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"abstract": "Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of 5-Fluorouracil (5-FU) and its prodrug capecitabine. We report cases from our institute with colorectal cancer who experienced severe toxicities to standard dose 5-FU based chemotherapy. DPYD gene sequencing revealed rare different polymorphisms that prompted dose adjustments of administered 5-FU and capecitabine. To our knowledge, this is the first case series looking at DPYD polymorphisms in the Saudi Arabian population.",
"affiliations": "Department of Medical Oncology, King Fahad Specialist Hospital, Dammam 31444, Saudi Arabia.;Department of Medical Oncology, King Fahad Specialist Hospital, Dammam 31444, Saudi Arabia.;Oncology Centre, King Abdullah Medical City, Makkah 24246, Saudi Arabia.;Oncology Department, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia.;Department of Oncology, Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi 999041, United Arab Emirates.;Department of Pathology and Laboratory Medicine, King Fahad Specialist Hospital, Dammam 31444, Saudi Arabia.",
"authors": "Bukhari|Nedal|N|0000-0002-6166-5490;Alshangiti|Abdulraheem|A|;Tashkandi|Emad|E|0000-0002-0260-8947;Algarni|Mohammed|M|;Al-Shamsi|Humaid O|HO|;Al-Khallaf|Hamoud|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/clinpract11030062",
"fulltext": "\n==== Front\nClin Pract\nClin Pract\nclinpract\nClinics and Practice\n2039-7275\n2039-7283\nMDPI\n\n10.3390/clinpract11030062\nclinpract-11-00062\nArticle\nFluoropyrimidine-Induced Severe Toxicities Associated with Rare DPYD Polymorphisms: Case Series from Saudi Arabia and a Review of the Literature\nhttps://orcid.org/0000-0002-6166-5490\nBukhari Nedal 12*\nAlshangiti Abdulraheem 1\nhttps://orcid.org/0000-0002-0260-8947\nTashkandi Emad 34\nAlgarni Mohammed 56\nAl-Shamsi Humaid O. 789\nAl-Khallaf Hamoud 10\nCapasso Anna Academic Editor\n1 Department of Medical Oncology, King Fahad Specialist Hospital, Dammam 31444, Saudi Arabia; Dralshangiti@gmail.com\n2 Department of Internal Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia\n3 Oncology Centre, King Abdullah Medical City, Makkah 24246, Saudi Arabia; Emad_tashkandi@hotmail.com\n4 College of Medicine, Umm Al-Qura University, Makkah 24211, Saudi Arabia\n5 Oncology Department, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia; Garnimo2@gmail.com\n6 King Saud bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia\n7 Department of Oncology, Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi 999041, United Arab Emirates; humaid.al-shamsi@medportal.ca\n8 Emirates Oncology Society, Dubai 22107, United Arab Emirates\n9 College of Medicine, University of Sharjah, Sharjah 999041, United Arab Emirates\n10 Department of Pathology and Laboratory Medicine, King Fahad Specialist Hospital, Dammam 31444, Saudi Arabia; drhhk@hotmail.com\n* Correspondence: nedal.bukhari36@gmail.com\n27 7 2021\n9 2021\n11 3 467471\n22 5 2021\n24 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nDihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of 5-Fluorouracil (5-FU) and its prodrug capecitabine. We report cases from our institute with colorectal cancer who experienced severe toxicities to standard dose 5-FU based chemotherapy. DPYD gene sequencing revealed rare different polymorphisms that prompted dose adjustments of administered 5-FU and capecitabine. To our knowledge, this is the first case series looking at DPYD polymorphisms in the Saudi Arabian population.\n\ndihydropyrimidine dehydrogenase\n5-Fluorouuracil\nchemotherapy\nDPYD\npolymorphism\n==== Body\n1. Introduction\n\n5-FU has been the backbone of chemotherapy used in many different cancers since the late 1950s [1]. Capecitabine is an oral prodrug and has also been approved for medical use since 1998 [2]. Both drugs are widely prescribed and generally well-tolerated [3].\n\nDPD is the initial and rate-limiting enzyme in the catabolism of 5-FU. More than 80% of the administered doses of 5-FU and capecitabine are rapidly degraded by DPD to inactive compounds within 24 h [3,4,5].\n\nComplete or intermediate deficiency of DPD can result in severe, life-threatening side effects, including severe mucositis, diarrhea, and pancytopenia. Genetic polymorphism in its encoding gene DPYD has an established impact on enzyme level, and toxicity risks [3,4].\n\n2. Case 1\n\nA 65-year-old female referred to our academic institute with a diagnosis of locally advanced distal rectal adenocarcinoma staged at T2N2 underwent neoadjuvant long course concurrent chemoradiation with capecitabine at 625 mg/m2 twice daily on radiation days. She required an abdominoperineal resection (APR) and end colostomy. She was found to have a left lower lobe metastatic lesion, resected 6 weeks following her APR.\n\nThe patient initially received a XELOX regimen, with capecitabine at 1000 mg/m2 twice daily. Few days after starting treatment, she developed Grade III diarrhea, GIII fatigue, and GII mucositis reported as per Common Terminology Criteria for Adverse Events (CTCAE criteria). Capecitabine was stopped on day eight of treatment. Grade II pancytopenia was also noted on her laboratory investigations.\n\nShe was switched to a Q 2 weekly FOLFOX-6 regimen where she received a bolus of 5-FU, dosed at 400 mg/m2 on the first day of treatment, leucovorin, and oxaliplatin—followed by a 46 h of 5-FU infusion at 2400 mg/m2. Four days after completion of 5-FU infusion, she developed GIII mucositis, GIII diarrhea, and fever, for which she required hospital admission. She was clinically dehydrated, septic, with GIII pancytopenia on her CBC.\n\nShe also developed alopecia and phlebitis immediately after receiving one cycle of FOLFOX.\n\nThe patient required intravenous (IV) antibiotics and IV rehydration during her hospital stay. After obtaining informed consent, a blood sample was sent to Mayo Clinic for full DPYD gene sequencing. Result confirmed heterozygosity for c.2434G>A, rs371313778. Her report stated the following:Variation identified: Het rs371313778 Genomic position: Chr1: 97700416;\n\ncDNA change: c.2434G>A (Heterozygous) Amino acid change: p.Val812lle.\n\nThe patient’s symptoms and blood count improved in 10 days. The following cycle of chemotherapy was restarted after 2 weeks of rest. The dose of 5-FU chemotherapy was reduced by 50% with no change made to the oxaliplatin dose. 5-FU dose was gradually increased by 5% in subsequent cycles. Sixty percent of the standard dose of 5-FU was tolerated without severe toxicities.\n\n3. Case 2\n\nThe second is a 64-year-old female, a cousin of case 1, who had a diagnosis of stage III colon adenocarcinoma, sigmoid primary, underwent a left hemicolectomy without complications.\n\nShe was found to have T4N2 disease, and the decision was made to start adjuvant treatment. Based on her family history of severe toxicity to 5-FU chemotherapy secondary to DPD deficiency, screening for DPYD polymorphism was done, and she was started on adjuvant XELOX at 40% dose-reduction in her capecitabine. The only side effect she reported was G1 diarrhea and mucositis, which was successfully managed with antidiarrheals and 2% oral viscous lidocaine. There were no unexpected changes in her CBC parameters.\n\nA whole gene sequencing was performed at the CGC genetics lab. Additionally, the variant c.1601G>A p.(Ser534Asn), also known as DPYD*4, was detected in apparent homozygosity (Table 1).\n\nA trial of increasing the capecitabine dose by 5–10% was done. Shortly after completion of her second cycle of capecitabine, she developed GIII diarrhea, mucositis, and pancytopenia and eventually required short hospital admission for IV rehydration. We decided to continue adjuvant treatment with no changes made to the dose she received on the first cycle of chemotherapy, which was 60% of the standard dose of capecitabine. No changes were made to the oxaliplatin dose.\n\n4. Case 3\n\nThe third case regards a previously healthy 66-year-old male patient with a diagnosis of a T3N1 upper rectal moderately differentiated adenocarcinoma. He was planned for long-course concurrent chemoradiation (CCRT), and capecitabine at 625 mg/m2 twice daily was given on radiation (RT) days only. He developed diarrhea during the third week of treatment and was managed with loperamide. In the middle of the fourth week of CCRT, he experienced a decrease in his energy levels, his diarrhea worsened to 7 times/daily (GIII), and he was clinically dehydrated, which required hospital admission. A repeat blood work showed a grade IV neutropenia with WBC: 0.59 × 109/L, neutrophil count: 0.27 × 109/L, HGB: 12.1 g/dL, and a platelet count of 136 × 109/L. Treatments were put on hold, and intravenous rehydration was given to him throughout his 10-day stay in hospital. His oncologist elected to put his chemotherapy on hold throughout his neoadjuvant radiation treatment course. The patient completed his neoadjuvant radiation without experiencing the side effects reported with radiation.\n\nA whole gene sequencing was performed at the CGC labs. The c.257C>T p.(Pro86Leu) was detected in heterozygosity in the DPYD gene (Table 1).\n\nHe subsequently underwent Lower anterior resection surgery. The pathology report indicated a complete response with no residual malignancies. Seventeen lymph nodes were examined and were all negative for malignancy. No adjuvant systemic treatment was offered to this patient, and he is currently under surveillance with no evidence of disease recurrence as per the last colonoscopy and CT scan.\n\n5. Methods\n\nDPYD gene sequencing was performed as follows: exons and eight base pairs of intron-exon boundaries of the DPYD gene (NM_000110.3; chr.1) were amplified by polymerase chain reaction. Performed by tagmentation (QXT, Agilent Technologies, Santa Clara, CA, USA) and next-generation sequencing (MiSeq, Illumina). The dragen workflow (Illumina) was utilized for variant call and alignment. The classification and reporting of the variants were performed according to the international recommendations [6].\n\n6. Discussion\n\nFlouropyrimidines (FLPN) have been used in the treatment of many different types of cancer. Of the patients treated, 10%–30% experience severe treatment-related toxicity, which is lethal in 0.5%–1% of the patients. The most studied biochemical cause of intolerance to FLPN is a deficiency of the metabolic enzyme, DPD [7,8,9].\n\nApproximately, up to 60% of the severe toxicities induced by FLPN can be attributed to DPYD mutations [10,11].\n\nThe DPYD gene is polymorphic with over a hundred mutations reported so far [12]. A few of those variants are the most extensively studied and strongly linked to DPD deficiency polymorphisms such as c.1905+1G>A, rs3918290 (∗2A), c.2846A>T, rs67376798 (D949V), I560S c.1679T>G (∗13), rs55886062, c.1129–5923C>G, and rs75017182 (HapB3) [4]. These variants are most abundant in Caucasians and clinically validated through genotype-guided dosing adjustment as per Clinical Pharmacogenetics Implementation Consortium (CPIC) [4].\n\nThe DPYD variant identified in Case 1 is a novel mutation reported and published previously by Bukhari et al. Case 1 is the first report, to the best of our knowledge, to identify the c.2434G>A, rs371313778 polymorphism in a patient with severe toxic effects secondary to standard dose of a 5-FU-based regimen [13].\n\nCase 2 carried the polymorphism c.1601G>A p.(Ser534Asn), also known as DPYD*4 is a rare mutation identified previously and linked to clinical DPD deficiency [14,15,16]. This case represents an intermediate metabolizer despite being homozygous for DPYD*4.\n\nCase 3 was heterozygous for the very rare c.257C>T (p. Pro86Leu) variant which was also reported prior to associate with clinical DPD deficiency. His Oncologist elected not to proceed with capecitabine after discovering this variant [15,16,17,18].\n\nBased on the treatment course of reported cases, we believe carriers of these polymorphisms may behave clinically like intermediate metabolizers. Therefore, a reduced starting dose followed by further titration based on toxicity, or even therapeutic drug monitoring may be a preferred approach in patients harboring those polymorphisms [4]. This practice was based on the Clinical Pharmacogentics Implementation Consortium (CPIC) recommendations [4].\n\nThere are genetic biomarkers that were previously investigated like the thymidalate synthetase (TYMS) gene polymorphisms [19]. Another promising phenotypic biomarker is pretreatment uracil, which is elevated in a proportion of patients with DPD deficiency. Meulendijks et al. concluded that a uracil level of more than 16 ng mL−1 is strongly linked to 5-FU severe toxicities. This study also found that pretreatment uracil of 16 ng mL−1 is strongly correlated with certain polymorphisms like DPYD*2, DPYD *13 and DPYD *9B [7].\n\nBased on accumulating evidence, we believe pre-emptive pharmacogenomic testing will help with selecting the most appropriate treatment and dosing, thus reducing the potentially severe and lethal side effects. Cost-effectiveness studies are needed and will potentially expediate the implementation of pharmacogenomic-based practice in this field [3,19,20]. To our knowledge, this is the first case series from Saudi Arabia looking at DPYD polymorphisms in patients with severe toxicity to 5-FU- based chemotherapy.\n\n7. Conclusions\n\nThis case series clearly demonstrates the benefit of DPYD gene sequencing in detecting rare variants in our population for whom there is limited pharmacogenetic knowledge. It also illustrates that genotype-based dosing in the presence of c.2434G>A, c.1601G>A and c.257C>T. DPYD variants are effective for preventing deleterious 5-FU side effects. We will need more studies to determine the cost-effectiveness of gene sequencing in this setting. Other genotypic and phenotypic biomarkers such as TYMS variants screen and pretreatment uracil level could serve as potential predictors of toxicity however need further clinical validation.\n\nAuthor Contributions\n\nAll authors participated in writing this manuscript. Methodology: H.A.-K. and N.B. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nNo source of funding other than the authors.\n\nInformed Consent Statement\n\nObtained from all subjects in this case series.\n\nConflicts of Interest\n\nNo conflict of interest present.\n\nclinpract-11-00062-t001_Table 1 Table 1 Patients clinical characteristics, polymorphisms identified and treatments received.\n\nCase\tAge\tGender\tChemotherapy Received\tManifestations\t5-FU or Capectabine Dose-Modification\tDPYD Polymorphism\t\nCase 1\t65\tF\tFOLFOX\tG3 mucositis, diarrhea, and pancytopenia\t40% dose-reduction\tHeterozygous for c.2434G>A.\nAmino acid change: p.Val812lle\t\nCase 2\t64\tF\tXOLOX\n(Capecitabine starting dose 1000 mg/m2 twice daily)\tG3 mucositis, diarrhea, and pancytopenia\t40% dose-reduction\tHomozygous for c.1601G>A.\nAmino acid change: p.(Ser534Asn)\t\nCase 3\t66\tM\tCapecitabine with radiation (RT).\n(Capecitabine dose at 625 mg/m2 twice daily on RT days)\tG3 diarreha and GIV neutropenia\tCapecitabine was stopped on week 4 of CCRT\tHeterozygous for c.257C>T.\nAmino acid change: p.(Pro86Leu)\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Sneader W. Drug Discovery 2005 255 Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1276005/ (accessed on 7 July 2021)\n2. Miwa M. Ura M. Nishida M. Sawada N. Ishikawa T. Mori K. Shimma N. Umeda I. Ishitsuka H. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue Eur. J. Cancer 1998 34 1274 1281 10.1016/S0959-8049(98)00058-6 9849491\n3. Deenen M.J. Meulendijks D. Cats A. Sechterberger M.K. Severens J.L. Boot H. Smits P.H. Rosing H. Mandigers C.M. Soesan M. Upfront genotyping of DPYD∗2A to individualize uoropyrimidine therapy: A safety and cost analysis J. Clin. Oncol. 2016 34 227 234 10.1200/JCO.2015.63.1325 26573078\n4. Amstutz U. Henricks L.M. Offer S.M. Barbarino J. Schellens J.H. Swen J. Klein T.E. McLeod H.L. Caudle K.E. Diasio R.B. Clinical pharmacogenetics implementation consortium (CPIC) guide- line for dihydropyrimidine dehydrogenase genotype and u- oropyrimidine dosing: 2017 update Clin. Pharmacol. Ther. 2018 103 210 216 10.1002/cpt.911 29152729\n5. Al Khallaf H.H. He M. Wittenauer A. Woolley E.E. Cunto M. Pervaiz M.A. An incidental case of dihydropyrimidine dehydrogenase deficiency: One case, multiple challenges Indian J. Hum. Genet. 2013 19 483 486 10.4103/0971-6866.124382 24497719\n6. Richards S. Aziz N. Bale S. Bick D. Das S. Gastier-Foster J. Grody W.W. Hegde M. Lyon E. Spector E. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet. Med. 2015 17 405 423 10.1038/gim.2015.30 25741868\n7. Meulendijks D. Henricks L.M. Jacobs B.A.W. Aliev A. Deenen M.J. De Vries N. Rosing H. van Werkhoven E. De Boer A. Beijnen J.H. Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity Br. J. Cancer 2017 116 1415 1424 10.1038/bjc.2017.94 28427087\n8. Mikhail S.E. Sun J.F. Marshall J.L. Safety of capecitabine: A review Expert Opin. Drug Saf. 2010 9 831 841 10.1517/14740338.2010.511610 20722491\n9. Van Kuilenburg A.B. Meijer J. Maurer D. Dobritzsch D. Meinsma R. Los M. Knegt L.C. Zoetekouw L. Jansen R.L. Dezentjé V. Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2017 1863 721 730 10.1016/j.bbadis.2016.12.010 28024938\n10. Daher G.C. Harris B.E. Diasio R.B. Metabolism of pyrimidine analogues and their nucleosides Pharmacol. Ther. 1990 48 189 222 10.1016/0163-7258(90)90080-L 2293239\n11. Saif M.W. Dihydropyrimidine Dehydrogenase Gene (DPYD) Polymorphism among Caucasian and non-Caucasian Patients with 5-FU- and Capecitabine-Related Toxicity Using Full Sequencing of DPYD Cancer Genom. Proteom. 2013 10 89 92 Available online: https://pubmed.ncbi.nlm.nih.gov/23603345/ (accessed on 1 July 2021)\n12. Meulendijks D. Henricks L.M. Sonke G. Deenen M.J. Froehlich T.K. Amstutz U. Largiadèr C.R. Jennings B. Marinaki A.M. Sanderson J.D. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe uoropyrimidine-associated toxicity: A systematic review and meta-analysis of individual patient data Lancet Oncol. 2015 16 1639 1650 10.1016/S1470-2045(15)00286-7 26603945\n13. Bukhari N. Azam F. Alfawaz M. Zahrani M. Identifying a Novel DPYD Polymorphism Associated with Severe Toxicity to 5-FU Chemotherapy in a Saudi Patient Case Rep. Genet. 2019 2019 1 3 10.1155/2019/5150725 31531249\n14. Mukherji D. Massih S.A. Tfayli A. Kanso M. Faraj W. Three different polymorphisms of the DPYD gene associated with severe toxicity following administration of 5-FU: A case report J. Med. Case Rep. 2019 13 76 10.1186/s13256-019-2013-z 30898145\n15. Van Kuilenburg A.B.P. Meijer J. Meinsma R. Pérez-Dueñas B. Alders M. Bhuiyan Z.A. Artuch R. Hennekam R.C.M. Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1 JIMD Reports Springer Berlin/Heidelberg, Germany 2018 Volume 45 65 69 10.1007/8904_2018_138\n16. Del Re M. Cinieri S. Michelucci A. Salvadori S. Loupakis F. Schirripa M. Cremolini C. Crucitta S. Barbara C. Di Leo A. DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: A comprehensive analysis in 1254 patients Pharm. J. 2019 19 556 563 10.1038/s41397-019-0077-1 30723313\n17. Van Kuilenburg A.B.P. Haasjes J. Meinsma R. Waterham H.R. Vrelem P. Van Gennip A.H. Dihydropyrimidine dehydrogenase (DPD) deficiency: Novel mutations in the DPD gene Purine and Pyrimidine Metabolism in Man X Springer Boston, MA, USA 2002 247 250\n18. Palles C. Fotheringham S. Chegwidden L. Lucas M. Kerr R. Mozolowski G. Rosmarin D. Taylor J. Tomlinson I. Kerr D. An Evaluation of the Diagnostic Accuracy of a Panel of Variants in DPYD and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities Cancers 2021 13 1497 10.3390/cancers13071497 33805100\n19. Pullarkat S. Stoehlmacher J. Ghaderi V.S. Xiong Y.-P. Ingles S.A. Sherrod A. Warren R.M. Tsaowei D.D. Groshen S. Lenz H.-J. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy Pharm. J. 2001 1 65 70 10.1038/sj.tpj.6500012 11913730\n20. Cortejoso L. García-González X. I García M. García-Alfonso P. Sanjurjo M. López-Fernández L.A. Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines Pharmacogenomics 2016 17 979 984 10.2217/pgs-2016-0006 27248859\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2039-7275",
"issue": "11(3)",
"journal": "Clinics and practice",
"keywords": "5-Fluorouuracil; DPYD; chemotherapy; dihydropyrimidine dehydrogenase; polymorphism",
"medline_ta": "Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101563282",
"other_id": null,
"pages": "467-471",
"pmc": null,
"pmid": "34449540",
"pubdate": "2021-07-27",
"publication_types": "D016428:Journal Article",
"references": "2293239;11913730;27248859;26573078;30349988;28427087;9849491;25741868;23603345;26603945;33805100;31531249;29152729;30898145;20722491;24497719;30723313;28024938",
"title": "Fluoropyrimidine-Induced Severe Toxicities Associated with Rare DPYD Polymorphisms: Case Series from Saudi Arabia and a Review of the Literature.",
"title_normalized": "fluoropyrimidine induced severe toxicities associated with rare dpyd polymorphisms case series from saudi arabia and a review of the literature"
} | [
