, 9% of adolescents had significant hepatic fibrosis (TE ≥7.4 kPa) in the first assessment which was lower than that observed in HIV-monoinfected adults [8,11,40–43]. In a recent systematic review and meta-analysis, a pooled prevalence of significant hepatic fibrosis, based on liver histology, was 22% among HIV-monoinfected US, Canadian, French, Italian, Japanese, and Chinese adults [41]. In addition, a recent UK study showed the 21% prevalence of significant hepatic fibrosis (TE ≥7.4 kPa) among their HIV-monoinfected adults with persistent raised aminotransferases [42], which was much greater than the 8% prevalence in our adolescents with history of elevated aminotranferases. Hepatic fibrosis usually takes years to develop; therefore, the prevalence is expected to be lower in adolescents compared with adults.\n\nWith the one-year follow-up, we noted that 8% of our adolescents with history of elevated aminotransferases demonstrated the evidence of persistent hepatic abnormalities. Meanwhile, none of the adolescents with history of normal hepatic enzymes showed such hepatic abnormalities. As participants with history of elevated hepatic enzymes had more frequent laboratory measurements compared with those having normal enzyme levels, selection bias might be occurred because participants classified in the former subgroup would be more likely to have hepatic abnormalities than those in the latter subgroup. Although, in this study, we did not perform liver biopsy, a benchmark for diagnosis of NAFLD and hepatic fibrosis, 3 participants (patient number 1, 2 and 3) were likely to have hepatic diseases since several evaluations, both conventional and advanced, concordantly showed the significant and persistent abnormalities. Moreover, such participants had insulin resistance and central obesity. For patient number 4, the observed persistent NAFLD might be due to measurement error of liver ultrasonography because the abnormalities did not demonstrate by CAP and liver MRI. For patient number 5, who demonstrated persistent hepatic fibrosis without evidences of NAFLD, we hypothesized that this might be attributed to measurement error of TE or other causes of hepatic fibrosis that were not investigated under this study. Liver MRI/MRE might provide more information for this patient, but were not conducted due to patient incorporation. For adolescents with transient hepatic abnormalities, we could not conclude whether this is the observational error of measurement or the actual disease regression. The advanced techniques such as liver MRI/MRE or liver histopathology would help confirming the diagnosis, but unfortunately were not performed in these individuals.\n\nIn this study, elevated ALT was independently associated with protocol-defined persistent hepatic abnormalities. Previous studies in HIV-monoinfected adults found that ALT elevation was correlated with NASH and significant hepatic fibrosis [8,9,27]. Furthermore, we noted that all adolescents with persistent hepatic abnormalities had at least two episodes of aminotransferase elevation within the past 12 months. So, although single ALT elevation might be attributed to measurement variation, persistent hepatic enzyme elevation might be used as a clue for further investigations that yield the diagnosis in clinical practices. However, there are some controversial evidence showing that elevated ALT might not be a good indicator of NAFLD in adolescents [38]. Therefore, larger clinical studies are needed to better establish the diagnostic accuracy of ALT for detecting NAFLD in HIV-infected adolescent population.\n\nWe also found that insulin resistance was associated with persistent hepatic abnormalities in our adolescents. Insulin resistance is the pathophysiological hallmark of NAFLD and hepatic fibrosis. It reduces insulin sensitivity at the levels of adipose tissue and liver, causing an accelerated hepatic fatty acid synthesis and an increased intrahepatic fat accumulation, which consequently results in hepatic steatosis, inflammation, and fibrosis [6,44]. The tight association between insulin resistance and hepatic abnormalities in HIV-infected populations was supported by several evidence. Two cross-sectional studies in HIV-monoinfected US adults with elevated aminotransferases demonstrated that insulin resistance was associated with NASH and hepatic fibrosis [9,22].\n\nPostnatal exposure to NRTIs, particularly stavudine and didanosine, is a common factor associated with NAFLD and hepatic fibrosis among HIV-infected individuals [7,45]. The mechanism of the linkage is that NRTI directly induce mitochondrial toxicity [46]. In a previous study among HIV-monoinfected Italian adults, previous NRTI exposure was independently associated with NAFLD. Importantly, the risk of NAFLD in this population was increased 1.12 times for each year of NRTI exposure [7]. Additionally, treatment with didanosine was found to be a significantly associated factor of hepatic fibrosis among HIV-monoinfected Spanish adults [45]. Nevertheless, our study did not note the linkage between NRTI exposure and persistent hepatic abnormalities, including NAFLD and/or hepatic fibrosis. This might be due to a short duration of exposure to these drugs (1.9 years for stavudine and 3.4 years for didanosine) among our participants compared to the previous study [7].\n\nNoninvasive liver biomarkers, such as APRI and FIB-4, have been well studied as the surrogate markers of hepatic fibrosis in HIV-infected children and adolescents [24]. However, this study did not demonstrate any statistically significant associations between these biomarkers and persistent hepatic abnormalities. This might be attributed to the low number of participants with abnormal APRI (3%) and FIB-4 (0%), as majority of them had no or mild degree hepatic fibrosis, resulting in the insufficient power to detect such associations. Additionally, we noted that participants with persistent hepatic abnormalities had greater CK-18 M30 levels compared to those with transient abnormalities at enrollment and one-year follow-up visits. This is similar to the previous studies which found that CK-18 M30 levels were significantly higher in youth with NAFLD/NASH than those without such hepatic abnormalities [20,21].\n\nThe adverse outcomes of NAFLD and hepatic fibrosis include the occurrences of cirrhosis, HCC and liver-related deaths. Several studies reported that NAFLD and hepatic fibrosis are significant risk factors for the development of cirrhosis and HCC [47]. Additionally, a previous study found that HIV-uninfected US adults with NAFLD had significantly increased overall mortality compared with general population of the same age and sex [48]. Promptly providing the appropriate managements at the early stage of NAFLD, including weight reduction, diet modification, physical exercise, and treatment with antidiabetic medications have demonstrated benefits in prevention or delay harmful complications in general population, but the evidences in HIV-infected individuals are still scarce [49].\n\nTo the best of our knowledge, this is the first study evaluating hepatic co-morbidities by noninvasive diagnostic measurements among HIV-infected adolescents in resource-constrained settings. Additionally, we use stringent criteria to define the persistent hepatic abnormalities, and confirm the diagnosis by several imaging modalities, including advanced techniques such as CAP and liver MRI/MRE. Nevertheless, this study has some limitations that should be acknowledged. Since NAFLD and hepatic fibrosis are long-term, progressive complications, evaluating such conditions while these individuals are adolescents might be too early to observe significant clinical outcomes. The prospective research with greater length of follow-up is required. In addition, using noninvasive radiologic measurements might contain some limitations, e.g., degraded image quality and reduced accuracy of liver ultrasonography and TE when perform in obese participants. Furthermore, since we performed the advanced radiologic techniques, including CAP and liver MRI/MRE, in only participants with persistent hepatic abnormalities at one-year follow-up, this might limit our ability to confirm hepatic abnormalities in the rest of the cohort. Also, a small number of participants, particularly those with persistent hepatic abnormalities, might limit our power to make a strong conclusion for this study. Finally, since this study was conducted in Asian adolescents whom might have distinct risk of metabolic disorders, our findings may have limited generalizability to populations in other regions.\n\nConclusions\nAmong perinatally HIV-monoinfected Asian adolescents with history of elevated aminotransferase enzymes, persistent hepatic abnormalities, including NAFLD and/or hepatic fibrosis, are not uncommon. Persistent ALT elevation and insulin resistance appear to be associated with persistent hepatic abnormalities. Noninvasive diagnostic assessments might be considered in these at risk individuals to early detect significant hepatic complications. Future clinical studies with a larger sample size are needed to provide more evidence to make a recommendation on hepatic comorbidity screening for this population.\n\nThe NAFLD study group\nFaculty of Medicine and Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand: Sudjaritruk T, Aurpibul L, Chotecharoentanan T, Wongnum N, Rungruengthanakit K, and Suwannamas N;\n\nHIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand: Puthanakit T, Bunupuradah T, Sophonphan J, Thamsala S, Pitimahajanaka T, Suwanlerk T, Thongpunchang B; Ubolyam S, Mahanontharit A, Laopraynak N, and Jaimulwong T;\n\nSrinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand: Kosalaraksa P, Sopharuk C, and Tharnprisan P;\n\nCipto Mangunkusumo General Hospital, Jakarta, Indonesia: Kurniati N, Wicaksana P,\n\nSupporting information\nS1 Table NAFLD study dataset.\n(XLSX)\n\nClick here for additional data file.\n\n The authors would like to thank participants and families for their participation in the study. The authors would also like to thank Professor Sombat Tanprasertsuk, Faculty of Medicine, Chulalongkorn University for the advice on controlled attenuation parameter, and Dr. Natthaporn Tanpowpong, Faculty of Medicine, Chulalongkorn University for the advice on liver magnetic resonance imaging and magnetic resonance elastography.\n==== Refs\nReferences\n1 Brady MT , Oleske JM , Williams PL , Elgie C , Mofenson LM , Dankner WM , et al\nDeclines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era . J Acquir Immune Defic Syndr . 2010 ; 53 (1 ):86 –94 . 10.1097/QAI.0b013e3181b9869f \n20035164 \n2 Palella FJ Jr, Baker RK , Moorman AC , Chmiel JS , Wood KC , Brooks JT , et al\nMortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study . J Acquir Immune Defic Syndr . 2006 ; 43 (1 ):27 –34 . 10.1097/01.qai.0000233310.90484.16 \n16878047 \n3 World Health Organization. Prevalence of obesity among children and adolescents, BMI>+2 standard deviation above the median (crude estimates) by WHO region. 2017 [cited 2019 July 19]. Available from: http://apps.who.int/gho/data/view.main.BMIPLUS2REGv?lang=en\n4 Schwimmer JB , Deutsch R , Kahen T , Lavine JE , Stanley C , Behling C . Prevalence of fatty liver in children and adolescents . Pediatrics . 2006 ; 118 (4 ):1388 –93 . 10.1542/peds.2006-1212 \n17015527 \n5 Angulo P . Nonalcoholic fatty liver disease . N Engl J Med . 2002 ; 346 (16 ):1221 –31 . 10.1056/NEJMra011775 \n11961152 \n6 Crum-Cianflone N , Dilay A , Collins G , Asher D , Campin R , Medina S , et al\nNonalcoholic fatty liver disease among HIV-infected persons . J Acquir Immune Defic Syndr . 2009 ; 50 (5 ):464 –73 . 10.1097/QAI.0b013e318198a88a \n19225402 \n7 Guaraldi G , Squillace N , Stentarelli C , Orlando G , D'Amico R , Ligabue G , et al\nNonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors . Clin Infect Dis. \n2008 ; 47 (2 ):250 –7 . 10.1086/589294 \n18532884 \n8 Vuille-Lessard E , Lebouché B , Lennox L , Routy JP , Costiniuk CT , Pexos C , et al\nNonalcoholic fatty liver disease diagnosed by transient elastography with controlled attenuation parameter in unselected HIV monoinfected patients . AIDS . 2016 ; 30 (17 ):2635 –2643 . 10.1097/QAD.0000000000001241 \n27603289 \n9 Sterling RK , Smith PG , Brunt EM . Hepatic steatosis in human immunodeficiency virus: a prospective study in patients without viral hepatitis, diabetes, or alcohol abuse . J Clin Gastroenterol . 2013 ; 47 (2 ):182 –7 . 10.1097/MCG.0b013e318264181d \n23059409 \n10 McCullough AJ . 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Chiang Mai Med J . 2012 ; 51 (2 ):29 –37 .\n29 Alberti KG , Eckel RH , Grundy SM , Zimmet PZ , Cleeman JI , Donato KA , et al\nHarmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity . Circulation . 2009 ; 120 (16 ):1640 –5 . 10.1161/CIRCULATIONAHA.109.192644 \n19805654 \n30 Centers for Disease Control and Prevention. BMI percentile calculator for child and teen English version. 2019 [cited 2019 July 19]. Available from: https://www.cdc.gov/healthyweight/bmi/calculator.html.\n31 Barlow SE , Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report . Pediatrics . 2007 ; 120 \nSuppl 4 :S164 –92 .18055651 \n32 Centers for Disease Control and Prevention. Defining adult overweight and obesity. [cited 2019 July 19]. Available from: https://www.cdc.gov/obesity/adult/defining.html.\n33 Keskin M , Kurtoglu S , Kendirci M , Atabek ME , Yazici C . Homeostasis model assessment is more reliable than fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents . Pediatrics . 2005 ; 115 (4 ):e500 –3 . 10.1542/peds.2004-1921 \n15741351 \n34 Shannon A , Alkhouri N , Carter-Kent C , Monti L , Devito R , Lopez R , et al\nUltrasonographic quantitative estimation of hepatic steatosis in children with NAFLD . J Pediatr Gastroenterol Nutr . 2011 ; 53 (2 ):190 –5 . 10.1097/MPG.0b013e31821b4b61 \n21788761 \n35 Sasso M , Beaugrand M , de Ledinghen V , Douvin C , Marcellin P , Poupon R , et al\nControlled attenuation parameter (CAP): a novel VCTETM guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes . Ultrasound Med Biol. \n2010 ; 36 (11 ):1825 –35 . 10.1016/j.ultrasmedbio.2010.07.005 \n20870345 \n36 McGoogan KE , Smith PB , Choi SS , Berman W , Jhaveri R . Performance of the AST-to-platelet ratio index as a noninvasive marker of fibrosis in pediatric patients with chronic viral hepatitis . J Pediatr Gastroenterol Nutr . 2010 ; 50 (3 ):344 –6 . 10.1097/MPG.0b013e3181aed725 \n20118806 \n37 Sterling RK , Lissen E , Clumeck N , Sola R , Correa MC , Montaner J , et al\nDevelopment of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection . Hepatology . 2006 ; 43 (6 ):1317 –25 . 10.1002/hep.21178 \n16729309 \n38 Doycheva I , Watt KD , Alkhouri N . Nonalcoholic fatty liver disease in adolescents and young adults: The next frontier in the epidemic . Hepatology . 2017 ; 65 (6 ):2100 –9 . 10.1002/hep.29068 \n28103626 \n39 Lombardi R , Sambatakou H , Mariolis I , Cokkinos D , Papatheodoridis GV , Tsochatzis EA . Prevalence and predictors of liver steatosis and fibrosis in unselected patients with HIV mono-infection . Dig Liver Dis . 2016 ; 48 (12 ):1471 –7 . 10.1016/j.dld.2016.08.117 \n27623186 \n40 Pembroke T , Deschenes M , Lebouché B , Benmassaoud A , Sewitch M , Ghali P , et al\nHepatic steatosis progresses faster in HIV mono-infected than HIV/HCV co-infected patients and is associated with liver fibrosis . J Hepatol . 2017 ; 67 (4 ):801 –8 . 10.1016/j.jhep.2017.05.011 \n28527666 \n41 Maurice JB , Patel A , Scott AJ , Patel K , Thursz M , Lemoine M . Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection . AIDS . 2017 ; 31 (11 ):1621 –32 . 10.1097/QAD.0000000000001504 \n28398960 \n42 Lombardi R , Lever R , Smith C , Marshall N , Rodger A , Bhagani S , et al\nLiver test abnormalities in patients with HIV mono-infection: assessment with simple noninvasive fibrosis markers . Ann Gastroenterol . 2017 ; 30 (3 ):349 –56 . 10.20524/aog.2017.0141 \n28469366 \n43 Lui G , Wong VW , Wong GL , Chu WC , Wong CK , Yung IM , et al\nLiver fibrosis and fatty liver in Asian HIV-infected patients . Aliment Pharmacol Ther . 2016 ; 44 (4 ):411 –21 . 10.1111/apt.13702 \n27301337 \n44 Gaggini M , Morelli M , Buzzigoli E , DeFronzo RA , Bugianesi E , Gastaldelli A . Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease . Nutrients . 2013 ; 5 (5 ):1544 –60 . 10.3390/nu5051544 \n23666091 \n45 Merchante N , Pérez-Camacho I , Mira JA , Rivero A , Macías J , Camacho A , et al\nPrevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: role of didanosine . Antivir Ther . 2010 ; 15 (5 ):753 –63 . 10.3851/IMP1612 \n20710057 \n46 Debes JD , Bohjanen PR , Boonstra A . Mechanisms of accelerated liver fibrosis progression during HIV infection . J Clin Transl Hepatol . 2016 ; 4 (4 ):328 –35 . 10.14218/JCTH.2016.00034 \n28097102 \n47 Baffy G , Brunt EM , Caldwell SH . Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace . J Hepatol . 2012 ; 56 (6 ):1384 –91 . 10.1016/j.jhep.2011.10.027 \n22326465 \n48 Adams LA , Lymp JF , St Sauver J , Sanderson SO , Lindor , Feldstein A , et al\nThe natural history of nonalcoholic fatty liver disease: a population-based cohort study . Gastroenterology . 2005 ; 129 (1 ):113 –21 . 10.1053/j.gastro.2005.04.014 \n16012941 \n49 Chalasani N , Younossi Z , Lavine JE , Diehl AM , Brunt EM , Cusi K , et al\nThe diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology . Gastroenterology . 2012 ; 142 (7 ):1592 –609 . 10.1053/j.gastro.2012.04.001 \n22656328\n\n",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "We report on a case of intoxication with a mix of new psychoactive substances. A 38-year-old male was brought to the emergency department (ED) following the ingestion of an unknown drug in a suicide attempt. During the transport, he became progressively more somnolent and unresponsive to painful stimuli. Urine and stomach content were collected on admission to be screened for drugs of abuse and medicinal drugs. After admission, the patient's next of kin presented five small grip seal plastic bags containing different powders/crystals, and they were sent for analysis along with urine and stomach content to the toxicology laboratory. An easy and rapid sample preparation technique was applied for the extraction of urine and stomach content. Samples were extracted with liquid-liquid extraction (LLE) technique and analysed using gas chromatography-mass spectrometry (GC-MS). A small amount of powder material from the bags was diluted in methanol and injected directly into the GC-MS instrument. Obtained spectra (EI) were evaluated against SWGDRUG library. Five different designer drugs were identified in the powder material, including synthetic cannabinoids (AB-CHMINACA, AB-FUBINACA) and synthetic cathinones (alpha-PHP, alpha-PVP and 4-CMC). With the exception of 4-CMC, all of these substances were also detected in the stomach content along with the prescription drugs. This is the first time that a positive identification of these five drugs has been made by a clinical laboratory in Slovenia.",
"affiliations": "Department of Laboratory Diagnostics, University Medical Centre Maribor, Slovenia. Electronic address: [email protected].;Department of Laboratory Diagnostics, University Medical Centre Maribor, Slovenia.;Department of Internal Intensive Medicine, University Medical Centre Maribor, Slovenia.",
"authors": "Klavž|Janez|J|;Gorenjak|Maksimiljan|M|;Marinšek|Martin|M|",
"chemical_list": "D000470:Alkaloids; D002186:Cannabinoids; D011619:Psychotropic Drugs; C023665:cathinone",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "265()",
"journal": "Forensic science international",
"keywords": "Cathinone derivative; GC–MS.; Suicide; Synthetic cannabinoids",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000470:Alkaloids; D002186:Cannabinoids; D003937:Diagnosis, Differential; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D011041:Poisoning; D011619:Psychotropic Drugs; D013406:Suicide, Attempted",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "121-4",
"pmc": null,
"pmid": "26890319",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Suicide attempt with a mix of synthetic cannabinoids and synthetic cathinones: Case report of non-fatal intoxication with AB-CHMINACA, AB-FUBINACA, alpha-PHP, alpha-PVP and 4-CMC.",
"title_normalized": "suicide attempt with a mix of synthetic cannabinoids and synthetic cathinones case report of non fatal intoxication with ab chminaca ab fubinaca alpha php alpha pvp and 4 cmc"
}
|
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"actiondrug": "5",
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"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
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{
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{
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"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
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"medicinalproduct": "QUETIAPINE."
},
{
"actiondrug": "5",
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"activesubstancename": "AB-FUBINACA"
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"medicinalproduct": "AB-FUBINACA"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
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"medicinalproduct": "DIAZEPAM."
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],
"patientagegroup": null,
"patientonsetage": "38",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Somnolence",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Mydriasis",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Unresponsive to stimuli",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Dehydration",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Sinus tachycardia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Coma",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Overdose",
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"reactionoutcome": "1"
}
],
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},
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"literaturereference": "KLAVZ J, GORENJAK M, MARINSEK M. SUICIDE ATTEMPT WITH A MIX OF SYNTHETIC CANNABINOIDS AND SYNTHETIC CATHINONES: CASE REPORT OF NON-FATAL INTOXICATION WITH AB-CHMINACA, AB-FUBINACA, ALPHA-PHP, ALPHA-PVP AND 4-CMC. FORENSIC SCI INT. 2016;265:121-124",
"literaturereference_normalized": "suicide attempt with a mix of synthetic cannabinoids and synthetic cathinones case report of non fatal intoxication with ab chminaca ab fubinaca alpha php alpha pvp and 4 cmc",
"qualification": "3",
"reportercountry": "SI"
},
"primarysourcecountry": "SI",
"receiptdate": "20160427",
"receivedate": "20160427",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12309297,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160815"
},
{
"companynumb": "SI-ALLERGAN-1809826US",
"fulfillexpeditecriteria": "1",
"occurcountry": "SI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"drugcharacterization": "1",
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"medicinalproduct": "DIAZEPAM."
},
{
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},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021860",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"medicinalproduct": "FLUOXETINE HCL UNK"
},
{
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"medicinalproduct": "LAMOTRIGINE."
},
{
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"medicinalproduct": "VALPROATE"
},
{
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"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
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"medicinalproduct": "ZOLPIDEM"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROMAZINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugrecurreadministration": "3",
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"medicinalproduct": "PROMAZINE"
}
],
"patientagegroup": null,
"patientonsetage": "38",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Poisoning",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Mydriasis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Somnolence",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Dehydration",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Coma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KLAVZ, JANEZ (CORRESPONDENCE)? GORENJAK, MAKSIMILJAN? MARINSEK, MARTIN. SUICIDE ATTEMPT WITH A MIX OF SYNTHETIC CANNABINOIDS AND SYNTHETIC CATHINONES: CASE REPORT OF NON-FATAL INTOXICATION WITH AB-CHMINACA, AB-FUBINACA, ALPHA-PHP, ALPHA-PVP AND 4-CMC. FORENSIC SCIENCE INTERNATIONAL. 2016?265:121-124",
"literaturereference_normalized": "suicide attempt with a mix of synthetic cannabinoids and synthetic cathinones case report of non fatal intoxication with ab chminaca ab fubinaca alpha php alpha pvp and 4 cmc",
"qualification": "3",
"reportercountry": "SI"
},
"primarysourcecountry": "SI",
"receiptdate": "20180301",
"receivedate": "20180301",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14588840,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Individuals with autism spectrum disorder (ASD) often meet criteria for at least one additional psychiatric disorder. The present study evaluated the utility of the Mini International Neuropsychiatric Interview (MINI) in assessing co-occurring psychiatric disorders in children, adolescents, and young adults with ASD. Ninety-one percent of children/adolescents and thirty-one percent of young adults were diagnosed with one or more co-occurring diagnoses using the MINI. MINI diagnostic rates were comparable to those found in the literature on children/adolescents with ASD; however, in young adults, MINI diagnostic rates were lower relative to rates found in the literature on young adults with ASD. Implications for treatment, transitioning to adulthood, and the need for instruments developed specifically to diagnose co-occurring disorders in ASD are discussed.",
"affiliations": "Department of Psychology and Neuroscience, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27514, USA. [email protected].;Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, Chapel Hill, NC, 27510, USA.;Department of Psychology and Neuroscience, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27514, USA.;Department of Psychology and Neuroscience, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27514, USA.;Department of Psychology and Neuroscience, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27514, USA.;Department of Psychology and Neuroscience, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27514, USA.;Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Department of Psychology and Neuroscience, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27514, USA.",
"authors": "Mosner|Maya G|MG|http://orcid.org/0000-0001-6654-7875;Kinard|Jessica L|JL|;Shah|Jasmine S|JS|;McWeeny|Sean|S|;Greene|Rachel K|RK|;Lowery|Sarah C|SC|;Mazefsky|Carla A|CA|;Dichter|Gabriel S|GS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10803-019-04090-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0162-3257",
"issue": "49(9)",
"journal": "Journal of autism and developmental disorders",
"keywords": "Assessment; Autism spectrum disorder; Co-occurring; Comorbidity",
"medline_ta": "J Autism Dev Disord",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder; D002648:Child; D015897:Comorbidity; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders; D011569:Psychiatric Status Rating Scales; D055815:Young Adult",
"nlm_unique_id": "7904301",
"other_id": null,
"pages": "3819-3832",
"pmc": null,
"pmid": "31175504",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": "12672261;12959421;16401149;16845581;17031447;17551351;18645422;19082876;19106426;19434487;19515234;20177765;20309621;20331933;20824493;21243110;21735077;22399449;22639682;22642847;23076506;23090336;23118256;23143131;24013401;24450322;24882502;24958436;25995020;27407039;27875247;28291247;28343342;28699053;28710532;28749236;28933930;29497980;29524016;29683351;9204677;9699121;9881538",
"title": "Rates of Co-occurring Psychiatric Disorders in Autism Spectrum Disorder Using the Mini International Neuropsychiatric Interview.",
"title_normalized": "rates of co occurring psychiatric disorders in autism spectrum disorder using the mini international neuropsychiatric interview"
}
|
[
{
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}
],
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},
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"literaturereference": "Mosner MG, Kinard JL, Shah JS, McWeeny S, Greene RK, Lowery SC et al.. Rates of Co-occurring Psychiatric Disorders in Autism Spectrum Disorder Using the Mini International Neuropsychiatric Interview. Journal of Autism and Developmental Disorders. 2019;49 (9):3819-3832",
"literaturereference_normalized": "rates of co occurring psychiatric disorders in autism spectrum disorder using the mini international neuropsychiatric interview",
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{
"abstract": "Acute interstitial nephritis (AIN) is characterized by an inflammatory infiltrate in the kidney interstitium and a decline in the creatinine clearance. Medications used for the treatment of tuberculosis have been implicated in the development of AIN, but there is limited data on how to manage AIN in this setting and which medications and dosages should be used to treat tuberculosis once AIN occurs. We describe two cases of AIN in the setting of disseminated tuberculosis in which AIN was successfully managed. It is recommended that Infectious Diseases and Nephrology be involved early in the care of these patients, preferably in an inpatient setting in order to expedite diagnosis and management.",
"affiliations": "Texas Center for Infectious Disease, Internal Medicine, University of Texas Northeast, University of Texas Health Science Center, San Antonio, USA.",
"authors": "Kizilbash|Quratulain|Q|",
"chemical_list": "D000995:Antitubercular Agents; D015415:Biomarkers; D003404:Creatinine",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.tube.2016.09.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1472-9792",
"issue": "101S()",
"journal": "Tuberculosis (Edinburgh, Scotland)",
"keywords": "Acute interstitial nephritis; Diagnosis; Management; Tuberculosis",
"medline_ta": "Tuberculosis (Edinb)",
"mesh_terms": "D000995:Antitubercular Agents; D015415:Biomarkers; D001806:Blood Urea Nitrogen; D003404:Creatinine; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D016896:Treatment Outcome; D014391:Tuberculosis, Miliary; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "100971555",
"other_id": null,
"pages": "S135-S136",
"pmc": null,
"pmid": "27729256",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful management of acute interstitial nephritis in two cases of disseminated tuberculosis.",
"title_normalized": "successful management of acute interstitial nephritis in two cases of disseminated tuberculosis"
}
|
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"medicinalproduct": "ISONIAZID."
},
{
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"activesubstancename": "EFAVIRENZ\\EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
},
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"drugdosagetext": "UNK",
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"drugindication": "HIV INFECTION",
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],
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},
{
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"reactionmeddraversionpt": "19.1",
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{
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"reactionoutcome": "1"
}
],
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},
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},
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},
{
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"abstract": "Cardiotoxicity associated with 5-fluorouracil (FU) is an uncommon, but potentially lethal, condition. The case of an 83-year-old man with colon cancer who developed chest pain during 5-FU infusion is presented. The electrocardiogram (ECG) showed pronounced ST elevation in the lateral leads, and the chest pain was resolved after infusion of nitroglycerin. A coronary angiogram (CAG) revealed that the patient had significant atherosclerosis in the proximal left circumflex artery. Coronary artery spasm with fixed stenosis was considered, and a drug-eluting stent was implanted. After 8 hours, the patient complained of recurring chest pain, paralleled by ST elevation on the ECG. The chest pain subsided after administration of intravenous nitroglycerin followed by sublingual nifedipine. Repeated CAG showed patency of the previous stent. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective in the prevention or treatment of 5-FU cardiotoxicity.",
"affiliations": "Department of Internal Medicine, Cardiovascular Center, Inje University Seoul Paik Hospital, Seoul, Korea.",
"authors": "Kim|Sang-Min|SM|;Kwak|Cheol-Hoon|CH|;Lee|Bora|B|;Kim|Seong Beom|SB|;Sir|Jung-Ju|JJ|;Cho|Wook-Hyun|WH|;Choi|Suk-Koo|SK|",
"chemical_list": "D002121:Calcium Channel Blockers; D009944:Organoplatinum Compounds; D014665:Vasodilator Agents; D005996:Nitroglycerin; D009543:Nifedipine; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Korea (South)",
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"doi": "10.3904/kjim.2012.27.3.342",
"fulltext": "\n==== Front\nKorean J Intern MedKorean J. Intern. MedKJIMThe Korean Journal of Internal Medicine1226-33032005-6648The Korean Association of Internal Medicine 10.3904/kjim.2012.27.3.342Case ReportA Case of Severe Coronary Spasm Associated with 5-Fluorouracil Chemotherapy Kim Sang-Min 1Kwak Cheol-Hoon 1Lee Bora 1Kim Seong Beom 1Sir Jung-Ju 2Cho Wook-Hyun 1Choi Suk-Koo 11 Department of Internal Medicine, Cardiovascular Center, Inje University Seoul Paik Hospital, Seoul, Korea.2 Department of Internal Medicine, Cardiovascular Center, National Medical Center, Seoul, Korea.Correspondence to Jung-Ju Sir, M.D. Department of Internal Medicine, Cardiovascular Center, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul 100-799, Korea. Tel: 82-2-2260-7430, Fax: 82-2-2262-4749, [email protected] 2012 01 9 2012 27 3 342 345 22 3 2008 16 6 2008 30 7 2008 Copyright © 2012 The Korean Association of Internal Medicine2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cardiotoxicity associated with 5-fluorouracil (FU) is an uncommon, but potentially lethal, condition. The case of an 83-year-old man with colon cancer who developed chest pain during 5-FU infusion is presented. The electrocardiogram (ECG) showed pronounced ST elevation in the lateral leads, and the chest pain was resolved after infusion of nitroglycerin. A coronary angiogram (CAG) revealed that the patient had significant atherosclerosis in the proximal left circumflex artery. Coronary artery spasm with fixed stenosis was considered, and a drug-eluting stent was implanted. After 8 hours, the patient complained of recurring chest pain, paralleled by ST elevation on the ECG. The chest pain subsided after administration of intravenous nitroglycerin followed by sublingual nifedipine. Repeated CAG showed patency of the previous stent. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective in the prevention or treatment of 5-FU cardiotoxicity.\n\nFluorouracilCoronary vasospasmCalcium channel blockersAngina pectoris\n==== Body\nINTRODUCTION\nThe antimetabolite 5-fluorouracil (FU) is widely used in the treatment of solid tumors, including gastrointestinal, breast, head, and neck cancers. Cardiotoxicity, a rare adverse effect of 5-FU, has a reported incidence of 1.2% to 18% [1,2]. The pathogenesis of 5-FU cardiotoxicity is unclear. The prevalent hypothesis suggests that 5-FU induces coronary vasospasm [1]. We report here a case of 5-FU cardiotoxicity. The patient presented with typical angina and electrocardiographic changes suggestive of an ischemic coronary event during the continuous infusion of 5-FU. The ischemia recurred when the infusion was stopped, and was relieved by administration of nitroglycerin followed by a sublingual calcium channel blocker.\n\nCASE REPORT\nAn 83-year-old man who had been diagnosed with stage IIIC (T4N2M0) adenocarcinoma of the ascending colon and who had undergone a right hemicolectomy was admitted to Inje University Seoul Paik Hospital to begin adjuvant chemotherapy, using the FOLFOX4 regimen (400 mg/m2 5-FU bolus infusion followed by the continuous infusion of 600 mg/m2 5-FU for 22 hours on days 1 and 2; 200 mg/m2 leucovorin as a continuous infusion for 2 hours before 5-FU infusion on days 1 and 2; and infusion of 85 mg/m2 oxaliplatin on day 1). The patient's medical history included no cardiovascular risk factors. Baseline echocardiography performed 1 month before admission showed normal left ventricular systolic function and no regional wall motion abnormality. He was treated with 1,500 mg high-dose 5-FU (1,000 mg/m2) per day. On the morning of the 3rd day, he developed a severe, substernal, crushing chest pain during the continuous intravenous infusion of 5-FU (cumulative dose 1,679 mg/m2), which was partially relieved by administering sublingual nitroglycerin. The electrocardiogram (ECG) showed ST segment elevation with a tall T wave in leads I, aVL, and V4-6, and reciprocal ST segment depression in leads V1-2 (Fig. 1A). The troponin-I and CK-MB levels were 0.010 ng/mL (reference range, ≤ 0.1) and 3.73 ng/mL (reference range, ≤ 4.94), respectively. Severe hypokinesia of the lateral wall of the left ventricle was noted on a portable bedside echocardiogram. The 5-FU infusion was stopped, and the chest pain and electrocardiographic changes resolved after intravenous infusion of nitroglycerin at 30 µg/min. Emergency coronary angiography was then performed, which revealed significant stenosis in the proximal left circumf lex coronary artery (LCx). Intracoronary nitroglycerin (200 µg) was injected to exclude coronary vasospasm, but no change occurred (Fig. 2). Intravenous ultrasound (IVUS) showed severe luminal narrowing with a heavy concentric plaque in the proximal LCx. Coronary artery spasm with fixed stenosis was considered. Percutaneous coronary intervention of the proximal LCx lesion was performed successfully with the implantation of a drug-eluting stent (3.5 × 16 mm; TAXUS, National Medical Center, Seoul, Korea) (Fig. 3). The patient was transferred to the coronary-care unit, where 8 hours later, he reported a recurrence of the anterior chest pain. The ECG also showed ST segment elevation and reciprocal ST changes similar to those seen in the previous ischemic events (Fig. 1B). The chest pain and ECG changes persisted despite a 100 µg/min nitroglycerin infusion. To rule out acute stent thrombosis, the patient was taken to the cardiac catheterization laboratory. The chest pain and ECG changes were relieved after sublingual administration of 10 mg nifedipine. Repeated coronary angiography showed a widely patent stent (Fig. 4). The postprocedural troponin-I and CK-MB levels were 0.010 and 4.62 ng/mL, respectively. Echocardiography performed the next day also showed the absence of the regional wall motion abnormality and normal left ventricular systolic function. The patient refused chemotherapy and was discharged in a stable condition. He remained free of the symptoms of recurrent angina pectoris.\n\nDISCUSSION\nWe present here a case of severe cardiotoxicity mimicking acute anterolateral myocardial infarction occurring in a patient receiving 5-FU chemotherapy for adenocarcinoma of the colon. The cessation of 5-FU administration and the subsequent initiation of treatment with a sublingual calcium channel blocker and nitrate resulted in a successful outcome. Although the mechanism by which 5-FU exerts its cardiotoxic effects is unknown, the resolution of the patient's chest pain and the normalization of his ECG changes with a vasodilator strongly support the vasospastic hypothesis of 5-FU cardiotoxicity.\n\nMany hypotheses regarding 5-FU-induced cardiotoxicity have been formulated. One study postulated that 5-FU-associated cardiotoxicity is due to the uncoupling of the electromechanical mechanisms that underlie normal myocardial function, which might be mediated at the level of the cell membrane [3]. Recently, Kuzel et al. [4] suggested that 5-FU promotes a hypercoagulable state (e.g., coronary artery thrombosis) and observed a significant increase in fibrinopeptide A and a decrease in protein C activity during 5-FU administration.\n\nThe incidence of clinically apparent 5-FU cardiotoxicity is less than 10% in patients receiving the drug [5]. Patients with a history of coronary artery disease (CAD) have a significantly increased risk of 5-FU-induced cardiotoxicity [6]. Although our patient did not have a history of CAD, a large atheromatous plaque was found on coronary angiography and IVUS. Therefore, during 5-FU infusion, close, careful monitoring of patients, especially those with pre-existing CAD or CAD risk factors, is mandatory. Prophylactic calcium channel blockers or nitrates should be administered to patients with CAD during 5-FU administration, to prevent vasospasm [7]. One study proposed that impaired renal function is also a risk factor for 5-FU cardiotoxicity. Although it is not clear whether the cardiotoxic metabolites undergo renal excretion, the pathophysiological effect of 5-FU on the myocardium is likely to increase with decreased renal function. Thus it is necessary to clarify which patients may benefit from optimum anti-angina prophylaxis and careful, close monitoring [1].\n\nThe incidence of 5-FU-related cardiotoxicity appears to be dependent on the dosage and delivery system. Infusion of 5-FU, which is now being used more frequently and at higher doses instead of bolus therapy, may be a significant factor in the development of 5-FU cardiotoxicity [5]. In one study, nine patients treated with a higher-dose (> 800 mg/m2) continuous infusion of 5-FU died suddenly [5].\n\nInterestingly, despite stopping the 5-FU, the chest pain and ECG changes recurred in our case. One series reported that 19% of the patients developed reversible angina pectoris during treatment, which lasted for up to 12 hours after cessation of the infusion [2]. The possible mechanisms of delayed angina are the late release of potent vasoactive 5-FU metabolites, which accumulate over time due to degradation of 5-FU [8]. Therefore, a calcium channel blocker or nitrates should be administered after stopping the 5-FU when 5-FU-induced cardiotoxicity occurs.\n\nThe long-term outcome of patients with 5-FU-related cardiotoxicity has not been investigated extensively. As with our case, Patel et al. [8] recently reported interval improvements in the left ventricular wall motion abnormalities in echocardiography performed 8 to 15 days following the initial study. Other investigators have reported similar reversible left ventricular dysfunction [9]. When cardiotoxicity occurs, 5-FU treatment is usually discontinued due to its very high recurrence rate (90%) [10]. The re-administration of 5-FU is not recommended, and a different chemotherapy regimen should be considered. Interestingly, Meydan et al. [10] continued 5-FU chemotherapy in one group who experienced 5-FU cardiotoxicity due to the absence of an alternative drug and found that subsequent serious, hemodynamic consequences were easily controlled with nitrate treatment. For the remaining patients, either 5-FU was removed from the combination regimen or an alternative drug was started and no cardiotoxicity developed subsequently.\n\nIn summary, although 5-FU-associated cardiac toxicity is rare, it may cause angina, myocardial infarction, and even sudden death. Physicians should be aware of this potentially lethal side effect and should start the proper treatment when 5-FU cardiotoxicity develops. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective for prevention or treatment of 5-FU cardiotoxicity.\n\nNo potential conflict of interest relevant to this article is reported.\n\nFigure 1 (A) 12-lead electrocardiogram obtained during the chest pain showed ST segment elevation with tall T waves in leads I, aVL, and V4-6 and reciprocal ST segment depression in leads V1-2. (B) During a recurrence of the chest pain, ST segment elevation was seen in leads II, III, aVF, and V4-6 and reciprocal ST segment depression in leads V1-3.\n\nFigure 2 The left coronary angiogram in a right anterior oblique caudal projection showed a significant ostial lesion (arrow) in the left circumflex coronary artery.\n\nFigure 3 The left coronary angiogram in a left anterior oblique caudal projection after percutaneous coronary intervention with drug-eluting stent implantation (3.5 × 1.6 mm; TAXUS).\n\nFigure 4 Repeated left coronary angiogram in a right anterior oblique caudal projection showed a widely patent stent.\n==== Refs\n1 Jensen SA Sorensen JB Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine Cancer Chemother Pharmacol 2006 58 487 493 16418875 \n2 Wacker A Lersch C Scherpinski U Reindl L Seyfarth M High incidence of angina pectoris in patients treated with 5-fluorouracil: a planned surveillance study with 102 patients Oncology 2003 65 108 112 12931015 \n3 Robben NC Pippas AW Moore JO The syndrome of 5-fluorouracil cardiotoxicity: an elusive cardiopathy Cancer 1993 71 493 509 8422644 \n4 Kuzel T Esparaz B Green D Kies M Thrombogenicity of intravenous 5-f luorouracil alone or in combination with cisplatin Cancer 1990 65 885 889 2297659 \n5 Gradishar WJ Vokes EE 5-Fluorouracil cardiotoxicity: a critical review Ann Oncol 1990 1 409 414 2083185 \n6 Rezkalla S Kloner RA Ensley J Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study J Clin Oncol 1989 7 509 514 2466960 \n7 Kleiman NS Lehane DE Geyer CE Jr Pratt CM Young JB Prinzmetal's angina during 5-fluorouracil chemotherapy Am J Med 1987 82 566 568 3826112 \n8 Patel B Kloner RA Ensley J Al-Sarraf M Kish J Wynne J 5-fluorouracil cardiotoxicity: left ventricular dysfunction and effect of coronary vasodilators Am J Med Sci 1987 294 238 243 3661619 \n9 Baker WP Dainer P Lester WM Marty AM Blair TP Ischemic chest pain after 5-fluorouracil therapy for cancer Am J Cardiol 1986 57 497 498 3946274 \n10 Meydan N Kundak I Yavuzsen T Cardiotoxicity of de Gramont's regimen: incidence, clinical characteristics and long-term follow-up Jpn J Clin Oncol 2005 35 265 270 15855175\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1226-3303",
"issue": "27(3)",
"journal": "The Korean journal of internal medicine",
"keywords": "Angina pectoris; Calcium channel blockers; Coronary vasospasm; Fluorouracil",
"medline_ta": "Korean J Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D000787:Angina Pectoris; D000971:Antineoplastic Combined Chemotherapy Protocols; D002121:Calcium Channel Blockers; D003110:Colonic Neoplasms; D017023:Coronary Angiography; D003329:Coronary Vasospasm; D054855:Drug-Eluting Stents; D004562:Electrocardiography; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D009543:Nifedipine; D005996:Nitroglycerin; D009944:Organoplatinum Compounds; D062645:Percutaneous Coronary Intervention; D012008:Recurrence; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014665:Vasodilator Agents",
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"pages": "342-5",
"pmc": null,
"pmid": "23019400",
"pubdate": "2012-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15855175;3661619;2297659;16418875;3826112;3946274;2083185;8422644;2466960;12931015",
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"abstract": "•Young women with dermatomyositis are at high risk for underlying ovarian cancer.•Dermatomyositis symptoms can be used to assess treatment and recurrence of disease.•Immunosuppression can complicate postoperative recovery in ovarian cancer patients.•Ovarian cancer patients with dermatomyositis should have genetic testing.",
"affiliations": "Department of Obstetrics and Gynecology, University of Washington Medical Center, Seattle, WA, United States.;Department of Obstetrics and Gynecology, University of Washington Medical Center, Seattle, WA, United States.",
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"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(17)30121-210.1016/j.gore.2017.11.009Case ReportDermatomyositis - key to diagnosing ovarian cancer, monitoring treatment and detecting recurrent disease: Case report Field Carlie [email protected]⁎Goff Barbara A. Department of Obstetrics and Gynecology, University of Washington Medical Center, Seattle, WA, United States⁎ Corresponding author at: Department of Obstetrics and Gynecology, University of Washington Medical Center, 1959 NE Pacific Street, Campus Box 356460, Seattle, WA 98195, United States.Department of Obstetrics and GynecologyUniversity of Washington Medical Center1959 NE Pacific StreetCampus Box 356460SeattleWA98195United States [email protected] 11 2017 2 2018 28 11 2017 23 1 3 27 10 2017 22 11 2017 25 11 2017 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Young women with dermatomyositis are at high risk for underlying ovarian cancer.\n\n• Dermatomyositis symptoms can be used to assess treatment and recurrence of disease.\n\n• Immunosuppression can complicate postoperative recovery in ovarian cancer patients.\n\n• Ovarian cancer patients with dermatomyositis should have genetic testing.\n\n\n\nKeywords\nOvarian cancerDermatomyositisBRCA mutationImmunosuppressionAnti-p155/140 autoantibody\n==== Body\n1 Introduction\nDermatomyositis is an idiopathic inflammatory myopathy characterized by proximal skeletal muscle weakness, muscle inflammation and distinct cutaneous eruptions. The disease is rare, with an incidence of 0.5–0.89 per 100,000 with a female to male predominance of 2:1 (Mammen et al., 2013). There is an association between dermatomyositis and malignancy. The most common cancers in female patients are ovarian (13.3–26%) and breast cancer (13.5%) (Sigurgeirsson et al., 1992).\n\nIn this case report, we describe two premenopausal women with skin and muscle symptoms consistent with dermatomyositis. They were started on high-dose immunosuppressive therapy without resolution of symptoms and were subsequently diagnosed with stage III ovarian cancer. After debulking surgery and adjuvant chemotherapy their symptoms associated with dermatomyositis resolved.\n\n2 Case 1\nCase 1 is a 38-year-old G0 healthy female presenting with an erythematous facial rash, muscle pain and weakness in her shoulders and hips and swelling in the proximal nail folds [Fig. 1a]. She was diagnosed with dermatomyositis and started on mycophenolate mofetil 1000 mg BID, prednisone 30 mg daily and topical tacrolimus. Labs showed an elevated anti-p155/140 autoantibody. PET-CT showed a hyper-metabolic left para-aortic mass and lymph node (SUV 15.6 and SUV 4.6, respectively) with a focus of uptake in the right ovary (SUV 8.1). A retroperitoneal biopsy of the left para-aortic lymph node showed metastases from a Mullerian primary with serous differentiation. CA-125 level was 65. Prior to surgery, mycophenolate mofetil was held and prednisone was decreased to 20 mg daily. The patient underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, omentectomy and argon beam ablation. Intraoperatively, there was a right ovarian mass and disease in the para-aortic region requiring radical dissection for optimal cytoreduction. Stress dose steroids were given during surgery and for 24 h postoperatively and she was continued on prednisone 20 mg daily. Final pathology revealed stage IIIAi2 high-grade serous carcinoma. The patient was of Ashkenazi Jewish ancestry and had a maternal great-grandmother with ovarian cancer. Her genetic testing was negative. She received adjuvant chemotherapy with IV carboplatin and paclitaxel. Her symptoms and rash resolved after surgery and two cycles of chemotherapy [Fig. 1b]. Her CA125 trended down to 55.6. After surgery and two cycles of chemotherapy, she developed a pelvic abscess that required drainage and antibiotic therapy. Cycle 3 of chemotherapy was delayed due to infection. At the time of this report, the patient had completed chemotherapy and has no evidence of disease.Fig. 1 A) Case 1 - Dermatomyositis skin manifestations including Gottron's papules, heliotrope facial rash and periorbital edema prior to surgery and chemotherapy B) Case 1 - Resolution of skin manifestations after surgery and chemotherapy.\n\nFig. 1\n\n3 Case 2\nCase 2 is a 43-year-old G1P0010 healthy female, who presented with a 6-week history of flu symptoms, muscle and joint pain and skin rash. Her OBGYN history was notable for one prior termination of pregnancy and OCP use for 20 years. She had a paternal and maternal grandmother with breast cancer. She was started on high-dose prednisone and antibiotics. Symptoms did not improve and she continued to have a macular erythema over shoulders, neck and face with periorbital edema. A MRI of bilateral thighs and muscle biopsy showed changes consistent with dermatomyositis. CT imaging revealed a right adnexal mass with omental caking. Immediately before surgery, CA125 was 338. She underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy and radical ovarian tumor debulking. She was sub-optimally debulked. Intraoperatively, there were bilateral complex adnexal masses, extensive omental caking with numerous small implants on the mesentery of the small bowel. Stress dose steroids were given during surgery and for 24 h postoperatively. She was continued on prednisone 60 mg daily. Final pathology revealed Stage IIIC high-grade serous ovarian carcinoma. Genetic testing confirmed BRCA2 mutation. She received adjuvant chemotherapy with 6 cycles of IV carboplatin and paclitaxel with bevacizumab starting cycle 2. She had improvement in symptoms and remained on maintenance bevacizumab for 16 months, but it was discontinued due to toxicity. About 1 year later, she had recurrence of her rash and muscle symptoms and was noted to have an elevated CA125. CT imaging confirmed recurrence and she was started on carboplatin and doxorubicin. She had an excellent response with downtrending CA125 and resolution of dermatomyositis symptoms. She is currently enrolled in a clinical trial with randomization between oral PARP inhibitor rucaparib versus placebo. Recent imaging shows no evidence of recurrent disease.\n\n4 Discussion\nDermatomyositis is an autoimmune connective tissue disease that presents with cutaneous eruptions including discoloration on the eyelids with edema, a flat rash on the face and upper trunk, and erythema of the knuckles with raised violaceous scaly eruptions (Mammen et al., 2013). Most patients also have symmetric proximal muscle weakness (Mammen et al., 2013). An elevated creatine kinase, aldolase, AST, ALT and lactate dehydrogenase, which are released from damaged muscle, are often present, but not required for diagnosis (Mammen et al., 2013). Other myositis-specific autoantibodies can be associated with dermatomyositis including anti-Mi-2, anti-Jo-1, anti-U1-RNP and anti-155/140 (Mammen et al., 2013, Wolff et al., 2017). The anti-p155/140 autoantibody increases the risk of an underlying malignancy by 18-fold and previous reports have shown that 71% of patients with this antibody will be diagnosed with cancer (Mammen et al., 2013, Selva-O'Callaghan et al., 2010).\n\nThe most common malignancies associated with dermatomyositis are ovarian, breast and colon cancer, melanoma and non-Hodgkin's lymphoma (Dalakas, 2014, Hill et al., 2001). Ovarian cancer was found in 8.3% of patients with dermatomyositis (Dobloug et al., 2015). Cancer is most commonly diagnosed simultaneously with or during the first year after the diagnosis of dermatomyositis although there continues to be an elevated risk of malignancy even after 5 years (Hill et al., 2001). Malignancies are usually identified through a history, physical exam, basic labs and/or age-appropriate screening tests (Dalakas, 2014). In women, a transvaginal ultrasound and CA125 may be helpful to identify ovarian cancer (Mammen et al., 2013). If malignancy is clinically suspected, a whole body PET scan can be considered (Dalakas, 2014). It has been proposed that patients with dermatomyositis and anti-p155/140 autoantibody should have a whole body PET scan due to the high association of this antibody with underlying cancers (Selva-O'Callaghan et al., 2010). Other studies have shown that malignancy is increased in all patients with dermatomyositis, even those less than 45 years old (Hill et al., 2001). Our patients were both under 45 and highlight the importance of maintaining a high clinical suspicion regardless of age. Patients who have a negative malignancy screen initially should have careful surveillance. Current recommendations for ovarian cancer surveillance in women with dermatomyositis include pelvic exam, CA125 level and transvaginal ultrasound at 6–12 month intervals for at least 2 years after diagnosis, but observation for up to 5 years may have benefit (Sontheimer et al., 2012).\n\nIn patients with dermatomyositis, there are some important considerations regarding preoperative and postoperative management due to immunosuppression. Preoperatively and postoperatively, our patients were continued on their outpatient oral steroid regimen along with supplemental perioperative IV steroids. In patients with functional adrenal insufficiency from high dose steroids, there is concern for adrenal crisis induced by the stress of surgery and historically patients have received preoperative stress dose steroids (Marik and Varon, 2008). For an ovarian debulking surgery, the patient would continue their outpatient regimen of steroids and receive hydrocortisone 100 mg IV once and continue hydrocortisone 50 mg IV q8hours for 24 h postoperatively (Jackson et al., 2015).\n\nHigh dose steroids have negative impacts including poor wound healing, risk of infection, fluid retention and hyperglycemia. In one of our patients, steroids may have contributed to the development of a postoperative wound abscess. New evidence suggests that if patients continue their outpatient steroid regimen, no preoperative stress dose steroids should be required to prevent adrenal crisis (Marik and Varon, 2008, Kelly and Domajnko, 2013). A Cochrane review showed that supplemental perioperative steroids did not decrease adverse effects or complications in patients with adrenal insufficiency undergoing surgery, although results were limited by small number of patients (Yong et al., 2012). The team should be aware that the patient has been on high-dose corticosteroids, but clinicians may consider giving stress dose steroids only if the patient develops volume refractory hypotension consistent with adrenal crisis (Marik and Varon, 2008).\n\nDermatomyositis symptoms can lead to the initial diagnosis of ovarian cancer, but can also be used to monitor treatment and recurrence. Both of these patients and other case reports describe resolution of symptoms after surgery and chemotherapy that parallel down trending CA125 levels (Chao and Wei, 2009, Christie et al., 2013). In a similar fashion, relapse of dermatomyositis can be the first sign of recurrent ovarian cancer (Chao and Wei, 2009, Christie et al., 2013). In Case 2, the patient represented with recurrent skin manifestations, followed by muscle symptoms and was then found to have a rising CA125. During ovarian cancer surveillance in patients with dermatomyositis, it is important to be vigilant in asking about recurrent skin manifestations or muscle weakness, as this could be the first indication of recurrent malignancy.\n\nDermatomyositis patients who are diagnosed with breast or ovarian cancer should have genetic testing for BRCA mutations. Case 2 in this case report was positive for the BRCA2 gene mutation, while the other patient's genetic testing returned negative. There is only one other case report related to dermatomyositis and ovarian cancer in which genetic testing has been reported and was positive for BRCA1 mutation (Arshad and Barton, 2016). Other patients with dermatomyositis who were subsequently diagnosed with breast cancer have been found to have BRCA1 gene mutations (Selva-O'Callaghan et al., 2010). Genetic testing is an important component in caring for these patients to ensure they have appropriate risk reduction surveillance if they have positive testing.\n\nClinicians should have a high clinical suspicion for underlying ovarian cancer, especially with an elevated anti-p155/140 autoantibody, in women of all ages diagnosed with dermatomyositis. Dermatomyositis patients are often immunosuppressed, which can present unique challenges at the time of surgery for ovarian cancer. Treatment response and recurrence of disease can be monitored with dermatomyositis symptoms. All women diagnosed with dermatomyositis and ovarian cancer should have genetic testing.\n\nConsent\nWritten informed consent was obtained from the patients for review by the Editor-in-Chief of this journal on request.\n\nConflicts of interest\nThe authors have no conflicts of interest.\n==== Refs\nReferences\nArshad Ilyas Barton Desmond Dermatomyositis as a paraneoplastic phenomenon in ovarian cancer BMJ Case Rep. Aug. 2016 \nChao Lai-Wan Wei Lin-Hung Dermatomyositis as the initial presentation of ovarian cancer Taiwanese J. Obst. Gynecol. 48 2 2009 178 180 19574184 \nChristie Alan Dermatomyositis as presenting feature of ovarian cancer, treated with neo-adjuvant chemotherapy and interval Debulking surgery Gynecologic Oncol. Case Rep. 6 2013 13 15 \nDalakas M.C. Polymyositis, dermatomyositis, and inclusion body myositis Kasper D. Fauci A. Hauser S. Longo D. Jameson J. Loscalzo J. Harrison's Principles of Internal Medicine, 19e 2014 McGraw-Hill New York, NY http://accessmedicine.mhmedical.com/content.aspx?bookid=1130§ionid=79750722 (Accessed October 05, 2017) \nDobloug Gerd Cecilie Survival and cancer risk in an unselected and complete Norwegian idiopathic inflammatory myopathy cohort Semin. Arthritis Rheum. 45 3 2015 301 308 26190563 \nHill Catherine L. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study Lancet 357 9250 2001 96 100 11197446 \nJackson Molly Blackley The Perioperative Medicine Consult Handbook 2015 Springer International Publishing \nKelly Kristin Domajnko Bastian Perioperative stress-dose steroids Clin. Colon. Rectal Surg. 26 03 2013 163 167 24436668 \nMammen Andrew L. Imboden John B. “Chapter 27. Dermatomyositis, Polymyositis, & Immune-Mediated Necrotizing Myopathy” CURRENT Diagnosis & Treatment: Rheumatology 3 edn 2013 McGraw-Hill New York, NY http://accessmedicine.mhmedical.com/content.aspx?bookid=506§ionid=42584912 \nMarik P.E. Varon J. Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature Arch. Surg. 143 12 2008 1222 1226 19075176 \nSelva-O'Callaghan Albert Malignancy and myositis: novel autoantibodies and new insights Curr. Opin. Rheumatol. 22 6 2010 627 632 20827204 \nSigurgeirsson B. Risk of cancer in patients with dermatomyositis or polymyositis N. Engl. J. Med. 326 6 June 1992 363 367 1729618 \nSontheimer RD, Hansen CB, Costner MI. Chapter 156. Dermatomyositis. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Eds. Fitzpatrick's Dermatology in General Medicine, 8 edn New York, NY: McGraw-Hill; 2012. http://accessmedicine.mhmedical.com.offcampus.lib.washington.edu/content.aspx?bookid=392§ionid=41138880. (Accessed November 12, 2017).\nWolff M. Paraneoplastic dermatomyositis with cutaneous and Myopathic disease responsive to adrenocorticotropic hormone therapy J. Clin. Aesthet. Dermatol. 10 1 2017 57 62 \nYong Sin Leong Supplemental Perioperative Steroids for Surgical Patients with Adrenal Insufficiency Dec. 2012 Cochrane Database of Systematic Reviews\n\n",
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"abstract": "BACKGROUND\nIV acetaminophen at 4 g per day is considered safe, producing no hepatic failure in more than 1400 cases. Oxidation of acetaminophen forms a reactive intermediate that binds to cellular proteins resulting in acetaminophen-protein adducts (APAP-CYS). Serum concentrations of APAP-CYS have been found to correlate with acetaminophen-induced hepatotoxicity. We report a case of hepatotoxicity associated with therapeutic doses of IV acetaminophen, with elevated serum APAP-CYS.\n\n\nMETHODS\nThe patient was a 92-year-old, 68 kg woman without known hepatic disease or ethanol abuse. On hospital day 3 she underwent laparoscopic reduction of internal hernias under general anesthesia. Surgery was uncomplicated and postoperatively she was treated with subcutaneous heparin and IV acetaminophen, 1 g every 6 h for almost 4 days (total dose = 13 g). At the start of therapy, transaminases were normal. On hospital day 5, she was noted to have marked transaminase elevations (AST: 4698 IU/L; ALT: 3914 IU/L) with increases in INR (1.68), ammonia (60 mcg/dL), and total bilirubin (1.8 mg/dL). Serum acetaminophen concentration was 15.3 mcg/mL 26 h after her last dose. Acetaminophen was discontinued and IV acetylcysteine was given and continued at the second maintenance dose rate for a second 16-hour infusion, at which time transaminases, INR, ammonia and total bilirubin were all improving. The patient was discharged 2 days later. Serum APAP-CYS concentrations in serum samples obtained during her hospitalization were elevated (peak = 4.81 μM on hospital day 5; expected range for therapeutic dosing <1.1 μM).\n\n\nMETHODS\nWe have identified a case of acute liver injury associated with therapeutic dosing of IV acetaminophen. The serum APAP-CYS concentrations are consistent with that seen in cases of hepatotoxicity following repeated supratherapeutic acetaminophen ingestion. Several factors that likely contributed to her susceptibility included advanced age, post-operative status, a likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury.\n\n\nCONCLUSIONS\nThis case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury.",
"affiliations": "a Department of Emergency Medicine and New Mexico Poison and Drug Information Center , University of New Mexico Health Sciences Center , Albuquerque , NM , USA ;;b Christus St. Vincent Regional Medical Center , Santa Fe , NM , USA ;;c Rocky Mountain Poison and Drug Center, Denver Health , Denver , CO , USA ;;c Rocky Mountain Poison and Drug Center, Denver Health , Denver , CO , USA ;;c Rocky Mountain Poison and Drug Center, Denver Health , Denver , CO , USA ;;d Department of Emergency Medicine , University of Colorado School of Medicine , Aurora , CO , USA.",
"authors": "Seifert|Steven A|SA|;Kovnat|Daniel|D|;Anderson|Victoria E|VE|;Green|Jody L|JL|;Dart|Richard C|RC|;Heard|Kennon J|KJ|",
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"mesh_terms": "D000082:Acetaminophen; D061605:Administration, Intravenous; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D005260:Female; D059685:Herniorrhaphy; D006801:Humans; D010535:Laparoscopy; D008111:Liver Function Tests; D010146:Pain",
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"pmc": null,
"pmid": "26763284",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen.",
"title_normalized": "acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen"
}
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{