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"companynumb": "SA-ACCORD-155667",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nLemierre's syndrome is often misdiagnosed as a common cold or viral infection. Fusobacterium necrophorum is the most common causative organism. The recommended treatment regimen is 6 weeks of a beta-lactam antibiotic along with metronidazole.\n\n\nMETHODS\nWe present two cases of Lemierre's syndrome with internal jugular vein thrombophlebitis and positive blood cultures for F. necrophorum. The first case was successfully treated with 6 weeks of a beta-lactam antibiotic and 4 weeks of metronidazole, while the second case was successfully treated with 4 weeks of a beta-lactam antibiotic and 2 weeks of metronidazole.\n\n\nCONCLUSIONS\nTwo cases of Lemierre's syndrome were treated successfully with only 2-4 weeks of metronidazole therapy. Shorter duration of metronidazole therapy should be explored in future studies.",
"affiliations": "Touro College of Pharmacy, New York, New York.;Long Island University Pharmacy, Brooklyn, New York.;Touro College of Pharmacy, New York, New York.;Long Island University Pharmacy, Brooklyn, New York.;Long Island University Pharmacy, Brooklyn, New York.;Touro College of Pharmacy, New York, New York.;Touro College of Pharmacy, New York, New York.",
"authors": "Le|Christine|C|;Gennaro|Dean|D|;Marshall|Derek|D|;Alaev|Orly|O|;Bryan|Alicia|A|;Gelfman|Aleksandra|A|;Wang|Zhe|Z|",
"chemical_list": "D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D008795:Metronidazole",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12774",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "44(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "beta-lactam antibiotic; jugular; lemierre's syndrome; metronidazole; thrombophlebitis; thrombosis; tonsillar",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D005260:Female; D005674:Fusobacterium Infections; D005675:Fusobacterium necrophorum; D006801:Humans; D007601:Jugular Veins; D057831:Lemierre Syndrome; D008297:Male; D008795:Metronidazole; D035583:Rare Diseases; D013924:Thrombophlebitis; D047090:beta-Lactams",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "122-124",
"pmc": null,
"pmid": "30484880",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Lemierre's syndrome: One rare disease-Two case studies.",
"title_normalized": "lemierre s syndrome one rare disease two case studies"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP025609",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
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"abstract": "BACKGROUND\nNatural and unexpected death that happens within less than one hour of first symptom occurrence is called sudden death. Cardiovascular diseases are the main known reason of sudden death and more than 75% of sudden deaths in athletes are assigned to it. Here we reported the autopsy results of all cases with sudden death following exercise that were referred to forensic center of Tehran, Iran, from 2009 to 2014.\n\n\nMETHODS\nIn this cross sectional study all subjects who were registered to forensic medicine center of Tehran, Iran, from 2009 to 2014, as a case of sudden death following exercise were evaluated. Demographic data and medical history as well as autopsy and toxicology findings were retrospectively gathered using profiles of the deceased. Results were reported using descriptive analysis.\n\n\nRESULTS\n14 cases were registered as sudden death following exercise in forensic medicine profiles during the study period. Exploring the files of the mentioned deceased, revealed five non-compatible cases in this regard. Finally, 9 eligible cases were enrolled (88.9% male). The mean age of the deceased was 28.66 ± 10.86 years (range: 7 - 40). Toxicological tests were available for 7 cases, one of which was positive for tramadol. Sudden death following football was reported most frequently (44.4%). Only 3 (33.3%) cases had herald signs such as chest pain, syncope, or loss of consciousness. 1 case (11.11%) had a positive history of sudden death in relatives.\n\n\nCONCLUSIONS\nAlthough most sudden death victims are asymptomatic until the event, all those who suffer from symptoms such as chest pain, shortness of breath, dizziness, fatigue and irregular heart rate during physical activities, should be screened regarding common probable causes of sudden death.",
"affiliations": "Faculty Member of Shahid Beheshti University of Medical Science, Tehran, Iran.;Center of Forensic Medicine Researches, Forensic Medicine of Iran.;Forensic Medicine Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Najari|Fares|F|;Alimohammadi|Alimohammad|A|;Ghodrati|Parisa|P|",
"chemical_list": null,
"country": "Iran",
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"fulltext": "\n==== Front\nEmerg (Tehran)Emerg (Tehran)EmergEmergency2345-45632345-4571Shahid Beheshti University of Medical Sciences Tehran, Iran emerg-4-097Brief ReportSudden Death Following Exercise; a Case Series Najari Fares 1*Alimohammadi Alimohammad 2Ghodrati Parisa 31 Faculty Member of Shahid Beheshti University of Medical Science, Tehran, Iran.2 Center of Forensic Medicine Researches, Forensic Medicine of Iran.3 Forensic Medicine Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran.* Corresponding Author: Fares Najari; Department of forensic Medicine, Shohadaye Tajrish Hospital, Tajrish Square, Tehran, Iran. Tal: 00989123195140, Email: fares.hospital@yahoo.comSpring 2016 4 2 97 100 6 2015 8 2015 This open-access article distributed under the terms of the Creative Commons Attribution Noncommercial 3.0 License (CC BY-NC 3.0)., (https://creativecommons.org/licenses/by-nc/3.0/).Introduction:\nNatural and unexpected death that happens within less than one hour of first symptom occurrence is called sudden death. Cardiovascular diseases are the main known reason of sudden death and more than 75% of sudden deaths in athletes are assigned to it. Here we reported the autopsy results of all cases with sudden death following exercise that were referred to forensic center of Tehran, Iran, from 2009 to 2014. \n\nMethods:\nIn this cross sectional study all subjects who were registered to forensic medicine center of Tehran, Iran, from 2009 to 2014, as a case of sudden death following exercise were evaluated. Demographic data and medical history as well as autopsy and toxicology findings were retrospectively gathered using profiles of the deceased. Results were reported using descriptive analysis. \n\nResults:\n14 cases were registered as sudden death following exercise in forensic medicine profiles during the study period. Exploring the files of the mentioned deceased, revealed five non-compatible cases in this regard. Finally, 9 eligible cases were enrolled (88.9% male). The mean age of the deceased was 28.66 ± 10.86 years (range: 7 – 40). Toxicological tests were available for 7 cases, one of which was positive for tramadol. Sudden death following football was reported most frequently (44.4%). Only 3 (33.3%) cases had herald signs such as chest pain, syncope, or loss of consciousness. 1 case (11.11%) had a positive history of sudden death in relatives. \n\nConclusion:\nAlthough most sudden death victims are asymptomatic until the event, all those who suffer from symptoms such as chest pain, shortness of breath, dizziness, fatigue and irregular heart rate during physical activities, should be screened regarding common probable causes of sudden death.\n\nKey Words\nSudden deathexerciseautopsyforensic medicine\n==== Body\nIntroduction:\nNatural and unexpected death that happens within less than one hour of first symptom occurrence is called sudden death (1-4). Sudden death is more common among men and the black race (5, 6). In a systematic review based on data related to 1980-2007, annual incidence of sudden cardiac death (SCD) in the United States varied between 180000 and 450000 (7). In some other studies, SCD rate range was reported 50-100 per 100000 of general population in countries such as Netherlands, Ireland, and China (8). Cardiovascular diseases are among the main known causes of sudden death. Interestingly, in about 25% of patients who die of coronary artery atherosclerosis, the first sign is sudden death. After coronary artery diseases, cardiomyopathies including hypertrophic and dilated types are among the second cardiac causes of sudden death (1). Dysfunctions of the heart valves, especially aortic stenosis, are considered as other underlying cardiac causes of sudden death (9). Hypertrophic cardiomyopathy is the most common cause of sudden death in people under thirty years of age (10). Most patients with hypertrophic cardiomyopathy are asymptomatic and death can occur at rest or with mild physical activity, however, sudden death often occurs during intense physical activity (10, 11). In many cases, hypertrophic cardiomyopathy is the only autopsy finding in young victims of sudden death and is the most common reason of sudden death during exercise (12). Drug abuse (such as stimulants, anabolic steroids, opioids, and etc.), bronchoconstriction, heat stroke, and drowning can be mentioned as non-cardiac causes of sudden death in athletes but cardiac causes are more important (9, 13-15). About 69% of sudden deaths in general population are attributed to cardiovascular diseases, while more than 75% of sudden deaths in athletes are assigned to it (13, 16). To emphasize the importance of this topic, here we review the forensic reports of all cases of sudden death following exercise, referred to forensic medicine center of Tehran, Iran, from 2009 to 2014.\n\nMethods:\nIn this cross sectional study, all subjects who were registered to forensic medicine center of Tehran, Iran, from 2009 to 2014, as a case of sudden death following exercise were evaluated. Demographic data (age, sex) and medical history as well as autopsy and toxicology findings were gathered using deceased profiles, retrospectively. Cause of death was reported based on final conclusion of forensic medicine specialists. There were not any age or sex limitations. The protocol of study was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences. Authors adhered to Helsinki declarations during the study period. Results were reported using descriptive analysis.\n\nResults:\n 14 cases were registered as sudden death following exercise in forensic medicine profiles during the study period. Exploring the files of the mentioned deceased, revealed five non-compatible cases in this regard. The cause of death was homicide in one case (4.5 years old boy), drowning in another (38 year-old female), and myocardial infarction in the last three cases (all above 40 years old). Finally, 9 eligible cases were enrolled (88.9% male). The mean age of the deceased was 28.66 ± 10.86 years (range: 7 – 40). Toxicological tests were available for 7 cases, which was positive for tramadol in one case. Table 1 summarizes the baseline characteristics, pathology and autopsy findings of the deceased. Sudden death following football was reported most frequently (44.4%). Only 3 (33.3%) cases had herald signs such as chest pain, syncope, or loss of consciousness. 1 case (11.11%) had positive history of sudden death among relatives.\n\nTable 1 Baseline characteristics and autopsy findings of the studied deceased\n\n\t\nAge\n*\n\t\nSex\n\t\nActivity\n\t\nHistory\n\t\nToxicology\n\t\nAutopsy\n\t\nConclusion\n\t\n\n1 \n\t31\tMale\tFootball \t- Sudden drop one year ago\n- 2 weeks intermittent chest pain\n- father sudden death \tNegative\t- Aortic stenosis\n- Left ventricular hypertrophy\tAortic stenosis and hypertrophic cardiomyopathy\t\n\n2\n\t35\tFemale\tSwimming\tNegative\tNA\t- Lung congestion\n- Liver stiffness\n- Hepatocyte necrosis\n- Coronary atherosclerosis\tAcute coronary syndrome\t\n\n3\n\t7\tMale\tGymnastics\tNegative\tNegative\t- Lung congestion\n- Brain edema\n- Liver stiffness\n- Plural effusion\n- Ascites\tAcute cardiopulmonary syndrome \t\n\n4\n\t40\tMale\tFootball\t- Transient chest pain during last year\tNegative\t- Congested cranial vessels\n- Edematous lungs\n- Enlarged heart\n- Aortic entrance plaques\tIschemic cardiovascular disease\t\n\n5\n\t17\tMale\tFootball\tNegative\tNegative\t- Congested spleen\n- Coronary atherosclerosis\n- Myocarditis\n- Hepatocyte necrosis\tAcute cardiac syndrome\t\n6\t36\tMale\tFitness\tNegative\tNA\t- brain congestion\n- Emphysematous lung\n- Coronary atherosclerosis\tIschemic heart disease on coronary atherosclerosis\t\n7\t24\tMale\tFootball\t- Congenital heart disease\n- Cardiac surgery\tTramadol\t- Emphysematous lung\n- Cardiac hypertrophy\n- Aortic valve calcification\n- Aortic valve dilatation\n- Dilated ventricles\tAcute heart syndrome due to advance heart disease\t\n8\t30\tMale\tLifting\tNegative\tNegative\t- Brain edema\n- Subarachnoid hemorrhage\n- Edematous lung\n- Cardiac hypertrophy\n- Fatty liver changes\tDiffuse cerebral hemorrhage\t\n9\t38\tMale\tSwimming\tNegative\tNegative\t- Stomach erosion\n- Brain vascular congestion\n- Lung congestion\n- Fatty liver\n- Coronary atherosclerosis changes\n- Cardiomyocytes fibrosis\tAcute myocardial syndrome\t\n* : Year; NA: not available.\n\nTable 2 Necessary questions to figure out warning signs of sudden death in athletes\n\n1\tDo you have a positive family history of sudden death or not?\t\n2\tIs there any family history of congenital heart disease or not?\t\n3\tIs there any history of chest pain after activity or not?\t\n4\tDo you experience dizziness or loss of consciousness for a moment following activities or not?\t\n5\tIs there a history of dyspnea with physical activity or not?\t\n6\tDo you have a history of severe heart palpitations during physical activity or not?\t\n7\tIs there a history of connective tissue diseases such as Marfan syndrome in the family or not?\t\n8\tHave you become ill during exercise or after it?\t\n9\tWhen you exercise, do you get tired more quickly than your friends?\t\n10\tDo you have high blood pressure?\t\n11\tHas any doctor ever prohibited you from participating in sports due to heart reasons?\t\nDiscussion:\nIn recent years, concerns and interests of the people and physicians regarding causes of sudden death in athletes have impressively increased. Causes of SCD in athletes can be divided into two groups according to age. Congenital heart defects, hypertrophic cardiomyopathy, coronary artery disease, and myocarditis are among the most prevalent causes of SCD in patients under 35 years of age. On the other hand, acquired coronary artery disease is a common cause of sudden death in over 35 year old population (13-16).\n\nSudden death can occur in approximately all types of sports but it has been more frequently reported in sports like football and basketball. In the current study, most deaths had occurred after football and swimming. In some studies, the risk of sudden death following exercise in men has been reported to be 5 times more than women and the findings of this study has demonstrated this matter (16). Two new studies have confirmed the efficacy of screening before participation in matches. Baggish and colleagues studied cardiovascular screening effects with and without electrocardiography (ECG) in the 510 collegiate athletes of United States. Involving ECG, compared to its non-use in the screening, increased identification of cardiomyopathy cases, sensitivity of screening program (from 45.5% to 90.9%), and negative predictive value (from 98.7% to 99.8 %) (17). Mild symptoms such as slight chest pain and other symptoms that indicate heart problems such as exertional dyspnea should be seriously regarded and taught to all people, so that similar cases can be prevented. The authors of this article recommend asking the necessary questions listed in table 2 for primary screening of at risk patients for sudden death following exercise. In case of any positive answer to the mentioned questions, the participant should be referred for further medical investigations. \n\n\nLimitation:\n\n\nIt should be mentioned that not all cases of sudden death are referred to forensic medicine center for autopsy, especially in cases of clear diagnosis such as acute myocardial infarction or brain insults (hemorrhagic, ischemic, etc.).\n\nConclusion:\nAlthough most sudden death victims are asymptomatic until the event, all those who suffer from symptoms such as chest pain, shortness of breath, dizziness, fatigue and irregular heart rate during physical activities, should be screened regarding common probable causes of sudden death.\n\nAcknowledgments:\nWe would like to express our special thanks to the Forensic center of Tehran, Iran. \n\nConflict of interest:\nNone\n\nFunding support:\nNone\n\nAuthors’ contributions:\nAll authors passed four criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors.\n==== Refs\nReferences\n1 Saukko P Knight B Knight's forensic pathology 2004 CRC Press \n2 Naneix A-L Périer M-C Beganton F Jouven X de la Grandmaison GL Sudden adult death: An autopsy series of 534 cases with gender and control comparison Journal of forensic and legal medicine 2015 32 10 5 25882142 \n3 Yousuf O Chrispin J Tomaselli GF Berger RD Clinical management and prevention of sudden cardiac death Circulation research 2015 116 12 2020 40 26044254 \n4 Van Der Werf C Van Langen IM Wilde AA Sudden Death in the Young What Do We Know About It and How to Prevent? Circulation: Arrhythmia and Electrophysiology 2010 3 1 96 104 20160177 \n5 Kannel WB Cupples LA D'Agostino RB Sudden death risk in overt coronary heart disease: the Framingham Study American heart journal 1987 113 3 799 804 3825868 \n6 Kuller LH Sudden death—definition and epidemiologic considerations Progress in cardiovascular diseases 1980 23 1 1 12 6994170 \n7 Kong MH Fonarow GC Peterson ED Systematic review of the incidence of sudden cardiac death in the United States Journal of the American College of Cardiology 2011 57 7 794 801 21310315 \n8 Deo R Albert CM Epidemiology and genetics of sudden cardiac death Circulation 2012 125 4 620 37 22294707 \n9 Harris KM Tung M Haas TS Maron BJ Under-Recognition of Aortic and Aortic Valve Disease and the Risk for Sudden Death in Competitive Athletes Journal of the American College of Cardiology 2015 65 8 860 2 25720631 \n10 Sovari AA Kocheril AG Baas AS Sudden cardiac death. Medscape Reference 2011 \n11 Kuriachan VP Sumner GL Mitchell LB Sudden Cardiac Death Current problems in cardiology 2015 40 4 133 200 25813838 \n12 Maron BJ Casey SA Chan RH Garberich RF Rowin EJ Maron MS Independent Assessment of the European Society of Cardiology Sudden Death Risk Model for Hypertrophic Cardiomyopathy The American journal of cardiology 2015 \n13 Corrado D Baritussio A Siciliano M Sudden Death in Athletes Electrical Diseases of the Heart: Springer 2013 363 80 \n14 Futterman LG Myerburg R Sudden death in athletes Sports Medicine 1998 26 5 335 50 9858396 \n15 Futterman L Lemberg L Sudden death in athletes American Journal of critical care 1995 4 3 239 43 7787919 \n16 Patel V Elliott P Sudden death in athletes Clinical Medicine 2012 12 3 253 6 22783778 \n17 Wheeler MT Heidenreich PA Froelicher VF Hlatky MA Ashley EA Cost-effectiveness of preparticipation screening for prevention of sudden cardiac death in young athletes Annals of Internal Medicine 2010 152 5 276 86 20194233\n\n",
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"abstract": "We report the disparate clinical progression of a couple infected by SARS-CoV-2 based on their immune checkpoint (IC) levels and immune cell distribution in blood from admission to exitus in patient 1 and from admission to discharge and recovery in patient 2. A detailed clinical follow-up accompanied by a longitudinal analysis of immune phenotypes and IC levels is shown. The continuous increase in the soluble IC ligand galectin-9 (Gal-9) and the increment in T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) protein in T cells in patient 1 suggests an activation of the Gal-9/TIM-3 axis and, subsequently, a potential cell exhaustion in this patient that did not occur in patient 2. Our data indicate that the Gal-9/TIM-3 axis could be a potential target in this clinical setting, along with a patent effector memory T-cell reduction.",
"affiliations": "Emergency Department and Emergent Pathology Research Group, IdiPAZ La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;Emergency Department and Emergent Pathology Research Group, IdiPAZ La Paz University Hospital, Madrid, Spain.;Emergency Department and Emergent Pathology Research Group, IdiPAZ La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;CIBER of Respiratory Diseases (CIBERES), Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.;The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.",
"authors": "Martín-Quirós|Alejandro|A|;Maroun-Eid|Charbel|C|;Avendaño-Ortiz|José|J|;Lozano-Rodríguez|Roberto|R|;Valentín Quiroga|Jaime|J|;Terrón|Verónica|V|;Montalbán-Hernández|Karla|K|;García-Garrido|Miguel A|MA|;Muñoz Del Val|Elena|E|;Del Balzo-Castillo|Álvaro|Á|;Rubio|Carolina|C|;Cubillos-Zapata|Carolina|C|;Aguirre|Luis A|LA|;López-Collazo|Eduardo|E|",
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"title": "Potential Role of the Galectin-9/TIM-3 Axis in the Disparate Progression of SARS-CoV-2 in a Married Couple: A Case Report.",
"title_normalized": "potential role of the galectin 9 tim 3 axis in the disparate progression of sars cov 2 in a married couple a case report"
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"abstract": "Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients.\n\n\n\nCaucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina.\n\n\n\nAmong the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10-8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI.\n\n\n\nHLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.\n\n\n\nDevelopment of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.",