"abstract": "BACKGROUND\nLung cancer is the leading cause of cancer-associated deaths all over the world. Although the prognosis of lung cancer has improved over the past decade due to progression in surgical techniques and systematic treatments, the patients with advanced disease still suffer poor survival. There are no standard treatment strategies for patients who have failed to respond to at least 2 lines of chemotherapy in non-small cell lung cancer (NSCLC). Apatinib, one of the latest small-molecule oral anti-angiogenesis targeted agents developed first in China, has shown remarkable anti-tumor efficacy in a variety of solid tumor types.\nA 72-year-old woman underwent radical resection of the left lung cancer in July 2011, but was found a recurrence of cancer after 2 years.\nThe histopathological examination of the resected specimen identified the lesion as lung adenocarcinoma.\n\n\nMETHODS\nShe received gemcitabine and carboplatin regimen as adjuvant chemotherapy for 4 cycles following the surgery in August 2011. After the tumor relapsed, she received multiple lines of chemotherapy including paclitaxel, cisplatin, docetaxel, and gemcitabine from July 2013, but still suffered progressive disease in February 2017. Then apatinib alone was used to defend against the tumor at a dose of 250 mg/d orally till December 2017.\n\n\nRESULTS\nThe efficacy was assessed as partial response 1 month later in March 2017. And the use of apatinib was continued till the patient died of tumor progression, achieving a progression-free survival for 10 months. During the treatment with apatinib, the patient experienced hypertension of grade 1, which was well-tolerated and manageable.\n\n\nCONCLUSIONS\nApatinib might be efficient and well-tolerated for patients with advanced NSCLC who have failed to respond to multi-line treatments, even at a low dose.",
"affiliations": "Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.",
"authors": "Liu|Jin|J|;Zheng|Yulong|Y|;Xu|Nong|N|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C553458:apatinib; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000014328",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30702616MD-D-18-0673210.1097/MD.0000000000014328143285700Research ArticleClinical Case ReportLow dose of apatinib in treating chemotherapy and EGFR-TKI refractory non-small cell lung cancer A case reportLiu Jin MDZheng Yulong MDXu Nong MD∗NA. Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.∗ Correspondence: Nong Xu, Department of Medical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou 310000, Zhejiang, China (e-mail: [email protected]).2 2019 01 2 2019 98 5 e1432818 9 2018 27 12 2018 8 1 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nLung cancer is the leading cause of cancer-associated deaths all over the world. Although the prognosis of lung cancer has improved over the past decade due to progression in surgical techniques and systematic treatments, the patients with advanced disease still suffer poor survival. There are no standard treatment strategies for patients who have failed to respond to at least 2 lines of chemotherapy in non-small cell lung cancer (NSCLC). Apatinib, one of the latest small-molecule oral anti-angiogenesis targeted agents developed first in China, has shown remarkable anti-tumor efficacy in a variety of solid tumor types.\n\nPatient concerns:\nA 72-year-old woman underwent radical resection of the left lung cancer in July 2011, but was found a recurrence of cancer after 2 years.\n\nDiagnoses:\nThe histopathological examination of the resected specimen identified the lesion as lung adenocarcinoma.\n\nInterventions:\nShe received gemcitabine and carboplatin regimen as adjuvant chemotherapy for 4 cycles following the surgery in August 2011. After the tumor relapsed, she received multiple lines of chemotherapy including paclitaxel, cisplatin, docetaxel, and gemcitabine from July 2013, but still suffered progressive disease in February 2017. Then apatinib alone was used to defend against the tumor at a dose of 250 mg/d orally till December 2017.\n\nOutcomes:\nThe efficacy was assessed as partial response 1 month later in March 2017. And the use of apatinib was continued till the patient died of tumor progression, achieving a progression-free survival for 10 months. During the treatment with apatinib, the patient experienced hypertension of grade 1, which was well-tolerated and manageable.\n\nLessons:\nApatinib might be efficient and well-tolerated for patients with advanced NSCLC who have failed to respond to multi-line treatments, even at a low dose.\n\nKeywords\nanti-angiogenesisapatinibnon-small cell lung cancerOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nLung cancer results in the largest number of cancer-related deaths worldwide, and more than 85% of the populations are diagnosed as non-small cell lung cancer (NSCLC). For lung cancer with all stages at diagnosis, the 5-year survival rate is only 16.8% and much lower for those with advanced disease, approximately 2%.[1] NSCLC at early stage is primarily treated by surgical resection combined with adjuvant chemotherapy for selected patients, whereas advanced NSCLC remains an incurable disease, which should be managed comprehensively based on systemic therapy. As backbone of treatment in advanced NSCLC, platinum-based doublet chemotherapy does have clear clinical benefits, but seems to have reached the bottleneck in efficacy due to the limited benefits in overall survival (OS). Targeted therapies for patients with mutated EGFR and ALK have shown better results when compared with chemotherapy; however, most of them gain drug resistance inevitably and still have to undergo chemotherapy. Thus, making new strategies to treat patients with advanced NSCLC who suffered PD after 2 or more lines of chemotherapy is urgent.\n\nAngiogenesis is a key process for cell growth. And vast data have shown that it plays a pivotal role in tumor growth, progression, local invasion, and distant metastasis.[2] Based on this theory, anti-angiogenesis has been one of the most promising anti-cancer means. Apatinib, a small molecule oral anti-angiogenesis biologic agent targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has been studied in multiple solid tumors and shown tremendous antitumor efficacy. Owing to favorable side effects profile and prolonged PFS and OS in advanced gastric cancer, apatinib has been approved to treat patients with advanced gastric cancer and adenocarcinoma in the gastroesophageal junction who failed to 2 or more lines of prior chemotherapy in China.[3] Several studies focusing on efficacy and safety of apatinib in treating patients with breast cancer also obtained positive results.[4,5] However, for lung cancer, such clinical trials and clinical practice are relatively rare. Herein, we report an old woman with lung adenocarcinoma who received apatinib as fourth-line treatment and got long PFS.\n\n2 Case presentation\nA 72-year-old female patient underwent radical resection of the left lung cancer in July 2011 because of a mass revealed by computed tomography (CT) of chest. Pathological examination confirmed the diagnosis of lung adenocarcinoma, with a stage of IIIA (pT1N2M0) based on the NCCN tumor-node-metastasis classification system. Then she proceeded with gemcitabine and carboplatin regimen as adjuvant chemotherapy for 4 cycles. During her routine review on July 19, 2013, thickened left pleura and small nodular lesions of both lungs were revealed by the chest CT, which were considered as tumor recurrence and intrapulmonary metastases. Subsequently, the patient was treated with paclitaxel and carboplatin as first-line chemotherapy for 4 cycles. She was also recommended to take icotinib orally at a dose of 125 mg 3× a day as maintenance therapy due to the active EGFR mutation (L858R in exon 21) found in November 2013. Unfortunately, in October 2014, the tumor was evaluated as PD again, which led to second-line chemotherapy involving docetaxel monotherapy for 4 cycles. Ten months later on August 27, 2015, the chest CT showed progressive tumor in the left lung and carcinoembryonic antigen (CEA) also increased; so, gemcitabine and cisplatinum were prescribed as third-line chemotherapy. However, the regimen was discontinued on the first day due to her severe nausea, vomiting, anorexia, and fatigue. Then the strategy switched to paclitaxel monotherapy for 4 cycles. At the same time, the genetic analysis using her peripheral blood sample displayed that T790 M was negative, so icotinib was continued as maintenance therapy. More than 1 year later on February 8, 2017, the patient was admitted to our department complaining of severe cough and white sputum with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. The chest CT identified PD in left lung (Fig. 1A) and serum CEA level markedly increased to 715.3 ng/mL. No evidence of metastasis was observed in abdomen, brain, and bone with the CT examination or bone scan. After comprehensive assessment, apatinib alone was prescribed at a dose of 250 mg/d orally to defend against the tumor. Remarkable tumor regression (Fig. 1B) was observed, and CEA also sharply decreased to normal level 1 month later on March 8, 2017. Therefore, the regimen was continued and the chest CT was performed every 2 months to assess the tumor. On October 23, 2017, the chest CT indicated stable disease in the left lung (Fig. 1C). But 2 months later on December 15, 2017, the woman attended our hospital for chest pain with a bad ECOG PS of 3. The chest CT verified PD of left lung cancer and serious infection of both lungs. Although received anti-infective and supportive treatment, she died of respiratory failure 2 weeks later. Hypertension of grade 1 occurred in her whole course of apatinib treatment, which was tolerated and manageable with no dose adjustment or drug withdrawal. What deserves to be mentioned was that the patient had been taking icotinib as maintenance therapy between line-to-line chemotherapy until the administration of apatinib in her whole course of anti-tumor treatment.\n\nFigure 1 A: Metastatic lesions in the left lung and left pleural before apatinib usage on February 8, 2017 when failed to third-line chemotherapy; B: A month later on March 8, 2017, the metastasis in the left lung shrank by 25% compared with that a month ago, the efficacy was partial response. C: The tumor was evaluated as sable disease on August 21, 2017 after the use of apatinib for 6 months.\n\n3 Discussion\nNew blood vessel provides oxygen and nutrition for tumor cell growth, contributing to tumor survival, local invasion, and distant metastasis. Anti-angiogenesis therapy has been greatly investigated since the 1970s when Folkman first put forward that targeting the angiogenesis could interfere in tumorigenesis.[6] Vascular endothelial growth factor (VEGF) protein members and their receptors may be the most crucial factors involved in angiogenesis in malignant tumors. VEGF protein family consists of VEGF A, B, C, D, F, placental growth factor (PIGF), and their receptors VEGFR-1, 2, 3, among which VEGF-A (or VEGF) and VEGFR-2 are widely accepted as mostly responsible for tumor development.[7]\n\nApatinib is an orally administered small molecule inhibitor of VEGFR-2, which binds to VEGFR-2 and inhibits VEGF binding and subsequent VEGFR-2 autophosphorylation, while VEGFR-2 undergoes autophosphorylation when stimulated by VEGF, inducing a signal transduction cascade that finally leads to vascular endothelium proliferation and survival.[8] Apatinib can also reverse multidrug resistance through inhibiting transport function of multidrug resistance proteins and enhance the antitumor effect of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) after T790M.[9,10]\n\nIn terms of lung cancer, a retrospective study reported that NSCLC patients who received apatinib monotherapy as third-line treatment achieved an objective response rate (ORR) of 18.2%, a disease control rate (DCR) of 95.5%, and a median PFS of 6.7 months. The major adverse effects including hypertension, gastrointestinal reactions and hand-foot syndrome were controllable and tolerable.[11] In another retrospective study, 25 patients with advanced NSCLC took apatinib alone at a dose of 500 mg/d as palliative therapy.[12] The overall ORR and DCR were 8.0% and 68.0%, respectively. The overall median PFS was 5.17 months (95% CI: 0.76–9.57). For 13 patients in the second-line setting, the median PFS was 7.37 months (95% CI: 0.01–14.72), and for the 12 patients in the third-line or beyond therapy, which was 5.17 months (95% CI: 1.78–8.55). All patients had good tolerance to apatinib and no grade 3/4 adverse events occurred. Zeng found that patients with lung adenocarcinoma who received apatinib monotherapy at a small dose (250–500 mg/d) as second-line treatment finally obtained an ORR of 18.75%, a DCR of 68.75%, and a median PFS of 4.4 months. Main toxicities such as hypertension, hand-foot syndrome, proteinuria, and thrombocytopenia were also tolerable and manageable.[13]\n\nFor our patient, apatinib was prescribed at a low dose of 250 mg/d, considering the female's failure to multi-line chemotherapy and ECOG PS of 2. Generally, apatinib at an initial dose of 750 mg/d shows clinical benefits in advanced NSCLC, and a dose of 500 mg/d is more commonly adopted in previous trials in case of unbearable adverse events.[14,15] Dose modification to 250 mg/d in advanced NSCLC was also reported in literature before and the patient even achieved PR just like our case.[16] Our patient finally achieved a PFS of 10 months, which was encouraging, as the median PFS of apatinib in treating advanced NSCLC was approximately 5 months according to previous reports.[11–13] The most common adverse effects of apatinib are hypertension, hand-foot syndrome, and proteinuria. The patient experienced only hypertension of grade 1 in the course of using aptinib, which might be attributed to the small dose.\n\nOur patient used another targeted drug icotinib as maintenance therapy in her whole course of antitumor treatment. It has been thought that apatinib could enhance efficacy of EGFR-TKIs in advanced NSCLC, however, whether prior use of EGFR-TKIs makes positive influence on efficacy of apatinib and contributes to our patient's long PFS are still unclear and need to be confirmed in the future.\n\nTherefore, our case suggests that apatinib might be efficient and well-tolerated for advanced NSCLC patients who failed to respond to multi-line chemotherapy, even at a low dose. However, this is only a case report and more clinical trials should be launched to confirm.\n\nAcknowledgments\nThe authors acknowledge the support of the Department of Radiology, the First Affiliated Hospital, Zhejiang University School of Medicine.\n\nAuthor contributions\nConceptualization: Jin Liu, Nong Xu.\n\nData curation: Yulong Zheng.\n\nResources: Jin Liu.\n\nSupervision: Yulong Zheng.\n\nVisualization: Nong Xu.\n\nWriting – original draft: Jin Liu.\n\nWriting – review & editing: Nong Xu.\n\nAbbreviations: CEA = carcinoembryonic antigen, CT = computed tomography, DCR = disease control rate, ECOG = Eastern Cooperative Oncology Group, EGFR-TKIs = epidermal growth factor receptor-tyrosine kinase inhibitors, NSCLC = non-small cell lung cancer, ORR = objective response rate, OS = overall survival, PD = progressive disease, PFS = progression-free survival, PIGF = placental growth factor, PR = partial response, PS = performance status, VEGF = vascular endothelial growth factor, VEGFR-2 = vascular endothelial growth factor receptor-2.\n\nThe patient has provided informed consent.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Ettinger DS Wood DE Akerley W \nNon-small cell lung cancer, version 6.2015 . J Natl Compr Canc Netw \n2015 ;13 :515–24 .25964637 \n[2] Dimova I Popivanov G Djonov V \nAngiogenesis in cancer—general pathways and their therapeutic implications . J BUON \n2014 ;19 :15–21 .24659637 \n[3] Li J Qin S Xu J \nRandomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction . J Clin Oncol \n2016 ;34 :1448–54 .26884585 \n[4] Hu X Cao J Hu W \nMulticenter phase II study of apatinib in non-triple-negative metastatic breast cancer . BMC Cancer \n2014 ;14 :820.25376790 \n[5] Hu X Zhang J Xu B \nMulticenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer . Int J Cancer \n2014 ;135 :1961–9 .24604288 \n[6] Folkman J \nTumor angiogenesis: therapeutic implications . N Engl J Med \n1971 ;285 :1182–6 .4938153 \n[7] Costache MI Ioana M Iordache S \nVEGF expression in pancreatic cancer and other malignancies: a review of the literature . Rom J Intern Med \n2015 ;53 :199–208 .26710495 \n[8] Scott AJ Messersmith WA Jimeno A \nApatinib: a promising oral antiangiogenic agent in the treatment of multiple solid tumors . Drugs Today (Barc) \n2015 ;51 :223–9 .26020064 \n[9] Mi YJ Liang YJ Huang HB \nApatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters . Cancer Res \n2010 ;70 :7981–91 .20876799 \n[10] Li F Zhu T Cao B \nApatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance . Eur J Cancer \n2017 ;84 :184–92 .28822888 \n[11] Yang C Feng W Wu D \nApatinib for advanced nonsmall-cell lung cancer: a retrospective case series analysis . J Cancer Res Therap \n2018 ;14 :159–62 .29516980 \n[12] Xu J Liu X Yang S \nClinical response to apatinib monotherapy in advanced non-small cell lung cancer . Asia-Pacific J Clin Oncol \n2018 ;14 :264–9 .\n[13] Zeng DX Wang CG Lei W \nEfficiency of low dosage apatinib in post-first-line treatment of advanced lung adenocarcinoma . Oncotarget \n2017 ;8 :66248–53 .29029508 \n[14] Song Z Yu X Lou G \nSalvage treatment with apatinib for advanced non-small-cell lung cancer . OncoTargets Ther \n2017 ;10 :1821–5 .\n[15] Fang SC Zhang HT Zhang YM \nApatinib as post second-line therapy in EGFR wild-type and ALK-negative advanced lung adenocarcinoma . OncoTargets Ther \n2017 ;10 :447–52 .\n[16] Peng Y Cui H Liu Z \nApatinib to combat EGFR-TKI resistance in an advanced non-small cell lung cancer patient with unknown EGFR status: a case report . OncoTargets Ther \n2017 ;10 :2289–95 .\n\n",
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{
"abstract": "Presently, the use of atypical antipsychotics is getting increasingly widespread. There are several mania/hypomania cases that have been associated with atypical antipsychotic treatment that also display antimanic, antidepressive and anxiolytic effects in addition to their antipsychotic effects. In this study, a case of schizophrenia in which manic symptoms developed after increasing the dosage of quetiapine to 300 mg/day, and subsequently disappeared after cessation of treatment is presented. Although the blockage of 5HT2 receptors and the disinhibition of frontal dopamine secretion seemed to be the reasons for the development of the mania/hypomania related to atypical antipsychotics, the mechanism is not clear. During the use of atypical antipsychotics, clinicians should be cautious to patients' mood fluctuations.",
"affiliations": null,
"authors": "Cam|Birmay|B|;Gülseren|Seref|S|",
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"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D003937:Diagnosis, Differential; D003987:Dibenzothiazepines; D006801:Humans; D008297:Male; D000069348:Quetiapine Fumarate; D012559:Schizophrenia",
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"pubdate": "2014",
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"title": "Mania associated with quetiapine treatment.",
"title_normalized": "mania associated with quetiapine treatment"
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"abstract": "Didymella pedeiae is a dematiaceous fungus that belongs to the Coelomycetes class. While species within this class are known to cause human infection, D. pedeiae had previously only been known as phytopathogens and had never been isolated from a human sample.\nA 51-year-old Iranian female patient with ovarian cancer was admitted with unilateral lesions in paranasal sinuses and a five-month history of nasal obstruction, headache, postnasal drainage, swelling on the left side of the face, and orbital pain. Paranasal sinus computerized tomography scan revealed a soft tissue mass that filled the left nasal cavity, ethmoid, sphenoid, and frontal sinuses with more involvement in the maxillary and ethmoid sinuses. Antifungal treatment was simultaneously initiated with itraconazole+prednisolone 15 mg/day, and levofloxacin. Due to poor clinical response, IV voriconazole and amphotericin B were added to the treatment as well. The patient recovered completely after 10 weeks of therapy.\nHere, we report the first case of human D. pedeiae infection in a patient with ovarian cancer.",
"affiliations": "Department of Medical Parasitology and Mycology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Department of Medical Parasitology and Mycology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Department of Medical Microbiology and Parasitology, College of Health Sciences, Bayero University, PMB 3011, Kano, Nigeria.;Department of Medical Parasitology and Mycology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Department of Otorhinolaryngology, Faculty of Medicine, Tehran University of Medical Sciences, Amiralam Hospital, Tehran, Iran.;Department of Medical Parasitology and Mycology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Department of Medical Parasitology and Mycology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.;Department of Medical Parasitology and Mycology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Raiesi|Omid|O|;Hashemi|Seyed Jamal|SJ|;Getso|Muhammad Ibrahim|MI|;Ardi|Pegah|P|;Mohammadi Ardehali|Mojtaba|M|;Raissi|Vahid|V|;Shamsaei|Sina|S|;Borjian Boroujeni|Zeinab|Z|",
"chemical_list": null,
"country": "Iran",
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"doi": "10.18502/cmm.7.1.6244",
"fulltext": "\n==== Front\nCurr Med Mycol\nCurr Med Mycol\nCurrent Medical Mycology\n2423-3439\n2423-3420\nIranian Society of Medical Mycology Iran, Sari\n\nCMM-7-1\n10.18502/cmm.7.1.6244\nCase Report\nFirst report of chronic invasive fungal rhinosinusitis in a patient with ovarian cancer caused by Didymella pedeiae and successful treatment with voriconazole: A case report\nRaiesi Omid 1\nHashemi Seyed Jamal 1*\nGetso Muhammad Ibrahim 2\nArdi Pegah 1\nMohammadi Ardehali Mojtaba 3\nRaissi Vahid 1\nShamsaei Sina 4\nBorjian Boroujeni Zeinab 1\n1 Department of Medical Parasitology and Mycology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran\n2 Department of Medical Microbiology and Parasitology, College of Health Sciences, Bayero University, PMB 3011, Kano, Nigeria\n3 Department of Otorhinolaryngology, Faculty of Medicine, Tehran University of Medical Sciences, Amiralam Hospital, Tehran, Iran\n4 Department of Medical Parasitology and Mycology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran\n* Corresponding author: Seyed Jamal Hashemi Department of Medical Parasitology and Mycology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Email: [email protected]\n3 2021\n7 1 5558\n17 3 2021\n16 4 2021\n29 12 2020\nCopyright: © 2021, Published by Mazandaran University of Medical Sciences on behalf of Iranian Society of Medical Mycology and Invasive Fungi Research Center.\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 Unported License, ( http://creativecommons.org/licenses/by/4.0/ ) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground and Purpose:\n\nDidymella pedeiae is a dematiaceous fungus that belongs to the Coelomycetes class. While species within this class are known to cause human infection, D. pedeiae had previously only been known as phytopathogens and had never been isolated from a human sample.\n\nCase report:\n\nA 51-year-old Iranian female patient with ovarian cancer was admitted with unilateral lesions in paranasal sinuses and a five-month history of nasal obstruction, headache, postnasal drainage, swelling on the left side of the face, and orbital pain. Paranasal sinus computerized tomography scan revealed a soft tissue mass that filled the left nasal cavity, ethmoid, sphenoid, and frontal sinuses with more involvement in the maxillary and ethmoid sinuses. Antifungal treatment was simultaneously initiated with itraconazole+prednisolone 15 mg/day, and levofloxacin. Due to poor clinical response, IV voriconazole and amphotericin B were added to the treatment as well. The patient recovered completely after 10 weeks of therapy.\n\nConclusion:\n\nHere, we report the first case of human D. pedeiae infection in a patient with ovarian cancer.\n\nChronic invasive fungal rhinosinusitis\nDidymella pedeiae\nIran\nPhoma species\nVoriconazole\n==== Body\npmcIntroduction\n\nFungal rhinosinusitis (FRS) involves a number of sinonasal disorders caused by fungal agents and runs a variable clinical course, histopathologic findings, and disease outcomes. The FRS can be categorized into invasive and noninvasive diseases based on the degree to which the mucosal layer is invaded by the fungi. Non-invasive FRS includes those caused by saprophytic fungi, the fungal ball, and allergic FRS. Furthermore, the invasive FRS is classified into acute and chronic invasive FRS [ 1 ].\n\nChronic invasive fungal rhinosinusitis (CIFRS) is a rare form of fungal rhinosinusitis, which follows a prolonged clinical course with slow disease development, typically more than 12 weeks. The disease shows radiologic and histopathological evidence of hyphae in sinus mucosa, submucosa, blood vessels, or bone [ 2 ].\n\nPhoma spp. (synonym Didymella) are dematiaceous fungi that belong to the class Coelomycetes, order Sphaeropsidales, and family Dematiaceous with over 2000 species described. They are phytopathogens and ubiquitous; commonly found in plants, soil, water sources, and organic matter. In the existing literature, few cases of human and animal phaeohyphomycosis caused by Phoma spp. have been described [ 3 ]. In this study, we report the first case of CIFRS due to Didymella pedeiae in a patient with ovarian cancer.\n\nCase report\n\nA 51-year-old Iranian female patient with ovarian cancer was admitted with unilateral lesions in paranasal sinuses and five-month history of nasal obstruction, headache, postnasal drainage, swelling on the left side of the face, and orbital pain. At the time of admission, the vital signs of the patient were as follows: temperature: 37.8°C, blood pressure: 115/65 mm Hg, heart rate: 85 beats/min, respiratory rate: 32 breaths/min, and O2 saturation: 90% in ambient air.\n\nThe patient had no history of any immune-suppressing condition and no history of steroid intake prior to the current event. However, during the course of her cancer treatment, she received induction chemotherapy with platinum agents (cisplatin, carboplatin, and paclitaxel). Moreover, she simultaneously received prednisolone 15 mg/day, levofloxacin, and itraconazole for empirical treatment of rhinosinusitis, which did not improve, raising suspicion of fungal rhinosinusitis.\n\nThe patient was subjected to diagnostic nasal endoscopy and CT scan of paranasal sinuses (PNS). Results of the PNS CT scan revealed a soft tissue mass that filled the left nasal cavity, ethmoid, sphenoid, and frontal sinuses with much involvement of the maxillary and ethmoid sinuses. Bone destruction and chronic sinus osteomyelitis were also observed. The endoscopic examination revealed a polypoid mass in the left nasal cavity with intense purulent secretion; consequently, surgery was performed to completely remove the lesions. The brown-green substance was fully resected from all sinuses through endoscopic sinus surgery. Biopsied tissues were also sent separately, submerged both in 0.9% sterile saline and 10% formalin, to the mycology and pathology department.\n\nThe wet mount (KOH 10%) preparation of the sample showed septated, branched, and pigmented fungal hyphae suggestive of Phoma spp.\n\nFungal culture was done two days after surgical debridement and was positive for Phoma spp. To cultivate the fungal agent, the sample was inoculated onto the brain-heart infusion agar (BHIA), Sabouraud’s dexterous agar (SDA), and Sabouraud’s dextrose agar containing chloramphenicol (SC), under sterile conditions. The SDA and SC culture media were incubated at 25 °C and BHIA at 35 °C. The culture growth was powdery to velvety, white-cinnamon in color with yellowish-brown reverse attaining a diameter of six cm within one week. After three weeks of incubation at 25 °C, partially submerged pycnidia were microscopically seen (Figure 1).\n\nFigure 1 Phoma pedeiae: (a) colony on 2% dextrose Sabouraud Agar with 0.05 g/L chloramphenicol, (b) yellowish-brown reverse of colony, (c) pycnidia typical of the genus Phoma\n\nHistologically, the slides were stained with Haematoxylin and Eosin (H&E), Periodic acid-Schiff (PAS), and Gomori Methenamine-Silver (GMS). One week after debridement, the results of H&E, PAS, and GMS-stained were available. Investigation of H&E, PAS, and GMS-stained sections showed invasion of fungal hyphae into submucosa surrounded with evidence of chronic inflammation and fibrosis in the lesion (Figure 2).\n\nFigure 2 Gomori Methenamine-Silver and periodic acid-Schiff stain showing an invasion of fungal forms into the submucosa (a, b), and Haematoxylin and Eosin stain showing surrounding chronic inflammation and fibrosis (c)\n\nThe fungus grown on Sabouraud dexterous agar (SDA) was then transferred to a 2 ml Eppendorf tube containing 400 ml TEX buffer (Tris 1.2 % w/v, Na-EDTA 0.38 % w/v, pH 9.0) with glass beads (Sigma) and homogenized by MO-BIO vortexing for 15 min. The DNA was extracted and subjected to molecular identification. The obtained sequences were analyzed in the GenBank database using NCBI BLAST search tools (https://blast.ncbi.nlm.nih.gov/Blast.cgi) and the fungal identities were determined through comparison with the highest matches in DNA databases [ 4 ]. The nearest neighbor to our isolate within the ITS BLAST in GenBank was Phoma pedeiae, with 99 % similarity. The sequence generated and analyzed during the current study is available in the GenBank under the code MT755856.1.\n\nSusceptibility of the Didymella pedeiae isolates to amphotericin B, voriconazole, itraconazole, and fluconazole was determined using the Clinical and Laboratory Standards Institute M38-A2 standard method [ 5 ]. Results of the in vitro susceptibility tests revealed that the isolate was susceptible to amphotericin B, and voriconazole. Antifungal treatment was immediately initiated with IV voriconazole (400 mg/day for the first day and then 200 mg bid/po) and amphotericin B (1–1.5 mg/kg/day) until the total dose of amphotericin B reached 2 grams. The patient recovered completely after 10 weeks of therapy.\n\nEthical Considerations\n\nThe work was approved by the Research Council of Tehran University of Medical Sciences with the project ethic number IR.TUMS.SPH.REC.1397.247. Written informed consent for publication of this case report was obtained from the patient. The sequence generated and analyzed during the current study is available in the GenBank under the code MT755856.1.\n\nDiscussion\n\nBased on the available literature, human Phoma spp. infections are extremely rare. For the first time, Phoma hibernica was isolated from a lesion on the left leg of a young girl in Ontario, Canada [ 3 ]. In 1987, Baker et al. reported the first case of subcutaneous phaeohy-phomycosis of the foot caused by Phoma minutella in a 75-year-old diabetic farmer from the Dominican Republic [ 6 ]. In 2016, Hernández reported the first case of chromoblastomycosis due to phoma insulana [ 7 ]. A rare case of keratitis caused by Phoma gardeniaea was reported by Miyakubo et al. in a 66-year-old man with a history of bronchial asthma and duodenal ulcer [ 8 ]. In another study, Phoma spp. was isolated from keratitis in a 72-year-old man [ 9 ]. More, recent studies have also reported cases of Phoma infections in other parts of the human body. For instance, Phoma cava from the left ear, subcutaneous, and hand [ 10 , 11 ]; Phoma sorghina from face, neck, and hands [ 12 ]; Phoma exigua from lung [ 13 ]; Phoma macrostoma from onychomycosis[ 14 ]; Phoma herbarum from nail and toe [ 15 ]; and Phoma spp. from corneal infection [ 16 ].\n\nManagement of CIFRS involves surgical removal of the affected tissue, antifungal treatment, and supportive therapy to help reverse the predisposing factors. Different therapeutic options have been used in clinical cases, most of which had satisfactory outcomes. In the studies performed by Salehi (2019) [ 17 ], Roehm (2012) [ 18 ], and Errera (2008) [ 7 ], voriconazole and amphotericin B showed the best activity against Phoma isolates. These last findings are similar to those observed for P. pedeiae. Due to the rare reports of cases caused by Phoma species and the insufficient knowledge on specific treatment modalities of these patients, there is a need for further studies. The choice of treatment protocol and duration of treatment can vary with the overall clinical condition of the patients and the type of Phoma spp.\n\nConclusion\n\nAlthough this fungus is ubiquitous in the environment, its poor invasive capacity could be assumed to be a factor linked to its low incidence in deep infection. However, immunosuppression should be considered as a possible additional factor for phoma spp infection, especially among patients from rural settings. Therefore, accurate characterization of rare fungal pathogens from clinical material of immunocompromised patients is of medical and epidemiological significance.\n\nAuthors’ contribution\n\nS.J.H. conduction of the study, O.R., M.I.G. and Z.B. morphological and molecular analysis of the isolated strain. M.A., P.A. and V.R. collection of clinical data. O.R. histopathological examination. O.R., M.I.G., and S.J.H. design of the study and preparation of the final draft of the manuscript. All authors read and approved the final manuscript.\n\nFinancial disclosure\n\nThis study was supported by the Research Council of Tehran University of Medical Science and the project funding number is IR.TUMS.SPH.REC.1397.247.\n\nAcknowledgement\n\nThe authors would like to acknowledge the financial support of the Tehran University of Medical Sciences for this study. They would also like to express their sincere gratitude to all professors and students of the Otorhinolaryngology and Mycology Departments of Tehran University of Medical Sciences, Imam Khomeini Hospital, and Amir Alam Hospital.\n\nConflict of Interest: Authors and coauthors declare that they have no conflict of interest that affects this study.\n==== Refs\nReferences\n\n1 Montone KT Livolsi VA Feldman MD Palmer J Chiu AG Lanza DC et al Fungal rhinosinusitis: a retrospective microbiologic and pathologic review of 400 patients at a single university medical center Int J Otolaryngol 2012 2012 684835 22518160\n2 Stringer SP Ryan MW Chronic invasive fungal rhinosinusitis Otolaryngol Clin North Am 2000 33 2 375 87 10736411\n3 Bakerspigel A The isolation of Phoma hibernica from a lesion on a leg Sabouraudia 1969 7 3 261 4\n4 Boroujeni ZB Shamsaei S Yarahmadi M Getso MI Khorashad AS Haghighi L et al Distribution of invasive fungal infections: molecular epidemiology, etiology, clinical conditions, diagnosis and risk factors: a 3-year experience with 490 patients under intensive care Microbial Pathog 2020 152 104616\n5 Clinical and Laboratory Standards Institute Reference method for broth dilution antifungal susceptibility testing of yeasts Wayne, PA: Clinical and Laboratory Standards Institute; 2008\n6 Baker JG Salkin I Forgacs P Haines JH Kemna ME First report of subcutaneous phaeohyphomycosis of the foot caused by Phoma minutella J Clin Microbiol 1987 25 12 2395 3429630\n7 Hernández-Hernández F Vargas-Arzola J Ríos-Cruz OP Córdova-Martínez E Manzano-Gayosso P Segura-Salvador A First case of chromoblastomycosis due to Phoma insulana Enferm Infecc Microbiol Clin 2018 36 2 95 9\n8 Miyakubo T Todokoro D Makimura K Akiyama H Fungal keratitis caused by Didymella gardeniae (formerly Phoma gardeniae) successfully treated with topical voriconazole and miconazole Med Mycol Case Rep 2019 24 90 2 31080716\n9 Rishi K Font RL Keratitis caused by an unusual fungus, Phoma species Cornea 2003 22 2 166 8 12605055\n10 Gordon M Salkin I Stone W Phoma (Peyronellaea) as zoopathogen Sabouraudia 1975 13 3 329 33 1224289\n11 Zaitz C Heins-Vaccari EM Freitas RS Arriagada GL Ruiz L Totoli SA et al Subcutaneous pheohyphomycosis caused by Phoma cava Report of a case and review of the literature Rev Inst Med Trop Sao Paulo 1997 39 1 43 8\n12 Rai M Phoma sorghina infection in human being Mycopathologia 1989 105 3 167 70 2761610\n13 Balis E Velegraki A Fragou A Pefanis A Kalabokas T Mountokalakis T Lung mass caused by Phoma exigua Scand J Infect Dis 2006 38 6-7 552 5 16798712\n14 Kukhar E Smagulova A Kiyan V Biological properties of Phoma macrostoma related to non-dermatophyte onychomycosis Med Mycol Case Rep 2020 27 55 8 31993320\n15 Tullio V Banche G Allizond V Roana J Mandras N Scalas D et al Non-dermatophyte moulds as skin and nail foot mycosis agents: Phoma herbarum, Chaetomium globosum and Microascus cinereus Fungal Biol 2010 114 4 345 9 20943144\n16 Adamopoulou A Sakellaris D Koronis S Balidis M Zachariadis Z Tranos P et al Rare persistent corneal infection by Phoma sp -a case report Ophthalmol Ther 2019 8 1 143 8\n17 Salehi M Zibafar E Mahmoudi S Hashemi S Gatmiri S Shoar MG et al First report of invasive pulmonary infection by Didymella microchlamydospora and successful treatment with voriconazole Clin Microbiol Infect 2019 25 3 392 3 30391584\n18 Roehm CE Salazar JC Hagstrom N Valdez TA Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review Int J Pediatr Otorhinolaryngol 2012 76 10 1387 91 22818128\n\n",
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"keywords": " Voriconazole; Chronic invasive fungal rhinosinusitis; Didymella pedeiae; Iran; Phoma species",
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"title": "First report of chronic invasive fungal rhinosinusitis in a patient with ovarian cancer caused by Didymella pedeiae and successful treatment with voriconazole: A case report.",
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"abstract": "OBJECTIVE\nStandard dose of external beam radiotherapy seems to be insufficient for satisfactory control of loco-regionally advanced cervical cancer. Aim of our study is to evaluate the outcome as well as early and chronic toxicities in patients with loco-regionally advanced cervical cancer, treated with dose escalated intensity modulated radiotherapy (IMRT) combined with cisplatin chemotherapy.\n\n\nMETHODS\nThirty-nine patients with cervical carcinoma FIGO stage IB2 - IVA were treated with curative intent between 2006 and 2010. The dose of 50.4 Gy was prescribed to the elective pelvic nodal volume. Primary tumors < 4 cm in diameter (n = 6; 15.4 %) received an external beam radiotherapy (EBRT) boost of 5.4 Gy, primary tumors > 4 cm in diameter (n = 33; 84.6 %) received an EBRT boost of 9 Gy. Patients with positive lymph nodes detected with (18)FDG-PET/CT (n = 22; 56.4 %) received a boost to a total dose of 59.4 - 64.8 Gy. The para-aortic region was included in the radiation volume in 8 (20.5 %) patients and in 5 (12.8 %) patients the para-aortic macroscopic lymph nodes received an EBRT boost. IMRT was followed with a 3D planned high dose rate intrauterine brachytherapy given to 36 (92.3 %) patients with a total dose ranging between 15-18 Gy in three fractions (single fraction: 4-6.5 Gy). Patients without contraindications (n = 31/79.5 %) received concomitantly a cisplatin-based chemotherapy (40 mg/kg) weekly. Toxicities were graded according to the common terminology criteria for adverse events (CTCAE v 4.0).\n\n\nRESULTS\nMean overall survival for the entire cohort was 61.1 months (±3.5 months). Mean disease free survival was 47.2 months (±4.9 months) and loco-regional disease free survival was 55.2 months (±4.4 months). 65 % of patients developed radiotherapy associated acute toxicities grade 1, ca. 30 % developed toxicities grade 2 and just two (5.2 %) patients developed grade 3 toxicities, one acute diarrhea and one acute cystitis. 16 % of patients had chronic toxicities grade 1, 9 % grade 2 and one patient (2.6 %) toxicities grade 3 in the form of vaginal dryness.\n\n\nCONCLUSIONS\nDose escalated IMRT appears to have a satisfactory outcome with regards to mean overall survival, disease free and loco-regional disease free survival, whereas the treatment-related toxicities remain reasonably low.",
"affiliations": "Department of Radiation Oncology, Bern University Hospital & University of Bern, Bern, Switzerland. [email protected].;Department of Radiation Oncology, Bern University Hospital & University of Bern, Bern, Switzerland. [email protected].;University of Bern, Institute for Pathology, Murtenstrasse 31, Bern, 3010, Switzerland. [email protected].;Department of Radiation Oncology, Bern University Hospital & University of Bern, Bern, Switzerland. [email protected].;University of Bern, Institute for Pathology, Murtenstrasse 31, Bern, 3010, Switzerland. [email protected].;Department of Radiation Oncology, Bern University Hospital & University of Bern, Bern, Switzerland. [email protected].",
"authors": "Cihoric|Nikola|N|;Tsikkinis|Alexandros|A|;Tapia|Coya|C|;Aebersold|Daniel M|DM|;Zlobec|Inti|I|;Lössl|Kristina|K|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1186/s13014-015-0551-0",
"fulltext": "\n==== Front\nRadiat OncolRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central London 55110.1186/s13014-015-0551-0ResearchDose escalated intensity modulated radiotherapy in the treatment of cervical cancer http://orcid.org/0000-0003-1534-8520Cihoric Nikola [email protected] Tsikkinis Alexandros [email protected] Tapia Coya [email protected] Aebersold Daniel M. [email protected] Zlobec Inti [email protected] Lössl Kristina [email protected] Department of Radiation Oncology, Bern University Hospital & University of Bern, Bern, Switzerland University of Bern, Institute for Pathology, Murtenstrasse 31, Bern, 3010 Switzerland Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center Life Science Plaza, 2130 W. Holcombe, Blvd. Unit 2951, Houston, 77030 TX USA 24 11 2015 24 11 2015 2015 10 24023 5 2015 18 11 2015 © Cihoric et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Purpose\nStandard dose of external beam radiotherapy seems to be insufficient for satisfactory control of loco-regionally advanced cervical cancer. Aim of our study is to evaluate the outcome as well as early and chronic toxicities in patients with loco-regionally advanced cervical cancer, treated with dose escalated intensity modulated radiotherapy (IMRT) combined with cisplatin chemotherapy.\n\nMaterial and methods\nThirty-nine patients with cervical carcinoma FIGO stage IB2 – IVA were treated with curative intent between 2006 and 2010. The dose of 50.4 Gy was prescribed to the elective pelvic nodal volume. Primary tumors < 4 cm in diameter (n = 6; 15.4 %) received an external beam radiotherapy (EBRT) boost of 5.4 Gy, primary tumors > 4 cm in diameter (n = 33; 84.6 %) received an EBRT boost of 9 Gy. Patients with positive lymph nodes detected with 18FDG-PET/CT (n = 22; 56.4 %) received a boost to a total dose of 59.4 - 64.8 Gy. The para-aortic region was included in the radiation volume in 8 (20.5 %) patients and in 5 (12.8 %) patients the para-aortic macroscopic lymph nodes received an EBRT boost. IMRT was followed with a 3D planned high dose rate intrauterine brachytherapy given to 36 (92.3 %) patients with a total dose ranging between 15–18 Gy in three fractions (single fraction: 4–6.5 Gy). Patients without contraindications (n = 31/79.5 %) received concomitantly a cisplatin-based chemotherapy (40 mg/kg) weekly. Toxicities were graded according to the common terminology criteria for adverse events (CTCAE v 4.0).\n\nResults\nMean overall survival for the entire cohort was 61.1 months (±3.5 months). Mean disease free survival was 47.2 months (±4.9 months) and loco-regional disease free survival was 55.2 months (±4.4 months). 65 % of patients developed radiotherapy associated acute toxicities grade 1, ca. 30 % developed toxicities grade 2 and just two (5.2 %) patients developed grade 3 toxicities, one acute diarrhea and one acute cystitis. 16 % of patients had chronic toxicities grade 1, 9 % grade 2 and one patient (2.6 %) toxicities grade 3 in the form of vaginal dryness.\n\nConclusion\nDose escalated IMRT appears to have a satisfactory outcome with regards to mean overall survival, disease free and loco-regional disease free survival, whereas the treatment-related toxicities remain reasonably low.\n\nKeywords\nCervical cancerChemo radiationDose escalated radiotherapyIMRTissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nThe last major advancement in the treatment of cervical cancer was made more than 15 years ago. Several large prospective randomized clinical trials have shown that the combination of radiotherapy with chemotherapy prolongs the disease-free survival while also reducing mortality. Even though the outcome of radio-chemotherapy is better than that of radiation alone, the combined regimen was associated with a higher incidence of side effects while loco-regional control and overall survival still remained unsatisfactory [1–4]. Between twenty to forty percent of patients treated with conventional radiotherapy will relapse loco-regionally, not only outside of the treatment field but also within the treated volume [5]. Unfortunately, the prognosis for these patients is very poor with only a few therapeutic options available such as pelvic exenteration or palliation. The reasons for the loco-regional failure may be attributed to geographical target miss, insufficient dose of radiation delivered to the primary tumor and/or to the nodal area [5, 6].\n\nAt the same time, a rapid development of the radiation delivery machines and cancer imaging has been achieved. These changes are well-mirrored in a significantly improved therapeutic ratio of IMRT for various tumor entities, including cervical cancer [7]. External beam dose escalation results in more favorable treatment outcome while the incidence of radiation induced toxicities, early and chronic, is sinking. Incorporation of multimodal imaging, especially in patients with cervical cancer, enhances the detection of nodal or systemic disease, and leads to a better definition of local disease [6].\n\nHowever the level of evidence in the utilization of IMRT and of new imaging modalities, in the treatment of gynecological malignancies is still low. There is currently only one phase II prospective randomized trial, comparing conventional radiotherapy to IMRT, with published results [8]. In the available literature, there are many suggestions and different approaches in the treatment of cervical cancer using highly conformal radiotherapy and yet there is still no well-defined concept concerning the required total dose, the volume and the required constraints. Furthermore, even though there is a known potential benefit on quality of life, as well as a favorable toxicity profile of IMRT compared to 3D conformal radiotherapy, there is still an ongoing debate about its general use in gynecological cancer. In addition, there is still not enough data available, concerning the possibility of dose escalation using external beam radiotherapy for the treatment of both the primary tumor as well as nodal disease [9].\n\nIn 2006, our group began using IMRT as a standard radiation delivery method for cervical cancer patients. Our treatment concept was based on usage of escalated external beam radiotherapy dosage for treating the infiltrated regional lymph nodes and of the primary tumor compared to the standard dosage (45-50Gy). We conducted this retrospective study in order to evaluate the treatment-related toxicities, early and chronic, as well as the clinical outcome of cervical cancer patients treated with escalated dose of IMRT.\n\nMaterial and methodes\nPatients\nPatients with histologically confirmed cervical cancer, FIGO stage IBII to IVA, treated with IMRT at the Bern University Hospital Department of Radiation Oncology were included in this retrospective study according to the institutional ethical standards. We evaluated all medical and radiotherapy records, pretreatment and follow-up images of 39 patients treated between October 2006 and January 2011. Patient characteristics are summarized in Table 1. Median follow-up time was 35 months.Table 1 Patient characteristic\n\nAge at time of diagnosis: median (range)\t59.5 year (range: 26 to 89)\t\n\tNo.\t%\t\nFIGO stage\t\n IB2\t4\t10.3\t\n IIA\t2\t5.1\t\n IIB\t20\t51.3\t\n IIIB\t9\t23.1\t\n IVA\t4\t10.3\t\nSize of primary tumors\t\n Tumors < 4 cm\t6\t15.4\t\n Tumors > 4 cm\t33\t84.6\t\nLymph nodes status\t\n N0\t15\t38.5\t\n N1\t24\t61.5\t\n Paraaortic Positive LN\t5\t12.8\t\n Median number of positive LN per patient\t2.5 (range: 1 to 5)\t\nTumor histology\t\n\tNo\t%\t\n Adenocarcinoma\t9\t23.1\t\n Squamous Cell Carcinoma\t30\t76.9\t\nTumor grade\t\n Grade 1\t1\t2.6\t\n Grade 2\t25\t64.1\t\n Grade 3\t13\t33.3\t\n\n\nBefore treatment all patients underwent pretreatment staging workup, including medical history, general physical and gynecological examination, digital rectal examination, tumor biopsy, comprehensive laboratory analysis and in cases of suspected rectal or bladder infiltration, additional rectoscopy and cystoscopy. The primary tumor was clinically assessed by an experienced gynecologist and radiation oncologist. Tumor staging was defined according to the International Federation of Obstetrics and Gynecology (FIGO) and the TNM-UICC system. In addition, local tumor extension was assessed by MRI, but the initial tumor stage was not influenced by the findings. All patients with cervical cancer clinically staged as IB2-IIB underwent pretreatment staging with 18FDG-PET/CT scan. If the PET-CT revealed, clear signs of metastatic lymph nodes, the patients were selected for definitive radio-/chemotherapy. In case of negative PET-CT findings, patients were selected for surgery, were a sentinel lymph node dissection was performed with frozen section pathological evaluation. If the sentinel lymphadenectomy revealed positive lymph nodes, or an advanced tumor stage was intraoperatively detected, the surgery was stopped and the patients were referred for definitive radio-/chemotherapy. If the sentinel lymphadenectomy revealed no positive lymph nodes, a complete surgery was performed, including a paraaortal lymphadenectomy. Any further therapy decisions were made in a multidiscipline tumor board setting after complete pathological evaluation. Patients with clinical stage FIGO IIB or greater were selected for radio-chemotherapy. In cases with doubtful or suspicious findings regarding lymph node status those were surgically evaluated.\n\nAt the beginning of 2010 our policy was changed regarding surgical staging, and all patients, regardless of tumor stage, were surgically evaluated (n = 11). Two (5.1 %) patients have positive lymph nodes that were not previously detected by imaging and 3 (7.7 %) patients have advanced local tumor extension. These patients subsequently received definitive radio-chemotherapy. Information on surgery and concomitant therapy data are shown in Table 2.Table 2 Therapy data\n\nSurgery and concomitant therapy\t\n\tn\t%\t\nPatients with incomplete (primary) surgery\t4\t10.3\t\nPatients with surgical nodal staging\t11\t28.2\t\nClinical nodal staging\t28\t71.8\t\nComplete chemotherapy (Cisplatin 40 mg/m2 weekly)\t31\t79.5\t\nPatients without all cycles of chemotherapy due to hematological toxicities\t3\t7.7\t\nPatients without chemotherapy due to contraindication or refusal\t5\t12.8\t\nRadiotherapy dosage\t\n\tMedian (Gy)\tRange (Gy)\t\nRadiotherapy duration (days)\t60\t46 - 96\t\nEBRT elective pelvic nodal dose (Gy)\t50.4\t45-55.8\t\nEBRT elective paraaortral dose (Gy)\t47.7\t45 - 50.4\t\nEBRT Tumor Boost dose (Gy)\t9\t5.4 - 21.6\t\nEBRT Total Tumor Dose (Gy)\t59.4\t50.4 - 72\t\nLN Boost dose (Gy)\t62\t59.4 - 64.8\t\nBrachytherapy total dose (Gy)\t18\t10 - 24\t\nBrachytherapy single dose (Gy)\t6\t5-6\t\n\n\nRadiotherapy planning: treatment volumes and dose prescription\nAll patients underwent a planning computer tomography (CT) without contrast in supine position. Patients were instructed to come for the planning CT as well as the daily radiotherapy fractions with a full bladder. No particular instructions were given regarding rectal filling. The CT slice thickness was 3 mm. A personalized adjusted immobilization device was created for each patient.\n\nImage sets acquired by CT, diagnostic 18FDG-PET/CT and MRI were imported into the Eclipse Planning System (Varian Medical System, Palo Alto, CA). We used the “automatic matching algorithm”, with manual correction as needed. Registration quality was regarded as acceptable, when bony structure misalignment did not exceed </=1 mm. External beam radiotherapy was delivered using a dynamic multi-leaf linear accelerator with a photon energy of 6 MV.\n\nThe gross tumor volume of the cervix (GTVc) was defined as the visible macroscopic tumor based on all the available clinical and imaging data. Clinical target volume for primary tumor area (CTVc) encompassed GTVc, uterus, parametria and the upper third of the vagina. In cases of vaginal involvement, CTVc expanded 2 cm into the vagina caudally of the tumor. The planning target volume of primary tumor (PTVc) was created using anisotropic expansion, considering cervical and surrounding structure movements. The PTVc was expanded to 15 mm in the antero-dorsal direction and 10 mm in the lateral direction. PTVc was manually corrected if needed. The asymmetrical margin for PTV was chosen based on the fact, that in cervical cancer, movement is not uniform in all directions [10]. In the dorsal direction PTVc margin extended maximally to the posterior rectal wall and in frontal direction maximally 1.5 cm into the bladder.\n\nIn the first phase PTVc was irradiated with a total dose of 50.4 Gy. After 45 Gy a control MRI was performed to evaluate tumor response and measure tumor size. In cases where the remaining tumor was larger than 4 cm in diameter, an additional EBRT boost of 9 Gy was administered to the PTVc. Otherwise, for tumors smaller than 4 cm in diameter, the PTVc was irradiated with an EBRT boost of 5.4 Gy. Single dose was 1.8 Gy.\n\nNodal PTV and SIB volume\nThe elective clinical target lymph nodes (LN) volume encompassed the common, external and internal iliac lymphatic chain to the aortic bifurcation and presacral LN area. In case of LN involvement at the level of the common artery or aortic LN, we extended the elective nodal volume to the level of the renal arteries. A safety margin of 7 mm was added to define the nodal planning target volume (PTVn). PTVc and PTVn were merged to one single planning target volume (PTVsum).\n\nNodal gross tumor volume (GTVn) was based on data acquired by 18FDG-PET/CT including assessment of other imaging modalities (CT, MRI). Positive LNs were delineated separately as nodal gross tumor volume (GTVn). PTVn boost was formed by adding a safety margin of 5 mm to the GTVn. A total of 22 (56.4 %) patients were given a nodal boost, 12 (30.8 %) with consecutive and 10 (25.6 %) with simultaneous integrated boost (SIB). Rational and methods for SIB delivery are described in our previous work [11].\n\nAn example of a treatment plan is shown in Fig. 1.Fig. 1 Example of treatment plan\n\n\n\nConstraints for organs at risk\nOrgans at risk were delineated on the axial CT slices. We delineated the rectum up to the sigmoid. The bowel was contoured to the level extending one vertebral body beyond the upper border of the PTV, including large and small intestines. The bladder and femoral heads were also contoured. Dose constraints for organs at risk were standardized as follows: 60 % of rectal volume should receive not more than 50 Gy, 35 % of bowel volume should receive no more than 35Gy, 50 % of bladder volume should receive no more than 50 Gy and 10 % of the femoral heads volume should receive no more than 50 Gy.\n\nBrachytherapy\nEBRT was followed by a HDR boost to the primary tumor in 36 (92.3 %) patients, administered one week after completion of EBRT. Brachytherapy consisted of a total dose between 15 to 18 Gy delivered in 2 to 4 weekly fractions, with a single dose of 4 to 6.5 Gy. We used a microSelectron® HDRB Unit and a Vienna Ring CT-MRI Applicator Set. MRI images were evaluated together with our radiology department to define the high and intermediate risk areas. Afterwards, we reconstructed the high risk and intermediate risk areas detected in the MRI images on our planning CT images. Planning volumes were planned according to the GEC-ESTRO guidelines [12]. Because of the dose escalation of EBRT we adapted our brachytherapy dose constraints as suggested in the ABS guideline [13]. Three patients (7.7 %) refused the administration of a brachytherapy boost.\n\nChemotherapy\nPatients were scheduled to receive concomitant cisplatin based chemotherapy (40 mg/kg) weekly during the full course of radiotherapy. 31 (79.5 %) patients received the chemotherapy as planned. The details for the remaining patients (n: 8, 20.5 %) are listed in Table 2.\n\nToxicities assessment and follow-up\nWe assessed patients for acute toxicities weekly during the course of radiotherapy and once 6 weeks after therapy completion. Toxicities were graded according to the CTCAE v 4.0. The initial tumor response was evaluated clinically by a gynecological oncologist 3 months after radiotherapy with a follow up 3 months thereafter for the next two years, and every 6 months afterwards. Clinical evaluation includes a PAP smear. We conducted an 18FDG-PET/CT 6 months after therapy to evaluate the local control as well for the detection of systemic metastases, as recommended in the NCCN guidelines.\n\nFailure was defined as persistent disease or tumor recurrence following radiotherapy. The date of failure was defined as the date of any signs of disease, either clinical or by imaging. The site of failure was recorded as local, nodal (regional) and distant. Furthermore, a distinction was made between in-volume nodal failures or “out of volume” nodal failures. Moreover, we distinguished between nodal failures in the boost region from failure in the elective volume.\n\nStatistical consideration\nPrimary endpoints of interest were overall survival (OS, time between the first day of radiotherapy to the date of death, independent of cause, or the date of the last follow-up), disease-free survival (DFS, time between the first day of radiotherapy to the date of any sign of tumor relapse) and loco-regional disease-free survival (LRDFS, time between the first day of radiotherapy to the date of any sign of tumor relapse in the former tumor bed or the nodal CTV region). Differences in survival time were analyzed using the log-rank or Wilcoxon’s test and plotted using Kaplan-Meier curves. P-values <0.05 were considered statistically significant. All analyses were carried out using SAS (V9.2; The SAS Institute, Cary, NC).\n\nResults\nRecurrence rate and site of recurrence\nDuring follow-up 25 (64.1 %) patients had complete response three months after therapy and remained disease free within follow-up. Median follow-up time was 35.5 months. Fourteen (35.9 %) patients developed a recurrence. One (2.6 %) patient developed isolated local relapse and one (2.6 %) patient isolated nodal relapse. Nine (23.1 %) patient developed loco-regional recidive [8 (20.5 %) local and 5(12.8 %) nodal]. All but, two loco-regional recidive was within treated volume. Twelve (30.8 % of all patients, or 85.7 % of patients with relapse) patients developed systemic disease. Isolated systemic disease occurred in 5 (12.8 %) patients.\n\nThe pattern of recurrence follows in the majority of patients the natural course of cervical cancer, where the loco-regional relapse occurs first, followed by systemic metastasis in 5 patients. Two patients had simultaneously loco-regional and systemic relapse and only 1 patient had systemic metastasis preceding loco-regional failure. Median time to relapse at any site was 9 months (range 3 to 38 months), with median time to systemic metastasis being 12 months (range 3 to 38 months) and loco-regional metastasis being 9 months (range 5–25 months).\n\nWe did not record any failures in the regions of positive lymph nodes treated with boost (consecutive or SIB).\n\nSurvival time\nOS, DFS and LRFS were analysed and stratified by FIGO stage, tumor grading (G1/G2 versus G3), number of positive lymph nodes and tumor size (cut-off 4 cm).\n\nIn terms of OS (5-year OS was 76.3 %), there was no association with FIGO stage (p = 0.771), number of positive lymph nodes (p = 0.9173) or tumor size (p = 0.301) although a statistically significant difference was observed in patients with a higher tumor grading (p = 0.035; Fig. 2a and b).\n\n5-year DFS was 60.3 %. There was no statistically significant relationship between FIGO stage and DFS (p = 0.3937) or tumor size (p = 0.283). Patients with higher tumor grade tended toward a worse DFS than their low tumor grade counterparts (p = 0.0619, Fig. 2c and d), while no difference in survival time was found for patients with a high or low number of affected lymph nodes (p = 0.3597).Fig. 2 Kaplan-Meier curves of a) overall survival time for the entire cohort followed by b) stratification by tumor grade, c) Disease-free survival time for the entire cohort and d) stratified by tumor grade (log-rank test)\n\n\n\nNo association of FIGO (p = 0.739), tumor size (p = 0.65), tumor grade (p = 0.778), or lymph node positivity (p = 0.691) was observed in terms of LRFS (5-year LRFS was 75.1 %).\n\nToxicities\nThere were no acute or chronic toxicities greater than grade 3 and we did not record any toxicity related treatment breaks.\n\nThe most common acute toxicity was diarrhea, recorded in 15 (38.5 %) patients, followed by vaginal mucositis in 12 (30.8 %), cystitis in 9 (23.1 %) and proctitis in 7 (17.9 %) patients. The majority of acute side effects were grade 1 and 2, self-limited or treated with dietary interventions or symptomatic therapy. One (2.6 %) patient experienced acute diarrhea grade 3 and one (2.6 %) acute cystitis grade 3. All acute toxicities were resolved within 6 weeks after radiotherapy.\n\nThe most common chronic toxicity was vaginal stricture recorded in 8 (20.5 %) patients followed by cystitis in 3 (7.7 %) patients; one (2.6 %) patient developed a chronic proctitis grade 2. An overview of the acute and late toxicities is summarized in Table 3.Table 3 Overview of early and late toxicities\n\n\tAcute: n (%)\tChronic: n (%)\t\nToxicities grade\tSmall bowel\tRectum\tBladder\tVagina\tSmall bowel\tRectum\tBladder\tVagina\t\n0\t24 (61.5)\t32 (82.1)\t30 (76.9)\t27 (69.2)\t39(100.0)\t38 (97.4)\t36 (92.3)\t31 (79.5)\t\n1\t9 (23.1)\t4 (10.3)\t6 (15.4)\t7 (17.9)\t0 (0.0)\t0 (0.0)\t1 (2.6)\t3 (7.7)\t\n2\t5(12.8)\t3 (7.7)\t2 (5.1)\t5 (12.8)\t0 (0.0)\t1 (2.6)\t1 (2.6)\t4 (10.3)\t\n3\t1 (2.6)\t0 (0.0)\t1 (2.6)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t1 (2.6)\t1 (2.6)\t\n4\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n5\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n\n\nDiscussion\nThe experience with IMRT in the treatment of cervical cancer is limited and there is currently only one phase II prospective randomized trial, comparing conventional radiotherapy to IMRT, with published results [8], Even less is known about external beam dose escalation using IMRT for this tumor entity.\n\nThe outcome and toxicities of conventional external beam radiotherapy combined with concomitant chemotherapy, is well summarized in the meta-analysis of the “Meta-Analysis Group, Medical Research Council Clinical Trials Unit” [14]. The group analyzed individual data from 13 trials, comparing concomitant radio chemotherapy versus chemotherapy alone in patients with cervical cancer FIGO stage IB to IVA. Delivered dose ranged from 40 Gy to 45 Gy to the whole pelvis with EBRT boost in the primary tumor region up to 61.2 Gy and consecutive low dose rate or HDR brachytherapy boost from 18 to 50 Gy. The combined regime showed an improvement in the overall DFS and the loco regional DFS of 8 % and 9 % at 5 years respectively. Disease free survival at 5 years was 58 %. The benefit in survival was accompanied by higher rates of serious adverse events including gastrointestinal toxicities.\n\nCompared to conventional or 3D radiotherapy, IMRT achieves a better conformity and sparing of normal tissue. Roeske et al. showed a reduced dose to the small bowel [15]. Several other authors showed a good target coverage with a significantly lower dose to the bladder, rectum, and small bowel [16–18]. Ahmed et al. and Esthappan et al. introduced a more aggressive approach for patients with metastatic paraaortic lymph nodes while sparing risk structures and achieving an acceptable level of early and chronic unwanted events. Dosimetric studies were followed by several retrospective analyses, where authors showed a favorable toxicities profile of IMRT (Table 4) [19–23].Table 4 Literature overview\n\nAuthor and year of publication\tTherapy seetings and study type\tIMRT EBRT total dose/EBRT daily dose\tBrachytherapy total dose\tNumber of patients treated with IMRT\tFIGO Stage\tNumber of patients with positive pelvic lymph nodes\tNumber of patients with negative lymph nodes\tFollow-up (median) in months\tTotal number of patients with disease relapse\tLoco-regional failure\tDFS/patient alive without sign of disease\tOS/alive at last follow up\tAcute gastrointestinal or genitourinary toxicites Gr 3 or greater\tChronic gastrointestinal or genitourinary toxicites Gr 3 or greater\tNormal tissue planning constraints\t\n\nGerszten et al., [23]\tDefinitive, extended field IMRT, retrospective\t45 Gy and 55 Gy to involved nodes\t25 Gy/5 Gy\t22\tIB-IIIB\t9 (receiving nodal boost) 2 positive on surgical staging\t11\tNo data\tNo data\tNo data\tNo data\tNo data\t0\tNot evaluated\trectal maximum dose: 54 Gy with no more than 40 % of the rectal volume receiving 40 Gy; bladder maximum dose 54 Gy with no more than 50 % at 40 Gy; small bowel maximum 50 Gy with no more than 35 % of small bowel receiving 35 Gy.\t\n\nKidd et al., [6]\tDefinitive 18 FDG PET based IMRT, retrospective comparison with non-IMRT radiochemotherapy\t50 Gy to whole pelvis and additional 20 Gy to central region (cervix)\t6 weekly fraction of 6.5 Gy HDR\t135\tIBI-IVA\t41 (30.4 %)\t68 (50.4 %)\t22 (range, 5–47 months)\t39\t11 (8.1 %)\t91 (67.4 %) pts\tNo data\tNo data\t8 (6 %)\t<40 % of bowel to receive 30 Gy, <40 % of rectum to receive 40 Gy, <40 % of pelvic bones to receive 40 Gy, and <40 % of femoral heads to receive 30 Gy.\t\n\nHasselle et al., [25]\tDefinitive IMRT in 81 patients. Retrospective multicentric study.\tmedian 45 Gy (range: 39.6 - 50.4 Gy)/1.8 Gy\tLDR 35 to 40 Gy; 5 HDR fractions to 27.5 to 30 Gy\t111 (22 postop, 8 with consecutive surgery)\tI–IVA\tNo data\tNo data\t26.6 (range, 5.4–99.0 months)\tNo data\tThe 3-year pelvic failure rate - 29.2 %\t69 % (95 % CI, 59–81 %)\t78 % (95 % confidence interval [CI], 68–88 %)\t2 % (95 % CI, 0–7 %)\t7 % (95 % CI, 2–13 %)\trectum: maximum dose < 50 Gy; bowel V45 < 250 mL, pelvic BM V20 < 75 %, V10 < 90 %; bladder: as low as reasonably achievable\t\n\nChen et al., [26]\tDefinitive, IMRT, retrospective\t45–54 Gy, (54–60 nodes simultan boost)\tHDR 20 – 33.5 Gy/4–6 Gy/Fraction 2 x Week\t109\tIB2 - IVA\t14\t82\t32.5 for survival pts (5–75)\t5 (4.6 %) locoregional only; 14(12.8 %) distant only; 29 (26.6 %) in total;\t21.9 % at 3 year\t67.6 % at 3 year\t78.2 % at 3 year\t3 pts (GI Only)\t5 (4.6 %) GI 7 (6.4 %) GU\trectum: V30 < 50 %; small bowel: V30 < 15 %;\t\n\nDu XL et al., [29]\tDefinitive RT-CH. Comparison of reduced field IMRT with conventional EBRT.\t30 Gy to whole pelvis with additional boost of 30 Gy to lymphatic drainage region as well as paracervix and parametrium.\tHDR 10–30 Gy/5–6 Gy SD\t60\tIIB–IIIB\tNo data\tNo data\t7 months (range, 6 - 68 months)\t64.90 %\tNo data\t64.9 % PFS at 5 y\t82.5 % at 3 y; 71.2 % at 5 y\t7\t0\tNo data\t\n\nGandhi et al. [8]\tDefinitive radio chemotherapy. Nonblind, prospective, randomized, phase II trial. Comparison with whole pelvis conventional radiotherapy\t50.4 Gy/1.8 Gy\t21 Gy/7 Gy SD\t22\tIIB-IIIB\tNo data\tNo data\t21.6 months (range, 7.7-34.4 months).\t5 (22.7 %)\t2 (9.1 %)\t60 % at 27 months\t85.7 % at 27 months\t2\t0\tsmall bowel: volume receiving 40 Gy (V40) <32 %, maximum dose <50 Gy; rectum: V40 < 40 %, maximum dose <50 Gy; bladder: V40 < 40 %, maximal dose < 50 Gy\t\n\nJensen LG et al., [31]\tDefinitive, extended-field intensity-modulated radiotherapy\t45 to 50.4, median boost dose to parametrian: 9 Gy or pelvic LN 10 Gy in 16 pts, PA boost of median 10.4 Gy in 6 pts\tLDR 35 to 40 Gy 1 or 2 x; HDR 19.8 to 30 3 to 5 x\t21\tIB1 - IIIB\t14 patients had paraaortic LN and 20 pelvic LN\t0\t22 (range, 12 to 56 months) for survived patients\t11\tNo data\t42.9 % (95 % CI, 26.2 % Y70.2 %). At 11 months\t59.7 % (95 % confidence interval [CI], 41.2 % Y86.4 %) at 11 months\t4(19 %)\t2 (9.5 %)\trectum: maximum dose < 50 Gy; bowel: V45 < 250 cm3; bladder: as low as reasonably achievable.\t\n\nCihoric et al. [11]\tDefinitive dose escalated IMRT, retrospective\t50.4 to whole pelvis, 5.4 to 9 Gy boost to central disease, 62 Gy to lymph nodes\tHDR TD 15–18 Gy with 4–6.5 Gy SD\t39\tIB2 to IVA\t24 (61.5 %)\t15\t36 (3–71 months)\t14 (35.9 %)\t9 (23.1 %) patient with pelvic failure; LRFS was 55.2 ± 4.4 months\t25 (64.1 %). The mean DFS: 47.2 ± 4.9 months\tMean OS time for the entire cohort: 61.1 ± 3.5 months\t2 (5.2 %)\t2 (5.2 %)\t60 % of rectum < 50 Gy, 35 % of bowel < 35Gy, 50 % of bladder < 50 Gy and 10 % of the femoral heads < 50 Gy.\t\n\n\nTraditionally, EBRT whole-pelvic doses are limited to 45 to 50 Gy, primarily due to the small bowel tolerance as a limiting factor. As already discussed, IMRT has an improved therapeutic ratio and therefore introduces the possibility of sparing healthy organs without a compromise to the target volume dosage. Incidence of early grade 3 or higher gastrointestinal (GIT) and urogenital (UG) toxicities for conventional radio-chemotherapy is more than 25 % [3, 24]. Compared with conventional radiotherapy overall incidence of toxicity in our cohort was low. We did not record any serious adverse event grade 4 or 5, and despite of the EBRT dose intensification, acute toxicities in our patient cohort remain within reasonable range. A similar incidence of serious adverse events ranging between 2 % to 4.6 % for acute and 6.4 to 7 % for late toxicities is reported by other authors. A review of the literature with their corresponding results is presented in Table 4 [8, 25–31].\n\nIn our institution we defined our treatment concept based on two goals. Firstly, by using an escalated dose we tried to sterilize the macroscopic metastatic disease in the lymphatic pathways while reducing the primary tumor size, which in turn had a benefit for the application of the brachytherapy boost. We managed to achieve treatment results, comparable with results reported in the literature.\n\nKidd et al. compared outcome and toxicities of 317 cervical cancer patients treated with step-wedge intensity modulation technique and 135 patients treated with PET/CT-guided IMRT. The majority of patients were diagnosed with FIGO IIB and IIIB. 30.4 % and 17.0 % of patients treated with IMRT were diagnosed with metastatic pelvic and para-aortic lymph nodes respectively. The IMRT group showed better disease specific survival and overall survival [6].\n\nHasselle et al. treated 81 patients (FIGO IIB-IVA) with definitive IMRT followed by HDR or LDR brachytherapy. The prescription dose for IMRT ranged between 39.6 and 50.4 Gy with median dose of 45 Gy. Three-year OS and the DFS were 61.4 % and 51.4 %, respectively. The 3-year pelvic failure rate (PF) was 29.2 %. The 3-year cumulative incidences of PF alone, DF alone, synchronous PF/DF, and CM as first events were 8.6 %, 10.1 %, 4.8 %, and 7.0 %, respectively. Six patients had isolated PF, and five had synchronous PF and DF. For all patients, the 3-year cumulative incidence of PF was 13.6 %. Pelvic failure locations included the cervix in 5 patients, vagina in 4 patients, vulva in 1 patient, and cervix plus a pelvic lymph node in 1 patient [25].\n\nChen et al. conducted a retrospective study with 109 patients with cervical cancer (FIGO IB2-IVA). Positive pelvic LN and PALN were diagnosed in 12.8 % and 11.9 % respectively. IMRT dose given to the GTV ranged from 45 to 54 Gy with concomitant boost of 54 to 60 Gy to the involved lymph nodes. The median follow up time for all surviving patients was 32.5 months, with a range from 5 to 75 months. The 3-year OS, LFFS (local failure free survival) and DFS were 78.2 %, 78.1 % and 67.6 %, respectively [26]. The treatment concept used, was similar to ours.