"affiliations": "Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA.;Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA.;Indiana University School of Medicine, Indianapolis, IN, USA.;National Institute of Diabetes Digestive and Kidney Diseases, Bethesda, MD, USA.;University of Southern California, Los Angeles, CA, USA.;Newcastle University, Newcastle upon Tyne, United Kingdom.;National Institute for Health Research Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham, United Kingdom.;University of Dundee, Dundee, United Kingdom.;Einstein Medical Center, Philadelphia, PA, USA.;Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Duke University, Durham, NC, USA.;University of Florida College of Medicine, Gainesville, FL, USA.;Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA.;Duke University, Durham, NC, USA.;Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Institute for Drug Safety Sciences, Durham, NC, USA.;University of Michigan, Ann Arbor, MI, USA. Electronic address: rfontana@med.umich.edu.",
"authors": "Urban|Thomas Jacob|TJ|;Nicoletti|Paola|P|;Chalasani|Naga|N|;Serrano|José|J|;Stolz|Andrew|A|;Daly|Ann K|AK|;Aithal|Guruprasad P|GP|;Dillon|John|J|;Navarro|Victor|V|;Odin|Joseph|J|;Barnhart|Huiman|H|;Ostrov|David|D|;Long|Nanye|N|;Cirulli|Elizabeth Trilby|ET|;Watkins|Paul Brent|PB|;Fontana|Robert John|RJ|;|||;|||;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D015797:HLA-B35 Antigen; D008911:Minocycline",
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"journal": "Journal of hepatology",
"keywords": "Autoimmunity; Drug-induced liver injury; Genetic association; Human leukocyte antigen; Single nucleotide polymorphism",
"medline_ta": "J Hepatol",
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"references": "24768677;16862161;22987284;24037963;21570397;24879978;19505990;21544079;20512999;19399780;22138821;27311619;20415545;8229111;22594502;25414341;11386265;22722860;24927181;19483685;23419359;24114350;22645359;25747410;18955056;24399259;19132805;20512992;12484709;20639878;20634204;17701901;23712092;21245432;12824332;19543373",
"title": "Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor.",
"title_normalized": "minocycline hepatotoxicity clinical characterization and identification of hla b 35 02 as a risk factor"
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"abstract": "The prevalence of chemotherapy associated liver injuries (CALI), especially SOS (sinusoidal obstruction syndrome) and NRH (nodular regenerative hyperplasia) might be reduced since the introduction of routine use of biological agents with chemotherapy in colorectal liver metastases (CRLM).\n\n\n\nOne hundred patients with CRLM having undergone at least one liver segment resection were prospectively included, and chemotherapy data recorded. Specimens were reviewed by a single pathologist and CALI were described. Prevalence of CALI was compared to our previous experience published in 2013. NRH diagnosis was performed on reticulin special stain, by contrast to our previous study. Postoperative outcome was analysed.\n\n\n\nBevacizumab was more frequently administrated in patients of the present study: 53/100 (53%) compared to 20/151 (13%), p < 0.0001. Overall, in the present series, SOS was only observed in 28/100 (28%) patients compared to 116/151 (77%) in 2013 (p < 0.001). When looking specifically to patients receiving Bevacizumab with Folfox, we observed a reduced SOS prevalence compared to Folfox alone (p = 0.008). A higher prevalence of NRH was found in the present study, related to increased detection accuracy, but in patients receiving Bevacizumab in association with Folfox, this prevalence was also reduced compared to Folfox alone (p = 0.03). Both SOS and NRH were associated with severe complications (p = 0.008 and p = 0.005, respectively) and postoperative liver insufficiency (p < 0.001 and p < 0.01, respectively).\n\n\n\nThe routine use of Bevacizumab in association with Folfox significantly reduced CALI prevalence, in turn linked to severe postoperative complications.",
"affiliations": "Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Saint-Luc University Hospital, Université Catholique de Louvain (UCL), Hippocrate Avenue, 10 1200 Brussels, Belgium. Electronic address: Catherine.hubert@uclouvain.be.;Department of Digestive Surgery, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.;Department of Digestive Surgery, Clinique St Joseph, 4000 Liège, Belgium.;Department of Digestive Surgery, Hopital de Jolimont, 7100 Jolimont, Belgium.;Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.;Department of Pathology, Clinique St Joseph, 4000 Liège, Belgium.;Department of Pathology, Saint-Luc University Hospital Université Catholique de Louvain (UCL), 1200 Brussels, Belgium.;Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Saint-Luc University Hospital, Université Catholique de Louvain (UCL), Hippocrate Avenue, 10 1200 Brussels, Belgium.;Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Saint-Luc University Hospital, Université Catholique de Louvain (UCL), Hippocrate Avenue, 10 1200 Brussels, Belgium.;Division of Hepato-Biliary and Pancreatic Surgery, Department of Abdominal Surgery and Transplantation, Saint-Luc University Hospital, Université Catholique de Louvain (UCL), Hippocrate Avenue, 10 1200 Brussels, Belgium.;Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.",
"authors": "Hubert|Catherine|C|;Lucidi|Valerio|V|;Weerts|Joseph|J|;Dili|Alexandra|A|;Demetter|Pieter|P|;Massart|Brigitte|B|;Komuta|Mina|M|;Navez|Julie|J|;Reding|Raymond|R|;Gigot|Jean-François|JF|;Sempoux|Christine|C|",
"chemical_list": "D000970:Antineoplastic Agents; D001688:Biological Products; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejso.2018.07.050",
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"issue": "44(10)",
"journal": "European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology",
"keywords": "Biological agents; CALI; Colorectal liver metastases",
"medline_ta": "Eur J Surg Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001530:Belgium; D000068258:Bevacizumab; D001688:Biological Products; D056486:Chemical and Drug Induced Liver Injury; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011183:Postoperative Complications; D015995:Prevalence",
"nlm_unique_id": "8504356",
"other_id": null,
"pages": "1532-1538",
"pmc": null,
"pmid": "30093084",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Impact of biological agents on the prevalence of chemotherapy associated liver injury (CALI): Multicentric study of patients operated for colorectal liver metastases.",
"title_normalized": "impact of biological agents on the prevalence of chemotherapy associated liver injury cali multicentric study of patients operated for colorectal liver metastases"
} | [
{
"companynumb": "BE-SA-2018SA311272",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"d... |
{
"abstract": "OBJECTIVE\nNon-tuberculous mycobacteria (NTM) represents an important etiology of cervicofacial lymphadenitis (CFL) and skin/soft tissue infections in children. It can also affect the salivary glands, including the parotid gland, which is unique due to the presence of intra-salivary lymph nodes. There are no established guidelines for treatment of NTM CFL. NTM lymphadenitis was historically surgically treated; recently the literature supports initial medical treatment. Treatment decisions have been dependent on the extent of disease, preference of providers, and risk of surgical complications. The goal is to report our experience in surgical outcomes of NTM CFL with involvement of the parotid gland after pre-operative medical management.\n\n\nMETHODS\nA retrospective case series of patients with NTM affecting the parotid gland at a tertiary care pediatric hospital between 2004 and 2020.\n\n\nRESULTS\nSeventy-two patients were referred for surgical evaluation of possible parotid NTM. Thirty-three patients underwent surgical excision. Fifteen patients were identified with presumed NTM infection involving the parotid gland. There were twelve females and three males with a mean age of 2.0 years (SD 1.55; range 1-6 days) at the time of surgery. All underwent surgical excision with parotidectomy. The most common pre-operative antimycobacterial therapy used was a combination of clarithromycin and rifampin. All 15 patients had pathological findings consistent with NTM infection (granulomatous lymphadenitis). Forty percent (n = 6) of patients had positive stains with acid-fast bacilli (AFB), with Mycobacterium avium as the most common species (n = 5). The majority of patients, 86.67% (n = 13), had complete resolution of infection after surgery. Clarithromycin and rifampin were the most common post-operative antimycobacterial treatment (mean 81.5 days, SD 110.14, range 2-411 days). The most common complication experienced was acute (<3 months) lower facial nerve paresis (40%, n = 6), but no patient had permanent facial paralysis.\nParotidectomy is a safe and efficacious treatment in patients with NTM CFL affecting the parotid gland after incomplete resolution with antimycobacterial therapy. Further investigation to optimize duration of antimycobacterial treatment is necessary. We highlight the experience of a high-volume tertiary care pediatric hospital with surgical management of this disease.",
"affiliations": "Department of Otolaryngology - Head & Neck Surgery University of Illinois Chicago, Chicago, IL, USA; Division of Pediatric Otolaryngology Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA. Electronic address: ekoo3@uic.edu.;Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Pediatric Otolaryngology Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Division of Pediatric Otolaryngology Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Pediatric Otolaryngology Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Division of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Division of Infectious Disease, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Pediatric Otolaryngology Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Pediatric Otolaryngology Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Pediatric Otolaryngology Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.",
"authors": "Koo|Elliot Y|EY|;Maksimoski|Matthew T|MT|;Herron|Monica M|MM|;Bhushan|Bharat|B|;Reynolds|Meredith A|MA|;Katz|Ben Z|BZ|;Johnston|Douglas R|DR|;Rastatter|Jeffrey C|JC|;Maddalozzo|John|J|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ijporl.2021.110960",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5876",
"issue": "151()",
"journal": "International journal of pediatric otorhinolaryngology",
"keywords": "Lymphadenitis; Non-tuberculous mycobacteria; Parotidectomy",
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": null,
"nlm_unique_id": "8003603",
"other_id": null,
"pages": "110960",
"pmc": null,
"pmid": "34736012",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Surgical management of parotid non-tuberculous mycobacteria lymphadenitis in children: A pediatric tertiary-care hospital's experience.",
"title_normalized": "surgical management of parotid non tuberculous mycobacteria lymphadenitis in children a pediatric tertiary care hospital s experience"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-06073",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional":... |
{
"abstract": "The prevalence of opioid use in therapeutic and recreational settings has steadily increased throughout the western world. The addition of fentanyl into heroin products can produce potentially dangerous consequences, even to opioid tolerant individuals who may be unaware of such additions. Following an observed spike of heroin-fentanyl related deaths in Melbourne, Australia, a study was undertaken to determine the prevalence of these cases. All reportable deaths occurring in Victoria during 2015 and submitted to the toxicology laboratory were analysed using LC-MS-MS to confirm the combination of the heroin marker 6-acetylmorphine and/or morphine, and fentanyl. Over 4,000 coronial cases in 2015 underwent toxicological analysis for these drugs, there were nine cases identified that involved fentanyl-laced heroin. There was no specific mention of fentanyl use in any of these cases. All occurred within 2 months and in two distinct locations. The first four deaths occurred within 3 days of each other, in neighboring suburbs. The ages ranged from 25 to 57 years with an average of 40 and median of 37 years, and consisted of eight males and one female. The average and median femoral blood concentration of fentanyl was 18 and 20 ng/mL (range: <1-45 ng/mL), and morphine 140 and 80 ng/mL (range: 20-400 ng/mL), respectively. All nine cases had 6-acetylmorphine detectable in blood. Urine analysis was also performed where available. A syringe, powder and spoon found at the scene of one case were also analysed and found to be positive for both heroin and fentanyl, which supported the likelihood of fentanyl-laced heroin. This is the first reported case series of fatalities involving heroin and fentanyl outside of North America in published literature. These findings may help inform public health and prevention strategies serving to decrease the potential for such fatalities in the future.",
"affiliations": "Department of Forensic Medicine, Monash University, Southbank, Victoria, Australia.;Department of Forensic Medicine, Monash University, Southbank, Victoria, Australia.;Department of Forensic Medicine, Monash University, Southbank, Victoria, Australia.;Victorian Institute of Forensic Medicine, 65 Kavanagh Street, Southbank, 3006 Victoria, Australia.;Department of Forensic Medicine, Monash University, Southbank, Victoria, Australia.;Department of Forensic Medicine, Monash University, Southbank, Victoria, Australia.",
"authors": "Rodda|Luke N|LN|;Pilgrim|Jennifer L|JL|;Di Rago|Matthew|M|;Crump|Kerryn|K|;Gerostamoulos|Dimitri|D|;Drummer|Olaf H|OH|",
"chemical_list": "D003932:Heroin; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkx013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "41(4)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D002423:Cause of Death; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D053593:Forensic Toxicology; D003932:Heroin; D006801:Humans; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D015995:Prevalence; D015813:Substance Abuse Detection; D014739:Victoria",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "318-324",
"pmc": null,
"pmid": "28158759",
"pubdate": "2017-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Cluster of Fentanyl-Laced Heroin Deaths in 2015 in Melbourne, Australia.",
"title_normalized": "a cluster of fentanyl laced heroin deaths in 2015 in melbourne australia"
} | [
{
"companynumb": "AU-INSYS THERAPEUTICS, INC-INS201706-000378",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIAMORPHINE"
},
"drugadditi... |
{
"abstract": "Autoimmune encephalitis can result in significant neurological and psychiatric morbidity and mortality in patients of all ages and often does not respond to standard therapies. Recent reports suggest efficacy of tocilizumab, a monoclonal antibody against interleukin 6, in refractory autoimmune encephalitis.\n\n\n\nWe describe three children with refractory autoimmune encephalitis who experienced a robust, immediate clinical response following treatment with tocilizumab.\n\n\n\nThese findings support the efficacy and short-term safety of tocilizumab as a third-line treatment for refractory autoimmune encephalitis in children.",
"affiliations": "Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina. Electronic address: rachel.randell@duke.edu.;Duke University School of Medicine, Durham, North Carolina.;Division of Pediatric Rheumatology, Department of Pediatrics, Duke University, Durham, North Carolina.",
"authors": "Randell|Rachel L|RL|;Adams|Ashley V|AV|;Van Mater|Heather|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.pediatrneurol.2018.07.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "86()",
"journal": "Pediatric neurology",
"keywords": "Autoimmune encephalitis; Pediatric autoimmune encephalitis; Refractory autoimmune encephalitis; Tocilizumab",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D004351:Drug Resistance; D004660:Encephalitis; D005260:Female; D050031:Hashimoto Disease; D006801:Humans; D007155:Immunologic Factors; D008297:Male",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "66-68",
"pmc": null,
"pmid": "30177347",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tocilizumab in Refractory Autoimmune Encephalitis: A Series of Pediatric Cases.",
"title_normalized": "tocilizumab in refractory autoimmune encephalitis a series of pediatric cases"
} | [
{
"companynumb": "US-ACCORD-094325",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nCytomegalovirus (CMV) infection has been well described as an opportunistic infection of patients with human immunodeficiency virus (HIV). To the best of our knowledge, this is the first case report of a patient with AIDS and lumbosacral polyradiculopathy, associated with gastroparesis resulting from CMV infection.\n\n\nMETHODS\nA 46-year-old Hispanic woman with a history of HIV for 10 years was admitted to our hospital for nausea, vomiting, urinary retention, and generalized weakness. Bilateral lower extremity examination revealed flaccid paraplegia, decreased sensations from the groin downwards, bilateral lower extremity areflexia, and absent plantar reflexes, with enlarged urinary bladder. CMV was detected in CSF by PCR, and cervical and lumbar magnetic resonance imaging (MRI) revealed intense nodular leptomeningeal enhancement from the lower thoracic cord and extending along the conus medullaris/filum terminalis and nerve roots. Gastric emptying scintigraphy revealed severe delayed gastric emptying time. Ganciclovir was initiated and her neurological symptoms and gastrological symptoms gradually improved. Over 8 weeks, nausea and vomiting resolved and the patient was able to walk before being discharged from the hospital.\n\n\nCONCLUSIONS\nPolyradiculopathy and gastroparesis can result from CMV infection in AIDS patients. Whether the mechanism is secondary to viral infection or immune systems remains unclear. It is important for physicians to be aware of this uncommon presentation in the antiretroviral therapy (ART) era. CMV treatment should be initiated immediately once diagnosis is confirmed.",
"affiliations": "Department of Internal Medicine, Queens Hospital Center/Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Internal Medicine, Queens Hospital Center/Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Internal Medicine, Queens Hospital Center/Icahn School of Medicine at Mount Sina, New York, NY, USA.;Department of Internal Medicine, Queens Hospital Center/Icahn School of Medicine at Mount Sina, New York, NY, USA.;Department of Internal Medicine, Queens Hospital Center/Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Internal Medicine, Queens Hospital Center/Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Medicine, Nassau University Medical Center, New York, NY, USA.",
"authors": "Thongpooswan|Supat|S|;Chyn|Eric|E|;Alfishawy|Mostafa|M|;Restrepo|Erfidia|E|;Berman|Charles|C|;Ahmed|Kawser|K|;Muralidharan|Sethu|S|",
"chemical_list": "D004279:DNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.894512",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "16()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D003937:Diagnosis, Differential; D005260:Female; D018589:Gastroparesis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D011128:Polyradiculopathy; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "801-4",
"pmc": null,
"pmid": "26552851",
"pubdate": "2015-11-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11994020;3031543;2841381;2535917;2541335;17258320;11871407;8815757;9110064;9403659;10320384;17374867;8445399;8394748",
"title": "Polyradiculopathy and Gastroparesis due to Cytomegalovirus Infection in AIDS: A Case Report and Review of Literature.",
"title_normalized": "polyradiculopathy and gastroparesis due to cytomegalovirus infection in aids a case report and review of literature"
} | [
{
"companynumb": "US-ROCHE-1671419",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
"dru... |
{
"abstract": "Insulin autoimmune syndrome (IAS), defined as hyperinsulinemic hypoglycemia with high titers of anti-insulin antibodies, is frequently reported in Japanese patients but rarely observed in whites. We report in this study on a 79-year-old white male without diabetes who developed IAS following exposure to clopidogrel, a drug not previously known to cause hypoglycemia. The patient presented with recurrent symptomatic hypoglycemia. During one episode, serum glucose was 45 mg/dL, whereas insulin and C-peptide levels were 40,000 mIU/mL and 40 ng/mL, respectively. Additional studies revealed no intake of insulin or its secretagogues, whereas anti-insulin antibody titer was high (59.3 nmol/L). Although total insulin levels were consistently high, free insulin concentrations (polyethylene glycol precipitation) were appropriate for ambient glycemia. The patient was found to have HLA-DRB1*0404, a feature often reported in Japanese patients with IAS. Three weeks prior to symptom onset, he was started on clopidogrel, a drug that does not have a sulfhydryl group, but its active metabolite does. Clopidogrel was switched to a nonsulfhydryl antiplatelet agent, and glucocorticoid therapy was initiated. Shortly thereafter, the frequency of hypoglycemic episodes decreased, and glucocorticoids were tapered over the ensuing 3 months. No hypoglycemic episodes were noted during 6 months of observation after discontinuing glucocorticoids, whereas the total insulin and anti-insulin antibody levels normalized. The data indicate that IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia in seemingly well individuals, even when no drugs known to cause IAS were used. Clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.",