\n\nThe major difference in patient population between the cited studies and ours is seen in the incidence of detected nodal metastasis and patients with bulky tumors > 4 cm. A significantly lower percentage of patients were diagnosed with metastatic lymph nodes in contrast to our cohort (61.5 % with lymph nodes metastases). Even though a review of the available literature would suggest a worse outcome in lymph node positive patients, this was not the case in our patient collective [32]. It could be hypothesized that an efficient control in the pelvic region contributed to the overall disease control. An important result of our study is the fact that we have achieved an excellent control of the metastatic lymph nodes with a median dose of 62 Gy [range 59.4 to 64 Gy]. During follow-up, there was no nodal failure detected within the high dose nodal volume.\n\nHowever, 8 patients developed loco-regional recidive within irradiated volume and one patient outside irradiated volume in form of distant vaginal failure. Reasons for failure cannot be precisely determined in this moment. Several potential factors, such as tumor resistance, geographical miss or insufficient dose, are stated in literature. In our cohort potential reason for local failure can be insufficient brachytherapy dose. In early stages of IMRT technique adoption we were cautious due to potential excess of toxicity due to escalated external beam dose. Our median summed EQD2 dose was 77.1 Gy (calculated using the formula: EQD2 = BED/(1 + 2/α/β), where BED = ED* (1 + ED/α/β) and α/β = 10). At the time of our protocol development there were not much data about combined escalated dose EBRT with HDR BT. However, this dose may be not sufficient for treatment of bulky tumors. Due to findings of our interim institutional analysis we changed policy and from 2011 onwards our dose prescription for HDR brachytherapy was 4 × 6 Gy prescribed to high risk tumor volume as defined by GEC-ESTRO guideline [12].\n\nFurther possible reasons for therapy failure are geographical miss or failure to detect gross disease, either local or nodal, and irradiate with sufficient dose. Although we used three imaging modalities including clinical evaluation, it is possible that we did not succeed to recognize all area needed to be irradiated with high dose. Every imaging modality has some limitation to detect local or nodal disease. However, the most appropriate staging is a topic of an ongoing debate. Although, surgical staging is more reliable than CT based staging and several retrospective studies have shown an advantage of surgical node extirpation, there is still no high level evidence to incorporate surgical staging or therapy of bulky lymph nodes into clinical practice. This must be observed in the context of more advanced imaging and radiotherapy techniques. Although not perfect, PET-CT appears to be a valid addition to clinical staging of patients with cervical cancer [33, 34]. Extensive lymphadenectomy combined with radio chemotherapy may be connected with excess toxicity and bulky lymph nodes may be treated with advanced IGRT technique [11]. Prospective clinical trials are required to answer this questions.\n\nEven though, lymph node involvement is one of the most important prognostic factors in cancer, evaluation and staging is not well defined in cervical cancer patients [35]. In addition several questions remain open regarding planning volumes and up to date there is still no clear concept regarding nodal PTV. A recent retrospective analysis of 665 primarily operated patients, revealed 168 patients with nodal metastases, with the most common site of occurrence, being the obturator and iliacal nodal stations, were affection of other nodal region was rare. These findings may help for further future optimization of the PTV [36].\n\nAlmost all patients with a loco-regional failure have a systemic failure as well. It is still unclear, whether metastatic cancer cells are already present at the time of therapy begin or if they are a result of seedling from tumor recurrence. A potential therapeutic answer for the treatment of microscopic systemic disease and at the same time, for a better loco-regional control, could be the introduction of an additional chemotherapeutic agent to cisplatin. Duenas-Gonzales et al. showed encouraging results, by combining gemcitabine with cisplatin, but a broader adoption of that concept was abandoned, as a result of the higher incidence of toxicities [37]. A dual chemotherapy concept should be evaluated in the future, together with IMRT as radiation delivery method.\n\nIt should also be noted that our study has several limitations. The small patient cohort prevents us from reaching a valid statistical conclusion in regards to possible risk factors and the therapy outcome. At the same time, there is no comparison to an additional arm comparing a different treatment dose. Furthermore, our cohort is heterogeneous, with some of our patients being partially operated prior to administering chemoradiation. Late toxicities of the proposed treatment concept are also an important issue. Late gastrointestinal toxicities occur in ca. 10 % of all patients and most occur within the first two years, but can still emerge up to 20 years after treatment. The urological toxicities can rise up to 10 % and their incidence can increase over time. Our relatively short follow-up is limited in the detection of potential late toxicities [38].\n\nWe managed to show that the intensified radiation therapy is well tolerated by patients with advanced cervical cancer; however we could not show survival benefit, potentially as a result of our small patient cohort. Therefore, the results of this study have to be validated on a larger patient cohort in order to show its impact on recurrence rate and survival. Nevertheless, our study can be used for new treatment strategies for patients with loco-regionally advanced cervical cancer.\n\nConclusion\nPatients with loco-regionally advanced cervical cancer treated with intensified IMRT seem to have a satisfactory outcome with reasonably low levels of treatment related toxicities. Although being limited due to its small size and retrospective nature, the present study contributes to the notion that the application of a high dose of radiation in the pelvic region by means of IMRT is feasible, with an acceptable profile of unwanted events and good loco-regional control, comparable with other published studies.\n\nAbbreviations\n3Dthree-dimensional\n\n18FDG-PET/CTF-18-fluordeoxyglucose positron emission tomography\n\nCTcomputed tomography\n\nCTVcclinical target volume for primary tumor area\n\nDFSdisease-free survival\n\nEBRTexternal beam radiation therapy\n\nFIGOinternational federation of gynecology and obstetrics\n\nGTVcgross tumor volume of the cervix\n\nGTVnnodal gross tumor volume\n\nIMRTintensity modulated radiotherapy\n\nLRDFSloco-regional disease-free survival\n\nLNlymph nodes\n\nMRImagnetic resonance imaging\n\nOSoverall survival\n\nPTVcplanning target volume of primary tumor\n\nPTVnnodal planning target volume\n\nPTVsumsingle planning target volume\n\nSIBsimultaneous integrated boost\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nEach author had participated sufficiently in the work to take public responsibility for appropriate portions of the content. NC and KL design the study. The manuscript was written by NC, KL, AT, IZ and DA. CT, NC and AT collected the data and together with NC, KL and IZ interpreted the data. All authors helped and finally approved the manuscript.\n==== Refs\nReferences\n1. Rose PG Bundy BN Watkins EB Thigpen JT Deppe G Maiman MA Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer N Engl J Med 1999 340 15 1144 1153 10.1056/NEJM199904153401502 10202165 \n2. Morris M Eifel PJ Lu J Grigsby PW Levenback C Stevens RE Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer N Engl J Med 1999 340 15 1137 1143 10.1056/NEJM199904153401501 10202164 \n3. Keys HM Bundy BN Stehman FB Muderspach LI Chafe WE Suggs CL 3rd Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma N Engl J Med 1999 340 15 1154 1161 10.1056/NEJM199904153401503 10202166 \n4. Green JA Kirwan JM Tierney JF Symonds P Fresco L Collingwood M Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis Lancet 2001 358 9284 781 786 10.1016/S0140-6736(01)05965-7 11564482 \n5. Beadle BM Jhingran A Yom SS Ramirez PT Eifel PJ Patterns of regional recurrence after definitive radiotherapy for cervical cancer Int J Radiat Oncol Biol Phys 2010 76 5 1396 1403 10.1016/j.ijrobp.2009.04.009 19581056 \n6. Kidd EA Siegel BA Dehdashti F Rader JS Mutic S Mutch DG Clinical outcomes of definitive intensity-modulated radiation therapy with fluorodeoxyglucose-positron emission tomography simulation in patients with locally advanced cervical cancer Int J Radiat Oncol Biol Phys 2010 77 4 1085 1091 10.1016/j.ijrobp.2009.06.041 19880262 \n7. Veldeman L Madani I Hulstaert F De Meerleer G Mareel M De Neve W Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies Lancet Oncol 2008 9 4 367 375 10.1016/S1470-2045(08)70098-6 18374290 \n8. Gandhi AK Sharma DN Rath GK Julka PK Subramani V Sharma S Early clinical outcomes and toxicity of intensity modulated versus conventional pelvic radiation therapy for locally advanced cervix carcinoma: a prospective randomized study Int J Radiat Oncol Biol Phys 2013 87 3 542 548 10.1016/j.ijrobp.2013.06.2059 24074927 \n9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Cervical Cancer [http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf] Accessed date 15 Dec 2014.\n10. Beadle BM Jhingran A Salehpour M Sam M Iyer RB Eifel PJ Cervix regression and motion during the course of external beam chemoradiation for cervical cancer Int J Radiat Oncol Biol Phys 2009 73 1 235 241 10.1016/j.ijrobp.2008.03.064 18513882 \n11. Cihoric N Tapia C Kruger K Aebersold DM Klaeser B Lossl K IMRT with (1)(8)FDG-PET\\CT based simultaneous integrated boost for treatment of nodal positive cervical cancer Radiat Oncol 2014 9 83 10.1186/1748-717X-9-83 24661323 \n12. Potter R Dimopoulos J Kirisits C Lang S Haie-Meder C Briot E Recommendations for image-based intracavitary brachytherapy of cervix cancer: the GYN GEC ESTRO Working Group point of view: in regard to Nag et al. (Int J Radiat Oncol Biol Phys 2004;60:1160–1172) Int J Radiat Oncol Biol Phys 2005 62 1 293 295 10.1016/j.ijrobp.2005.01.036 15850940 \n13. Nag S Erickson B Thomadsen B Orton C Demanes JD Petereit D The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix Int J Radiat Oncol Biol Phys 2000 48 1 201 211 10.1016/S0360-3016(00)00497-1 10924990 \n14. Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database of Systematic Reviews. 2010;(1):CD008285. doi:10.1002/14651858.\n15. Roeske JC Lujan A Rotmensch J Waggoner SE Yamada D Mundt AJ Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies Int J Radiat Oncol Biol Phys 2000 48 5 1613 1621 10.1016/S0360-3016(00)00771-9 11121668 \n16. Chan P Yeo I Perkins G Fyles A Milosevic M Dosimetric comparison of intensity-modulated, conformal, and four-field pelvic radiotherapy boost plans for gynecologic cancer: a retrospective planning study Radiat Oncol 2006 1 13 10.1186/1748-717X-1-13 16722546 \n17. Portelance L Chao KS Grigsby PW Bennet H Low D Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation Int J Radiat Oncol Biol Phys 2001 51 1 261 266 10.1016/S0360-3016(01)01664-9 11516876 \n18. Kavanagh BD Schefter TE Wu Q Tong S Newman F Arnfield M Clinical application of intensity-modulated radiotherapy for locally advanced cervical cancer Semin Radiat Oncol 2002 12 3 260 271 10.1053/srao.2002.32471 12118391 \n19. Esthappan J Chaudhari S Santanam L Mutic S Olsen J Macdonald DM Prospective clinical trial of positron emission tomography/computed tomography image-guided intensity-modulated radiation therapy for cervical carcinoma with positive para-aortic lymph nodes Int J Radiat Oncol Biol Phys 2008 72 4 1134 1139 10.1016/j.ijrobp.2008.02.063 18472358 \n20. Ahmed RS Kim RY Duan J Meleth S De Los Santos JF Fiveash JB IMRT dose escalation for positive para-aortic lymph nodes in patients with locally advanced cervical cancer while reducing dose to bone marrow and other organs at risk Int J Radiat Oncol Biol Phys 2004 60 2 505 512 10.1016/j.ijrobp.2004.03.035 15380585 \n21. Salama JK Mundt AJ Roeske J Mehta N Preliminary outcome and toxicity report of extended-field, intensity-modulated radiation therapy for gynecologic malignancies Int J Radiat Oncol Biol Phys 2006 65 4 1170 1176 10.1016/j.ijrobp.2006.02.041 16730136 \n22. Beriwal S Gan GN Heron DE Selvaraj RN Kim H Lalonde R Early clinical outcome with concurrent chemotherapy and extended-field, intensity-modulated radiotherapy for cervical cancer Int J Radiat Oncol Biol Phys 2007 68 1 166 171 10.1016/j.ijrobp.2006.12.023 17321070 \n23. Gerszten K Colonello K Heron DE Lalonde RJ Fitian ID Comerci JT Feasibility of concurrent cisplatin and extended field radiation therapy (EFRT) using intensity-modulated radiotherapy (IMRT) for carcinoma of the cervix Gynecol Oncol 2006 102 2 182 188 10.1016/j.ygyno.2005.12.044 16516281 \n24. Peters WA 3rd Liu PY Barrett RJ 2nd Stock RJ Monk BJ Berek JS Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix J Clin Oncol 2000 18 8 1606 1613 10764420 \n25. Hasselle MD Rose BS Kochanski JD Nath SK Bafana R Yashar CM Clinical outcomes of intensity-modulated pelvic radiation therapy for carcinoma of the cervix Int J Radiat Oncol Biol Phys 2011 80 5 1436 1445 10.1016/j.ijrobp.2010.04.041 20708346 \n26. Chen CC Lin JC Jan JS Ho SC Wang L Definitive intensity-modulated radiation therapy with concurrent chemotherapy for patients with locally advanced cervical cancer Gynecol Oncol 2011 122 1 9 13 10.1016/j.ygyno.2011.03.034 21514629 \n27. Mundt AJ Lujan AE Rotmensch J Waggoner SE Yamada SD Fleming G Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies Int J Radiat Oncol Biol Phys 2002 52 5 1330 1337 10.1016/S0360-3016(01)02785-7 11955746 \n28. Mundt AJ Mell LK Roeske JC Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy Int J Radiat Oncol Biol Phys 2003 56 5 1354 1360 10.1016/S0360-3016(03)00325-0 12873680 \n29. Du XL Tao J Sheng XG Lu CH Yu H Wang C Intensity-modulated radiation therapy for advanced cervical cancer: a comparison of dosimetric and clinical outcomes with conventional radiotherapy Gynecol Oncol 2012 125 1 151 157 10.1016/j.ygyno.2011.12.432 22198339 \n30. Zhang G He F Fu C Zhang Y Yang Q Wang J Definitive extended field intensity-modulated radiotherapy and concurrent cisplatin chemosensitization in the treatment of IB2-IIIB cervical cancer J Gynecol Oncol 2014 25 1 14 21 10.3802/jgo.2014.25.1.14 24459576 \n31. Jensen LG Hasselle MD Rose BS Nath SK Hasan Y Scanderbeg DJ Outcomes for patients with cervical cancer treated with extended-field intensity-modulated radiation therapy and concurrent cisplatin Int J Gynecol Cancer 2013 23 1 119 125 10.1097/IGC.0b013e3182749114 23262521 \n32. Stehman FB Bundy BN DiSaia PJ Keys HM Larson JE Fowler WC Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group Cancer 1991 67 11 2776 2785 10.1002/1097-0142(19910601)67:11<2776::AID-CNCR2820671111>3.0.CO;2-L 2025841 \n33. Choi HJ Roh JW Seo SS Lee S Kim JY Kim SK Comparison of the accuracy of magnetic resonance imaging and positron emission tomography/computed tomography in the presurgical detection of lymph node metastases in patients with uterine cervical carcinoma: a prospective study Cancer 2006 106 4 914 922 10.1002/cncr.21641 16411226 \n34. Loft A Berthelsen AK Roed H Ottosen C Lundvall L Knudsen J The diagnostic value of PET/CT scanning in patients with cervical cancer: a prospective study Gynecol Oncol 2007 106 1 29 34 10.1016/j.ygyno.2007.03.027 17482666 \n35. Scheidler J Hricak H Yu KK Subak L Segal MR Radiological evaluation of lymph node metastases in patients with cervical cancer A meta-analysis. Jama 1997 278 13 1096 101 9315770 \n36. Li X Yin Y Sheng X Han X Sun L Lu C Distribution pattern of lymph node metastases and its implication in individualized radiotherapeutic clinical target volume delineation of regional lymph nodes in patients with stage IA to IIA cervical cancer Radiat Oncol 2015 10 1 352 \n37. Duenas-Gonzalez A Zarba JJ Patel F Alcedo JC Beslija S Casanova L Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix J Clin Oncol 2011 29 13 1678 1685 10.1200/JCO.2009.25.9663 21444871 \n38. Maduro JH Pras E Willemse PH de Vries EG Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer Cancer Treat Rev 2003 29 6 471 488 10.1016/S0305-7372(03)00117-8 14585258\n\n",
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"abstract": "Here, we report a case of severe thrombocytopenia induced by nivolumab. A 70‒year‒old woman with advanced gastric cancer was treated with nivolumab. After the first dose, she noticed an erythematous rash. During the second cycle, fever and purpura on the lower extremities were also noted. Laboratory examinations revealed severe thrombocytopenia of grade 4, mild hemolytic anemia, leukopenia, and coagulopathy. Immune‒related adverse events(irAE)were suspected, and we started 40 mg(0.7 mg/kg)prednisolone(PSL)per day. Her symptoms and laboratory data immediately improved. However, when we reduced the dose of PSL, she developed rash and thrombocytopenia again. We increased the dose of PSL to 40 mg, which was effective for improving these abnormalities. We then gradually reduced the PSL, paying attention to avoid a relapse of irAEs. We could not restart chemotherapy thereafter, and she died from progression of gastric cancer. As shown in this case, PSL is effective for immune‒related thrombocytopenia; however, determining how to reduce the dose of PSL and when to restart chemotherapy requires careful consideration.",
"affiliations": "Dept. of Gastroenterology and Hepatology, Kurashiki Central Hospital.",
"authors": "Ueno|Masayuki|M|;Takaya|Ryosuke|R|;Doi|Akira|A|;Mouri|Hirokazu|H|;Yamamoto|Hiroshi|H|;Mizuno|Motowo|M|",
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"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D007970:Leukopenia; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab; D013274:Stomach Neoplasms; D013921:Thrombocytopenia",
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"title": "Nivolumab‒Induced Severe Thrombocytopenia in a Patient with Advanced Gastric Cancer.",
"title_normalized": "nivolumab induced severe thrombocytopenia in a patient with advanced gastric cancer"
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"abstract": "BACKGROUND\nCerebral cryptococcomas is a rare form of central nervous system cryptococcosis. Most previous cases were mistaken for neoplasm before surgery. We present a case of cerebral cryptococcomas whose radiological profiles resembled demyelinating disease, especially tumefactive demyelinating lesion.\n\n\nMETHODS\nA 40-year-old male was admitted for 1-week-long unconsciousness. Brain MRI revealed a rim-enhanced mass within the corpus callosum body. Central nervous system demyelinating disease was suspected. Empirical corticosteroid treatment led to some improvement, but his condition deteriorated 2 months later. Brain MRI revealed punctate new foci. Cryptococcus neoformans was detected in cerebrospinal fluid. Cryptococcus antigen test was positive in his current and previous cerebrospinal fluid samples. The patient died despite standard antifungal treatment.\n\n\nCONCLUSIONS\nDiagnosis of cerebral cryptococcomas is challenging. It may mimic demyelinating diseases.",
"affiliations": "Department of neurology, 905th hospital of PLA Navy, No 1328 Huashan Road, Changning District, Shanghai, 200052, China.;Department of Laboratory Medicine, Huashan Hospital North, Fudan University, No 108 Luxiang Road, Baoshan District, Shanghai, 201907, China.;Department of Neurology, Huashan Hospital, Fudan University, No.12 Wulumuqi Road, Jing'an District, Shanghai, 200040, China. [email protected].",
"authors": "Wei|Jie|J|;Li|Xiang-Yu|XY|;Zhang|Yue|Y|http://orcid.org/0000-0002-1572-7910",
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"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1880\n10.1186/s12883-020-01880-4\nCase Report\nCentral nervous system Cryptococcoma mimicking demyelinating disease: a case report\nWei Jie 1 Li Xiang-Yu 2 http://orcid.org/0000-0002-1572-7910Zhang Yue [email protected] 3 1 Department of neurology, 905th hospital of PLA Navy, No 1328 Huashan Road, Changning District, Shanghai, 200052 China \n2 grid.8547.e0000 0001 0125 2443Department of Laboratory Medicine, Huashan Hospital North, Fudan University, No 108 Luxiang Road, Baoshan District, Shanghai, 201907 China \n3 grid.411405.50000 0004 1757 8861Department of Neurology, Huashan Hospital, Fudan University, No.12 Wulumuqi Road, Jing’an District, Shanghai, 200040 China \n12 8 2020 \n12 8 2020 \n2020 \n20 29719 1 2020 6 8 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\nCerebral cryptococcomas is a rare form of central nervous system cryptococcosis. Most previous cases were mistaken for neoplasm before surgery. We present a case of cerebral cryptococcomas whose radiological profiles resembled demyelinating disease, especially tumefactive demyelinating lesion.\n\nCase presentation\nA 40-year-old male was admitted for 1-week-long unconsciousness. Brain MRI revealed a rim-enhanced mass within the corpus callosum body. Central nervous system demyelinating disease was suspected. Empirical corticosteroid treatment led to some improvement, but his condition deteriorated 2 months later. Brain MRI revealed punctate new foci. Cryptococcus neoformans was detected in cerebrospinal fluid. Cryptococcus antigen test was positive in his current and previous cerebrospinal fluid samples. The patient died despite standard antifungal treatment.\n\nConclusion\nDiagnosis of cerebral cryptococcomas is challenging. It may mimic demyelinating diseases.\n\nKeywords\nCentral nervous system cryptococcosisCryptococcomasTumefactive demyelinating lesionCorticosteroidissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nCentral nervous system (CNS) cryptococcosis results from infection with the yeast fungus cryptococcus. A large proportion of patients with CNS cryptococcosis are immunosuppressed individuals, such as those with AIDS. Meningitis or meningoencephalitis is the most common form of the disease. Parenchymal involvements, including cryptococcomas and gelatinous pseudocysts have been occasionally reported [1–3]. Cryptococcoma is parenchyma granuloma caused by cryptococcal organisms. It is more common in immunocompetent host than in immunosuppressed individuals. Cryptococcus gattii is a more common causative pathogen than Cryptococcus neoformans [4]. Diagnosis of cryptococcoma is challenging, especially when it appears as a solitary lesion. In previous literature, most cryptococcomas were mistaken for neoplasms before surgery [2]. .As some special demyelinating diseases may look similar to neoplasms, we assume cryptococcoma should also be considered a differential to demyelinating diseases. Tumefactive demyelinating lesion (TDL) is a locally aggressive form of demyelination, usually manifesting as a solitary lesion. It tends to be large and ring-enhanced on imaging. Corticosteroid is effective in this condition. Here we report a case of CNS cryptococcoma whose radiological profiles and early response to corticosteroid resembled demyelinating disease. Initial positive response to corticosteroid was followed by deterioration and death.\n\nCase presentation\nA previously healthy 40-year-old male was admitted to a hospital in Yinshang An’hui province on April 24, 2016. About 1 week before admission, the patient was found to be apathetic, uncommunicative and slow to move at home. Soon after that, he became unresponsive and bedridden and thus was sent to the hospital where feeding tube and urinary catheter were placed. Brain computed tomography (CT) revealed a hypodense lesion in the corpus callosum. Patient’s consciousness level continued to decline during admission. When he was referred to 905th hospital, Navy, PLA, he was in vegetative state. Both axial muscles and appendicular muscles were rigid; the arms were in flexion position and legs were in extension position.\n\nBody temperature was 36.5 °C. Heart rate was 80 beats per minute. Blood pressure was 135/78 mmHg. Glasgow coma scale was scored 7 (eye opening: 3, verbal response: 1; motor response: 3). Pupil size was 3.5 mm in diameter bilaterally. Pupillary reaction to light was brisk. Corneal reflex was present. Axial and appendicular muscle tone increased. Upper extremities flexed. Lower extremities extended. Babinski and Chaddock signs were positive bilaterally. Blood leukocyte count was 3.79*10^9/L. N% was74.34%. C-reactive protein was 6.07 mg/L (normal range: 0–8.2). Liver and renal function were normal. Erythrocyte sediment rate was 21 mm/h. Serological testing was negative for HIV, syphilis, hepatitis B and C. anti-nuclear antibody, anti-cardiolipin antibody, anti-neutrophil cytoplasmic antibodies and T-SPOT test were negative. Lumbar puncture revealed opening pressure of 50mmH2O. Cerebrospinal fluid (CSF) was transparent and colorless. CSF protein elevated to 3.64 g/L (normal range: 0.15–0.45 g/L). CSF glucose level was 2.6 mmol/L (normal range: 2.4–4.5,) and simultaneous blood glucose was 5.38 mmol/L. CSF chloride level was 123 mmol/L (normal range: 120–132). Leukocyte count was 0 × 106/L. Oligoclonal band, aquaporin 4, myelin oligodendrocyte glycoprotein and glial fibrillary acidic protein antibodies were negative. Bacterial culture and Indian ink stain were negative. CSF sediment was cultured on Sabouraud’s agar for 72 h and no fungi was found. Histopathological analysis of the CSF with Wright staining did not find malignant cells. Lung CT revealed pulmonary nodules in the lower lobes. Brain MRI revealed a homogenous solid mass within the corpus callosum body. It was hypointense on T1W1 and isointense on T2 FLAIR. Post-contrast T1WI showed rim-enhancement and vasogenic edema (Fig. 1a-c).\nFig. 1 Axial postcontrast T1-weighted MR (a-c), demonstrated a rim-enhanced corpus callosum mass surrounded by vasogenic edema. Initial diffusion weighted images (d) showed rim hyperintensity but no restricted diffusion within the mass. Forty-two days after corticosteroid treatment, the mass shrank and the enhancement decreased (e-g). Seventy days after treatment, diffusion weighted images (h) revealed multiple punctate foci in addition to the corpus callosum mass. Cryptococcus neoformans was found in CSF with India ink stain (i).\n\n\n\nNeoplasm was considered, but acute onset and rapid disease progression were not consistent with neoplastic infection. TDL is a special demyelinating disease whose characteristic MR finding is a solitary tumor-like lesion greater than 2 cm with ring-enhancement [5]. Brain abscess was not considered because diffusion weighted imagine (DWI) did not show restricted diffusion (Fig. 1d). On the assumption that corticosteroid may ameliorate demyelinating disease, but may aggravate infectious disease, while having little impact on neoplasms, empirical corticosteroid treatment (methylprednisolone 500 mg once daily) was initiated on April 26. Brain biopsy would be the option if improvement could not be achieved or symptoms continued to deteriorate.\n\nThree days later, the patient showed response to verbal stimuli. One week later (on May 4), he was alert, oriented and cooperative. Speech was slurred. Muscle tone was stiff in the left extremities but was normal in the other parts of the body. Muscle strength was measured as 3/5 in the left leg and 4/5 in other extremities. Babinski sign was positive in the left. Feeding tube and urinary catheter were removed. On May 10, 2 weeks after corticotherapy, he was able to speak fluently and move with aid. Blood glucose was 6.6 mmol/l. Liver function, renal function and electrode were normal. When he was discharged on May 19, he could speak and walk normally. No obvious neurologic deficits remained. Oral prednisone of 60 mg daily was prescribed and was tapered by 5 mg every week. A repeat MRI on June 8 demonstrated lesion shrinkage and reduced rim enhancement (Fig. 1e-g). His condition remained stable until July 2016 when he became lethargic and apathetic again. MRI revealed punctate new foci in the centrum semiovale in addition to the corpus callosum mass (Fig. 1h). Lumbar puncture revealed open pressure of 250mmH2O. CSF glucose decreased to 2.03 mmol/l with simultaneous blood glucose of 9.11 mmol/l. CSF protein was elevated to 0.86 g/L, which was lower than that in the first lumbar puncture. Chloride was 118 mmol/L. Leucocyte count was 1*10^6/L. Cryptococcus neoformans was detected in the CSF by Indian ink staining. (Fig. 1i) CSF cryptococcus antigen test was positive at 1:640. Previously collected and stored CSF was tested for cryptococcus antigen and found to be positive as well. Intravenous amphotericin B 25 mg/d was given initially and then gradually increased to 50 mg/d. Oral flucytosine 6 g/d was also administered. However, his consciousness level declined rapidly. One week after treatment, he became comatose. Two weeks later, the patient developed status epilepticus. His relatives withdrew treatment based on his condition and the patient died.\n\nDiscussion and conclusions\nCryptococcosis is an infectious disease caused by invasive encapsulated yeasts in the genus cryptococcus, including Cryptococcus neoformans and Cryptococcus. gattii [6]. Cryptococcosis may manifest as meningitis, meningoencephalitis, hydrocephalus, dilation of the perivascular spaces, cryptococcomas and gelatinous pseudocysts [1]. Meningitis and meningoencephalitis are the most common manifestations usually caused by Cryptococcus neoformans in immunosuppressed patients. Cryptococcomas are granulomas caused by cryptococcus within the brain parenchyma. They are more common in immunocompetent patients and the causative agent is usually Cryptococcus gattii [7]. In this case, no evidence of HIV infection was identified, but the pathogen was Cryptococcus neoformans.\n\nThe diagnosis of CNS cryptococcoma is challenging. Patients with cryptococcoma can be either immunosuppressed or immunocompetent. CSF profiles can be normal or show unspecific changes. Lung CT scans do not always show typical pulmonary changes [6, 8]. On brain MRI, the lesion may present as low signals on T1 weighted images and high signals on T2 weighted images or T2 FLAIR. Post contrast T1 weighted images can be variable, ranging from no enhancement to peripheral nodular enhancement [9]. But these findings are not specific [10]: Glioma and tumefactive demyelination may have similar radiological manifestation. Most previous cases, whether immunosuppressed or immunocompetent, were misdiagnosed as neoplasms before brain biopsy or resection [8, 10]. In this case, fever was not recorded and regular laboratory tests of blood and CSF did not show signs of infection during the first admission: That is why we ignored the possibility of infectious disease at first. The unexpected response to corticosteroid further interfered with diagnosis. Similar case reports were rare. Hagan JE, et al. reported a patient with cryptococcoma received dexamethasone before surgery because the lesion was mistaken for glioma initially. Corticotherapy led to some improvement, but after the diagnosis was confirmed dexamethasone was soon suspended [11]. We assume temporary clinical and radiological alleviation may result from anti-inflammatory and anti-edematous effect of corticosteroids. But corticosteroids should not be used in cryptococcosis, even as adjuvant treatment [12].\n\nIn conclusion, we describe an immunocompetent patient with CNS cryptococcoma misdiagnosed as demyelinating disease. Corticosteroid alleviated symptoms temporarily but led to death. Diagnosis of CNS cryptococcoma is difficult, and the radiological profile or short-term response to corticosteroid can be deceptive. With regard to rim-enhancing mass, cryptococcoma should be included in differential diagnosis list.\n\nAbbreviations\nCNSCentral nervous system\n\nCSFCerebrospinal fluid\n\nTDLTumefactive demyelinating lesion\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\nJ.W: patient management, literature review, analysis of the radiologic data, initial draft manuscript preparation. X.Y.L: literature review, initial draft manuscript preparation, providing pathological images. Y.Z: concept and design of the study, analysis of the radiologic data, final approval of the version to be published. J.W. and X.Y.L contribute equally to the work. All authors have read and approved the manuscript of “Central Nervous System Cryptococcoma Mimicking Demyelinating Disease: A Case Report”.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nThe study is approved by ethics committee of Huashan hospital.\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. Caldemeyer KS Mathews VP Edwards-Brown MK Smith RR Central nervous system cryptococcosis: parenchymal calcification and large gelatinous pseudocysts AJNR Am J Neuroradiol 1997 18 1 107 109 9010527 \n2. Ulett KB Cockburn JW Jeffree R Woods ML Cerebral cryptococcoma mimicking glioblastoma BMJ Case Rep 2017 2017 bcr2016218824 10.1136/bcr-2016-218824 \n3. Velamakanni SS Bahr NC Musubire AK Boulware DR Rhein J Nabeta HW Central nervous system cryptococcoma in a Ugandan patient with human immunodeficiency virus Med Mycol Case Rep 2014 6 10 13 10.1016/j.mmcr.2014.08.003 25379390 \n4. Perfect JR Dismukes WE Dromer F Goldman DL Graybill JR Hamill RJ Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america Clin Infect Dis 2010 50 3 291 322 10.1086/649858 20047480 \n5. Lucchinetti CF Gavrilova RH Metz I Parisi JE Scheithauer BW Weigand S Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis Brain. 2008 131 Pt 7 1759 1775 10.1093/brain/awn098 18535080 \n6. Maziarz EK Perfect JR Cryptococcosis Infect Dis Clin N Am 2016 30 1 179 206 10.1016/j.idc.2015.10.006 \n7. Chen SC Slavin MA Heath CH Playford EG Byth K Marriott D Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death Clin Infect Dis 2012 55 6 789 798 10.1093/cid/cis529 22670042 \n8. Uppar A Raj ARP Konar S Kandregula S Shukla D Somanna S Intracranial Cryptococcoma-Clinicopathologic correlation and surgical outcome: a single-institution experience World Neurosurg 2018 115 e349 ee59 10.1016/j.wneu.2018.04.056 29678697 \n9. Smith AB Smirniotopoulos JG Rushing EJ From the archives of the AFIP: central nervous system infections associated with human immunodeficiency virus infection: radiologic-pathologic correlation Radiographics. 2008 28 7 2033 2058 10.1148/rg.287085135 19001657 \n10. Li Q You C Liu Q Liu Y Central nervous system cryptococcoma in immunocompetent patients: a short review illustrated by a new case Acta Neurochir 2010 152 1 129 136 10.1007/s00701-009-0311-8 19404577 \n11. Hagan JE Dias JS Villasboas-Bisneto JC Falcao MB Ko AI Ribeiro GS Puerperal brain cryptococcoma in an HIV-negative woman successfully treated with fluconazole: a case report Rev Soc Bras Med Trop 2014 47 2 254 256 10.1590/0037-8682-0215-2013 24861306 \n12. Day J Imran D Ganiem AR Tjahjani N Wahyuningsih R Adawiyah R CryptoDex: a randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis: study protocol for a randomised control trial Trials. 2014 15 441 10.1186/1745-6215-15-441 25391338\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "20(1)",
"journal": "BMC neurology",
"keywords": "Central nervous system cryptococcosis; Corticosteroid; Cryptococcomas; Tumefactive demyelinating lesion",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000328:Adult; D000946:Antigens, Fungal; D020806:Central Nervous System Bacterial Infections; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003711:Demyelinating Diseases; D003937:Diagnosis, Differential; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Central nervous system Cryptococcoma mimicking demyelinating disease: a case report.",
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"medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)"
},
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},
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"drugdosageform": "UNKNOWN",
"drugdosagetext": "TAPERED BY 5MG EVERY WEEK",
"drugenddate": "2016",
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"drugindication": "DEMYELINATION",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "PREDNISONE."