"affiliations": "Division of Clinical and Molecular Endocrinology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio 44106.;Division of Clinical and Molecular Endocrinology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio 44106.;Division of Clinical and Molecular Endocrinology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio 44106.;Division of Clinical and Molecular Endocrinology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio 44106.",
"authors": "Rajpal|Aman|A|;Kassem|Laure Sayyed|LS|;Moscoso-Cordero|Maria|M|;Arafah|Baha M|BM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/js.2017-00316",
"fulltext": "\n==== Front\nJ Endocr SocJ Endocr SocJSJSJournal of the Endocrine Society2472-1972Endocrine Society Washington, DC JS_20170031610.1210/js.2017-00316Case ReportsDiabetes, Pancreatic and Gastrointestinal HormonesClopidogrel-Induced Insulin Autoimmune Syndrome: A Newly Recognized Cause of Hypoglycemia in a Patient Without Diabetes Rajpal Aman 1Kassem Laure Sayyed 1Moscoso-Cordero Maria 1Arafah Baha M. 11 Division of Clinical and Molecular Endocrinology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio 44106Address all correspondence to: Baha M. Arafah, MD, Case Western Reserve University and University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: baha.arafah@case.edu.01 9 2017 28 8 2017 28 8 2017 1 9 1217 1223 18 7 2017 23 8 2017 Copyright © 2017 Endocrine SocietyThis article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Insulin autoimmune syndrome (IAS), defined as hyperinsulinemic hypoglycemia with high titers of anti-insulin antibodies, is frequently reported in Japanese patients but rarely observed in whites. We report in this study on a 79-year-old white male without diabetes who developed IAS following exposure to clopidogrel, a drug not previously known to cause hypoglycemia. The patient presented with recurrent symptomatic hypoglycemia. During one episode, serum glucose was 45 mg/dL, whereas insulin and C-peptide levels were 40,000 mIU/mL and 40 ng/mL, respectively. Additional studies revealed no intake of insulin or its secretagogues, whereas anti-insulin antibody titer was high (59.3 nmol/L). Although total insulin levels were consistently high, free insulin concentrations (polyethylene glycol precipitation) were appropriate for ambient glycemia. The patient was found to have HLA-DRB1*0404, a feature often reported in Japanese patients with IAS. Three weeks prior to symptom onset, he was started on clopidogrel, a drug that does not have a sulfhydryl group, but its active metabolite does. Clopidogrel was switched to a nonsulfhydryl antiplatelet agent, and glucocorticoid therapy was initiated. Shortly thereafter, the frequency of hypoglycemic episodes decreased, and glucocorticoids were tapered over the ensuing 3 months. No hypoglycemic episodes were noted during 6 months of observation after discontinuing glucocorticoids, whereas the total insulin and anti-insulin antibody levels normalized. The data indicate that IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia in seemingly well individuals, even when no drugs known to cause IAS were used. Clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.\n\nWe report the development of insulin autoimmune syndrome in a Caucasian male after exposure to clopidogrel, a drug not previously known to cause hypoglycemia, and suggest a potential mechanism.\n\nclopidogreldrug-induced hypoglycemiahypoglycemiainsulin autoimmune syndrome\n==== Body\nClinical hypoglycemia is described as a serum glucose concentration low enough to cause symptoms and/or signs, including impairment of brain function [1]. Common causes of hyperinsulinemic hypoglycemia in patients without diabetes include surreptitious use of drugs, insulinoma, extra pancreatic tumors, and autoimmune hypoglycemia. There are two known forms of autoimmune hypoglycemia [2]. The first form is commonly referred to as insulin autoimmune syndrome (IAS), in which antibodies are directed against endogenous insulin molecule. In contrast, the second form of autoimmune hypoglycemia is associated with antibodies directed against the cell surface insulin receptor (type B insulin resistance). Thus, IAS is defined as hyperinsulinemic hypoglycemia associated with high titers of antibodies to the human insulin molecule in the absence of both pathologic abnormalities of the pancreatic islets and prior exposure to exogenous insulin.\n\nIAS, originally reported by Hirata et al. in 1970 from Japan [3], is the third leading cause of spontaneous hypoglycemia in that country [4]. It is still uncommon in Western countries, with only 58 cases of this disorder reported in white patients until 2009 [2]. In Japanese patients, the onset of IAS has been shown to be strongly associated with HLA-DR4 and the use of medications containing a sulfhydryl group [4]. In contrast, IAS in white patients is more frequently associated with autoimmune diseases or plasma cell dyscrasias, with only 47% triggered by exposure to sulfhydryl containing medications [2]. In this study, we describe a white male who developed IAS following exposure to clopidogrel, a drug not previously known to cause hypoglycemia.\n\n1. Case Report\nA 79-year-old white male experienced shakiness, sweating, and presyncope 4 hours after having breakfast. When the Emergency Medical Service evaluated him at home shortly thereafter, his blood glucose level was 29 mg/dL. The symptoms reversed promptly by intravenous dextrose infusion. He was seen subsequently at a nearby emergency room, where his serum glucose level was noted to be 145 mg/dL. No other abnormalities were found on his initial blood work or physical exam, and he was discharged home with follow-up with his primary care physician. He continued to have similar episodes of hypoglycemia, both during fasting and the postabsorptive states, which prompted hospital admission for further evaluation. He did not have diabetes and was not taking any drugs known to cause hypoglycemia. There was no family history of diabetes. General and systemic physical examination did not reveal any abnormalities. Results of routine investigations, including hemogram, renal, liver, and thyroid function tests, were normal. Relevant past medical history included coronary artery disease with coronary artery bypass surgery on two occasions ~20 years earlier and recent stent insertion for new angina. On admission to the hospital, his medications included torsemide, fluticasone nasal spray, ProAir HFA (Teva Respiratory, Horsham, PA) as needed, allopurinol, colchicine, vitamin D, doxazosin, metoprolol, Xarelto (Janssen Pharmaceuticals, Titusville, NJ), clopidogrel, and a multivitamin.\n\nDuring one of the witnessed symptomatic hypoglycemic episodes during hospitalization, he had serum glucose of 45 mg/dL, whereas the serum insulin and C-peptide levels were quite high at 40,000 mIU/mL and 40 ng/mL, respectively. The serum cortisol response was appropriately elevated at 23.6 µg/dL during the hypoglycemia. Serum proinsulin level was 420 pmol/L (normal fasting value <20 pmol/L). There was no evidence of exogenous insulin administration or its secretagogues, and imaging studies failed to localize an insulinoma. The anti-insulin antibody titer was high at 59.3 nmol/L (0.00–0.02 nmol/L). Although the total serum insulin levels were consistently high, free insulin levels determined by ultrafiltration or polyethylene glycol (PEG) precipitation were appropriate for ambient glycemia (Fig. 1). Thus, the presumptive diagnosis of IAS was made. Samples for HLA studies were collected, which showed HLA-DRB1*0404 (HLA-DR4 subtype).\n\nFigure 1. (a) Levels of total insulin (dashed line) and free insulin (solid line) plotted against the corresponding serum glucose levels on x-axis prior to treatment. The graph shows that although the total serum insulin levels were consistently high, free insulin levels when determined by PEG precipitation were appropriate for ambient glycemia during the initial treatment phase. (b) Levels of total insulin (dashed line) and free insulin (solid line) plotted against the corresponding serum glucose levels on x-axis during the 3 months of observation after discontinuing glucocorticoids. The graph shows that the total serum insulin levels have greatly decreased (note different scale), although the levels were still higher than free insulin levels. The latest levels are quite comparable with glucose of 84 mg/dL.\n\nReview of the patient’s drug intake revealed that he was started on clopidogrel 3 weeks prior to onset of his symptoms. Being the latest addition to his medications, clopidogrel was suspected to be related to his hypoglycemia. The chemical structure of clopidogrel does not include a sulfhydryl group, but the active metabolite of the drug does have that chemical feature (Fig. 2). Clopidogrel was discontinued and replaced with another nonsulfhydryl antiplatelet agent. He was initially treated with diazoxide with minimal response to hypoglycemia and subsequently started on glucocorticoid therapy along with small, frequent low-carbohydrate meals. The patient was treated with dexamethasone starting at 2 mg twice daily for 3 days, then 1 mg twice daily for next 2 months, followed by 0.5 mg once daily, which was discontinued over the ensuing 3 weeks. Within 7 days of starting the dexamethasone therapy, the frequency of hypoglycemic episodes decreased. Six months after discontinuing dexamethasone, the patient did not have any further hypoglycemic episodes, whereas his total insulin and insulin antibody levels drastically decreased to 18 μIU/mL and 0.31 nmol/L, respectively, when his serum glucose level was 81 mg/dL (Figs. 3 and 4).\n\nFigure 2. Chemical structure of clopidogrel is shown not to have a sulfhydryl group. A thiol derivative of the drug is shown after activation by the P450 enzyme system. The active metabolite does contain a sulfhydryl group (arrow).\n\nFigure 3. Levels of serum total insulin (y-axis) plotted against the time in months (x-axis) during the course of treatment. The initial drop in total insulin levels during the first month was due to methylprednisolone and prednisone given as a treatment of COPD exacerbation. One month after symptom onset, clopidogrel was discontinued, and he was started on dexamethasone (DEX). The graph shows that the total insulin levels decreased to normal levels by the end of 4 months. Inset figure is the magnification of the graph during the last 3 months of treatment and shows a drastic decrease of total insulin levels. CHO, carbohydrate; IV, intravenous.\n\nFigure 4. Levels of serum anti-insulin antibodies (y-axis) plotted against the time in months (x-axis) during the course of treatment. The initial drop in anti-insulin antibodies levels during the first month was due to methylprednisolone and prednisone given as a treatment of COPD exacerbation. One month after symptom onset, clopidogrel was discontinued, and he was started on dexamethasone (DEX). The graph shows that the anti-insulin antibodies decreased to normal levels by the end of 4 months. Inset figure is the magnification of the graph during the last 3 months of treatment and shows a drastic decrease of the anti-insulin antibodies titers. CHO, carbohydrate; IV, intravenous.\n\n2. Methods\nThe patient under discussion underwent routine hematologic, immunologic, and biochemical testing during the evaluation. Blood glucose, insulin, C-peptide, proinsulin, and HLA typing were determined at the University Hospitals Cleveland Medical Center laboratories using standard assay systems. Quantitative chemiluminescence immunoassay was used to measure proinsulin, total insulin, and C-peptide. The free insulin was determined in the supernatant after PEG precipitation. Anti-insulin antibodies were determined by radioimmunoassay performed at the Mayo Clinic laboratories (Rochester, MN).\n\n3. Discussion\nWe present a unique case of IAS in a white patient, with relatively sudden onset of hypoglycemia shortly after exposure to clopidogrel, a drug not previously known to be associated with that symptom. To our knowledge, this is the first case of IAS-induced hypoglycemia reported after exposure to clopidogrel. The case under discussion illustrates that there was more than a temporal association between the onset of symptoms and the introduction of clopidogrel to incriminate that drug as the offending agent. The initial impressive response to glucocorticoids administered to treat chronic obstructive pulmonary disease (COPD) when the patient was still on the drug, followed by the rebound rise in insulin antibody titer after their withdrawal, are supportive of clopidogrel being the offending agent. Similarly, the association of HLA typing and the identification of a sulfhydryl group in the active metabolite of the drug are also supportive of that.\n\nIAS can present with both fasting and postprandial hypoglycemia, and it occurs equally in both sexes. Although the total serum insulin levels are consistently high, the serum-free insulin levels determined by ultrafiltration or PEG precipitation are usually appropriate for the ambient glycemia. C-peptide and proinsulin levels are demonstrated to be high in this setting [2]. Insulin antibodies are typically polyclonal, although monoclonal antibodies have also been described [5]. IAS usually has acute onset, and the total serum insulin levels are high in comparison with those seen in the patients with insulinoma [6]. Thus, the diagnosis of IAS should be seriously considered in a patient with hypoglycemia when the serum levels of insulin, C-peptide, and proinsulin are extremely elevated. In Japanese patients, the development of IAS was shown to be associated with the use of medications containing a sulfhydryl group and HLA-DR4 subtypes [4]. Previously reported whites with IAS were likely to have associated autoimmune diseases or plasma cell dyscrasias, although 47% were triggered by exposure to sulfhydryl-containing medications [2].\n\nIAS usually occurs a few weeks after exposure to medications containing a sulfhydryl group [7]. The proposed mechanism of hypoglycemia in IAS is that sulfhydryl group interacts with the disulfide bond of the insulin molecule, making the latter more immunogenic [8], which, in the appropriate setting, allows the body to make more insulin antibodies. Various explanations have been proposed to account for the hypoglycemia, but the most widely accepted is the buffering effect of insulin antibodies resulting in a binding and release of secreted insulin that is out of synchrony with the prevailing glucose concentration [5]. These insulin antibodies have low affinity and high capacity, which triggers a swift binding of large amounts of insulin during postprandial peaks and then dissociates from the insulin–antibody complex in an unregulated way [8]. This binding reduces the bioavailability of the secreted insulin, resulting in hyperglycemia and further insulin secretion. However, 3 to 5 hours after a meal, due to the low affinity of these insulin antibodies, the insulin–antibody complex shifts toward dissociation, releasing large amounts of biologically active free insulin and triggering episodes of postprandial hypoglycemia [5]. Dozio et al. [9] studied the pattern of insulin biodistribution in a patient with IAS by using the 123I-labeled insulin infusion. They showed that the antibody-bound insulin forms a large and unstable insulin reservoir in patients with IAS, and the insulin is delivered to its receptors not according to blood glucose levels, thus causing hypoglycemia.\n\nClopidogrel is a prodrug that requires activation by the P450 enzyme system. The chemical structure of clopidogrel does not have a sulfhydryl group. However, the active metabolite of the drug does have a sulfhydryl group (Fig. 2). We postulate that the activated form of clopidogrel may bind with disulfide bond of the insulin molecule, making the latter more immunogenic, and cause hypoglycemia as described previously.\n\nUchigata et al. [5] suggested that the insulin assay might give erroneous results because of the interference of the antibodies with the assay, but by addition of PEG or ultrafiltration, insulin bound to antibodies, the heavy protein molecule settles down, and free insulin can be measured in the supernatant. Basu et al. [10] reported the clinical, biochemical, and immunologic characteristics of seven white patients with IAS, mostly females, ranging from 46 to 84 years of age. They showed that during hypoglycemia, concentrations of insulin, proinsulin, and C-peptide considerably exceeded those observed in patients with insulinoma, and these concentrations were spuriously elevated as a result of interference by the autoantibodies in the immunoassays. They confirmed the presumption of the high concentrations of insulin due to interference of the autoantibodies in the immunoassay by measuring free insulin during the mixed-meal test [10]. This was clearly evident in our patient (Fig. 1).\n\nLupsa et al. [2] reported 58 cases of IAS in non-Asians until 2009 (50% in Europe and 41% in the United States), with no sex difference. In non-Asian patients, this syndrome was often associated with other autoimmune diseases or plasma cell dyscrasias, whereas 47% of these patients had a recent exposure to sulfhydryl group–containing medications (captopril, penicillamine, pyritinol, carbimazole, imipenem, propylthiouracil, hydralazine, procainamide, isoniazid, and penicillin G). In that review [2], most patients were treated with a low-carbohydrate diet, whereas only 11 patients (38%) were treated with glucocorticoids. If sulfhydryl-containing medications were implicated, discontinuing the drug led to resolution of the symptoms [2]. There were no data regarding HLA association in non-Asian patients with IAS. Our case is one of the few documented cases of IAS in a non-Asian patient not associated with other autoimmune diseases. However, our patient had a genetic predisposition and was recently exposed to a drug containing a sulfhydryl group, and, given the cumulative clinical and biochemical parameters and spontaneous remission of hypoglycemia, it fits well with this syndrome.\n\nManagement of IAS includes discontinuation of the offending agent, a low-carbohydrate diet, and often the use of glucocorticoids. The duration of treatment is ∼3 to 6 months, when a sulfhydryl-containing drug is identified and discontinued. Most of the patients respond to small, frequent low-carbohydrate meals, which serves to lower postprandial hyperglycemia and the subsequent rise in insulin secretion. Although spontaneous improvement of symptoms was reported in the literature [2], most patients were treated differently by various investigators [2]. The therapeutic options used include a low-carbohydrate diet and the use of drugs such as glucocorticoids, diazoxide, acarbose, and somatostatin [2]. In light of our patient’s age, the history of heart disease, and the impressive response observed during the administration of glucocorticoids for the treatment of COPD, we elected to treat him with dexamethasone for several weeks. We chose dexamethasone over other glucocorticoids so that we could maximize the anti-inflammatory benefit and minimize or even eliminate the potential for salt retention. Although it would have been of interest to rechallenge the patient, we did not feel this would be appropriate in light of his medical history.\n\nIn summary, this case suggests that IAS should be considered as the differential diagnosis of endogenous hyperinsulinemic hypoglycemia in seemingly well individuals, even when no drugs known to cause IAS were used. Very high total serum insulin levels with relatively low free insulin levels should raise the suspicion for IAS. A clinical suspicion of IAS can avoid expensive imaging and unnecessary surgery in affected patients.\n\nAbbreviations: COPDchronic obstructive pulmonary disease\n\nIASinsulin autoimmune syndrome\n\nPEGpolyethylene glycol.\n\n\n\nAcknowledgments\nFinancial Support: This study received departmental support.\n\nDisclosure Summary: The authors have nothing to disclose.\n==== Refs\nReferences and Notes\n1. Cryer PE , Axelrod L , Grossman AB , Heller SR , Montori VM , Seaquist ER , Service FJ ; Endocrine Society \nEvaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline . J Clin Endocrinol Metab . 2009 ;94 (3 ):709 –728 .19088155 \n2. Lupsa BC , Chong AY , Cochran EK , Soos MA , Semple RK , Gorden P \nAutoimmune forms of hypoglycemia . Medicine (Baltimore) . 2009 ;88 (3 ):141 –153 .19440117 \n3. Hirata Y , Ishizu H , Ouchi N , Motomura M , Abe M , Hara Y , Wakasugi H , Takahashi L , Sakano H , Tanaka M , Kawano H , Kanesaki T \nInsulin autoimmunity in a case of spontaneous hypoglycemia . J Jpn Diabetes Soc. \n1970 ;13 :312 –320 .\n4. Uchigata Y , Hirata Y \nInsulin autoimmune syndrome (IAS, Hirata disease) . Ann Med Interne (Paris) . 1999 ;150 (3 ):245 –253 .10445096 \n5. Uchigata Y , Tokunaga K , Nepom G , Bannai M , Kuwata S , Dozio N , Benson EA , Ronningen KS , Spinas GA , Tadokoro K , Hirata Y , Juji T , Omori Y \nDifferential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata’s disease) and monoclonal insulin autoimmune syndrome . Diabetes . 1995 ;44 (10 ):1227 –1232 .7556962 \n6. Redmon JB , Nuttall FQ \nAutoimmune hypoglycemia . Endocrinol Metab Clin North Am . 1999 ;28 (3 ):603 –618, vii .10500933 \n7. Uchigata Y , Eguchi Y , Takayama-Hasumi S , Omori Y \nInsulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan . Diabetes Res Clin Pract . 1994 ;22 (2-3 ):89 –94 .8200300 \n8. Taylor SI , Barbetti F , Accili D , Roth J , Gorden P \nSyndromes of autoimmunity and hypoglycemia. Autoantibodies directed against insulin and its receptor . Endocrinol Metab Clin North Am . 1989 ;18 (1 ):123 –143 .2645123 \n9. Dozio N , Scavini M , Beretta A , Sarugeri E , Sartori S , Belloni C , Dosio F , Savi A , Fazio F , Sodoyez JC , Pozza G \nImaging of the buffering effect of insulin antibodies in the autoimmune hypoglycemic syndrome . J Clin Endocrinol Metab . 1998 ;83 (2 ):643 –648 .9467587 \n10. Basu A , Service FJ , Yu L , Heser D , Ferries LM , Eisenbarth G \nInsulin autoimmunity and hypoglycemia in seven white patients . Endocr Pract . 2005 ;11 (2 ):97 –103 .15901524\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "1(9)",
"journal": "Journal of the Endocrine Society",
"keywords": "clopidogrel; drug-induced hypoglycemia; hypoglycemia; insulin autoimmune syndrome",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
"other_id": null,
"pages": "1217-1223",
"pmc": null,
"pmid": "29264578",
"pubdate": "2017-09-01",
"publication_types": "D002363:Case Reports",
"references": "19440117;15901524;8200300;7556962;10500933;2645123;10445096;19088155;9467587",
"title": "Clopidogrel-Induced Insulin Autoimmune Syndrome: A Newly Recognized Cause of Hypoglycemia in a Patient Without Diabetes.",
"title_normalized": "clopidogrel induced insulin autoimmune syndrome a newly recognized cause of hypoglycemia in a patient without diabetes"
} | [
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"companynumb": "US-TEVA-792064USA",
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"activesubstancename": "CLOPIDOGREL BISULFATE"
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"abstract": "BACKGROUND\nBiomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity.\n\n\nMETHODS\nIn a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered.\n\n\nRESULTS\nAcross the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions.\n\n\nCONCLUSIONS\nIncreases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.",
"affiliations": "University of Pennsylvania, Philadelphia, PA;;University of Pennsylvania, Philadelphia, PA;;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, CA;;Baylor College of Medicine, Houston, TX;;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;University of Pennsylvania, Philadelphia, PA;;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, CA;;MD Anderson Cancer Center, Houston, TX;;Piedmont Heart Institute, Atlanta, GA.;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;Massachusetts General Hospital and Harvard Medical School, Boston, MA;;University of Pennsylvania, Philadelphia, PA; bonnie.ky@uphs.upenn.edu.",
"authors": "Putt|Mary|M|;Hahn|Virginia Shalkey|VS|;Januzzi|James L|JL|;Sawaya|Heloisa|H|;Sebag|Igal A|IA|;Plana|Juan Carlos|JC|;Picard|Michael H|MH|;Carver|Joseph R|JR|;Halpern|Elkan F|EF|;Kuter|Irene|I|;Passeri|Jonathan|J|;Cohen|Victor|V|;Banchs|Jose|J|;Martin|Randolph P|RP|;Gerszten|Robert E|RE|;Scherrer-Crosbie|Marielle|M|;Ky|Bonnie|B|",
"chemical_list": "D000970:Antineoplastic Agents; D015415:Biomarkers; D054715:Cardiotoxins; D037502:Galectin 3; D055436:Growth Differentiation Factor 15; D010446:Peptide Fragments; D019210:Troponin I; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D004317:Doxorubicin; D002097:C-Reactive Protein; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D000068878:Trastuzumab",
"country": "England",
"delete": false,
"doi": "10.1373/clinchem.2015.241232",
"fulltext": null,
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"issn_linking": "0009-9147",
"issue": "61(9)",
"journal": "Clinical chemistry",
"keywords": null,
"medline_ta": "Clin Chem",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D015415:Biomarkers; D001940:Breast; D001943:Breast Neoplasms; D002097:C-Reactive Protein; D066126:Cardiotoxicity; D054715:Cardiotoxins; D004317:Doxorubicin; D005260:Female; D037502:Galectin 3; D055436:Growth Differentiation Factor 15; D006321:Heart; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D011379:Prognosis; D000068878:Trastuzumab; D019210:Troponin I; D040281:Vascular Endothelial Growth Factor Receptor-1",
"nlm_unique_id": "9421549",
"other_id": null,
"pages": "1164-72",
"pmc": null,
"pmid": "26220066",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "24291281;19470921;24755151;15932966;19631178;20679614;21169385;21371685;21636802;21718220;22465037;22949432;22744937;23158536;23989717;23687930;10600838;10933366;11213359;11331753;11870163;14747500;15148277;8647872;24904180;15977302;16376782;16412852;17005195;17572253;17652815;17686164;17646669;19054498;24554716",
"title": "Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab.",
"title_normalized": "longitudinal changes in multiple biomarkers are associated with cardiotoxicity in breast cancer patients treated with doxorubicin taxanes and trastuzumab"
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"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"abstract": "Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) showing longer progression free survival and overall survival than other EGFR-TKI with an improvement in tolerability.\n\n\n\nWe report about an advanced lung adenocarcinoma patient with severe aplastic anemia during first line osimertinib.\n\n\n\nSevere hematologic toxicity is extremely rare but possible with osimertinib and clinicians should be careful about changes in blood cell count during the use of it.",
"affiliations": "Department of Oncology, San Gerardo Hospital, Monza, Italy. Electronic address: lucasala318@gmail.com.;Department of Oncology, San Gerardo Hospital, Monza, Italy.;Department of Oncology, San Gerardo Hospital, Monza, Italy.;Department of Pathology, San Gerardo Hospital, Monza, Italy.;Department of Oncology, San Gerardo Hospital, Monza, Italy.;Department of Oncology, San Gerardo Hospital, Monza, Italy.;Department of Oncology, San Gerardo Hospital, Monza, Italy.",
"authors": "Sala|Luca|L|;Mancin|Maddalena|M|;Pastore|Alessia|A|;Seminati|Davide|D|;Cortinovis|Diego|D|;Bidoli|Paolo|P|;Alberti|Andrea|A|",
"chemical_list": "D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000596361:osimertinib",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2020.02.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "142()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Aplastic anemia; EGFR; Lung cancer; Osimertinib",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000178:Acrylamides; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000741:Anemia, Aplastic; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D011379:Prognosis",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "120-122",
"pmc": null,
"pmid": "32145595",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Aplastic anemia in a patient with advanced lung adenocarcinoma during first line osimertinib: A case report and literature review.",
"title_normalized": "aplastic anemia in a patient with advanced lung adenocarcinoma during first line osimertinib a case report and literature review"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020058157",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
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"activesubstancename": "FILGRASTIM"
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{
"abstract": "Adults treated with topiramate may develop nephrolithiasis, but its frequency in children on topiramate is unknown. Topiramate inhibits renal carbonic anhydrase, which can lead to renal tubular acidosis and hypercalciuria. We studied 40 consecutive children who initiated topiramate therapy for seizures between January 1997 and February 2003, followed for a mean of 36 months.\nSerum electrolytes, urinary calcium/creatinine ratios, and renal ultrasonography were performed before topiramate and every 6 months thereafter.\nFour children developed nephrolithiasis and/or nephrocalcinosis, which resolved on discontinuation of topiramate. In 40 patients, the mean urinary calcium/creatinine ratio increased over time (P < 0.001). The mean serum bicarbonate in 40 patients decreased over time (P < 0.01). Twenty-three children had urinary calcium/creatinine ratios before topiramate. Nine children with baseline hypercalciuria (defined as urinary calcium/creatinine >0.21) were compared with the 14 children with baseline normal urinary calcium excretion. A greater increase in urinary calcium/creatinine ratios occurred in hypercalciuric children (P < 0.001) and a greater decrease in serum bicarbonate levels occurred in the hypercalciuric children (P < 0.05) compared with children with baseline normal calcium excretion. Greater urinary calcium excretion was associated with increasing doses of topiramate (P = 0.039).\nOur study shows that long-term therapy with topiramate in children is associated with persistent hypercalciuria and metabolic acidosis, which can lead to nephrocalcinosis and/or nephrolithiasis. All children initiating topiramate therapy should have baseline and follow-up urinary calcium/creatinine studies, serum electrolytes, and periodic renal ultrasonography, if the urinary calcium/creatinine ratio increases to a level above normal for age.",
"affiliations": "Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Pediatrics, Baystate Medical Center Children's Hospital, Springfield, Massachusetts, USA.;Department of Pediatrics, Baystate Medical Center Children's Hospital, Springfield, Massachusetts, USA.;Baystate Medical Center Children's Hospital, Springfield, Massachusetts, USA.;Baystate Medical Center Children's Hospital, Springfield, Massachusetts, USA.",
"authors": "Barnett|Sarah M|SM|;Jackson|Anthony H|AH|;Rosen|Beth A|BA|;Garb|Jane L|JL|;Braden|Gregory L|GL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ekir.2018.02.005",
"fulltext": "\n==== Front\nKidney Int RepKidney Int RepKidney International Reports2468-0249Elsevier S2468-0249(18)30036-610.1016/j.ekir.2018.02.005Clinical ResearchNephrolithiasis and Nephrocalcinosis From Topiramate Therapy in Children With Epilepsy Barnett Sarah M. 123Jackson Anthony H. 345Rosen Beth A. 345Garb Jane L. 456Braden Gregory L. gregory.braden@baystatehealth.org456∗1 Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA2 Harvard Medical School, Boston, Massachusetts, USA3 Department of Pediatrics, Baystate Medical Center Children’s Hospital, Springfield, Massachusetts, USA4 Baystate Medical Center Children’s Hospital, Springfield, Massachusetts, USA5 University School of Medicine, Boston, Massachusetts, USA6 Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA∗ Correspondence: Gregory Braden, Chief, Renal Division, Baystate Medical Center, 759 Chestnut Street, Springfield, Massachusetts 01199, USA. gregory.braden@baystatehealth.org21 2 2018 5 2018 21 2 2018 3 3 684 690 28 4 2017 26 1 2018 13 2 2018 © 2018 International Society of Nephrology. Published by Elsevier Inc.2018International Society of NephrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nAdults treated with topiramate may develop nephrolithiasis, but its frequency in children on topiramate is unknown. Topiramate inhibits renal carbonic anhydrase, which can lead to renal tubular acidosis and hypercalciuria. We studied 40 consecutive children who initiated topiramate therapy for seizures between January 1997 and February 2003, followed for a mean of 36 months.\n\nMethods\nSerum electrolytes, urinary calcium/creatinine ratios, and renal ultrasonography were performed before topiramate and every 6 months thereafter.\n\nResults\nFour children developed nephrolithiasis and/or nephrocalcinosis, which resolved on discontinuation of topiramate. In 40 patients, the mean urinary calcium/creatinine ratio increased over time (P < 0.001). The mean serum bicarbonate in 40 patients decreased over time (P < 0.01). Twenty-three children had urinary calcium/creatinine ratios before topiramate. Nine children with baseline hypercalciuria (defined as urinary calcium/creatinine >0.21) were compared with the 14 children with baseline normal urinary calcium excretion. A greater increase in urinary calcium/creatinine ratios occurred in hypercalciuric children (P < 0.001) and a greater decrease in serum bicarbonate levels occurred in the hypercalciuric children (P < 0.05) compared with children with baseline normal calcium excretion. Greater urinary calcium excretion was associated with increasing doses of topiramate (P = 0.039).\n\nConclusion\nOur study shows that long-term therapy with topiramate in children is associated with persistent hypercalciuria and metabolic acidosis, which can lead to nephrocalcinosis and/or nephrolithiasis. All children initiating topiramate therapy should have baseline and follow-up urinary calcium/creatinine studies, serum electrolytes, and periodic renal ultrasonography, if the urinary calcium/creatinine ratio increases to a level above normal for age.\n\nKeywords\nhypercalciurianephrocalcinosisnephrolithiasistopiramate\n==== Body\nTopiramate is an effective drug in treating pediatric patients with refractory partial status epilepticus,1 infantile spasms,2 and other catastrophic epilepsies of infancy.3 Dose-controlled studies show that topiramate can be effectively used as monotherapy for seizures in both children and adults.4 Although topiramate causes nephrolithiasis in approximately 1.5% of adults, the frequency of nephrolithiasis or nephrocalcinosis in children receiving long-term topiramate is not completely elucidated.5 Shields and Wu6 reported 1 case of nephrolithiasis in 313 children treated for a mean of 722 days with topiramate. A retrospective cross-sectional study of 96 children receiving topiramate therapy identified 5 children (5%) who developed nephrolithiasis on random renal ultrasonography performed between 18 and 33 months of topiramate.7 There were no data in this study on nephrocalcinosis or on topiramate dosing or biochemical parameters during topiramate. In addition, Corbin Bush et al.8 found that 5% of children in a prospective cross-sectional study receiving topiramate for a mean of 27 months developed asymptomatic nephrolithiasis that was found on screening renal ultrasonography. Most of these children had lithogenic abnormalities, such as hypercalciuria, hypocitraturia, and a high urine pH. Finally, clinical kidney stone events occurred in 13 (54%) of 24 nonambulatory and neurologically impaired children living in a home for disabled children during topiramate therapy after a mean duration of 36 months.9 There were no data on topiramate dosing or biochemical parameters in this study.\n\nTopiramate is similar in structure to acetazolamide, and both drugs inhibit carbonic anhydrase in the renal tubule, although the inhibitory effect of acetazolamide is greater than topiramate.10, 11 Inhibition of renal tubular carbonic anhydrase has several effects. Metabolic acidosis occurs secondary to impairment of carbonic anhydrase-dependent proximal tubular bicarbonate reabsorption, resulting in increased urinary excretion of bicarbonate.12, 13, 14, 15 Alkalinizing the urine can lead to calcium phosphate super-saturation and nephrolithiasis. Moreover, inhibition of carbonic anhydrase impairs proximal tubular reabsorption of calcium, leading to increased urinary calcium excretion; this in turn could predispose patients to renal calcium stones or nephrocalcinosis.16 In addition, metabolic acidosis stimulates proximal tubule reabsorption and metabolism of citrate, leading to hypocitraturia, which is a risk factor for calcium stone formation and nephrocalcinosis.16, 17 These biochemical mechanisms have been identified in adult patients on topiramate.18, 19 Indeed, we have previously shown that acetazolamide induces metabolic acidosis and hypercalciuria, leading to nephrocalcinosis and nephrolithiasis in children treated with this drug for post hemorrhagic hydrocephalus.20\n\nOur study, which followed 40 children on topiramate therapy for seizures over an average of 36 months, sought to define the incidence of nephrolithiasis, nephrocalcinosis, or both, as well as the effect that topiramate had on serum bicarbonate (HCO3) levels and on urinary calcium/creatinine (UCa/Cr) ratios.\n\nMethods\nTo analyze the effects of topiramate (Topamax; Ortho-McNeil Neurologic, Titusville, NJ) on UCa/Cr ratios and serum HCO3 levels, we studied 40 consecutive children ages 11 months to 18 years who started topiramate for seizures between January 1997 and February 2003. Data on the age of initiation of topiramate, type of seizure disorder, duration of topiramate, and concomitant medications were collected. Baseline electrolytes were obtained in all 40 patients before topiramate but only 23 had baseline UCa/Cr ratios before topiramate.\n\nPatients were followed for a mean of 36 months with periodic measurements of serum electrolytes, UCa/Cr ratios, and renal ultrasonography approximately every 6 months, using a 7.5-MHz linear array transducer. All ultrasounds were read blindly by a radiologist skilled in renal ultrasonography. All patients had baseline renal ultrasounds that were normal.\n\nNo patients in our study had a previous history of renal disease, parathyroid disease, or rickets. None were concurrently on the carbonic anhydrase inhibitors zonisamide or acetazolamide. Furthermore, during the study period, no patient was on the ketogenic diet, which, like topiramate, induces metabolic acidosis.21\n\nNephrocalcinosis was defined as the presence of hyperechoic medullary pyramids seen in both transverse and longitudinal directions associated with significant corticomedullary echo differentiation. Nephrolithiasis was defined as a distinct echogenic focus with concomitant shadowing.22 A UCa/Cr ratio of 0.21 or greater was used as a cutoff value because prior studies have shown that this level of urinary calcium excretion in children is associated with hematuria, dysuria, urinary urgency, urinary tract infections, and nephrolithiasis.23, 24, 25, 26, 27, 28, 29 Of the 40 patients, 23 patients had baseline electrolytes and UCa/Cr ratio before the institution of topiramate. Nine of 23 patients had UCa/Cr ratios of 0.21 or greater before topiramate initiation; this group was compared with the 14 patients whose UCa/Cr ratios were normal, and both groups were analyzed for changes in UCa/Cr ratio and serum HCO3 over time by repeated measures analysis of variance rather than by the Student t test. The BMDP program 5V (unbalanced repeated measures analysis of variance) allows for missing measurements at different time periods.30 A maximum likelihood procedure using the Newton-Raphson algorithms was used to obtain estimates of the regression and covariance parameters.31 The Wald test was used to test the effects of the treatment group and the length of exposure to topiramate.32 The relationship of UCa/Cr and serum HCO3 at the time of the maximum topiramate dose in mg/kg was analyzed by linear regression analysis in 25 children who had a UCa/Cr ratio at the time when they were on their maximum dose of topiramate.\n\nApproval was granted for this study by the Institutional Review Board of Baystate Medical Center #03-133. Data were collected in a de-identified manner in compliance with the Health Insurance Portability and Accountability Act of 1996 and our institutional review board.\n\nResults\nThe seizure types in these 40 children included the following: complex partial seizures (n = 13), generalized tonic-clonic (n = 10), infantile spasms (n = 7), childhood absence (n = 5), and Lennox-Gastaut (n = 5). The mean age at time of topiramate initiation was 107 months. Only 3 children had a family history of nephrolithiasis and none of the 4 children who later developed nephrocalcinosis or nephrolithiasis had a family history of kidney stones. Ten children had a gastric tube and 9 did not ambulate and were immobile. Twelve children were on monotherapy with topiramate and 28 children received 1 or 2 additional drugs, including valproic acid (n = 8), levetiracetam (n = 11), lamotrigine (n = 9), or phenobarbital (n = 2). No children in the study received zonisamide.