}
],
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"patientonsetage": "40",
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Neurocryptococcosis",
"reactionmeddraversionpt": "23.1",
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},
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Infection masked",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WEI J, LI X, ZHANG Y. CENTRAL NERVOUS SYSTEM CRYPTOCOCCOMA MIMICKING DEMYELINATING DISEASE: A CASE REPORT. BMC NEUROLOGY. 2020 AUG 12?20:.",
"literaturereference_normalized": "central nervous system cryptococcoma mimicking demyelinating disease a case report",
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},
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"receivedate": "20201008",
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},
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},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210114"
},
{
"companynumb": "CN-PFIZER INC-2020377709",
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"occurcountry": "CN",
"patient": {
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{
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},
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"medicinalproduct": "PREDNISONE."
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"medicinalproduct": "PREDNISONE."
},
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},
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"medicinalproduct": "METHYLPREDNISOLONE."
}
],
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Neurocryptococcosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Coma",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Cryptococcosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Status epilepticus",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "3"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2016"
}
},
"primarysource": {
"literaturereference": "WEI, J.. CENTRAL NERVOUS SYSTEM CRYPTOCOCCOMA MIMICKING DEMYELINATING DISEASE: A CASE REPORT.. BMC NEUROLOGY. 2020?20(1):297",
"literaturereference_normalized": "central nervous system cryptococcoma mimicking demyelinating disease a case report",
"qualification": "1",
"reportercountry": "CN"
},
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"receiptdate": "20201015",
"receivedate": "20201002",
"receiver": {
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},
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"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20210113"
}
] |
{
"abstract": "Anaphylaxis during anesthesia is an unpredictable, severe, and rare reaction. It has an incidence of 1/10 000 to 1/20 000 surgeries. In most series, the responsible drugs include neuromuscular blocking agents, latex, or antibiotics. The frequency and etiology of systemic allergic reactions in other medical procedures are largely unknown. The identification of responsible drugs of anaphylaxis is a complex task, requiring testing of all medications and substances used during surgery. We describe our experience in a retrospective study of 15 patients. Ten subjects developed anaphylaxis during surgery, two in endoscopic studies and one in a trans-vaginal ultrasound. The remaining two subjects, one in a trans-vaginal ultrasound and another during a dental procedure had a systemic allergic reaction. We studied all patients with all medications administered during the procedures, including latex and detergents and disinfectants. Three surgeries had to be suspended at induction of anesthesia, five were stopped incomplete and two were completed. Both patients that presented a reaction during endoscopy required intensive care unit admission and the rest were observed in a Hospital. The responsible drugs during surgery anaphylaxis were neuromuscular blocking agents, latex, patent blue, and ranitidine. Ortho-phthalaldehyde (OPA) was identified during endoscopic studies; latex was responsible in transvaginal ultrasounds; and amoxicillin in the dental procedure. The aim of the present article is to review our experience studying allergic systemic reactions and anaphylaxis during general anesthesia and medical procedures, emphasizing the severity of these reactions and the need for causative drug identification.",
"affiliations": "Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina. E-mail: [email protected].;Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina.;Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina.;Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina.;Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina.;Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina.",
"authors": "Larrauri|Blas J|BJ|;Torre|María Gabriela|MG|;Malbrán|Eloísa|E|;Juri|María Cecilia|MC|;Fernández Romero|Diego S|DS|;Malbrán|Alejandro|A|",
"chemical_list": null,
"country": "Argentina",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7680",
"issue": "77(5)",
"journal": "Medicina",
"keywords": "OPA; allergy; latex; medical procedure; neuromuscular blocking drugs; ortho phthalaldehyde; perioperative anaphylaxis",
"medline_ta": "Medicina (B Aires)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000707:Anaphylaxis; D017548:Echocardiography, Transesophageal; D004724:Endoscopy; D019160:Endosonography; D005260:Female; D006801:Humans; D006967:Hypersensitivity; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013514:Surgical Procedures, Operative",
"nlm_unique_id": "0204271",
"other_id": null,
"pages": "382-387",
"pmc": null,
"pmid": "29044014",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaphylaxis and allergic reactions during surgery and medical procedures.",
"title_normalized": "anaphylaxis and allergic reactions during surgery and medical procedures"
}
|
[
{
"companynumb": "AR-FRESENIUS KABI-FK201808843",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VECURONIUM BROMIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "205390",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "VECURONIUM (MANUFACTURER UNKNOWN)"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATRACURIUM BESYLATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"medicinalproduct": "ATRACURIUM BESILATE"
}
],
"patientagegroup": null,
"patientonsetage": "73",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Anaphylactic reaction",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LARRAURI B, TORRE M, MALBRAN E, JURI M, FERNANDEZ ROMERO D, MALBRAN A. ANAPHYLAXIS AND ALLERGIC REACTIONS DURING SURGERY AND MEDICAL PROCEDURES. MEDICINA?B?AIRES. 2017?382?387.",
"literaturereference_normalized": "anaphylaxis and allergic reactions during surgery and medical procedures",
"qualification": "3",
"reportercountry": "AR"
},
"primarysourcecountry": "AR",
"receiptdate": "20180821",
"receivedate": "20180821",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15302901,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)-based therapy for antibody-mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement-1q (C1q)-fixing ability of their immunodominant (ID) donor-specific anti-human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ. DSA IgG mean fluorescence intensity (MFI) fell from 7664 (IQR 3230-11 874) to 1878 (653-7791) after therapy (p = 0.001) and to 1400 (850-8287) 2 weeks later (p = 0.001). DSA C1q MFI fell from 3596 (IQR 714-14 405) to <30 after therapy (p = 0.01) and <30 2 weeks later (p = 0.02). Forced expiratory volume in 1s ( FEV1 ) fell from mean 2.11 L pre-AMR to 1.92 L at AMR (p = 0.04). FEV1 was unchanged after CFZ (1.91 L) and subsequently rose to a maximum of 2.13 L (p = 0.01). Mean forced expiratory flow during mid forced vital capacity (25-75) (FEF25-75 ) fell from mean 2.5 L pre-AMR to 1.95 L at AMR (p = 0.01). FEF25-75 rose after CFZ to 2.54 L and reached a maximum of 2.91 L (p = 0.01). Responders had less chronic lung allograft dysfunction or progression versus nonresponders (25% vs. 83%, p = 0.04). No deaths occurred within 120 days and 7 patients died post CFZ therapy of allograft failure. Larger prospective interventional studies are needed to further describe the benefit of CFZ-based therapy for pulmonary AMR.",
"affiliations": "School of Pharmacy, Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA.;Department of Pathology, University of Pittsburgh, Pittsburgh, PA.;Department of Pathology, University of Pittsburgh, Pittsburgh, PA.;School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.;Department of Pathology, University of Pittsburgh, Pittsburgh, PA.;School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.;Division of Cardiothoracic Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.;Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.;Department of Pathology, University of Pittsburgh, Pittsburgh, PA.;Department of Pathology, University of Pittsburgh, Pittsburgh, PA.;School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.",
"authors": "Ensor|C R|CR|;Yousem|S A|SA|;Marrari|M|M|;Morrell|M R|MR|;Mangiola|M|M|;Pilewski|J M|JM|;D'Cunha|J|J|;Wisniewski|S R|SR|;Venkataramanan|R|R|;Zeevi|A|A|;McDyer|J F|JF|",
"chemical_list": "D007518:Isoantibodies; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.14222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "17(5)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "alloantibody; clinical research/practice; lung (allograft) function/dysfunction; lung transplantation/pulmonology; plasma cells; plasmapheresis/plasma exchange; rejection: antibody-mediated (ABMR)",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007518:Isoantibodies; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D011183:Postoperative Complications; D011379:Prognosis; D061988:Proteasome Inhibitors; D012307:Risk Factors",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1380-1388",
"pmc": null,
"pmid": "28173620",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings.",
"title_normalized": "proteasome inhibitor carfilzomib based therapy for antibody mediated rejection of the pulmonary allograft use and short term findings"
}
|
[
{
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},
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"medicinalproduct": "MYCOPHENOLIC ACID."
},
{
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"activesubstancename": "MYCOPHENOLIC ACID"
},
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{
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"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "25",
"patientonsetageunit": "801",
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Lung transplant rejection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Acute lung injury",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Restrictive allograft syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Obliterative bronchiolitis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory tract inflammation",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ENSOR CR, YOUSEM SA, MARRARI M, MORRELL MR, MANGIOLA M, PILEWSKI JM ET AL.. PROTEASOME INHIBITOR CARFILZOMIB-BASED THERAPY FOR ANTIBODY-MEDIATED REJECTION OF THE PULMONARY ALLOGRAFT: USE AND SHORT-TERM FINDINGS. AMERICAN JOURNAL OF TRANSPLANTATION. 2017;1-9",
"literaturereference_normalized": "proteasome inhibitor carfilzomib based therapy for antibody mediated rejection of the pulmonary allograft use and short term findings",
"qualification": "3",
"reportercountry": "US"
},
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"receiptdate": "20170323",
"receivedate": "20170320",
"receiver": {
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20170429"
}
] |
{
"abstract": "Statins are widely used for primary and secondary prevention of cardiovascular disease. For this reason, knowledge of the side effects and interactions pertaining to this class of pharmaceuticals is of utmost importance to all physicians. In this text a case report is presented of an eighty year old gentleman, referred to the respiratory clinic at Mater Dei Hospital Malta after developing dry cough on being treated with simvastatin and fluvastatin. An attempt at switching over to a placebo was made with resolution of symptoms. This is the second described case in the literature of lone cough associated with statin therapy necessitating treatment discontinuation in our patient. Possible hypothesis are discussed as well as suggestions for further research to unravel the underlying mechanisms of this association.",
"affiliations": "Mater Dei Hospital, 17, Floreat, Triq il-Kbira, Gharghur, Malta (EU). [email protected]",
"authors": "Psaila|Matthew|M|;Fsadni|Peter|P|;Montefort|Stephen|S|",
"chemical_list": "D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D019821:Simvastatin",
"country": "England",
"delete": false,
"doi": "10.1177/1753465812452192",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-4658",
"issue": "6(4)",
"journal": "Therapeutic advances in respiratory disease",
"keywords": null,
"medline_ta": "Ther Adv Respir Dis",
"mesh_terms": "D000369:Aged, 80 and over; D002908:Chronic Disease; D003371:Cough; D005229:Fatty Acids, Monounsaturated; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008297:Male; D019821:Simvastatin",
"nlm_unique_id": "101316317",
"other_id": null,
"pages": "243-6",
"pmc": null,
"pmid": "22761129",
"pubdate": "2012-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic cough as a complication of treatment with statins: a case report.",
"title_normalized": "chronic cough as a complication of treatment with statins a case report"
}
|
[
{
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"activesubstancename": "INSULIN NOS"
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},
{
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},
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"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "1",
"drugrecurrence": [
{
"drugrecuraction": "Cough"
}
],
"drugseparatedosagenumb": null,
"drugstartdate": "200906",
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"medicinalproduct": "SIMVASTATIN."
}
],
"patientagegroup": null,
"patientonsetage": "80",
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Cough",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PSAILA M, FSADNI P, MONTEFORT S. CHRONIC COUGH AS A COMPLICATION OF TREATMENT WITH STATINS: A CASE REPORT. THER ADV RESPIR DIS. 2012;AUG; 6(4):243-6",
"literaturereference_normalized": "chronic cough as a complication of treatment with statins a case report",
"qualification": "1",
"reportercountry": "MT"
},
"primarysourcecountry": "MT",
"receiptdate": "20150505",
"receivedate": "20121003",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 2,
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Serotonin syndrome (SS) is a complication after overdosage with antidepressants. SS increases the level of circulating serotonin. Fatal outcome of SS is most often seen in cases where there has been an overdosage with selective serotonin reuptake inhibitors (SSRI)/selective noradrenaline reuptake inhibitors (SNRI) in combination with other serotonin increasing drugs. This case report describes the rapid development of symptoms in a 54-year-old man who ingested a total amount of 6.5 g of SSRI and SNRI drugs as the only drug types. It proves the importance of being aware of the symptoms of SS when the patient is first seen in the emergency department.",
"affiliations": "Lungemedicinsk Afdeling, Aarhus Universitetshospital, Nørrebrogade 44, 8000 Aarhus C. [email protected].",
"authors": "Gude|Martin Faurholdt|MF|;Jensen|Lisbet Tokkesdal|LT|;Bjerre-Kristensen|Lars|L|",
"chemical_list": "D000928:Antidepressive Agents; D017367:Serotonin Uptake Inhibitors; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "176(7A)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000928:Antidepressive Agents; D003866:Depressive Disorder; D062787:Drug Overdose; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D013405:Suicide",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": "V07130443",
"pmc": null,
"pmid": "25347564",
"pubdate": "2014-02-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal outcome after overdosage with antidepressants.",
"title_normalized": "fatal outcome after overdosage with antidepressants"
}
|
[
{
"companynumb": "DK-PFIZER INC-2016327181",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
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{
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"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
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"drugdosagetext": "5000 MG, SINGLE",
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"drugindication": "COMPLETED SUICIDE",
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"medicinalproduct": "SERTRALINE HCL"
},
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"medicinalproduct": "RAPIFEN /00109201/"
},
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"medicinalproduct": "SUXAMETON SAD"
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"drugenddateformat": null,
"drugindication": "SEDATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "50",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "THIOPENTAL"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "020699",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "PROLONGED-RELEASE CAPSULE",
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"drugenddateformat": null,
"drugindication": "DEPRESSION",
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"medicinalproduct": "VENLAFAXINE HCL"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISOPROTERENOL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CARDIAC ARREST",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ISOPRENALINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "019839",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DEPRESSION",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SERTRALINE HCL"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "020699",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "PROLONGED-RELEASE CAPSULE",
"drugdosagetext": "1500 MG, SINGLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COMPLETED SUICIDE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1500",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VENLAFAXINE HCL"
}
],
"patientagegroup": null,
"patientonsetage": "54",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Serotonin syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Completed suicide",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GUDE, M.. FATAL OUTCOME AFTER OVERDOSAGE WITH ANTIDEPRESSANTS. UGESKRIFT FOR LAEGER. 2014;176(7A):V07130443",
"literaturereference_normalized": "fatal outcome after overdosage with antidepressants",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20161202",
"receivedate": "20160719",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12570267,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
},
{
"companynumb": "DK-TEVA-712297ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "76465",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "5000MG, SINGLE DOSE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COMPLETED SUICIDE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SERTRALINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "76690",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1500MG, SINGLE DOSE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COMPLETED SUICIDE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VENLAFAXINE"
}
],
"patientagegroup": null,
"patientonsetage": "54",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Muscle rigidity",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Flushing",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Heart rate increased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tremor",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Unresponsive to stimuli",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Agitation",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Completed suicide",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Blood pressure decreased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myoclonus",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Serotonin syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bradycardia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GUDE MF, JENSEN LT, BJERRE-KRISTENSEN L. FATAL OUTCOME AFTER OVERDOSAGE WITH ANTIDEPRESSANTS. UGESKR-LAEG 2014;:.",
"literaturereference_normalized": "fatal outcome after overdosage with antidepressants",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20170109",
"receivedate": "20161121",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12961613,
"safetyreportversion": 5,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170428"
}
] |
{
"abstract": "Low intracranial pressure headaches can, at times, be refractory to treatment including multiple blood patches and preventative medications. Imaging studies are often unable to demonstrate a cerebrospinal fluid leak that is causing headache and other associated symptoms. Onabotulinum toxin A (BTX) injection is a treatment that has proven efficacy for the treatment of chronic migraine and potentially other headache disorders. We report a patient with a long standing history of refractory low pressure headaches with brain imaging that demonstrated brain sag, and no CSF leak could be identified. She received no sustained benefit from numerous blood patches, and was unresponsive or intolerant to multiple preventative medications. With BTX treatment, the patient continued to have daily headaches, but her pain intensity improved from an average 7/10 to 3/10. This benefit has been sustained over 7 years. This case suggests that BTX may be an effective treatment for headaches due to low intracranial pressure. It also suggests that the beneficial effects of BTX in the treatment of headaches occur through a direct modulation of the nociceptive system rather than merely induction of pericranial muscle relaxation.",
"affiliations": "Brigham and Women's Hospital, Department of Neurology, John R. Graham Headache Center, Boston, MA, USA, [email protected].",
"authors": "Mathew|Paul G|PG|;Cutrer|F Michael|FM|",
"chemical_list": "D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A",
"country": "United States",
"delete": false,
"doi": "10.1007/s11910-014-0477-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1528-4042",
"issue": "14(9)",
"journal": "Current neurology and neuroscience reports",
"keywords": null,
"medline_ta": "Curr Neurol Neurosci Rep",
"mesh_terms": "D019274:Botulinum Toxins, Type A; D001921:Brain; D005260:Female; D006261:Headache; D006801:Humans; D019585:Intracranial Hypotension; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009465:Neuromuscular Agents; D011312:Pressure; D016896:Treatment Outcome",
"nlm_unique_id": "100931790",
"other_id": null,
"pages": "477",
"pmc": null,
"pmid": "25027263",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20647171;17901920;9415532;9748027;24694964;18385327;19912346;10759926;2300249;11112955;14991337;11376175",
"title": "Injecting under pressure: the pain of low CSF pressure headache responsive to botulinum toxin injections.",
"title_normalized": "injecting under pressure the pain of low csf pressure headache responsive to botulinum toxin injections"
}
|
[
{
"companynumb": "US-JNJFOC-20140908148",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "020505",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HEADACHE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TOPIRAMATE."
}
],
"patientagegroup": "5",
"patientonsetage": "46",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Dyspepsia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tinnitus",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MATHEW PG, CUTRER FM. INJECTING UNDER PRESSURE: THE PAIN OF LOW CSF PRESSURE HEADACHE RESPONSIVE TO BOTULINUM TOXIN INJECTIONS. CURRENT NEUROLOGY AND NEUROSCIENCE 2014;14:477.",
"literaturereference_normalized": "injecting under pressure the pain of low csf pressure headache responsive to botulinum toxin injections",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150525",
"receivedate": "20150321",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10947140,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
{
"abstract": "OBJECTIVE\nHemoptysis is a symptom that can be caused by airway disease, pulmonary parenchymal disease, or pulmonary vascular disease, or it can be idiopathic. Infection is the most common cause of hemoptysis, accounting for 60% to 70% of cases. Hemoptysis is also an initial symptom of diffuse alveolar hemorrhage syndrome, although it may be absent at presentation in one-third of patients. Diffuse alveolar hemorrhage is characterized by disruption of the alveolar-capillary basement membranes because of either injury or inflammation of the arterioles, venules, or capillaries, resulting in bleeding in alveolar spaces. To date, no study in the literature has investigated the cause of hemoptysis in renal transplant patients. In this retrospective study, we aimed to investigate the causes of hemoptysis in renal recipients.\n\n\nMETHODS\nThe data included in this study were obtained from 352 renal transplant patients who were consulted by the pulmonology department regarding hemoptysis between 2011 and 2017 at Baskent University. Patient medical records were reviewed for demographic, clinical, radiographic, bronchoscopic features, and microbiology data. Immunosuppressive drugs and clinical outcome data were also noted.\n\n\nRESULTS\nThis study included 352 renal transplant patients (139 male patients with mean age of 34.9 ± 7 years and 113 female patients with mean age of 31.1 ± 5 years). Hemoptysis was detected in 17 patients (4.8%),with 3 (0.85%) having massive hemoptysis as a result of diffuse alveolar hemorrhage syndrome. Fourteen of our patient group (4%) had pneumonia, and Aspergillus species was detected in 5 patients (1.4%). The only reason for diffuse alveolar hemorrhage was immunosuppressive agents, including sirolimus and mycophenolate mofetil.\n\n\nCONCLUSIONS\nHemoptysis is an important respiratory symptom in renal transplant patients. Although community- or hospital-acquired pneumonia may result in hemoptysis, drug-induced diffuse alveolar hemorrhage and Aspergillus infection should be considered for causes in renal transplant patients.",
"affiliations": "From the Department of Pulmonary Diseases, Baskent University, Ankara, Turkey.",
"authors": "Serifoglu|Irem|I|;Er Dedekarginoglu|Balam|B|;Ayvazoglu Soy|Ebru Hatice|EH|;Ulubay|Gaye|G|;Haberal|Mehmet|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.TOND-TDTD2017.O30",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "16 Suppl 1(Suppl 1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D006469:Hemoptysis; D006785:Hospitals, University; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008499:Medical Records; D011014:Pneumonia; D055732:Pulmonary Aspergillosis; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014421:Turkey",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "70-74",
"pmc": null,
"pmid": "29527996",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Causes of Hemoptysis in Renal Transplant Patients.",
"title_normalized": "causes of hemoptysis in renal transplant patients"
}
|
[
{
"companynumb": "TR-JUBILANT CADISTA PHARMACEUTICALS-2018JUB00163",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "090661",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Haemoptysis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pulmonary alveolar haemorrhage",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SERIFOGLU I, DEDEKARGINOGLU BE, AYVAZOGLU SOY EH, ULUBAY G, HABERAL M. CAUSES OF HEMOPTYSIS IN RENAL TRANSPLANT PATIENTS. EXP CLIN TRANSPLANT (10.6002/ECT.TOND-TDTD2017.O30). 2018?16(SUPPL 1):70-74",
"literaturereference_normalized": "causes of hemoptysis in renal transplant patients",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20180508",
"receivedate": "20180508",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14861000,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Sub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation integrase strand-transfer inhibitors (INSTI) such as raltegravir. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART).\n\n\n\nWe report a 65 years old Cameroonian, previously exposed to raltegravir, and failing on third-line treatment with multi-drug resistance to darunavir/r and dolutegravir. Genotypic resistance testing (GRT) and viral tropism were performed during monitoring time points. The patient initiated ART in August 2007. At the time point of the first (29.04.2010), second (01.12.2017) and third (08.08.2019) GRT, prior ART exposure included 3TC, d4T, NVP and EFV; additionally TDF, DRV/r and RAL; and additionally ABC and DTG respectively. First GRT revealed mutations associated with resistance only to first-generation Non-nucleoside reverse transcriptase inhibitors (NNRTI). Second GRT revealed mutations associated with high-level resistance to all NRTIs, first generation NNRTIs, all ritonavir boosted protease inhibitors (PI/r), and all INSTI, while viral tropism (using geno2pheno) revealed a CCR5-tropic virus with a false positive rate (FPR) of 60.9% suggesting effectiveness of maraviroc (MRV). The third GRT showed high-level resistance to NRTI, NNRTI, all PI and all INSTI, with additional mutations (H221HY for NNRTI and S147G for INSTI), and a CCR5-tropic virus with a slightly reduced FPR (57.0%). Without any locally available active therapeutic option, the patient has been on a maintenance therapy with \"DRV/r (600mg x 2/day)+TDF+3TC\" and patient/family-centered adherence has been reinforced. Since the first viral load (VL) measurement in 2010, the patient has had 12 VL tests with the VL ranging from 4.97 Log to 6.44 Log copies/mL and the CD4 count never exceeded 200 cells/μL.\n\n\n\nAs African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection (and potential transmission) of dolutegravir-resistance, supporting case surveillance.",
"affiliations": "Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon. [email protected].;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;University of Rome Tor Vergata, Rome, Italy.;HIV Treatment Centre, Yaoundé Central Hospital, Yaoundé, Cameroon.;Faculty of Health Sciences, University of Buea, Buea, Cameroon.;World Health Organisation, Regional Office for Africa (AFRO), Brazzaville, Congo.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Central Technical Group, National AIDS Control Committee, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.;HIV Treatment Centre, Military Hospital, Yaoundé, Cameroon.;Faculty of Health Sciences, University of Buea, Buea, Cameroon.;Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.;Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon.",
"authors": "Fokam|Joseph|J|0000-0002-1501-2763;Takou|Desire|D|;Semengue|Ezechiel Ngoufack Jagni|ENJ|;Teto|Georges|G|;Beloumou|Grace|G|;Dambaya|Beatrice|B|;Santoro|Maria-Mercedes|MM|;Mossiang|Leonella|L|;Billong|Serge Clotaire|SC|;Cham|Fatim|F|;Sosso|Samuel Martin|SM|;Temgoua|Edith Saounde|ES|;Nanfack|Aubin Joseph|AJ|;Moudourou|Sylvie|S|;Kamgaing|Nelly|N|;Kamgaing|Rachel|R|;Ngako Pamen|Joelle Nounouce|JN|;Etame|Mireille Mpoudi Ngole|MMN|;Bissek|Anne-Cecile Z-K|AZ|;Elat|Jean-Bosco N|JN|;Moussi|Emmanuel Eben|EE|;Colizzi|Vittorio|V|;Perno|Carlo-Federico|CF|;Ndjolo|Alexis|A|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; C562325:dolutegravir; D000069454:Darunavir",
"country": "England",
"delete": false,
"doi": "10.1186/s13756-020-00799-2",