\n\nChanges in urinary calcium excretion (UCa/Cr) and serum HCO3 levels in all 40 patients are presented in Figures 1 and 2. The UCa/Cr ratio increased 2-fold after 6 months of topiramate and there was a significant increase in mean UCa/Cr ratio after 30 months for all 40 patients, which was sustained after 54 months of topiramate therapy (P < 0.001). The serum HCO3 decreased significantly after 6 months of topiramate (Figure 2) and the decrease persisted for up to 60 months of therapy (P < 0.001). Nine of 23 children, who had pretreatment urinary determinations, had UCa/Cr ratios of 0.21 or greater before receiving topiramate. The mean age of these children was 36 months (range 7–123 months) and there were 4 girls and 5 boys. Their mean UCa/Cr ratio before topiramate was 0.35 ± 0.11. Fourteen children had UCa/Cr ratios <0.21 before topiramate and their mean age was 137 months (range 2–212 months), with 2 girls and 12 boys. Their mean UCa/Cr ratio was 0.07 ± 0.05. The mean age and mean UCa/Cr ratio was statistically different between the 2 groups (P < 0.05). There was no difference between these 2 groups in causes for seizures, family history of nephrolithiasis, gastric tube, or immobilization.Figure 1 Effects of topiramate on mean ± SE urinary calcium (Ca)/creatinine (Cr) ratios over time in all 40 patients, P < 0.001.\n\nFigure 2 Effects of topiramate on mean ± SE serum bicarbonate levels over time in all 40 patients, P < 0.001.\n\n\n\nFour children developed renal complications from topiramate, including 2 with nephrolithiasis and 2 who developed renal medullary nephrocalcinosis detected on ultrasound (Table 1). Patient 1 developed clinically significant nephrolithiasis and passed 1 kidney stone after 45 months of topiramate. His renal ultrasound 1 year before this episode showed no nephrolithiasis or nephrocalcinosis. His marked hypercalciuria during topiramate treatment resolved completely after drug discontinuation. He had a normal renal ultrasound 3 years later and, 5 years after topiramate discontinuation, showed no recurrence of nephrolithiasis. Patient 4 developed two 5-mm renal stones in the right kidney after 60 months of topiramate. His renal ultrasound 12 months before demonstrated no nephrolithiasis or nephrocalcinosis. These 2 stones gradually resolved after topiramate discontinuation and 18 months of potassium citrate. A renal ultrasound 2 years off topiramate showed complete resolution of both stones. Patient 2 developed medullary nephrocalcinosis demonstrated on renal ultrasound after 30 months of topiramate, which resolved off topiramate and without any other therapy after 9 months. Patient 3 developed ultrasound evidence of medullary nephrocalcinosis, which was no longer evident 6 months after discontinuation of topiramate. Three of these 4 children had baseline UCa/Cr ratios in the range of 0.21 to 0.49 before topiramate treatment. All 4 children had significantly higher UCa/Cr ratios and decreased serum HCO3 during topiramate, which improved once the drug was stopped (Table 1). All 4 children had a serum HCO3 level below the normal range at the time of diagnosis of nephrolithiasis or nephrocalcinosis while on topiramate. Patients 1 and 4 had low urinary citrate-to-creatinine ratios during topiramate at 0.15 and 0.23, respectively (normal >0.5). In addition, all 4 children with these complications received long-term topiramate for 30 to 60 months before complications were identified, and none had a family history of nephrolithiasis.Table 1 Characteristics of children who developed nephrocalcinosis (NC) or nephrolithiasis (NL) on topiramate (TPM)\n\nCase\tMale/Female\tNC or NL\tSeizure type\tAge at TPM initiation, mo\tDuration of TPM, mo\tUCa/Cr before TPM\tUCa/Cr on TPM\tUCa/Croff TPM\tSerum HCO3 before TPM\tSerum HCO3 on TPM, mEq/L\tSerum HCO3 off TPM, mEq/L\t\n1\tM\tNL\tInfant spasms\t19\t45\t0.49\t0.95\t0.08\t24\t20\t24\t\n2\tF\tNC\tComplex partial seizures\t11\t30\t0.39\t1.0\t0.08\t24\t19\t22\t\n3\tM\tNC\tInfant spasms\t70\t58\t0.21\t0.44\t0.25\t25\t21\t24\t\n4\tM\tNL\tComplex partial seizures\t24\t60\tNA\t0.52\t0.18\t26\t17\t27\t\nUCa/Cr, urinary calcium/creatinine ratio.\n\n\n\nThe 9 children with UCa/Cr ratios of ≥0.21 before topiramate were compared with the 14 children with normal calcium excretion before topiramate (Figures 3 and 4). There was a greater increase in UCa/Cr ratio while on topiramate in the children who had elevated UCa/Cr ratios before starting topiramate therapy (P < 0.001) compared with the children with normal calcium excretion (Figure 3). There was a greater decrease in serum HCO3 levels over time (Figure 4) from topiramate in the children with elevated UCa/Cr ratios before topiramate therapy (P < 0.05).Figure 3 Effects of topiramate on mean ± SE urinary calcium (Ca)/creatinine (Cr) ratios over time in children with baseline hypercalciuria versus children with normal calcium/creatinine ratios before topiramate, P < 0.001.\n\nFigure 4 Effects of topiramate on mean ± SE serum bicarbonate over time in children with baseline hypercalciuria versus children with normal calcium/creatinine ratios before topiramate, P < 0.05.\n\n\n\nThere was a significant correlation between the maximum topiramate dose (mg/kg) and urine calcium excretion measured as UCa/Cr ratio in the 25 children who had UCa/Cr ratios definitively measured at the maximum dose of topiramate. The maximum dose range of topiramate therapy was 2.2 to 21.4 mg/kg and the UCa/Cr ranged from 0.03 to 1.0. The r value for this correlation was 0.49 (P = 0.039). In addition, there was a significant inverse correlation between the maximum topiramate dose (mg/kg) and serum HCO3 levels. The range of serum HCO3 levels was 13 to 27 mEq/L. The r value for this correlation was −0.57 (P < 0.01).\n\nDiscussion\nThis study was initiated because of several authors’ prior experience using acetazolamide, which, like topiramate, inhibits carbonic anhydrase and induces nephrocalcinosis in children receiving this drug for seizures.20 In the months following the approval of topiramate by the US Food and Drug Administration, our standard of care included surveillance of serum electrolytes, UCa/Cr ratios, and a renal ultrasound every 6 to 12 months.\n\nOur study suggests that long-term topiramate, particularly in young children, can lead to either nephrolithiasis or nephrocalcinosis. In addition, increased urinary calcium excretion found frequently in young children can be worsened by chronic topiramate therapy and the increased calcium excretion persists for up to 5 years during topiramate therapy.\n\nIn addition, the decrease in serum HCO3 was greater in the children with baseline high urinary calcium excretion compared with the healthy control children. Greater systemic acidosis from the carbonic anhydrase inhibitory effect of topiramate could lead to hypercalciuria due to bone buffering of chronic metabolic acidosis. In addition, carbonic anhydrase inhibition may impair proximal tubular calcium reabsorption leading to hypercalciuria, which enhances the risk for nephrocalcinosis or urinary calcium phosphate stones that can have enhanced growth in a more alkaline urinary milieu.\n\nMoreover, carbonic anhydrase II is integral in alpha intercalated cells in cortical and medullary collecting tubules in supplying hydrogen ions to the H+-ATPase proton pump. Inhibition of carbonic anhydrase in the distal nephron could lead to impaired distal acidification, and renal tubular acidosis may be caused by topiramate.13, 14, 15 We did not perform any studies of distal urinary acidification to confirm this hypothesis. We also demonstrated that higher doses of topiramate are associated with increased urinary calcium excretion and lower serum bicarbonate levels.\n\nChildren have unique renal physiology that may predispose them to nephrocalcinosis or nephrolithiasis during topiramate therapy. There is an inverse relationship between a child’s age and the UCa/Cr ratio: a child younger than 1 year has a mean UCa/Cr level of <0.8 mg/mg, whereas a child older than 5 years can be expected to have an “adult” value of <0.21 mg/mg.23, 24 However, children with a UCa/Cr ratio >0.21 are at risk for developing gross hematuria, dysuria, urinary urgency, urinary tract infections, and nephrolithiasis.25, 26, 27, 28, 29 Hypercalciuria is an important predisposing factor in the development of renal calcium deposition; thus, younger children may be at higher risk for the adverse renal side effects of topiramate. We analyzed our patients using a UCa/Cr ratio of less than or greater than 0.21 because of the potential complications of this level of urinary calcium excretion. Indeed, in the only other cross-sectional study of children receiving topiramate for a mean of 27 months, 5% had hypercalciuria defined as calcium/creatinine >0.20 for children older than 12 months or >0.6 for children aged ≤12 months. Ninety-three percent had hypocitraturia defined as a citrate/creatinine ratio <0.5.8 In this study, there was no correlation of topiramate dose to the urinary calcium excretion, but the relationship of maximum topiramate dose was not analyzed.\n\nThe long-term renal effects of nephrocalcinosis are unknown, but studies in premature infants who develop this complication during the neonatal period have shown permanent reduction in glomerular filtration rate in half the children tested 3 to 7 years later.33, 34 In our 2 patients with nephrocalcinosis, this condition gradually resolved during serial ultrasounds obtained after stopping topiramate, but detailed measurements of glomerular filtration rate were not performed. Even before frank stones are formed, nephrocalcinosis can develop, which can lead to impaired renal function. Because these conditions can be clinically silent, there is the possibility that painless renal damage could go undetected. Our study underscores the importance of titrating the dose of topiramate to the lowest effective dose to control seizures to lessen the impact of this drug on urinary calcium excretion.\n\nThe potential negative impact on bone growth and mineralization in children during drug topiramate therapy has not been studied. Children who have higher-than-usual losses of calcium due to hypercalciuria may have less skeletal calcium accretion, particularly when the dietary intake of calcium is low and sodium is high.35, 36 Studies of the potential impact of hypercalciuria on children’s bone development during topiramate are needed.\n\nLimitations of our study include serum electrolytes and UCa/Cr ratios in only 23 of 40 patients before the initiation of topiramate therapy. In addition, the follow-up urinary data were incomplete at some of the 6-month intervals, making it more difficult to establish a more significant relationship of sustained topiramate therapy on urinary calcium excretion.\n\nBefore starting topiramate, we recommend baseline evaluation with a urinalysis, UCa/Cr ratio, and serum electrolytes. It also may be useful to measure urinary citrate/creatinine ratio, but this recommendation must await confirmation by additional longitudinal studies in children treated with topiramate. All children, regardless of their initial levels, should have serum electrolytes and UCa/Cr followed at 6-month intervals. For those children found to have baseline hypercalciuria, as defined as a calcium/creatinine ratio >0.21 we recommend renal ultrasounds at the initiation of topiramate and every 6 months to a year thereafter. Renal ultrasonography is safe and inexpensive, and it is preferable to standard plain film radiography for early detection of nephrocalcinosis.37 Grading scales for nephrocalcinosis are available to enhance intra- and interobserver reliability.38 Although computed tomography scans are more sensitive than ultrasonography in detecting nephrocalcinosis, the increased cost and radiation exposure are not justified and await further studies in children on topiramate therapy.\n\nFor those children who have hypercalciuria either at baseline or while on topiramate drug therapy, and for those children who develop decreased serum HCO3 levels, potassium citrate therapy may be useful to prevent nephrolithiasis or nephrocalcinosis. By providing anionic substrates that bind calcium ions, potassium citrate can prevent urinary calcium phosphate and oxalate stone formation by increasing urinary citrate; however, it also alkalinizes the urine, making it more conducive to calcium phosphate crystallization. Potassium citrate, instead of sodium citrate, is the preferred preparation, because increased sodium intake in the medication could lead to increases in urinary calcium excretion. When potassium citrate is dosed at 2 to 3 mEq/kg per day, it effectively decreases the UCa/Cr ratio in children with renal stones.39, 40 Further studies are needed of potassium citrate therapy in children receiving topiramate. Our study is limited by the lack of urinary pH and urinary citrate/creatinine ratios measured longitudinally.\n\nConclusion\nSignificant renal complications occurred in 10% (4/40) of this cohort of pediatric patients on topiramate: both nephrocalcinosis and nephrolithiasis were observed. A significant decrease in serum HCO3levels occur with prolonged topiramate therapy, consistent with its inhibitory effect on carbonic anhydrase. Because topiramate increases urinary calcium excretion, it must be used with care, particularly in the youngest patients whose baseline UCa/Cr ratios are highest.\n\nWe recommend that all children initiating topiramate therapy should have baseline UCa/Cr studies and serum electrolytes, which are measured approximately every 6 months during topiramate therapy. In children younger than 2 years and in children with UCa/Cr above normal for age, renal ultrasonography is indicated at 6-month intervals. Topiramate therapy should be withdrawn in children who develop nephrolithiasis or nephrocalcinosis with a high chance of resolution of these disorders. The long-term effects of these complications during topiramate are unknown.\n\nDisclosure\nAll the authors declared no competing interests.\n\nAcknowledgments\nThe Pediatric Resident Research Fund of Baystate Medical Center Children’s Hospital was the sole source of financial support for this project. We thank Debra Bibeau and Cheyenne Ferro for typing our manuscript. We are indebted to Debra Slattery, RN, for invaluable assistance in identifying patients for this study. Finally, we thank Robert Gillespie, MD, for assistance with age-normal renal data.\n==== Refs\nReferences\n1 Blumkin L. Lerman-Sagie T. Houri T. Pediatric refractory partial status epilepticus responsive to topiramate J Child Neurol 20 2005 239 241 15832617 \n2 Glauser T.A. Clark P.O. McGee K. Long-term response to topiramate in patients with West syndrome Epilepsia 41 Suppl 1 2000 S91 S94 10768309 \n3 Grosso S. Galimberti D. Farnetani M.A. Efficacy and safety of topiramate in infants according to epilepsy syndromes Seizure 14 2005 183 189 15797353 \n4 Arroyo S. Dodson W.E. Privitera M.D. Randomized dose-controlled study of topiramate as first-line therapy in epilepsy Acta Neurol Scand 112 2005 214 222 16146489 \n5 Shorvon S.D. Safety of topiramate: adverse events and relationships to dosing Epilepsia 37 Suppl 2 1996 S18 S22 8641242 \n6 Shields W.D. Wu S.C. Safety of topiramate (TPM) in children with epilepsy Epilepsia 40 1999 126 \n7 Mahmoud A.A. Rizk T. El-Bakri N.K. Incidence of kidney stones with topiramate treatment in pediatric patients Epilepsia 52 2011 1890 1893 21883178 \n8 Corbin Bush N. Twonbley K. Ahn J. Prevalence and spot urine risk factors for renal stones in children taking topiramate J Pediatr Urol 9 2013 884 889 23375465 \n9 Goyal M. Grossberg R.I. O’Riordan M.A. Urolithiasis with topiramate in nonambulatory children and young adults Pediatr Neurol 40 2008 289 294 \n10 Privitera M.D. Topiramate: a new antiepileptic drug Ann Pharmacother 31 1997 1164 1173 9337443 \n11 Dodgson S.J. Shank R.P. Maryanoff B.E. Topiramate as an inhibitor of carbonic anhydrase isoenzymes Epilepsia 41 Suppl 1 2000 S35 S39 \n12 Montenegro M.A. Guerreiro M.M. Scotoni A.E. Predisposition to metabolic acidosis induced by topiramate Arq Neuropsiquiatr 58 2000 1021 1024 11105067 \n13 Mirza N. Marson A.G. Pirmohamed M. Effect of topiramate on acid-base balance: extent, mechanism and effects Br J Clin Pharmacol 68 2009 655 661 19916989 \n14 Mirza N.S. Alfirevic A. Jorgensen A. Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors Pharmacogenet Genomics 21 2011 297 302 21278619 \n15 Sacré A. Jouret F. Manicourt D. Topiramate induces type 3 renal tubular acidosis by inhibiting renal carbonic anhydrase Nephrol Dial Transplant 21 2006 2995 2996 16735391 \n16 Akcay T. Konukoglu D. Celik C. Hypocitraturia in patients with urolithiasis Arch Dis Child 74 1996 350 351 8669940 \n17 Tekin A. Tekgul A. Atsu N. A study of the etiology of idiopathic calcium urolithiasis in children: hypocitruria is the most important risk factor J Urol 164 2000 162 165 10840454 \n18 Lamb E.J. Stevens P.E. Nashef L. Topiramate increases biochemical risk of nephrolithiasis Ann Clin Biochem 41 2004 166 169 15025812 \n19 Welch B.J. Graybeal D. Moe O.W. Biochemical and stone-risk profiles with topiramate treatment Am J Kidney Dis 48 2006 555 563 16997051 \n20 Stafstrom C.E. Gilmore H.E. Kurtin P.S. Nephrocalcinosis complicating medical treatment of posthemorrhagic hydrocephalus Pediatr Neurol 8 1992 179 182 1622512 \n21 Kossoff E.H. Pyzik P.L. Furth S.L. Kidney stones, carbonic anhydrase inhibitors, and the ketogenic diet Epilepsia 43 2002 1168 1171 12366731 \n22 Schell-Feith E.A. Holscher H.C. Zonderland H.M. Ultrasonographic features of nephrocalcinosis in preterm neonates Br J Radiol 73 2000 1185 1191 11144796 \n23 Sargent J.D. Stukel T.A. Kresel J. Normal values for random urinary calcium to creatinine ratios in infancy J Pediatr 123 1993 393 397 8355114 \n24 So N.P. Osorio A.V. Simon S.D. Normal urinary calcium/creatinine ratios in African-American and Caucasian children Pediatr Nephrol 16 2001 133 139 11261680 \n25 Stapleton F.B. Roy S. Noe N. Hypercalciuria in children with hematuria N Engl J Med 310 1984 1345 1348 6717506 \n26 Kalia A. Travis L.B. Brouhard B.H. The association of idiopathic hypercalciuria and asymptomatic gross hematuria in children J Pediatr 5 1981 716 719 \n27 Stapleton F.B. Idiopathic hypercalciuria: association with isolated hematuria and risk for urolithiasis in children Kidney Int 37 1990 807 811 2407891 \n28 Vachvanichsanong P. Malagon M. Moore E.S. Recurrent abdominal and flank pain in children with idiopathic hypercalciuria Acta Paediatr 6 2001 643 648 \n29 Biyikli N.K. Alpay H. Guran T. Hypercalciuria and recurrent urinary tract infections:incidence and symptoms in children over 5 years of age Pediatr Nephrol 10 2005 1435 1438 \n30 Dixon W.J. BMDP 5V/Dynamic 1993 UCLA Press Los Angeles, CA \n31 Jennrich R.I. Robinson S.M. A Newton-Raphson algorithm for maximum likelihood factor analysis Psychometrika 34 1969 111 123 \n32 Wald A. Tests of statistical hypotheses concerning several parameters when the number of observations is large Trans Am Math Soc 54 1943 426 482 \n33 Ezzedeen F. Adelman R.D. Ahlfors C.E. Renal calcification in preterm infants: pathophysiology and long-term sequelae J Pediatr 113 1988 532 539 3045282 \n34 Jones C.A. King S. Shaw N.H. Renal calcification in preterm infants: follow up at 4–5 years Arch Dis Child 76 1997 185 189 \n35 Matkovic V. Ilich J.Z. Andon M.B. Urinary calcium, sodium, and bone mass of young females Am J Clin Nutr 62 1995 417 425 7625351 \n36 Asplin J.R. Donahue S. Kinder J. Urine calcium excretion predicts bone loss in idiopathic hypercalciuria Int Society Nephrol 70 2006 1463 1467 \n37 Alon U. Brewer W.H. Chan J.C. Nephrocalcinosis: detection by ultrasonography Pediatrics 71 1983 970 973 6856410 \n38 Dick P.T. Shuckett B.M. Tang B. Observer reliability in grading nephrocalcinosis on ultrasound examinations in children Pediatr Radiol 29 1999 68 72 9880623 \n39 Osorio A.V. Alon U.S. The relationship between urinary calcium, sodium, and potassium excretion and the role of potassium in treating idiopathic hypercalciuria Pediatrics 100 1997 675 681 9310524 \n40 Tekin A. Tekgul S. Atsu N. Oral potassium citrate treatment for idiopathic hypocitruria in children with calcium urolithiasis J Urol 168 2002 2572 2574 12441986\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "3(3)",
"journal": "Kidney international reports",
"keywords": "hypercalciuria; nephrocalcinosis; nephrolithiasis; topiramate",
"medline_ta": "Kidney Int Rep",
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"nlm_unique_id": "101684752",
"other_id": null,
"pages": "684-690",
"pmc": null,
"pmid": "29854977",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "8641242;3045282;19916989;16146489;12366731;15832617;11261680;10768298;21883178;11144796;9310524;11440097;2407891;12441986;16941029;6717506;1622512;8355114;16047226;10768309;23375465;11105067;19302942;15025812;7299544;9880623;10840454;15797353;6856410;16735391;9337443;16997051;7625351;9175949;21278619;8669940",
"title": "Nephrolithiasis and Nephrocalcinosis From Topiramate Therapy in Children With Epilepsy.",
"title_normalized": "nephrolithiasis and nephrocalcinosis from topiramate therapy in children with epilepsy"
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"abstract": "Primary neuroendocrine tumour of the breast is a rare entity that first appeared in the 2003 World Health Organisation (WHO) classification of breast tumours. The data currently available on its prognosis are contradictory, although it seems clear that histological varieties such as small cell neuroendocrine carcinoma have a worse prognosis, due to their low degree of differentiation. The treatment of choice is surgery, and the indications for chemotherapy or radiotherapy do not differ greatly from those used for other breast tumours. It is crucial to underline the difficulty of establishing treatment protocols due to the low incidence of this histological type.",