"fulltext": "\n==== Front\nAntimicrob Resist Infect Control\nAntimicrob Resist Infect Control\nAntimicrobial Resistance and Infection Control\n2047-2994 BioMed Central London \n\n799\n10.1186/s13756-020-00799-2\nCase Report\nFirst case of Dolutegravir and Darunavir/r multi drug-resistant HIV-1 in Cameroon following exposure to Raltegravir: lessons and implications in the era of transition to Dolutegravir-based regimens\nhttp://orcid.org/0000-0002-1501-2763Fokam Joseph [email protected]@gmail.com 1234 Takou Desire 1 Semengue Ezechiel Ngoufack Jagni 156 Teto Georges 1 Beloumou Grace 1 Dambaya Beatrice 1 Santoro Maria-Mercedes 5 Mossiang Leonella 7 Billong Serge Clotaire 248 Cham Fatim 9 Sosso Samuel Martin 1 Temgoua Edith Saounde 8 Nanfack Aubin Joseph 1 Moudourou Sylvie 1 Kamgaing Nelly 1 Kamgaing Rachel 1 Ngako Pamen Joelle Nounouce 410 Etame Mireille Mpoudi Ngole 11 Bissek Anne-Cecile Z.-K. 2412 Elat Jean-Bosco N. 48 Moussi Emmanuel Eben 1 Colizzi Vittorio 156 Perno Carlo-Federico 1513 Ndjolo Alexis 134 On behalf of the VIROFORUM 1 Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon \n2 grid.29273.3d0000 0001 2288 3199Faculty of Health Sciences, University of Buea, Buea, Cameroon \n3 grid.415857.a0000 0001 0668 6654National HIV Drug Resistance Working Group, Ministry of Public Health, Yaoundé, Cameroon \n4 grid.412661.60000 0001 2173 8504Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon \n5 grid.6530.00000 0001 2300 0941University of Rome Tor Vergata, Rome, Italy \n6 Evangelic University of Cameroon, Bandjoun, Cameroon \n7 grid.460723.40000 0004 0647 4688HIV Treatment Centre, Yaoundé Central Hospital, Yaoundé, Cameroon \n8 grid.452676.4Central Technical Group, National AIDS Control Committee, Yaoundé, Cameroon \n9 World Health Organisation, Regional Office for Africa (AFRO), Brazzaville, Congo \n10 grid.415857.a0000 0001 0668 6654Department of Disease, Epidemics and Pandemics Control, Ministry of Public Health, Yaoundé, Cameroon \n11 HIV Treatment Centre, Military Hospital, Yaoundé, Cameroon \n12 Division of Health Operational Research, Yaoundé, Cameroon \n13 grid.4708.b0000 0004 1757 2822University of Milan, Milan, Italy \n26 8 2020 \n26 8 2020 \n2020 \n9 14325 3 2020 6 8 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\nSub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation integrase strand-transfer inhibitors (INSTI) such as raltegravir. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART).\n\nCase presentation\nWe report a 65 years old Cameroonian, previously exposed to raltegravir, and failing on third-line treatment with multi-drug resistance to darunavir/r and dolutegravir. Genotypic resistance testing (GRT) and viral tropism were performed during monitoring time points. The patient initiated ART in August 2007. At the time point of the first (29.04.2010), second (01.12.2017) and third (08.08.2019) GRT, prior ART exposure included 3TC, d4T, NVP and EFV; additionally TDF, DRV/r and RAL; and additionally ABC and DTG respectively. First GRT revealed mutations associated with resistance only to first-generation Non-nucleoside reverse transcriptase inhibitors (NNRTI). Second GRT revealed mutations associated with high-level resistance to all NRTIs, first generation NNRTIs, all ritonavir boosted protease inhibitors (PI/r), and all INSTI, while viral tropism (using geno2pheno) revealed a CCR5-tropic virus with a false positive rate (FPR) of 60.9% suggesting effectiveness of maraviroc (MRV). The third GRT showed high-level resistance to NRTI, NNRTI, all PI and all INSTI, with additional mutations (H221HY for NNRTI and S147G for INSTI), and a CCR5-tropic virus with a slightly reduced FPR (57.0%). Without any locally available active therapeutic option, the patient has been on a maintenance therapy with “DRV/r (600mg x 2/day)+TDF+3TC” and patient/family-centered adherence has been reinforced. Since the first viral load (VL) measurement in 2010, the patient has had 12 VL tests with the VL ranging from 4.97 Log to 6.44 Log copies/mL and the CD4 count never exceeded 200 cells/μL.\n\nConclusions\nAs African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection (and potential transmission) of dolutegravir-resistance, supporting case surveillance.\n\nKeywords\nHIV drug resistanceIntegrase inhibitorsProtease inhibitorsViral tropismCameroonChantal Biya International Reference center for research on HIV/AIDS prevention and management (CIRCB)issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nManagement of treatment-experienced HIV-patients remains very challenging in resource-limited settings where drug options are limited, poor adherence is frequent, and treatment monitoring (viral load essentially) remains sub-optimal [1, 2]. ART program was launched in Cameroon by May 2003, and genotyping drug resistance testing (GRT) is recommended essentially after failing a PI/r-based regimen [3]. Following the recent World Health Organisation (WHO) recommendations, most resource-limited settings, including Cameroon, are transitioning to dolutegravir (DTG)-based regimens for first-, second- and/or third-line ART [3], with no evidence of DTG-resistance reported in West-Central Africa [1, 3], and fewer cases in East Africa [4]. Of note, few studies reported lower rates of cross-resistance between raltegravir (first-generation integrase strand-transfer inhibitor) and dolutegravir (second-generation integrase strand transfer inhibitor) in Europe [5–8]. Exposure to raltegravir has been previously reported in managing patients with multi-resistant HIV in Africa, but little is known on their effects after transitioning to dolutegarvir-containing regimens [9]. Understanding the implications of prior exposure to raltegravir in routine clinical practice would serve as footprint for optimal ART-policies in this transition era, particularly in West and Central Africa and also in all resource-limited settings like Cameroon.\n\nCase presentation\nThis is a 65 years old married man, infected with HIV-1 CRF18_cpx. Therapeutic history, VL, CD4 cell counts and genotypic profiles are summarised in Fig. 1.\nFig. 1 CD4-cell and viral load monitoring, ART regimens, and resistance profiles since ART-initiation\n\n\n\nThe patient was diagnosed with HIV in 2002 and has been on ART for 14 years (since 2006). His initial ART regimen was stavudine (d4T) + lamivudine (3TC) + nevirapine (NVP) from August 2006 to August 2007. NVP was subsequently replaced by efavirenz (EFV) from August 2007 to August 2009. From August 2009, the patient voluntarily stopped treatment and returned to the clinic in 2010 for consultation. In 2010, the patient had a high VL (157,290 RNA copies/ml) and very-low CD4 cell count (87 cells/mm3). Prior to ART re-initiation in 2010, genotypic resistance testing (GRT) results, interpreted throughout using Stanford HIVDB (http://www.hivdb.stanford.edu) and International AIDS Society mutations list, showed the presence of one resistance associated mutation (RAM) to NRTI (V75I), two non-NRTI RAMs (K103I, V108I). With this mutational profile, the patient was recommended PI/r + 2NRTI but we have no precision on antiretrovirals used thereafter. From 2011 to 2012, the patient was diagnosed co-infected with pulmonary tuberculosis and treated accordingly, classified as WHO clinical stage 3. After completing anti-tuberculosis treatment in 2012, he was lost to follow-up (duration unclear) and later returned for clinical consultation. Following clinical assessment, he received a regimen consisting of super-boosted ritonavir with darunavir (DRV/r) + raltegravir (RAL) + tenofovir (TDF) +3TC (unclear start date) till November 2017, a period during which adherence was suboptimal (assessed by self-reporting). While completing anti-tuberculosis treatment the patient discontinued HIV-treatment. Following clinical assessment, he was re-initiated with a regimen consisting of ritonavir boosted darunavir (DRV/r) + raltegravir (RAL) + tenofovir (TDF) +3TC (unclear start date) till November 2017; a period during which adherence was suboptimal. A second GRT was performed and the resulting mutational profile suggested DRV/r(600 mg × 2/day) + DTG(50 mg × 2/day), possibly associated with ritonavir-boosted atazanavir (ATV/r) for its potential capacity to enhance DTG concentrations (https://www.hiv-druginteractions.org/drug_queries/326049/drug_query_interactions) as an optimal regimen. However, the patient was prescribed DRV/r(600 mg × 2/day) + DTG(50 mg × 1/day) + TDF + 3TC from November 2017 to May 2019. In May 2019, the patient was empirically switched to DRV/r(600 mg × 2/day) + DTG(50 mg × 1/day) + abacavir (ABC) +3TC. Then, ABC was changed to TDF until August 2019 when the third GRT was performed.\n\nOverall, reported VLs remained around 5 Log10 copies/mL while CD4-cell counts were consistently < 200 cells/mm3. Adherence to clinic appointments and drug refill was inconsistent, in spite of adherence supports from health care providers. Apart from anorexia and a 2.8% weight-loss reported over an undefined period, a physical examination, performed in May 2019, was unremarkable [3].\n\nFollowing GRTs performed on HIV-1 “pol” gene for detecting RAMs and gp120 V3-loop for coreceptor-usage (using the geno2pheno method [https://coreceptor.geno2pheno.org/]) at three different time points [10, 11], phylogeny consistently revealed the virus to be HIV-1 CRF18_cpx. All sequences generated were submitted to GeneBank (MN52015 – MN520219).\n\nThe first GRT (April 29, 2010) covered the protease (PR) and reverse transcriptase (RT) regions, with high-level resistance to first-generation NNRTI (K103I, V108I) and no major-RAM to NRTI and PI/r.\n\nThe second GRT (December 01, 2017) covered PR and RT regions. Detected RAMs were M41L, K70Q, V75I, Q151M, M184V and T215F for NRTI; K103N and V108I for NNRTI; and L10F, K20I, M36I, M46I, I47V, I54L, L63H, L76V, V82S and L89I for PI/r. These mutations revealed high-level resistance to all NRTIs, first generation NNRTIs (EFV and NVP) and to all PI/r, including DRV/r. Another GRT, covering HIV-1 integrase (IN) region, performed on the sample plasma aliquot, revealed major RAMs, L74I, E138KQ, G140A, Q148R, and E157Q, to integrase strand transfer inhibitors (INSTI) including raltegravir, dolutegravir, bictegravir and elvitegravir. Viral tropism revealed a CCR5-tropic virus, defined by a false positive rate (FPR) of 60.9%, suggesting eligibility for maraviroc (MRV).\n\nThe third GRT (August 08, 2019), encompassing PR, RT and IN regions, showed high-level resistance to NRTI, NNRTI, PI and all INSTI. Additional RAMs were H221HY for NNRTI and S147G for INSTI. Viral tropism was also re-performed and demonstrated CCR5-tropic virus with a slightly reduced FPR (57.0%). Pending access to required innovative regimen, a salvage therapy guided by GRT was recommended, consisting of either “DRV/r(600mg x 2/day), saquinavir/r, TDF+3TC”, or “3TC-monotherapy” which maintains M184V and as such limits the viral replicative fitness. None of the recommendations; in November 2019, VL appeared relatively stable (5.54 Log copies/mL) under “DRV/r(600mg x 2/day)+TDF+3TC” and with an active family-centered adherence monitoring. Following intensified/close adherence strategy implemented, the patient is compliant to treatment but the latest plasma viral load remains high, with a slight increment (5.86 Log copies/mL on January 27, 2020), which confirms the need of innovative drugs and close case surveillance, including MRV that is not locally available [3].\n\nDiscussion\nTo the best of our knowledge, this is the very first clinical case in West and Central Africa of complete four-class multidrug resistance to all antiretrovirals available in resource-limited settings with complete loss of DRV/r and DTG efficacies. Of note, previous report from Cameroon showed a case of successful raltegravir-containing ART for managing a case of multidrug-class-resistance [9]. Thus, patients with similar therapeutic management within the country might merit a close monitoring to ensure a successful management in case of ART failure with multi-drug resistance [9]. Fewer cases of four-class HIVDR have been recently reported mainly in East and southern African countries, with previous RAL-exposure contributing to ineffectiveness of DTG [4, 12–14]. Though these previously reported clinical cases were attributed to multi-factorial events, the present clinical case was due to recurrent poor adherence, leading to selection and accumulation of RAMs, followed by exposure to suboptimal drug regimens [14–16]. Specifically, previous exposure to RAL (a drug with a low-genetic barrier to resistance) in a context of poor adherence contributed to selecting mutations (E138KQ, G140A, Q148R) conferring cross-resistance to DTG [4, 15, 16]. In a context with 60–80% ADR after ART failure and with documented to RAL has been documented, limiting the use of RAL would preserve DTG for long-term use [1, 16]; and in case of previous exposure to RAL, transition to DTG-based regimens should be guided by GRT in people without VL-suppression [3] and if adopted, DTG-dose should be appropriate [6, 7]. In addition to non-adherence, consistent low CD4-cell counts (despite a relative increase of CD4 after a nadir of 39cells/mm3 is attribuable to the use of more potent antiretrovirals), high-VL since ART-initiation, and advanced-age (i.e. > 60 years) are risk-factors that might have contributed to ART-failure [14–16]. Additionally, the recombinant virus (HIV-1 CRF18_cpx) may explain to a certain extend the rapid emergence of drug-resistance and the predictive CCR5-tropism [17]. The case finding calls essentially for surveillance of acquired (ADR) drug resistance to INSTI in the DTG-era [1–3]. As patient remains clinically stable and sexually active, special patient/family-centered adherence approaches are necessary to limit risk of transmission of four-class drug resistant virus, which may have implications for scale-up of DTG-based ART in resource-limited settings [1, 4, 12–15]. Without any active therapeutic option locally, use of innovative drug combinations consisting preferentially of enfuvirtide, MRV and ibalizumab, is highly recommended (https://www.hiv-druginteractions.org/drug_queries/326049/drug_query_interactions). Also, as patients on DTG-containing regimens with high baseline VL (> 500,000 copies/mL) might experience challenges in viral suppression, close monitoring as well as specific case surveillance should be required even in resource-limited settings like Cameroon [18].\n\nConclusion\nIn the era of transition to DTG-based regimens in resource-limited settings, this clinical case highlights the need for routine ADR population-based surveys to understand the extent of HIVDR to INSTI. Importantly, optimised care/treatment on DTG-containing regimen, alongside adherence support and close VL monitoring, would sustain the efficacy of this therapeutic option. Finally, individual case surveillance after failure to third-line requires genotyping and policies for access to newer drugs in resource-limited settings with similar ART landscapes.\n\nAbbreviations\n3TCEmtricitabine\n\nABCAbacavir\n\nADRAcquired drug resistance\n\nAIDSAcquired Immunodeficiency Syndrome\n\nARTAntiretroviral therapy\n\nATV/rRitonavir boosted Atazanavir\n\nCCR5C-C chemokine receptor type 5\n\nCD4Cluster of differentiation four\n\nCRF18_cpxCirculating recombinant form complex 18\n\nD4TStavudine\n\nDRV/rRitonavir boosted Darunavir\n\nDTGDolutegravir\n\nEFVEfavirenz\n\nFPRFalse positive rate\n\nGP 120Envelope glycoprotein 120\n\nGRTGenotypic resistance testing\n\nHIVHuman immunodeficiency virus\n\nHIVDRHIV drug resistance\n\nINIntegrase\n\nINSTIIntegrase strand transfer inhibitor\n\nLPV/rRitonavir boosted Lopinavir\n\nMRVMaraviroc\n\nNNRTINon-nucleoside reverse-transcriptase inhibitor\n\nNRTINucleoside reverse-transcriptase inhibitor\n\nNVPNevirapine\n\nPDRPretreatment drug resistance\n\nPI/rritonavir boosted protease inhibitor\n\nPolPolymerase\n\nPRProtease\n\nRALRaltegravir\n\nRAMsResistance-associated mutations\n\nRNARibonucleic acid\n\nRTReverse transcriptase\n\nSSASub-Saharan Africa\n\nTDFTenofovir disoproxyl fumarate\n\nV3Envelope variable region 3\n\nVLViral load\n\nWHOWorld Health Organization\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nCarlo-Federico Perno and Alexis Ndjolo contributed equally to this work.\n\nWe are appreciative the medical and laboratory staffs involved in the care and monitoring of this patient. We thank Michael Jordan for a thorough review of this manuscript prior to submission.\n\nAuthors’ contributions\nJF, ENS, MMS, CFP, EST, GT, VC, DT, BD, GB, LM and AN, initiated the manuscript; All the other co-authors: interpreted the data and revised the manuscript; All the authors: approved the final version of the manuscript.\n\nFunding\nWe also acknowledge financial support from the Chantal Biya International Reference center for research on HIV/AIDS prevention and management (CIRCB), covering the viral load, CD4-cell count and sequencing of HIV-1 protease reverse transcriptase, integrase and V3 loop regions for this patient.\n\nAvailability of data and materials\nData and materials are fully available in the manuscript text and in the figure provided. Sequence data generated are deposited in the public repository of GeneBank, under the following accession numbers from MN52015 to MN520219.\n\nEthics approval and consent to participate\nAdministrative authorisation was provided by the Directorate General of the Chantal BIYA International Reference for research on HIV/AIDS prevention and management (CIRCB), under the reference number 0191/019/CIRCB/DG/SAA/BRH. Ethical clearance was obtained from the National Ethics Committee for Research on Human Health (reference number 2019/06/34/CE/CNERSH/SP of June 14, 2019). Written informed consent was provided.\n\nConsent for publication\nConsent has been provided by the patient.\n\nCompeting interests\nThe authors declare they have no personal relationship(s) or financial interests that may have influenced the writing of this report.\n==== Refs\nReferences\n1. 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"keywords": "Cameroon; HIV drug resistance; Integrase inhibitors; Protease inhibitors; Viral tropism",
"medline_ta": "Antimicrob Resist Infect Control",
"mesh_terms": "D000368:Aged; D019380:Anti-HIV Agents; D018791:CD4 Lymphocyte Count; D002163:Cameroon; D000069454:Darunavir; D024921:Drug Resistance, Multiple, Viral; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; D019562:Viral Load",
"nlm_unique_id": "101585411",
"other_id": null,
"pages": "143",
"pmc": null,
"pmid": "32843050",
"pubdate": "2020-08-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30631792;29568612;31339676;30601976;28369593;21465085;29894383;28329236;25558077;29765018;24446523;30165703;23225901;29435471;31371262;22889147;29595649",
"title": "First case of Dolutegravir and Darunavir/r multi drug-resistant HIV-1 in Cameroon following exposure to Raltegravir: lessons and implications in the era of transition to Dolutegravir-based regimens.",
"title_normalized": "first case of dolutegravir and darunavir r multi drug resistant hiv 1 in cameroon following exposure to raltegravir lessons and implications in the era of transition to dolutegravir based regimens"
}
|
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{
"abstract": "An 11-week pregnant, 32-year-old Japanese woman who had recovered from infectious mononucleosis visited our center due to fever, anorexia, and bilateral hypochondrial pain. Blood tests revealed leukopenia, thrombocytopenia and elevated ferritin. She was diagnosed with hemophagocytic lymphohistiocytosis (HLH). A high viral load of the Epstein-Barr virus (EBV) was recognized, indicating EBV-HLH. She was treated with a single dose of dexamethasone to protect the fetus. However, the disease was uncontrollable, necessitating etoposide and cyclosporine administration. Remission was obtained with these medications, and she has remained in remission for the 10 months since completion of chemotherapy. Although the occurrence of EBV-HLH during pregnancy is rare, it is possible that a change in cellular immunity associated with the pregnancy may contribute to EBV-HLH development.",
"affiliations": "Division of Hematology, Japanese Red Cross Medical Center.",
"authors": "Ikeda|Masahiro|M|;Oba|Rina|R|;Yoshiki|Yumiko|Y|;Shingaki|Sumito|S|;Takei|Tomomi|T|;Miyazaki|Kanji|K|;Abe|Yu|Y|;Tsukada|Nobuhiro|N|;Ishida|Tadao|T|;Suzuki|Kenshi|K|",
"chemical_list": "D005047:Etoposide; D016572:Cyclosporine",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(3)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D016572:Cyclosporine; D020031:Epstein-Barr Virus Infections; D005047:Etoposide; D005260:Female; D006801:Humans; D007244:Infectious Mononucleosis; D051359:Lymphohistiocytosis, Hemophagocytic; D011247:Pregnancy; D016896:Treatment Outcome",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "216-221",
"pmc": null,
"pmid": "28381688",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis during pregnancy.",
"title_normalized": "epstein barr virus associated hemophagocytic lymphohistiocytosis during pregnancy"
}
|
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{
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{
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}
] |
{
"abstract": "Nowadays, the retreatment of patients with Hepatitis C virus (HCV) genotype 3 (GT3) especially cirrhotic, who have already been treated with regimens containing a NS5A inhibitor represents a challenge. Use a novel retreatment option for patients with a difficult approach. We present three case reports of retreatment with a new combination of Direct-acting antivirals (DAAs), Sofosbuvir, Elbasvir/Grazoprevir in patients with GT3 with a previous failure with Sofosbuvir/Ledipasvir. All the cases achieved sustained virologic response (SVR) at week +12 without adverse effects. In our experience, this combo may represent an effective and safe option for these patients.",
"affiliations": "Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain; Infection, Immunity and Digestive Disease Group, Instituto de Investigation Valdecilla (IDIVAL), Santander, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain; Infection, Immunity and Digestive Disease Group, Instituto de Investigation Valdecilla (IDIVAL), Santander, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain; Infection, Immunity and Digestive Disease Group, Instituto de Investigation Valdecilla (IDIVAL), Santander, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain; Infection, Immunity and Digestive Disease Group, Instituto de Investigation Valdecilla (IDIVAL), Santander, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain; Infection, Immunity and Digestive Disease Group, Instituto de Investigation Valdecilla (IDIVAL), Santander, Spain.;Clinical Microbiology Department; Infectious Diseases and Clinical Microbiology Unit. Hospital Universitario San Cecilio, Granada. Spain.;Medical Service, Centro Penitenciario El Dueso, Santona, Spain.;Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain; Infection, Immunity and Digestive Disease Group, Instituto de Investigation Valdecilla (IDIVAL), Santander, Spain. Electronic address: [email protected].",
"authors": "Llerena|Susana|S|;Cabezas|Joaquín|J|;Cuadrado|Antonio|A|;Manuel Olmos|José|J|;González|Marta|M|;García|Federico|F|;Cobo|Carmen|C|;Crespo|Javier|J|",
"chemical_list": "C000589335:2-(pyrrolidin-2-yl)-5-(2-(4-(5-(pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole; D000577:Amides; D000998:Antiviral Agents; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D007093:Imidazoles; D011810:Quinoxalines; D012367:RNA, Viral; D013449:Sulfonamides; C578009:grazoprevir; D000069474:Sofosbuvir",
"country": "Mexico",
"delete": false,
"doi": "10.5604/01.3001.0012.7931",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "18(1)",
"journal": "Annals of hepatology",
"keywords": "Genotype 3; Grazoprevir + Elbasvir; Hepatitis C virus; Sofosbuvir; Treatment failure",
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000577:Amides; D000998:Antiviral Agents; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D011810:Quinoxalines; D012367:RNA, Viral; D019233:Retreatment; D000069474:Sofosbuvir; D013449:Sulfonamides; D017211:Treatment Failure",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "236-239",
"pmc": null,
"pmid": "31113598",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rescue Therapy for Genotype-3 DAA Non-responders, Almost all Done.",
"title_normalized": "rescue therapy for genotype 3 daa non responders almost all done"
}
|
[
{
"companynumb": "ES-GILEAD-2019-0384161",
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"occurcountry": "ES",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
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"medicinalproduct": "LEDIPASVIR/SOFOSBUVIR"
}
],
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{
"reactionmeddrapt": "Hepatitis C",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Genotype drug resistance test positive",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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},
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"receivedate": "20190115",
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "ES-GILEAD-2019-0384156",
"fulfillexpeditecriteria": "1",
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{
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"medicinalproduct": "EMTRICITABINE;RILPIVIRINE;TENOFOVIR DISOPROXIL FUMARATE"
},
{
"actiondrug": "6",
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"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
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"drugdosageform": "TABLET",
"drugdosagetext": "UNK, QD",
"drugenddate": null,
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"drugindication": "CHRONIC HEPATITIS C",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugseparatedosagenumb": "1",
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"medicinalproduct": "LEDIPASVIR/SOFOSBUVIR"
}
],
"patientagegroup": "5",
"patientonsetage": "48",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatitis C",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Genotype drug resistance test positive",
"reactionmeddraversionpt": "21.1",
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}
],
"summary": null
},
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"literaturereference": "LLERENA S, CABEZAS J, CUADRADO A, OLMOS JM, GONZALEZ M, GARCIA F ET AL. RESCUE THERAPY FOR GENOTYPE-3 DAA NON-RESPONDERS, ALMOST ALL DONE.. ANNALS OF HEPATOLOGY. 2019?18(1):236-239. DOI:DOI:10.5604/01.3001.0012.7931",
"literaturereference_normalized": "rescue therapy for genotype 3 daa non responders almost all done",
"qualification": "1",
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},
"primarysourcecountry": "ES",
"receiptdate": "20190116",
"receivedate": "20190116",
"receiver": {
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"receivertype": "6"
},
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "ES-GILEAD-2019-0384162",
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{
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"medicinalproduct": "EMTRICITABINE/TENOFOVIR/DOLUTEGRAVIR"
},
{
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},
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"drugdosageform": "TABLET",
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"drugindication": "CHRONIC HEPATITIS C",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"medicinalproduct": "HARVONI"
}
],
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{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatitis C",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Genotype drug resistance test positive",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "LLERENA S, CABEZAS J, CUADRADO A, OLMOS JM, GONZALEZ M, GARCIA F, COBO C, CRESPO J. RESCUE THERAPY FOR GENOTYPE-3 DAA NON-RESPONDERS, ALMOST ALL DONE.. ANNALS OF HEPATOLOGY. 2019?18(1):236-239. DOI:DOI:10.5604/01.3001.0012.7931",
"literaturereference_normalized": "rescue therapy for genotype 3 daa non responders almost all done",
"qualification": "1",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20190117",
"receivedate": "20190117",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15839213,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "OBJECTIVE\nPredniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH.\n\n\nMETHODS\nWe performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC.\n\n\nRESULTS\nThere was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal.\n\n\nCONCLUSIONS\nLong-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.",
"affiliations": "Department of Gastroenterology, Hacettepe University, Ankara, Turkey. Electronic address: [email protected].;Hepatology Division, Centre for Digestive Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.;Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Division of Gastroenterology and Liver Unit, University of Alberta, Alberta, Canada.;Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany.;Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.;Department of Gastroenterology, Hacettepe University, Ankara, Turkey.;Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, Università di Bologna, Bologna, Italy.;Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.;Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum, Università di Bologna, Bologna, Italy.;Department of Gastroenterology, Ege University, Bornova, Izmir, Turkey.;Department of Molecular and Clinical Medicine, Skåne University Hospital, Lund, Sweden; Division of Gastroenterology University of British Columbia, Vancouver General Hospital, Vancouver, Canada.;Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain.;Department of Hepato-Gastroenterology, Centre Hospitalier Universitaire Reims, Reims, France.;Division of Liver Diseases, The Mount Sinai Medical Center, New York, New York.;Department of Gastroenterology, Dr A.Y. Oncology Training and Research Hospital, Ankara, Turkey.;The Liver Center at University of California, San Francisco, Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California.;Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.;Division of Gastroenterology and Liver Unit, University of Alberta, Alberta, Canada.;Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany.;Department of Medicine, Brighton and Sussex Medical School, Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospital, Brighton, United Kingdom.;Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Department of Gastroenterology, Numune Research and Education Hospital, Ankara, Turkey.;Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom.;Division of Gastroenterology University of British Columbia, Vancouver General Hospital, Vancouver, Canada.;Hepatology Division, Centre for Digestive Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Efe|Cumali|C|;Hagström|Hannes|H|;Ytting|Henriette|H|;Bhanji|Rahima A|RA|;Müller|Niklas F|NF|;Wang|Qixia|Q|;Purnak|Tugrul|T|;Muratori|Luigi|L|;Werner|Mårten|M|;Marschall|Hanns-Ulrich|HU|;Muratori|Paolo|P|;Gunşar|Fulya|F|;Klintman|Daniel|D|;Parés|Albert|A|;Heurgué-Berlot|Alexandra|A|;Schiano|Thomas D|TD|;Cengiz|Mustafa|M|;May-Sien Tana|Michele|M|;Ma|Xiong|X|;Montano-Loza|Aldo J|AJ|;Berg|Thomas|T|;Verma|Sumita|S|;Larsen|Fin Stolze|FS|;Ozaslan|Ersan|E|;Heneghan|Michael A|MA|;Yoshida|Eric M|EM|;Wahlin|Staffan|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2017.06.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "15(12)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Autoimmune Liver Disease; Liver Failure; Liver Transplantation; Simplified Criteria",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002170:Canada; D002648:Child; D002681:China; D064420:Drug-Related Side Effects and Adverse Reactions; D005060:Europe; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D016559:Tacrolimus; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1950-1956.e1",
"pmc": null,
"pmid": "28603052",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis.",
"title_normalized": "efficacy and safety of mycophenolate mofetil and tacrolimus as second line therapy for patients with autoimmune hepatitis"
}
|
[
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2018-05497",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "200197",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "0.5-2.0 G/DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "AUTOIMMUNE HEPATITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Lymphoproliferative disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "EFE C, HAGSTROM H, YTTING H, BHANJI RA, ET AL.. EFFICACY AND SAFETY OF MYCOPHENOLATE MOFETIL AND TACROLIMUS AS SECOND-LINE THERAPY FOR PATIENTS WITH AUTOIMMUNE HEPATITIS. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY. 2017?15(12):1950-1956",
"literaturereference_normalized": "efficacy and safety of mycophenolate mofetil and tacrolimus as second line therapy for patients with autoimmune hepatitis",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20190102",
"receivedate": "20190102",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15781012,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2018-05496",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "200197",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
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"abstract": "BACKGROUND\nNuclear protein in testis carcinoma is a rare and very aggressive undifferentiated cancer which characteristically arises in the midline of the head, neck, and mediastinum.\n\n\nMETHODS\nWe describe the case of a 46-year-old white woman admitted for superior vena cava syndrome revealing a mediastinal tumor. Pathological examination of specimens obtained by mediastinoscopy revealed an undifferentiated tumor with solid growth and positive immunoreactivity for p40 and negative immunoreactivity for cytokeratin markers. Immunohistochemical staining was positive for nuclear protein in testis, allowing the diagnosis of nuclear protein in testis midline carcinoma of the mediastinum.\n\n\nCONCLUSIONS\nWe present a rare case of mediastinal nuclear protein in testis carcinoma with diagnosis based on nuclear protein in testis protein positivity and atypical immunohistochemical features including p40 positivity and anti-cytokeratin negativity. Physicians must remain aware of the possibility of nuclear protein in testis carcinoma especially in young patients with thoracic symptoms and suspicion of neoplasm.",
"affiliations": "Department of Respiratory Medicine, Reims University Hospitals, Reims, France. [email protected].;Department of Respiratory Medicine, Reims University Hospitals, Reims, France.;Department of Respiratory Medicine, Reims University Hospitals, Reims, France.;Department of Anatomy and Cytopathology, Cancer-Oncopole Institute, University of Toulouse, Toulouse, France.;INSERM UMR-S 903, Reims, France.;Department of Respiratory Medicine, Reims University Hospitals, Reims, France.;Department of Respiratory Medicine, Reims University Hospitals, Reims, France.;Department of Respiratory Medicine, Reims University Hospitals, Reims, France.;Department of Respiratory Medicine, Reims University Hospitals, Reims, France.;Department of Respiratory Medicine, Reims University Hospitals, Reims, France.",
"authors": "Boleto|Gonçalo|G|;Perotin|Jeanne-Marie|JM|;Launois|Claire|C|;Uro-Coste|Emmanuelle|E|;Birembaut|Philippe|P|;Dury|Sandra|S|;Vallerand|Hervé|H|;Lebargy|François|F|;Deslée|Gaëtan|G|;Vella-Boucaud|Juliette|J|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 132810.1186/s13256-017-1328-xCase ReportNuclear protein in testis carcinoma of the mediastinum: a case report Boleto Gonçalo +33 3 26 78 76 [email protected] 17Perotin Jeanne-Marie [email protected] 12Launois Claire [email protected] 1Uro-Coste Emmanuelle [email protected] 36Birembaut Philippe [email protected] 24Dury Sandra [email protected] 15Vallerand Hervé [email protected] 1Lebargy François [email protected] 15Deslée Gaëtan [email protected] 12Vella-Boucaud Juliette [email protected] 11 0000 0004 1937 0618grid.11667.37Department of Respiratory Medicine, Reims University Hospitals, Reims, France 2 INSERM UMR-S 903, Reims, France 3 0000 0001 2353 1689grid.11417.32Department of Anatomy and Cytopathology, Cancer-Oncopole Institute, University of Toulouse, Toulouse, France 4 0000 0004 1937 0618grid.11667.37Department of Pathology, Maison Blanche Hospital, Reims University Hospitals, Reims, France 5 0000 0004 1937 0618grid.11667.37EA 4683 Medical and Pharmacological University of Reims, Reims, France 6 INSERM UMR 1037, Cancer Research Centre, Toulouse, France 7 Service de Pneumologie, Hôpital Maison Blanche, CHU Reims, 45 rue Cogncaq-Jay, 51092 Reims cedex, France 9 6 2017 9 6 2017 2017 11 15213 1 2017 22 5 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNuclear protein in testis carcinoma is a rare and very aggressive undifferentiated cancer which characteristically arises in the midline of the head, neck, and mediastinum.\n\nCase presentation\nWe describe the case of a 46-year-old white woman admitted for superior vena cava syndrome revealing a mediastinal tumor. Pathological examination of specimens obtained by mediastinoscopy revealed an undifferentiated tumor with solid growth and positive immunoreactivity for p40 and negative immunoreactivity for cytokeratin markers. Immunohistochemical staining was positive for nuclear protein in testis, allowing the diagnosis of nuclear protein in testis midline carcinoma of the mediastinum.\n\nConclusions\nWe present a rare case of mediastinal nuclear protein in testis carcinoma with diagnosis based on nuclear protein in testis protein positivity and atypical immunohistochemical features including p40 positivity and anti-cytokeratin negativity. Physicians must remain aware of the possibility of nuclear protein in testis carcinoma especially in young patients with thoracic symptoms and suspicion of neoplasm.\n\nKeywords\nNUT carcinomaSuperior vena cava syndromeMediastinal neoplasmsissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nNuclear protein in testis (NUT) carcinoma is a rare and very aggressive undifferentiated cancer, which characteristically arises in the midline of the head, neck, and mediastinum [1] and shows aggressive behavior with early locoregional invasion and distant metastases [2]. Its incidence is unknown and it occurs mainly in adolescents and young adults [3]. Because of the rarity of this condition, no consensus has been reached concerning the optimal treatment strategy. The prognosis remains extremely poor with a 6.7-month median survival and a global survival of 19% within the first 2 years after diagnosis [2]. The pathophysiology involves a rearrangement of the NUT gene on chromosome 15q14 with members of the BRD gene family (BRD4 and BRD3) resulting in a BRD–NUT fusion product, which decreases histone acetylation and therefore suppresses squamous cell differentiation [4, 5]. Pathological examination may reveal positivity for cytokeratins (CKs) and p63, a squamous basal cell marker, leading to the incorrect diagnosis of squamous cell carcinoma [6]. We report a case of superior vena cava syndrome revealing a NUT carcinoma of the mediastinum.\n\nCase presentation\nA 46-year-old white woman with no medical history presented to our hospital with complaints of dyspnea, chest pain, dysphagia, cyanosis of the trunk and head, and distended superficial veins over her neck and chest of 3 weeks’ duration; these were all features of superior vena cava obstruction. She had no history of tobacco smoking, alcohol consumption, or illicit substance use. A physical examination showed decreased breathing sounds and dull percussion on the lower lobe of her right lung as well as diffuse wheezing of her right hemithorax. Laboratory tests did not reveal anemia, hydroelectrolytic, or coagulation disorders. A chest X-ray revealed widening of anterosuperior mediastinum (Fig. 1a). A contrast-enhanced chest computed tomography (CT) scan revealed a mediastinal mass with right-sided pleural effusion (Fig. 1b). No evidence of distant metastases was found. Fiberoptic bronchoscopy showed infiltration of the bronchial wall of her carina and her right main bronchus. However, histology of bronchial biopsies did not reveal any tumor infiltration. Mediastinoscopy was therefore performed and histological examination of right laterotracheal lymphadenopathy specimens demonstrated undifferentiated malignant tumor with solid growth composed of cells larger than lymphocytes with a round nucleus, variably prominent nucleoli, with dissociated growth pattern due to the presence of inflammatory cells, polymorphonuclear neutrophils, lymphocytes, and extensive necrosis (Fig. 2). Immunohistochemistry revealed tumor cells diffusely positive for p40 with some reactivity for vimentin. Tumor cells were negative for CK and epithelial membrane antigen (EMA) and for lymphocyte surface markers. Due to these typical findings, subsequent immunohistochemistry for NUT protein was performed and demonstrated marked nuclear positivity (Fig. 2).Fig. 1 \na Chest X-ray showing widening of anterosuperior mediastinum (white arrow). b Contrast-enhanced chest computed tomography scan showing a mediastinal mass with right-sided pleural effusion (blue arrow). The mass measures 78 by 40 mm and causes compression of the superior vena cava and pulmonary artery trunk (red arrow)\n\n\nFig. 2 Histomorphological details of nuclear protein in testis carcinoma. a The tumor demonstrates a population of cells larger than lymphocytes with a round nucleus, variably prominent nucleoli, with dissociated growth pattern and extensive necrosis; hematoxylin and eosin stain (×400 magnification). b Immunohistochemical staining revealed tumor cells diffusely positive for p40 (×400 magnification). c Immunohistochemical staining with nuclear protein in testis antibody (×400 magnification) shows nuclear positivity with a speckled pattern\n\n\n\n\nAfter multidisciplinary cancer team meeting discussions, our patient underwent a course of radiation therapy to her chest (20 Gy in five fractions) and received three cycles of carboplatin and paclitaxel. Her symptoms of vena cava syndrome improved and a chest CT scan showed that the size of the mediastinal mass had decreased by 32%: a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [7]. After the fourth cycle of chemotherapy, she developed severe peripheral neuropathy to paclitaxel leading to discontinuation of treatment. One month after discontinuation of chemotherapy, she developed recurrence of vena cava syndrome symptoms and a chest CT scan showed mediastinal progression of the thoracic mass. Due to her poor general state and despite second-line chemotherapy with carboplatin and pemetrexed, she rapidly progressed to the point of palliative care and died 6 months after the initial diagnosis.