"affiliations": "Clinical Management Unit, Gynaecology and Obstetrics, Hospital Universitario Virgen Macarena, Sevilla 41008, Spain.;Clinical Management Unit, Gynaecology and Obstetrics, Hospital Universitario Virgen Macarena, Sevilla 41008, Spain.;Pathological Anatomy Service, Hospital Universitario Virgen Macarena, Sevilla 41008, Spain.;Pathological Anatomy Service, Hospital Universitario Virgen Macarena, Sevilla 41008, Spain.;Clinical Management Unit, Gynaecology and Obstetrics, Hospital Universitario Virgen Macarena, Sevilla 41008, Spain.",
"authors": "Tato-Varela|Sara|S|;Albalat-Fernández|Rosa|R|;Pabón-Fernández|Sara|S|;Zarco|Enrique Rodríguez|ER|;Calle-Marcos|Manolo La|ML|",
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"doi": "10.3332/ecancer.2015.607",
"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2015.607can-9-607Case ReportPrimary neuroendocrine tumour of the breast: a case report and review of the literature Tato-Varela Sara 1Albalat-Fernández Rosa 1Pabón-Fernández Sara 2Zarco Enrique Rodríguez 2Calle-Marcos Manolo La 11 Clinical Management Unit, Gynaecology and Obstetrics, Hospital Universitario Virgen Macarena, Sevilla 41008, Spain2 Pathological Anatomy Service, Hospital Universitario Virgen Macarena, Sevilla 41008, SpainCorrespondence to: Sara Tato-Varela. s.tato.varela@gmail.com2015 22 12 2015 9 60704 9 2015 © the authors; licensee ecancermedicalscience.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary neuroendocrine tumour of the breast is a rare entity that first appeared in the 2003 World Health Organisation (WHO) classification of breast tumours. The data currently available on its prognosis are contradictory, although it seems clear that histological varieties such as small cell neuroendocrine carcinoma have a worse prognosis, due to their low degree of differentiation. The treatment of choice is surgery, and the indications for chemotherapy or radiotherapy do not differ greatly from those used for other breast tumours. It is crucial to underline the difficulty of establishing treatment protocols due to the low incidence of this histological type.\n\nneuroendocrine carcinomaendocrine carcinomainvasive carcinomabreast\n==== Body\nIntroduction\nMalignant neuroendocrine tumours of the breast are infrequently occurring growths that account for less than 0.1% of all breast cancers and less than 1% of all neuroendocrine tumours [1]. It is more common for this kind of tumour to originate in the gastrointestinal tract or in the bronchopulmonary system, where the global prevalence is one to two cases per 100,000 people [2]. Global survival rates for neuroendocrine breast cancers stand at 80% after five years, depending in each case on the histological grade and the anatomo-clinical stage [3]. The prognosis improves in cases of primary neuroendocrine tumours that are small in size, have no axillary involvement, and where hormonal receptors are positive [4]. Below, we present a clinical case study of a neuroendocrine breast cancer that began with axillary metastasis, together with a review of the literature related to this infrequent histological type.\n\nClinical case study\nIn 2013, the patient, a 62-year-old woman, consulted her primary care physician regarding a painful axillary lymph node that had recently appeared. She had no medical history of interest other than a laparoscopic cholecystectomy and grade 1 obesity. Palpation identified a 2 cm nodule in the inferior outer quadrant of the left breast and a 3 cm nodule in the ipsilateral axilla. The patient underwent a mammogram which showed increased trabeculation in the upper quadrants and irregular densities in the axillary region. The subsequent ultrasound showed a 3 cm irregular lesion in the inferior outer quadrant of the left breast (axillary region), which had multiple satellite lymphadenopathies, the largest of which was 2 cm. With a diagnosis highly suggestive of malignancy (BIRADS V), the patient underwent a core needle biopsy (CNB) on the breast nodule and an axillary fine-needle aspiration biopsy (FNAB). The breast CNB yielded the diagnosis of invasive pleomorphic carcinoma (Figure 1) with positive hormonal receptors (oestrogens 100% and progesterone 80%, Ki67 70%, HER-2 positive (3+) (Figure 2), CK19 positive, E-cadherin negative (Figure 3), and P63 negative. The positivity of synaptophysin (Figure 4) suggested that the tumour was neuroendocrine in origin. The axillary FNAB showed metastasis of the carcinoma.\n\nAfter taking her case to committee for study, the decision was made to start treatment with adjuvant chemotherapy and thereafter to consider surgery based on the outcome. Staging image tests were carried out on the breast lesion along with implantation of metal markers. Nuclear magnetic resonance imaging (NMRI) showed involvement of the pectoral fascia, 2 cm in length while computerised tomography (CT) showed the presence of suspicious supraclavicular adenopathies of also 2 cm. The definitive staging was T2 N+ M0.\n\nA month after diagnosis, the patient began chemotherapy treatment involving docetaxel, trastuzumab, and carboplatin. The decision was made to administer six cycles of treatment, one every 21 days. The first cycle involved 80 mg/m2 of docetaxel, 8 mg/kg of trastuzumab, and 6 UI of carboplatin, while those that followed involved lower doses (60 mg/m2 of docetaxel, 6 mg/kg of trastuzumab, and 4 UI of carboplatin). The patient required the administration of granulocyte colony stimulating factor and presented a good tolerance of the chemotherapy, experiencing only light diarrhoea after the first three cycles. The breast examination after completion of the six cycles of chemotherapy showed a notable reduction in the previously described lesions, a finding that was confirmed via NMRI, which showed a 10 mm lesion of the left breast and a 12 mm ipsilateral axillary lesion with no surrounding adenopathy.\n\nThe patient underwent surgery six months after the initial diagnosis, when a left mastectomy was performed along with an ipsilateral axillary lymphadenectomy. There were no postoperative incidents and pathological anatomy reported the absence of residual neoplasia (grade V on the Miller– Payne scale) and fibrosis. After surgery, the decision was made to administer adjuvant chemotherapy treatment (trastuzumab 6 mg/kg every 21 days for a year), hormone therapy with letrozole, and radiotherapy (40.05 Gray (Gy)) on left breast volume, with fractionation of 2.67 Gy/fraction and irradiation of the left supraclavicular region. The level III axillary treated with radiotherapy up to 40.14 Gy with fractionation of 2.23/fraction). The patient tolerated the adjuvant treatment adequately, presenting with just slight anteroseptal hypokinesis at the cardiac level which did not require treatment, and a grade 1 radiodermatitis in skin folds. Of note at the time of writing this article, she was asymptomatic.\n\nDiscussion\nNeuroendocrine breast tumours are extremely rare and may be both primary lesions and metastatic lesions. They derive from neuroendocrine cells that are present throughout the body, the most frequent primary localisations being the bronchopulmonary and digestive tracts (especially the small intestine) [5]. In 2003, the WHO first recognised the breast localisation as a differentiated entity that presents morphological tumour characteristics similar to those of neuroendocrine tumours in other localisations, with expression of neuroendocrine markers in more than 50% of the cell population [6]. Although it can be very difficult, it is vital to differentiate between the primary or metastatic origin of the neuroendocrine tumour in the breast as each requires a different therapeutic approach [5]. In general metastases to the breast are frequent tumours, accounting for 2% of breast tumours, whose most common localisations are melanoma in adults and rhabdomyosarcoma in children. In the case of neuroendocrine tumours, the most frequent primary localisations are the ilium followed by the appendix, the duodenum, the pancreas, and the lung [2]. Primary neuroendocrine cancer of the breast generally presents in mature women (between the sixth and seventh decade of life) and its incidence increases with age; this is not the case for metastatic neuroendocrine tumours, which appear an average of ten years before the primary tumours [7].\n\nThe diagnosis of a primary neuroendocrine tumour is always a diagnosis of exclusion [3], and it may be carried out as long as there is a component of ductal carcinoma in situ in the sample, and that the existence of tumours in other localisations has been ruled out [2]. The differentiation between a primary and metastatic neuroendocrine cancer of the breast is impossible to achieve based solely on mammogram or breast ultrasound [2]. Multiple imaging tests may be used to help localise the primary tumour. CT is the most commonly used test, since it enables a broad field of vision (pelvis, abdomen, and thorax) as well as a suitable level of detail of the vascular anatomy, although it has little sensitivity when it comes to detecting small hepatic lesions. NMRI is a powerful tool for the evaluation of neuroendocrine tumours, especially for visualising hepatic involvement. Acquisitions of multi-sequence images associated with the introduction of hepatocyte-specific contrast agent such as gadoxetic acid make it possible to measure lesions with a high level of precision. Ultrasound may be used both to guide the biopsy and diagnose hepatic lesions as well as to rule out secondary cardiac involvement in carcinoid syndrome prior to performing an operation. Endoscopy makes it possible to evaluate gastric, ileal, colonic, and rectal lesions directly. Functional imaging tests such as OctreoScan among others may prove useful in the evaluation of metastatic disease, or to decide the extent of the resection to be carried out prior to the operation. Moreover, multiple urinary and blood biomarkers have been described, such as chromogranin-A and pancreastatin, whose use as a complement to imaging tests can be useful when it comes to determining the localisation of the primary cancer, although the definitive diagnosis will always be carried out after the histological study of the sample or biopsy is obtained [8].\n\nNeuroendocrine tumours of the breast lack a specific clinic [9]: for the most part, patients consult physicians about a breast nodule, either in isolation or in association with other symptoms, such as a well-defined cutaneous erythematous or purple plaque [3]. Carcinoid syndrome (including diarrhoea, flushing, and bronchospasm) can appear in 5–10% of patients with a neuroendocrine tumour [2].\n\nRadiological diagnostics do not present any distinctive characteristics [9], Although frequent occurrence of masses with speculated or lobulated margins have been described in mammograms as well as microlobulated and homogeneously hypoechoic masses in breast ultrasound [10]. It is worth highlighting that in none of the cases described to date has posterior acoustic shadowing or a cystic component been detected in the ultrasound, although [11] none of the previously described characteristics represent a specific finding. On carrying out a biopsy, we must be very careful with regard to hormonally active tumours as we may trigger a carcinoid crisis with the puncture [2].\n\nGiven the low incidence of neuroendocrine breast cancer, the optimal treatment strategy remains controversial [12]. It seems clear that the principal treatment is surgery [1] and that the primary breast tumours must be dealt with in a similar way to ductal carcinoma of the breast. In the case of metastatic tumours, a lumpectomy is recommended to reduce the size of the tumour mass, avoiding mastectomy or axillary dissection [5]. The benefits of adjuvant therapy have not been demonstrated in the literature because of absence of clinical trials and the low incidence of the disease [7]. Inspite of this, it is administered following the same criteria as that for other breast tumours [3].\n\nOnce the sample has been removed, the microscopic examination shows alveolar structures or solid sheets of cells with a tendency to produce peripheral palisades [13]. According to the WHO classification, the diagnosis requires immunohistochemical expression of synaptophysin or chromogranin in more than 50% of the cells [4]. Positivity to hormonal receptors is a practically constant characteristic, whereas the expression of c-erbB-2 is less frequent, appearing in two of the 22 cases reported to date [11]. Expression of the oncoprotein HER-2 not only plays an important role in the prognosis and the nodal extension of the tumour, but a study carried out by Horiguchi and colleagues demonstrates that 80% of tumours with positive cytoplasmic staining for this marker also expressed chromogranin A or specific neuronal enolase–in other words they display neuroendocrine differentiation [14]. At the cytogenetic level, it seems that neuroendocrine tumours of the breast share more similarities with primary breast tumours than that with neuroendocrine tumours in other localisations, although they do share cytogenetic abnormalities with them, such as trisomy 7 and 12 [15]. Depending on the degree of differentiation and cellular morphology, neuroendocrine cancer of the breast may be classified into one of the following histopathological subtypes: solid carcinoma, oat cell, large cell [12], and atypical [3].\n\nThe prognosis for neuroendocrine cancer of the breast is controversial, although it is a slow-developing tumour [3] and it seems that global disease-free survival is greater in patients with primary neuroendocrine tumours of the breast than in patients with other breast tumours or other neuroendocrine tumours [12]. Its development essentially depends on the anatomo-clinical stage and the histological grade [3] (excepting small cell or oat cell carcinomas, 45% of neuroendocrine tumours of the breast are well differentiated, and 40% are moderately differentiated [12]). Other prognostic factors include mucinous differentiation, expression of hormonal receptors [4], HER-2 positivity [12], patient age, tumour markers, and tumour secretion [3].\n\nConclusion\nPrimary neuroendocrine tumours of the breast are infrequent tumours that appear in women aged 60–70 years. Their diagnosis is complex as they lack defining clinical and radiological characteristics and also given the fact that their low incidence makes it impossible to establish an optimal treatment protocol. In general, it is recommended to follow a treatment similar to that used for ductal carcinoma of the breast. Diagnosis is achieved via staining with neuroendocrine markers. Although survival depends on factors such as tumour differentiation and stage, it is found to be in excess of 80% after five years.\n\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\n\nAuthors’ contributions\nAll the authors participated in the bibliography search. STV was in charge of producing the text. All the authors approved the final version of the document.\n\nFigure 1. Tumour staining with hematoxylin and eosin.\nFigure 2. Positive tumour staining for HER-2 (3+).\nFigure 3. Absence of E-cadherin staining observed.\nFigure 4. Positive staining for synaptophysin in more than 50% of the tissue permits the diagnosis of a neuroendocrine tumour.\n==== Refs\nReferences\n1. El Fatemi H Carcinome neuroendocrine du sein: à propos d’un cas et revue de la littérature Pan Afr Med J 2012 13 40 1 7 \n2. Amin AL Kong AL Metastatic neuroendocrine tumor found on screening mammogram WMJ 2011 110 3 140 3 21749000 \n3. Laabadi K Tumeur neuroendocrine mammaire primitive: à propos d’un cas rare Pan Afr Med J 2013 16 92 1 6 10.11604/pamj.2013.16.92.2531 24570772 \n4. Abbasi NZ Solid neuroendocrine carcinoma of the breast J Coll Physicians Surg Pak 2013 23 10 820 2 24169396 \n5. Richter-Ehrenstein C Solid neuroendocrine carcinomas of the breast: metastases or primary tumors? Breast Cancer Res Treat 2010 124 2 413 7 10.1007/s10549-010-1178-3 20872069 \n6. Stita W Primary solid neuroendocrine carcinoma of the breast Can J Surg 2009 52 6 289 90 \n7. Graça S Neuroendocrine breast cancer BMJ Case Reports 2012 10 1136 \n8. Vinik AI Chaya C Clinical presentation and diagnosis of neuroendocrine tumors Hematol Oncol Clin N Am 2015 in press \n9. Fujimoto Y A case of solid neuroendocrine carcinoma of the breast in a 40-year-old woman Breast Cancer 2007 14 2 250 3 10.2325/jbcs.889 17485914 \n10. Chang ED Primary neuroendocrine tumor of the breast: imaging features Korean J Radiol 2013 14 3 395 9 10.3348/kjr.2013.14.3.395 23690703 \n11. Yoon YS Primary neuroendocrine carcinoma of the breast: radiologic and pathologic correlation Clinical Imaging 2014 38 5 734 8 10.1016/j.clinimag.2014.05.009 25052497 \n12. Yavas G HER-2 positive primary solid neuroendocrine carcinoma of the breast: a case report and review of the literature Breast Cancer 2015 22 4 432 6 10.1007/s12282-012-0382-x 22711316 \n13. Akhtar K Primary neuroendocrine carcinoma of the breast Indian J Pathol Microbiol 2009 52 1 71 3 10.4103/0377-4929.44970 19136787 \n14. Horiguchi S HER-2/neu cytoplasmic staining is correlated with neuroendocrine differentiation in breast carcinoma J Med Dent Sci 2010 57 2 155 63 21073134 \n15. Xiang DB Molecular cytogenetic characterization of mammary neuroendocrine carcinoma Human Pathol 45 9 1951 6 25074542\n\n",
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"title": "Primary neuroendocrine tumour of the breast: a case report and review of the literature.",
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"abstract": "Psychiatric symptoms are historically thought a relative contraindication to DBS for advanced Parkinson's disease (PD). However, in the case of drug-induced mental illness, DBS may provide an acceptable alternative for the treatment of motor symptoms. This allows reduction of pharmacological dopaminergic therapy that might otherwise cause negative psychiatric consequences. For example, DBS is increasingly used to ameliorate specific complications of PD treatment, such as impulse control disorders. We present a series of 3 cases of young male patients who developed Othello syndrome (OS) during treatment with dopamine agonists. In each case, the OS resolved with withdrawal of the offending drug. Subsequent treatment with bilateral STN DBS improved motor symptoms and allowed reduction in their dopaminergic drug regimen. We therefore propose that drug-induced psychopathology may be an indication (rather than a contraindication) for DBS in selected cases.",
"affiliations": "Movement Disorders Unit Department of Neurology Westmead Hospital Sydney Australia.;Westmead Clinical School University of Sydney Sydney Australia.;Movement Disorders Unit Department of Neurology Westmead Hospital Sydney Australia.;Prince of Wales Hospital Sydney Australia.;Department of Medical Psychology Westmead Hospital Sydney Australia.;Westmead Clinical School University of Sydney Sydney Australia.;Movement Disorders Unit Department of Neurology Westmead Hospital Sydney Australia.;Movement Disorders Unit Department of Neurology Westmead Hospital Sydney Australia.",
"authors": "Adam|Robert J|RJ|;McLeod|Robert|R|;Ha|Ainhi D|AD|;Colebatch|James G|JG|;Menzies|Graham|G|;de Moore|Gregory|G|;Mahant|Neil|N|;Fung|Victor S C|VSC|",
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"title": "Resolution of Othello Syndrome After Subthalamic Nucleus Deep Brain Stimulation in 3 Patients with Parkinson's Disease.",
"title_normalized": "resolution of othello syndrome after subthalamic nucleus deep brain stimulation in 3 patients with parkinson s disease"
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"abstract": "Severe toxicity from ingestions of oral sustained-release potassium is rare. While acute hyperkalaemia requires urgent intervention given the risk of cardiac toxicity, there is a lack of clinical consensus on optimal management. The aim of this study was to characterise the clinical manifestations of acute potassium overdose and its management approach.\nThis is a retrospective case series of patients presenting following oral potassium overdose of ≥6000mg between January 2009 and December 2020 in Queensland, Australia as recorded in the state's Poisons Information Centre database and a tertiary Clinical Toxicology Unit database. Patients were identified from prospective databases maintained by both units and data were extracted from these in addition to medical records.\nThirteen presentations in eleven patients occurred in the twelve-year period. The median age was 35 years (range 14-55 years). The median dose ingested was 6.4 mmol/kg (range 0.9-30.8 mmol/kg). Severe hyperkalaemia >7mmol/L occurred in five patients, four with ingestions ≥60,000mg. All patients with hyperkalaemia received multiple modes of intracellular potassium shifting therapy. Four patients had endoscopic removal of pharmacobezoars. One also underwent whole bowel irrigation. Three presentations were managed with haemodialysis. All patients were discharged home with a median length of stay of 20 h.\nAggressive medical therapy to shift potassium into cells appears to be the mainstay of treatment in patients with normal renal function. Early decontamination may limit peak potassium concentrations. It is unclear if haemodialysis provides significant additional benefit in patients with normal renal function.",