\n\nDiscussion\nNUT carcinoma is a rare carcinoma with only 39 cases of intrathoracic tumors published to date [3, 8]. Chronic cough, dyspnea, hemoptysis, chest pain, and fatigue are among the main presenting complaints [3].\n\nHistological findings typically show two types of tumor cell populations: (1) poorly differentiated carcinoma, and (2) well-differentiated squamous cell islands with focal keratinization [3, 6]. Positive immunoreactivity to anti-CK antibodies AE1/AE3, as well as EMA (a marker for the epithelial nature of neoplastic cells), p63, and p40 (markers of squamous and basal cell carcinomas) are the usual immunohistochemical findings and should raise the suspicion of NUT carcinoma in young individuals with a midline tumor [6]. The differential diagnosis of mediastinal NUT carcinomas includes undifferentiated malignancies including high-grade hematologic malignancies, endocrine carcinomas, and primitive neuroectodermal tumor [9]. In the case of negative anti-CK antibodies, Ewing sarcoma and small round cell tumors must be ruled out because they are difficult to discriminate morphologically from NUT carcinoma [6].\n\nIn our case, immunohistochemistry revealed positivity for p40 and negativity for CK. To the best of our knowledge, our patient is the third reported case of intrathoracic NUT carcinoma with positivity for p40 [3].\n\nNuclear positivity of more than 50% for anti-NUT antibody with fluorescence in situ hybridization (FISH) analysis allows the diagnosis of NUT carcinoma with 100% specificity [9]. Characterization of both fusion genes BRD4–NUT and BRD3–NUT, and more rarely NSD3–NUT, is not mandatory for the diagnosis, but is recommended for its possible association with unique prognostic features [2]. NUT carcinomas lacking BRD4 fusion gene rearrangements are more differentiated and therefore possibly less aggressive [10]. Fusion gene translocation assessment was not performed in our patient.\n\nAt present, there is no consensus concerning the optimal treatment strategy. A combination of multidrug chemotherapy with gemcitabine, docetaxel, and cisplatin and locoregional radiation therapy achieved complete response in a case of NUT midline carcinoma [11]. Administration of histone deacetylase inhibitors such as vorinostat is a promising therapeutic concept, with limitations due to severe side effects [12]. Bromodomain (BRD) and extra-terminal proteins (BET) inhibitors showed rapid antitumor activity in three patients with BRD4–NUT fusion NUT carcinoma [13].\n\nConclusion\nWe present a rare case of mediastinal NUT carcinoma revealed by superior vena cava obstruction with a definitive diagnosis based on NUT protein positivity and atypical immunohistochemical features including p40 positivity and anti-CK negativity.\n\nAcknowledgements\nNot applicable.\n\nFunding\nWe have received no funding.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nGB, GD, and JV-B contributed to the literature search, study design, and writing of the manuscript. PB contributed to histological examination of the specimens and writing of the manuscript. EU-C contributed to immunohistochemical staining with NUT antibody and performed critical review of the manuscript. CL, SD, J-MP, and HV contributed to the patient’s treatment and follow-up and performed a critical review of the manuscript for important intellectual content. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\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\nEthics approval and consent to participate\nThe authors have no ethical conflicts to disclose.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Mills AF Lanfranchi M Wein RO Mukand-Cerro I Pilichowska M Cowan J NUT midline carcinoma: a case report with a novel translocation and review of the literature Head Neck Pathol 2014 8 2 182 6 10.1007/s12105-013-0479-3 23912933 \n2. Bauer DE Mitchell CM Strait KM Lathan CS Stelow EB Lüer SC Clinicopathologic features and long-term outcomes of NUT midline carcinoma Clin Cancer Res 2012 18 20 5773 9 10.1158/1078-0432.CCR-12-1153 22896655 \n3. Harms A Herpel E Pfarr N Penzel R Heussel C-P Herth FJF NUT carcinoma of the thorax: case report and review of the literature Lung Cancer Amst Neth 2015 90 3 484 91 10.1016/j.lungcan.2015.10.001 \n4. French CA Demystified molecular pathology of NUT midline carcinomas J Clin Pathol 2010 63 6 492 6 10.1136/jcp.2007.052902 18552174 \n5. Reynoird N Schwartz BE Delvecchio M Sadoul K Meyers D Mukherjee C Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains EMBO J 2010 29 17 2943 52 10.1038/emboj.2010.176 20676058 \n6. Nakamura H Tsuta K Tsuda H Katsuya Y Naka G Iizuka T NUT midline carcinoma of the mediastinum showing two types of poorly differentiated tumor cells: a case report and a literature review Pathol Res Pract 2015 211 1 92 8 10.1016/j.prp.2014.07.006 25433996 \n7. Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer Oxf Engl 1990 2009 45 2 228 47 \n8. Samples S Gleditsch K Polimenakos A Intrapericardial NUT midline carcinoma: unusual presentation of a rare tumor and literature review with management considerations Pediatr Cardiol 2016 37 1 208 11 10.1007/s00246-015-1313-3 26667959 \n9. Stelow EB A review of NUT midline carcinoma Head Neck Pathol 2011 5 1 31 5 10.1007/s12105-010-0235-x 21221870 \n10. Haack H Johnson LA Fry CJ Crosby K Polakiewicz RD Stelow EB Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody Am J Surg Pathol 2009 33 7 984 91 10.1097/PAS.0b013e318198d666 19363441 \n11. Ueki H Maeda N Sekimizu M Yamashita Y Moritani S Horibe K A case of NUT midline carcinoma with complete response to gemcitabine following cisplatin and docetaxel J Pediatr Hematol Oncol 2014 36 8 e476 80 10.1097/MPH.0000000000000082 24322502 \n12. Maher OM Christensen AM Yedururi S Bell D Tarek N Histone deacetylase inhibitor for NUT midline carcinoma Pediatr Blood Cancer 2015 62 4 715 7 10.1002/pbc.25350 25557064 \n13. Stathis A Zucca E Bekradda M Gomez-Roca C Delord J-P de LM Rouge T Clinical response of carcinomas harboring the BRD4–NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628 Cancer Discov 2016 6 5 492 500 10.1158/2159-8290.CD-15-1335 26976114\n\n",
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"mesh_terms": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D035583:Rare Diseases; D012008:Recurrence; D013479:Superior Vena Cava Syndrome",
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"abstract": "Reactivation of chronic inactive hepatitis B infection can be spontaneous or triggered by chemotherapy or immunosuppression. Although the pathophysiology behind this remains unclear, several mechanisms have been proposed in the literature. Data describing hepatitis B flares caused by other classes of medications are sparse. We describe a case of reactivation of chronic hepatitis B in a 48-year-old man, who presented with generalized weakness after initiating terbinafine for a fungal toenail infection. He was found to have deranged liver function tests and elevated hepatitis B viral load. Both resolved after discontinuation of terbinafine and starting tenofovir.",
"affiliations": "Gastroenterology, BronxCare Health System, Bronx, USA.;Gastroenterology, BronxCare Health System, Bronx, USA.;Internal Medicine, BronxCare Health System, Bronx, USA.;Internal Medicine, BronxCare Health System, Bronx, USA.",
"authors": "Shehi|Elona|E|;Alemam|Ahmed|A|;Mantri|Nikhitha|N|;Patel|Harish|H|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.11958\nInternal Medicine\nGastroenterology\nInfectious Disease\nTerbinafine-Induced Hepatitis B Reactivation in a Patient With Chronic Hepatitis B\nMuacevic Alexander Adler John R Shehi Elona 1 Alemam Ahmed 1 Mantri Nikhitha 2 Patel Harish 2 \n1 \nGastroenterology, BronxCare Health System, Bronx, USA \n\n2 \nInternal Medicine, BronxCare Health System, Bronx, USA \n\nElona Shehi [email protected]\n7 12 2020 \n12 2020 \n12 12 e119587 12 2020 Copyright © 2020, Shehi et al.2020Shehi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/42753-terbinafine-induced-hepatitis-b-reactivation-in-a-patient-with-chronic-hepatitis-bReactivation of chronic inactive hepatitis B infection can be spontaneous or triggered by chemotherapy or immunosuppression. Although the pathophysiology behind this remains unclear, several mechanisms have been proposed in the literature. Data describing hepatitis B flares caused by other classes of medications are sparse. We describe a case of reactivation of chronic hepatitis B in a 48-year-old man, who presented with generalized weakness after initiating terbinafine for a fungal toenail infection. He was found to have deranged liver function tests and elevated hepatitis B viral load. Both resolved after discontinuation of terbinafine and starting tenofovir.\n\nterbinafinehepatitis bflaretransaminitisThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nDrug-induced hepatitis is a well-known clinical entity; however, reactivation of a previously chronic inactive viral hepatitis caused by medications does not have similar awareness among clinicians and can often be overlooked. Screening for hepatitis B infection and closely monitoring for hepatitis B reactivation is recommended in patients planned for chemotherapy or immune-suppressive therapy [1]. Serologic tests include hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis B DNA viral load. Hepatitis B reactivation can be asymptomatic, manifesting only as serologic evidence of flare, or can present with symptoms of weakness, fatigue, nausea, and malaise. Hepatitis B reactivation has been described in patients receiving the biological therapy for the inflammatory bowel disease [2], chemotherapy for solid and hematological malignancy [3,4] and those receiving chemoembolization for hepatocellular carcinoma [5]. Hepatitis B relapse is common after discontinuation of the nucleic acid analogs [6] and rarely can lead to fatal hepatitis B reactivation [7]. Terbinafine is an orally and topically active anti-fungal agent commonly used to treat superficial skin and nail infections, although the drug is known to cause multiple side effects commonly involving the gastrointestinal system like nausea, vomiting, dyspepsia, diarrhea, and rarely hepatic injury. Terbinafine has been reported to cause autoimmune hepatitis in a patient with chronic hepatitis B infection [8], but there is no available literature on terbinafine causing hepatitis B reactivation. We present a case of a patient developing an acute flare of hepatitis B infection after he was started on terbinafine for a fungal toe infection.\n\nCase presentation\nA 48-year-old African man with medical comorbidities of chronic hepatitis B was referred to our infectious disease clinic for hepatitis B management. The patient was born and raised in Ghana and moved to the United States 12 years ago. He was a non-smoker and denied using any alcohol or recreational drugs. He was not sexually active and worked as a security guard. Family history was positive for chronic hepatitis B in the mother. At the time of presentation, on physical examination patient was well appearing, skin exam showed no evidence of rash, icterus, spider angiomatas, palmar erythema, and no visible varicose veins. Cardiovascular and pulmonary exams were unremarkable, abdominal exam showed no organomegaly, absence of ascites, no tenderness on superficial or deep palpation. His laboratory were significant for normal liver function tests: aspartate aminotransferase (AST): 32 units/L and alanine aminotransferase (ALT): 36 units/L, albumin 5.2 g/dl, alkaline phosphatase (ALP) 119 units/l, total bilirubin 0.7 mg/dl and direct bilirubin 0.2 mg/dl. Other laboratories: HIV and hepatitis C virus (HCV) testing were negative, hepatitis A virus (HAV) antibodies positive, HBsAg positive, HBsAb negative, hepatitis B core antibody (HBcAb) total-positive, and hepatitis B viral load of 19,091 IU/L (normal: <20 IU/L).\n\nHe was started on emtricitabine and tenofovir combination (Truvada) for the treatment of hepatitis B, but shortly after starting treatment, he was lost to follow up. Ten months later, he presented to his primary care physician's office with what appeared to be a fungal toenail infection. During that encounter, he admitted that he stopped Truvada one month after it was initially prescribed. Labs done at that time showed normal liver function tests and viral load in the previous range. He was prescribed terbinafine 250 mg orally once a day for 12 weeks. One month after starting terbinafine, the patient presented to his primary care physician's office with complaints of generalized weakness and muscle aches of two weeks duration. The physical exam was unremarkable. As part of the basic workup, labs were done and were significant for transaminitis with AST of 294 u/l and ALT of 428 u/l. He denied any recent surgeries, blood transfusions, or dental work. He denied the use of any medications, herbal supplements, or intravenous drug use. The patient was referred to the hepatology clinic. He had repeated liver function tests which showed worsening transaminitis with AST of 601u/l and ALT of 943 u/l. The rest of his laboratory tests were: albumin 4.5 g/dl, alkaline phosphatase 165 unit/l, total bilirubin 1.3 mg/dl, direct bilirubin 0.7 mg/dl. Hepatitis B viral load was increased to 47 million copies. HBcIgM was negative. HIV and hepatitis C, A, D testing were negative. Anti-mitochondrial antibody and anti-smooth muscle antibody screening were negative. Lamisil (terbinafine) was stopped. He was started on tenofovir and two months later, his transaminitis resolved and hepatitis B viral load decreased to 3731 IU/ml.\n\nDiscussion\nTerbinafine, first introduced in 1998, has been associated with multiple cases of transaminitis and idiosyncratic liver injury. Clinically apparent liver injury from terbinafine occurs rarely (1 in 50,000 to 120,000 prescriptions). Abnormal liver chemistries usually arise within the first six weeks of therapy and resolve within three to six months after stopping the medication. The pattern of injury can be either hepatocellular or cholestatic initially, and typically evolves into a cholestatic pattern which can be prolonged and in some cases may progress to vanishing bile duct syndrome [9]. Signs of hypersensitivity (rash, fever, eosinophilia) are not common and, when present, are generally mild-to-moderate in severity [10]. Terbinafine is metabolized by the liver CYP (cytochrome P450) enzymes, and one of its metabolites 7,7-dimethylhept-2-ene-4-ynal (TBF-4), the allelic aldehyde metabolite, is believed to play a role in the pathogenesis of hepatotoxicity [11]. Another proposed mechanism of liver injury is through the activation of pro-inflammatory cytokines. Mizuno et al. proposed that terbinafine can stimulate monocytes and increases the release of IL-8 and tumor necrosis factor-alpha (TNF-alpha) [12].\n\nTo the best of our knowledge terbinafine has not been linked to hepatitis B or any other viral hepatitis reactivation. Reactivation of hepatitis B is a syndrome characterized by the abrupt appearance or rise of hepatitis B virus (HBV) DNA in the serum of a patient with previously inactive or resolved hepatitis B infection. At the initial encounter and prior to starting terbinafine, our patient was in the chronic inactive phase: he had normal aminotransferases levels, HbeAg negative, and HBV DNA < 20.000 IU/ml. One month after starting terbinafine, he presented with symptoms of fatigue, low energy, and muscle aches, and his laboratory tests were significant for elevated transaminases more than 10 times the upper level of normal, with a hepatocellular pattern of injury. Hepatitis B viral load was reported to be more than 40 million IU/ ml. Drug-induced liver injury from terbinafine was suspected, but the pattern of injury was hepatocellular and did not evolve into a cholestatic pattern, and the patient did not have any signs of hypersensitivity. Autoimmune hepatitis and other viral hepatitis were also excluded as a possible cause of transaminitis. The clinical presentation was consistent with hepatitis B reactivation, and terbinafine was suspected to be the possible trigger. Elevated HBV DNA levels are believed to be present in 40% of inactive carriers [12].\n\nReactivation of hepatitis B can be spontaneous, but it is mostly triggered by immunosuppression, chemotherapy, or alteration in the immune system [13]. Reactivation of hepatitis B is also reported after discontinuation of nucleoside analogs like lamivudine [7], but no cases of hepatitis B reactivation after stopping tenofovir are reported in the literature. The exact mechanism of hepatitis B reactivation is not known, but we propose that terbinafine promotes hepatitis B viral replication as a possible mechanism of reactivation. Mizuno et al. in their study found that terbinafine stimulates the release of pro-inflammatory cytokines: IL-8 and TNF-alpha [12]. Yu et al. studied in detail the role of inflammatory cytokines in hepatitis B replication and liver injury [14]. It was proposed that hepatitis B induces a regulatory loop of inflammatory cytokine network, in which three inflammatory cytokines IL-29, IL-8, and COX2 play a major role. IL-29 is able to inhibit the replication of a number of viruses, including HCV, and HBV. IL-8 may be a key mediator in the cytokine network induced by HBV. IL-8 not only impairs the antiviral activity of IL-29 and favors the establishment of persistent viral infection, but also induces the high expression of the pro-inflammatory factor COX-2 to maintain the inflammatory environment associated with HBV infection, playing so a major role in hepatitis B replication [14]. Spontaneous reactivation of hepatitis B cannot be fully excluded in our patient, but given that the time frame of the reactivation coincides with the time terbinafine was started, we believe that terbinafine was the culprit.\n\nConclusions\nDrug-induced liver injury is common and terbinafine related cholestatic hepatic injury is well reported. However, in patients with hepatitis B, terbinafine use can lead to hepatitis B reactivation. Though there is no prior data, we hypothesize that hepatitis B reactivation could due to terbinafine-related immune dyspepsia-regulation. Usage of terbinafine use should be cautious and careful monitoring is needed in patients with chronic inactive hepatitis B.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nAppendices\nTable 1 Laboratory tests \n \tDay 0 (Time of initial presentation)\tMonth 10 - Day 1 (Second presentation)\tMonth 10 - Day 21\tMonth 10 - Day 27\tMonth 13\tMonth 17\t\nTotal protein (g/dl)\t8.1\t7.2\t7.1\t7.4\t7.2\t7.2\t\nAlbumin(g/dl)\t5.2\t4.5\t4.5\t4.7\t4.9\t4.7\t\nAST (unit/L)\t32\t294\t601\t147\t32\t23\t\nALT (unit/L)\t36\t428\t943\t412\t27\t15\t\nALP (unit/L)\t114\t130\t165\t141\t109\t106\t\nTotal bilirubin (mg/dl)\t0.7\t0.8\t1.3\t1.3\t0.5\t0.6\t\nDirect bilirubin (mg/dl)\t0.4\t0.3\t0.7\t0.4\t0.2\t0.2\t\nHepatitis A total Ab\tPositive\t-\t-\t-\t-\t-\t\nHepatitis B core total Ab\tPositive\t-\t-\t-\t-\t-\t\nHepatitis B core IgM Ab\t-\t-\t-\tNegative\t-\t-\t\nHepatitis B surface Ab\tNegative\t-\t-\t-\t-\t-\t\nHepatitis B surface Ag\tPositive\t-\t-\t-\t-\t-\t\nHepatitis B e Ab\t-\tReactive\t-\t-\t-\t-\t\nHepatitis B e Ag\t-\tNon-reactive\t-\t-\t-\t-\t\nHepatitis D total Ab\t-\t-\t-\tNegative\t-\t-\t\nHepatitis B viral DNA cop/ml\t4.28\t7.68\t-\t-\t3.57\t2.9\t\nHepatitis B viral DNA IU/ml\t19091\t47933885\t-\t-\t3731\t800\t\nHepatitis C Ab\tNegative\tNegative\t-\t-\t-\t-\t\nHIV (1/2 ab EIA)\tNegative\tNegative\t-\t-\t-\t-\t\nSmooth muscle Ab screen\t-\t-\t-\tNegative\t-\t-\n==== Refs\nReferences\n1 American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy Gastroenterology Reddy KR Beavers KL Hammond SP Lim JK Falck-Ytter YT American Gastroenterological Association Institute 215 219 148 2015 25447850 \n2 Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis Gut Esteve M Saro C Gonzalez-Huix F Suarez F Forne M Viver JM 1363 1365 53 2004 15306601 \n3 Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy Ann Intern Med Loomba R Rowley A Wesley R Hoofnagle JH Pucino F Csako G 519 528 148 2008 18378948 \n4 Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study Gastroenterology Lok AS Liang RH Chiu EK Wong KL Chan TK Todd D 182 188 100 1991 1983820 \n5 Transarterial chemo-lipiodolization can reactivate hepatitis B virus replication in patients with hepatocellular carcinoma J Hepatol Jang JW Choi JY Bae SH 427 435 41 2004 15336446 \n6 Outcome after discontinuation of nucleot(s)ide analogues in chronic hepatitis B: relapse rate and associated factors Ann Gastroenterol Kranidioti H Manolakopoulos S Khakoo SI 173 181 28 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367206/ 25831071 \n7 Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B Gut Lim SG Wai CT Rajnakova A Kajiji T Guan R 597 599 51 2002 12235087 \n8 Level of hepatitis B virus DNA in inactive carriers with persistently normal levels of alanine aminotransferase Clin Gastroenterol Hepatol Chu CM Chen YC Tai DI Liaw YF 535 540 8 2010 20304099 \n9 Terbinafine-induced acute autoimmune hepatitis in the setting of hepatitis B virus infection Ann Pharmacother Paredes AH Lewis JH 880 884 41 2007 17426078 \n10 LiverTox: Clinical and Research Information on Drug-Induced Liver Injury Bethesda National Institute of Diabetes and Digestive and Kidney Diseases 2012 https://www.ncbi.nlm.nih.gov/books/NBK548617/ \n11 Terbinafine-associated hepatotoxicity Am J Med Sci Ajit C Suvannasankha A Zaeri N Munoz SJ 292 295 325 2003 12792250 \n12 Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway Life Sci Mizuno K Fukami T Toyoda Y Nakajima M Yokoi T 537 544 87 2010 20816994 \n13 Reactivation of hepatitis B Hepatology Hoofnagle JH 156 165 49 2009 https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.22945 \n14 Hepatitis B virus induces a novel inflammation network involving three inflammatory factors, iL-29, iL-8, and cyclooxygenase-2 J immunol Yu Y Gong R Mu Y 4845 4860 187 2011\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(12)",
"journal": "Cureus",
"keywords": "flare; hepatitis b; terbinafine; transaminitis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e11958",
"pmc": null,
"pmid": "33312827",
"pubdate": "2020-12-07",
"publication_types": "D002363:Case Reports",
"references": "12792250;12235087;25831071;19399803;15306601;1983820;21957142;20304099;17426078;25447850;20816994;15336446;18378948",
"title": "Terbinafine-Induced Hepatitis B Reactivation in a Patient With Chronic Hepatitis B.",
"title_normalized": "terbinafine induced hepatitis b reactivation in a patient with chronic hepatitis b"
}
|
[
{
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},
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}
],
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{
"reactionmeddrapt": "Myalgia",
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},
{
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},
{
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},
{
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},
{
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},
{
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},
{
"reactionmeddrapt": "Condition aggravated",
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}
],
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},
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"literaturereference": "SHEHI E, ALEMAM A, MANTRI N, PATEL H. TERBINAFINE-INDUCED HEPATITIS B REACTIVATION IN A PATIENT WITH CHRONIC HEPATITIS B. CUREUS. 2020?12 (12)",
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],
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"reaction": [
{
"reactionmeddrapt": "Hepatitis B reactivation",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
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},
"primarysource": {
"literaturereference": "SHEHI E, ALEMAM A, MANTRI N, PATEL H.. TERBINAFINE-INDUCED HEPATITIS B REACTIVATION IN A PATIENT WITH CHRONIC HEPATITIS B.. CUREUS.. 2020?12(12):E11958",
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},
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{
"abstract": "A 25-month-old boy ingested six sustained-release verapamil tablets, each containing 240 mg of drug. Charcoal and cathartic were given but were never passed per rectum. Third-degree heart block, hypotension, and hypocalcemia were only transiently responsive to calcium infusions, inotropic agents, and epicardial pacing. Cardiopulmonary arrest with electromechanical dissociation ensued. Standard cardiopulmonary bypass was used to allow sufficient time for liver detoxication. Serum levels of verapamil fell during the bypass procedure, and the patient's cardiac status improved. However, continued absorption of drug after bypass resulted in a level of 4 mg/L, unresponsive circulatory failure, and death. Early, aggressive gut decontamination and the potential value of cardiopulmonary bypass procedures in poisoning that lead to cardiac depression are emphasized.",
"affiliations": "Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30303.",
"authors": "Hendren|W G|WG|;Schieber|R S|RS|;Garrettson|L K|LK|",
"chemical_list": "D003692:Delayed-Action Preparations; D014700:Verapamil",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(89)80465-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "18(9)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D002315:Cardiopulmonary Bypass; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003692:Delayed-Action Preparations; D006801:Humans; D007022:Hypotension; D008297:Male; D012640:Seizures; D014700:Verapamil",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "984-7",
"pmc": null,
"pmid": "2669572",
"pubdate": "1989-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Extracorporeal bypass for the treatment of verapamil poisoning.",
"title_normalized": "extracorporeal bypass for the treatment of verapamil poisoning"
}
|
[
{
"companynumb": "US-RECRO GAINESVILLE LLC-REPH-2019-000157",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "019614",
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"drugcharacterization": "1",
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"drugdosageform": "CAPSULE",
"drugdosagetext": "6, 240 MILLIGRAM CAPLETS, ONE TIME DOSE",
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"drugstructuredosagenumb": "240",
"drugstructuredosageunit": "003",
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"medicinalproduct": "VERAPAMIL HYDROCHLORIDE SUSTAINED RELEASE"
}
],
"patientagegroup": null,
"patientonsetage": "25",
"patientonsetageunit": "802",
"patientsex": "1",
"patientweight": "13.5",
"reaction": [
{
"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Atrioventricular block complete",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Blood creatinine increased",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Brain oedema",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Calcium ionised increased",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Accidental poisoning",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Hypothermia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Pulseless electrical activity",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Acidosis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Lethargy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Hyperglycaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Prothrombin time prolonged",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Activated partial thromboplastin time prolonged",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Visceral congestion",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Clonus",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Pupillary reflex impaired",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Atrioventricular block first degree",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "W G HENDREN, R S SCHIEBER, L K GARRETTSON. EXTRACORPOREAL BYPASS FOR THE TREATMENT OF VERAPAMIL POISONING. ANNALS OF EMERGENCY MEDICINE. 1989?18(9):984-987",
"literaturereference_normalized": "extracorporeal bypass for the treatment of verapamil poisoning",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
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{
"abstract": "This phase I study evaluated the maximal tolerated dose of CPX-351 when administered sequentially with allogeneic hematopoietic stem cell transplantation (HSCT) in patients with refractory acute leukemia. CPX-351 is a novel liposomal formulation that combines cytosine arabinoside (ara-c) and daunorubicin in a fixed molar ratio of 5:1. Patients in cohorts of 3 were treated with CPX-351 followed by fludarabine and busulfan (Bu/Flu) conditioning at 4-week (schedule A) or 3-week (schedule B) intervals. CPX-351 doses were escalated in 20-U/m(2) increments starting at 60 U/m(2) for 3 doses. Of the 36 patients enrolled, 29 were able to undergo HSCT, and the other 7 (the majority on schedule A) did not proceed to HSCT because of rapid disease progression. The maximal tolerated dose of CPX-351 was not reached at the 120 U/m(2) × 3 dose level. All 29 patients who proceeded to HSCT demonstrated adequate neutrophil and platelet engraftment. The median follow-up on the study for all 36 patients was 205 days (range, 20 to 996 days). The 1-year cumulative incidence of relapse for the 36 patients was 60.1% (95% confidence interval [CI], 43.4% to 77.3%), and that of nonrelapse mortality was 23.8% (95% CI, 10.9% to 47.4%). The 1-year overall survival and leukemia-free survival were 37% (95% CI, 21% to 53%) and 27% (95% CI, 13% to 43%), respectively. Our data suggest that a phase II trial should incorporate CPX-351 120 U/m(2) × 3 dosing on schedule B. Patients with good performance status and those who achieve effective cytoreduction from CPX-351 derived the greatest benefit.",
"affiliations": "Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA. [email protected]",
"authors": "Gergis|Usama|U|;Roboz|Gail|G|;Shore|Tsiporah|T|;Ritchie|Ellen|E|;Mayer|Sebastian|S|;Wissa|Usama|U|;McKenna|Marshall|M|;Christos|Paul|P|;Pearse|Roger|R|;Mark|Tomer|T|;Scandura|Joseph|J|;van Besien|Koen|K|;Feldman|Eric|E|",
"chemical_list": "D019653:Myeloablative Agonists; D003561:Cytarabine; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D003630:Daunorubicin",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1083-8791",
"issue": "19(7)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": null,
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D002066:Busulfan; D016022:Case-Control Studies; D003561:Cytarabine; D003630:Daunorubicin; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists; D011379:Prognosis; D012008:Recurrence; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1040-5",
"pmc": null,
"pmid": "23648237",
"pubdate": "2013-07",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "A phase I study of CPX-351 in combination with busulfan and fludarabine conditioning and allogeneic stem cell transplantation in adult patients with refractory acute leukemia.",
"title_normalized": "a phase i study of cpx 351 in combination with busulfan and fludarabine conditioning and allogeneic stem cell transplantation in adult patients with refractory acute leukemia"
}
|
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"literaturereference": "GERGIS U, ROBOZ G, SHORE T, RITCHIE E, MAYER S, WISSA U ET AL. A PHASE I STUDY OF CPX-351 IN COMBINATION WITH BUSULFAN AND FLUDARABINE CONDITIONING AND ALLOGENEIC STEM CELL TRANSPLANTATION IN ADULT PATIENTS WITH REFRACTORY ACUTE LEUKEMIA. BIOL BLOOD MARROW TRANSPLANT. 2013;19(7):1040-5",
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},
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] |
{
"abstract": "Although allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment option for multiple myeloma (MM), it is not recognized as a standard of care because of the high associated incidences of both treatment related mortality and relapse. We administered lenalidomide (Len) as maintenance therapy for patients with MM undergoing allo-SCT who were at high risk of disease relapse. Graft-versus-host disease was induced by Len administration in two patients, but was manageable with dose reduction. Although Len has a direct anti-myeloma effect and can also induce tumor immunity against residual myeloma cells, it is important to identify how to optimize the safety and the effects of Len administration after allo-SCT. Further accumulation of data including those from prospective clinical trials is urgently needed.",
"affiliations": "Division of Hematology, Japanese Red Cross Medical Center.",
"authors": "Tsukada|Nobuhiro|N|;Shingaki|Sumito|S|;Ikeda|Masahiro|M|;Miyazaki|Kanji|K|;Meshitsuka|Sohsuke|S|;Yoshiki|Yumiko|Y|;Abe|Yu|Y|;Suzuki|Kenshi|K|",
"chemical_list": "D007155:Immunologic Factors; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.56.895",
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"issn_linking": "0485-1439",
"issue": "56(7)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007155:Immunologic Factors; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D013792:Thalidomide; D014184:Transplantation, Homologous",
"nlm_unique_id": "2984782R",
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"pages": "895-900",
"pmc": null,
"pmid": "26256927",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Graft-versus-host disease associated with lenalidomide maintenance after allogeneic transplantation for relapsed/refractory multiple myeloma.",
"title_normalized": "graft versus host disease associated with lenalidomide maintenance after allogeneic transplantation for relapsed refractory multiple myeloma"
}
|
[
{
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{
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{
"reactionmeddrapt": "Graft versus host disease in skin",
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}
],
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}
},
"primarysource": {
"literaturereference": "TSUKADA N. GRAFT VERSUS HOST DISEASE ASSOCIATED WITH LENALIDOMIDE MAINTENANCE AFTER ALLOGENEIC TRANSPLANTATION FOR RELAPSED REFRACTORY MULTIPLE MYELOMA. 2015 JUL;895-900.",
"literaturereference_normalized": "graft versus host disease associated with lenalidomide maintenance after allogeneic transplantation for relapsed refractory multiple myeloma",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20150831",
"receivedate": "20150831",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11434813,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20151125"
}
] |
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