"affiliations": "Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Australia.;Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Australia.;Queensland Poisons Information Centre, Queensland Children's Hospital, South Brisbane, Australia.;Clinical Toxicology Unit, Princess Alexandra Hospital, Brisbane, Australia.",
"authors": "Madan|Arushi|A|0000-0002-9412-0681;Morris|Christopher|C|0000-0003-4736-5077;Goggin|Anna|A|;Isoardi|Katherine Z|KZ|0000-0002-1176-7923",
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"title": "Oral potassium overdose: a case series.",
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"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a life threatening condition associated with formation of platelet thrombi. Deficiency of ADAM TS 13 with presence of inhibitory anti-ADAM TS 13 Immunoglobulin G antibody is seen in patients with acquired TTP. TTP in patients on interferon therapy for chronic hepatitis C has rarely been reported. Furthermore, successful treatment of an initial episode of acute refractory acquired TTP, in a patient of chronic hepatitis C during interferon therapy with Rituximab, has not been previously reported. Here we describe a case of acute refractory acquired TTP associated with pegylated interferon therapy for her chronic hepatitis C infection. Initially refractory to plasmapheresis and steroids, she was successfully treated with Rituximab and plasmaphersis without any evidence of reactivation of hepatitis.",
"affiliations": "Division of Hematology/Oncology, Brookdale University Hospital Medical Center , Brooklyn, NY, USA.",
"authors": "Poddar|Nishant|N|;Wang|Jen C|JC|",
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"medline_ta": "Hematol Rep",
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"title": "Thrombotic thrombocytopenic purpura in a patient with interferon treated hepatitis C successfully treated with rituximab.",
"title_normalized": "thrombotic thrombocytopenic purpura in a patient with interferon treated hepatitis c successfully treated with rituximab"
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"abstract": "Induction chemotherapy with docetaxel improved outcome in advanced head and neck squamous cell carcinoma (HNSCC) patients, but docetaxel was not recommended in liver dysfunction patients for treatment toxicities. Severe neutropenic events (SNE) including severe neutropenia (SN) and febrile neutropenia (FN) still developed in these patients with normal serum transaminases. Ultrasonography (US) fibrotic score represented degree of hepatic parenchymal damage and showed good correlation to fibrotic changes histologically. This study aims to evaluate the association of US fibrotic score with docetaxel treatment-related SNE in advanced HNSCC patients with normal serum transaminases. Between 1 January 2011 and 31 December 2013, a total of 47 advanced HNSCC patients treated with induction docetaxel were enrolled. The clinical features were collected to assess predictive factors for SNE. The patients were divided into two groups by the US fibrotic score with a cutoff value of 7. The Mann-Whitney U test and logistic regression method were used for the risk factor analysis. The background, treatment, and response were similar in both groups except for lower lymphocyte and platelet count in patients with higher US score. Twenty-seven patients (51 %) developed grade 3/4 neutropenia, and more SNE developed in patients with US score ≧7. In multivariate analysis, only US score ≥7 was independent predictive factor for developing SN (hazard ratio 7.71, p = 0.043) and FN (hazard ratio 20.95, p = 0.008). US score ≥7 is an independent risk factor for SNE in advanced HNSCC patients treated with induction docetaxel. US score could be used for risk prediction of docetaxel-related SNE.",
"affiliations": "Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.;Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi, Taiwan.;Biostatistics Unit, Clinical Trial Centre and Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.;Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Chiayi, Taiwan.;Department of Hematology and Oncology, Chang Gung Memorial Hospital, Linkou, Taiwan.;Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.;Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.;Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.;Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan. q12014@adm.cgmh.org.tw.",
"authors": "Wang|Ting-Yao|TY|;Chen|Wei-Ming|WM|;Yang|Lan-Yan|LY|;Chen|Chao-Yu|CY|;Chou|Wen-Chi|WC|;Chen|Yi-Yang|YY|;Chen|Chih-Cheng|CC|;Lee|Kuan-Der|KD|;Lu|Chang-Hsien|CH|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-016-3318-8",
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"issue": "24(11)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Docetaxel; Neutropenia; Risk factors; Ultrasonography",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077143:Docetaxel; D005260:Female; D005334:Fever; D006258:Head and Neck Neoplasms; D006801:Humans; D060828:Induction Chemotherapy; D008099:Liver; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D012307:Risk Factors; D043823:Taxoids; D014463:Ultrasonography",
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"references": "24996830;16020491;12640529;19018756;8514896;18509327;8640817;9440742;16765145;7718284;20855405;21266808;20700740;10914699;19318632;17960012;17960013;8875345;23602134;19064644;18248309;25980322;20811894;20032123;1269879;15552776;25196861;24875653;23188068;15637530;22095245;11392450;17595656;15900997;16544143;12598352;21296855;22126844;26464843;18183036;16275937",
"title": "Score of liver ultrasonography predicts treatment-related severe neutropenia and neutropenic fever in induction chemotherapy with docetaxel for locally advanced head and neck cancer patients with normal serum transamines.",
"title_normalized": "score of liver ultrasonography predicts treatment related severe neutropenia and neutropenic fever in induction chemotherapy with docetaxel for locally advanced head and neck cancer patients with normal serum transamines"
} | [
{
"companynumb": "TW-PFIZER INC-2017450563",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Atraumatic acute carpal tunnel syndrome is a rare type of median nerve neuropathy caused by etiologies that increase compartment pressure in the carpal tunnel. This report describes a patient with flexor tendon abrasion as an unusual complication of distal radioulnar joint arthritis. This abrasion caused a hematoma to form in the carpal tunnel during anticoagulant treatment with apixaban, resulting in recurrent acute carpal tunnel syndrome.",
"affiliations": "Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu, 501-1194, Japan. s_komura@gifu-u.ac.jp.;Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu, 501-1194, Japan.;Department of Orthopaedic Surgery, Kizawa Memorial Hospital, Gifu, Japan.;Department of Orthopaedic Surgery, Kizawa Memorial Hospital, Gifu, Japan.;Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu, 501-1194, Japan.",
"authors": "Komura|Shingo|S|http://orcid.org/0000-0002-7639-7484;Hirakawa|Akihiro|A|;Masuda|Takahiro|T|;Ito|Yoshiki|Y|;Akiyama|Haruhiko|H|",
"chemical_list": "D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00402-017-2730-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0936-8051",
"issue": "137(8)",
"journal": "Archives of orthopaedic and trauma surgery",
"keywords": "Acute carpal tunnel syndrome; Anticoagulant treatment; Complication; Distal radioulnar joint arthritis; Hematoma",
"medline_ta": "Arch Orthop Trauma Surg",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001168:Arthritis; D002349:Carpal Tunnel Syndrome; D006406:Hematoma; D006801:Humans; D008297:Male; D008475:Median Nerve; D011720:Pyrazoles; D011728:Pyridones; D014955:Wrist Joint",
"nlm_unique_id": "9011043",
"other_id": null,
"pages": "1161-1164",
"pmc": null,
"pmid": "28608274",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent atraumatic acute carpal tunnel syndrome due to hematoma caused by distal radioulnar joint arthritis during anticoagulant treatment with apixaban.",
"title_normalized": "recurrent atraumatic acute carpal tunnel syndrome due to hematoma caused by distal radioulnar joint arthritis during anticoagulant treatment with apixaban"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1056236",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CILOSTAZOL"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo describe the utility of microperimetry testing in the diagnosis of a bilateral occipital stroke.\n\n\nMETHODS\nRetrospective case report.\n\n\nRESULTS\nA 57-year-old male with hypertension presented with complaints of bilateral blurred central vision and bilateral hypertensive retinopathy with cotton-wool spots. Automated perimetry demonstrated a central scotoma in both eyes that did not respect the vertical midline; however, microperimetry testing revealed a bilateral homonymous hemianopia that suggested cerebrovascular disease which was subsequently confirmed with magnetic resonance imaging.\n\n\nCONCLUSIONS\nIn cases of unexplained central visual loss, microperimetry testing may be a useful ancillary test for the diagnosis of cerebrovascular disease.",
"affiliations": "Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, Pennsylvania.",
"authors": "Kasi|Sundeep K|SK|;Shahlaee|Abtin|A|;Adam|Murtaza K|MK|;Ehmann|David S|DS|;Sivalingam|Arunan|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000403",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "11 Suppl 1()",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D006801:Humans; D006973:Hypertension; D008266:Macula Lutea; D008297:Male; D008875:Middle Aged; D012607:Scotoma; D020521:Stroke; D058609:Visual Field Tests",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "S170-S173",
"pmc": null,
"pmid": "28009776",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "BILATERAL OCCIPITAL POLE HYPERTENSIVE STROKE DIAGNOSED WITH MACULAR INTEGRITY ASSESSMENT (MAIA) MICROPERIMETRY.",
"title_normalized": "bilateral occipital pole hypertensive stroke diagnosed with macular integrity assessment maia microperimetry"
} | [
{
"companynumb": "US-ALLERGAN-1816359US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Since the introduction of lenalidomide into induction therapy for multiple myeloma (MM), there have been conflicting reports about its impact on autologous peripheral blood stem cell (PBSC) mobilization. We evaluated the impact of previous lenalidomide exposure in a large cohort of patients with MM undergoing mobilization and collection at a tertiary stem cell transplantation center. We hypothesized that collection of PBSCs is feasible even with a prolonged duration of previous lenalidomide therapy. We examined patients with MM who attempted stem cell mobilization and collection, seen at our center between January 2012 and July 2015. The patients were categorized into 3 groups for analysis: (1) patients with previous receipt of >6 cycles lenalidomide, (2) patients with previous receipt of ≤6 cycles of lenalidomide, and (3) patients without previous lenalidomide exposure. We compared collection yields and days of apheresis among the 3 groups using linear regression analysis. We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 had received >6 cycles of lenalidomide (median, 8 cycles; range, 7 to 25 cycles), 156 had received ≤6 cycles of lenalidomide (median, 4 cycles; range, 1 to 6 cycles), and 106 had received no lenalidomide. Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34+ cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide. In this retrospective analysis of MM patients undergoing autologous PBSC transplantation, we show that the duration of previous lenalidomide exposure does not impact the total number of PBSCs collected or the number of days of apheresis. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response can be safe without impairing the ability to collect PBSCs, and that limiting lenalidomide use before mobilization does not appear warranted in all cases.",
"affiliations": "Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington.;Clinical Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington.;Seattle Cancer Care Alliance, Seattle, Washington; Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington. Electronic address: lholmber@fredhutch.org.",
"authors": "Cowan|Andrew J|AJ|;Stevenson|Philip A|PA|;Green|Damian J|DJ|;Tuazon|Sherilyn|S|;Libby|Edward N|EN|;Kwok|Mary|M|;Lee|Sarah|S|;Coffey|David G|DG|;Gopal|Ajay K|AK|;Holmberg|Leona A|LA|",
"chemical_list": "D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtct.2021.04.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2666-6367",
"issue": "27(8)",
"journal": "Transplantation and cellular therapy",
"keywords": "Apheresis; Lenalidomide; Mobilization; Myeloma",
"medline_ta": "Transplant Cell Ther",
"mesh_terms": "D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma; D000072916:Peripheral Blood Stem Cells; D012189:Retrospective Studies",
"nlm_unique_id": "101774629",
"other_id": null,
"pages": "661.e1-661.e6",
"pmc": null,
"pmid": "33895403",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prolonged Lenalidomide Therapy Does Not Impact Autologous Peripheral Blood Stem Cell Mobilization and Collection in Multiple Myeloma Patients: A Single-Center Retrospective Analysis.",
"title_normalized": "prolonged lenalidomide therapy does not impact autologous peripheral blood stem cell mobilization and collection in multiple myeloma patients a single center retrospective analysis"
} | [
{
"companynumb": "US-AMGEN-USASP2021187631",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Risperidone is commonly prescribed by pediatricians for a variety of behavioral and psychological disorders. We report a boy with autism-spectrum disorder, who developed frequent penile erections after an increase in risperidone dosage for a month. The patient fully recovered 2 days after risperidone discontinuation. This report concerns the youngest case of psychotropic medication-induced sexual disorders, which illustrates the differences in presentation between children and adults. Moreover, this case can serve as evidence that discontinuation should be recommended for the management of drug-induced sexual disorders.",
"affiliations": "Urology Unit, Department of Surgery, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.;Child Development Unit, Department of Pediatrics, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand. Electronic address: ttherd@gmail.com.",
"authors": "Bejrananda|Tanan|T|;Thongseiratch|Therdpong|T|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2018.04.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "118()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D014150:Antipsychotic Agents; D000067877:Autism Spectrum Disorder; D002648:Child; D057915:Drug Substitution; D006801:Humans; D008297:Male; D010410:Penile Erection; D018967:Risperidone; D012735:Sexual Dysfunction, Physiological",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "195-197",
"pmc": null,
"pmid": "29705578",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Frequent Penile Erection in a Boy With Autism-spectrum Disorder: Case Report.",
"title_normalized": "frequent penile erection in a boy with autism spectrum disorder case report"
} | [
{
"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-03134",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drug... |
{
"abstract": "BACKGROUND\nChronic refractory immune thrombocytopenic purpura can be a challenging condition to treat. By definition, the standard first and second line treatments have failed in these patients and modalities such as thrombopoiesis-stimulating agents and more intensive immunosuppressive drugs are therefore used. However, there still remains a subset of patients who continue to be refractory to treatment.\n\n\nMETHODS\nWe present the case of a 30-year-old Hispanic woman with recurrent intracranial bleeds, in whom multiple lines of treatment had failed. She was treated with a combination of bortezomib and rituximab based on previously published data that suggested this therapy effectively blocks all antibody-producing cells. Our patient's platelet counts rapidly improved and subsequently normalized following this treatment.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this case represents the first report of the effective use of bortezomib and rituximab in highly refractory immune thrombocytopenic purpura. We believe further study of this therapy is warranted in this setting.",
"affiliations": "University of Louisville, 529 South Jackson Street, Louisville, Kentucky 40202, USA. n0vina01@louisville.edu.",
"authors": "Vinayek|Namita|N|;Sharma|Vivek|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-19",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-192442882210.1186/1752-1947-8-19Case ReportA combination of bortezomib and rituximab yields a dramatic response in a woman with highly refractory immune thrombocytopenic purpura: a case report Vinayek Namita 1n0vina01@louisville.eduSharma Vivek 1vrshar01@louisville.edu1 University of Louisville, 529 South Jackson Street, Louisville, Kentucky 40202, USA2014 15 1 2014 8 19 19 13 9 2013 2 12 2013 Copyright © 2014 Vinayek and Sharma; licensee BioMed Central Ltd.2014Vinayek and Sharma; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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.Introduction\nChronic refractory immune thrombocytopenic purpura can be a challenging condition to treat. By definition, the standard first and second line treatments have failed in these patients and modalities such as thrombopoiesis-stimulating agents and more intensive immunosuppressive drugs are therefore used. However, there still remains a subset of patients who continue to be refractory to treatment.\n\nCase presentation\nWe present the case of a 30-year-old Hispanic woman with recurrent intracranial bleeds, in whom multiple lines of treatment had failed. She was treated with a combination of bortezomib and rituximab based on previously published data that suggested this therapy effectively blocks all antibody-producing cells. Our patient’s platelet counts rapidly improved and subsequently normalized following this treatment.\n\nConclusion\nTo the best of our knowledge, this case represents the first report of the effective use of bortezomib and rituximab in highly refractory immune thrombocytopenic purpura. We believe further study of this therapy is warranted in this setting.\n\nBortezomibChronic immune thrombocytopenic purpuraRituximab\n==== Body\nIntroduction\nImmune thrombocytopenic purpura (ITP) is characterized by immune-mediated platelet destruction and is often a chronic disease in adults. Although most patients achieve a ‘safe’ platelet count with immunosuppressive therapy or splenectomy, about 5% develop severe, refractory disease, defined as a failure to respond to both splenectomy and rituximab. When such patients become symptomatic with clinically overt bleeding, their management can be quite challenging. Bortezomib is a proteasome inhibitor that functions by inhibiting the ubiquitin-proteasome system, key to cell functioning. Its role in hematological malignancies like multiple myeloma has been well documented. This proteasome-inhibiting property is now being investigated in human autoimmunity [1]. We report the case of a patient with refractory and symptomatic ITP in whom multiple lines of therapy had failed but who responded to a combination of bortezomib and rituximab, with normalization of her platelet count.\n\nCase presentation\nA 30-year-old Hispanic woman with a history of ITP and autoimmune hemolytic anemia for almost 12 years presented with recurrent intracranial bleeds. She had developed chronic refractory disease following the failure of a splenectomy and rituximab therapy shortly after her diagnosis. Her hemoglobin level stayed between 8 and 10g/dL but she had severe thrombocytopenia with platelet counts typically in the range of 5000 to 10,000 cells/mm3. For the first seven years after diagnosis, she had experienced only intermittent minor bleeds, including epistaxis and menorrhagia. However, she then developed her first spontaneous intracranial hemorrhage, which was managed conservatively with platelet transfusions. Following that serious event, over the next four years she was treated with a variety of modalities in an attempt to raise her platelet counts to a safer level, including vincristine, cyclosporine, danazol, eltrombopag, romiplostim and rituximab as indicated in Table 1. She had little to no response to any of these agents, including rituximab, which was used on four different occasions (Table 1).\n\nTable 1 Platelet trends, associated events and treatments given to our patient over 12 years\n\nYear\tPlatelet count (thousand/mm\n3\n)\tTreatment\tEvents\t\n2001\t10\tRho(D) + prednisone\tMenorrhagia\t\n2002\t19 to 160\tSplenectomy\tMenorrhagia\t\n2003\t30 to 150\tRituximab (weekly ×4) + high dose prednisone\t \t\n2004\t15 to 40\tDanazol; rituximab (×2)\t \t\n2005\t13 to 22\tVincristine (weekly ×4)\t \t\n2006\t20 to 30\tObservation\tHysterectomy\t\n2007\t10 to 12\tHigh pulse decadron; rituximab×1; low dose cyclosporine 2.5mg/kg\tIntracranial hemorrhage\t\n2008\t4 to 6\tIntravenous immunoglobulin G; decadron; rituximab (weekly×4)\tRuptured ovarian cyst\t\n2009\t5 to 14\tEltrombopag 50mg to 75mg daily (×3 months)\t \t\n2010\t9 to 12\tObservation\t \t\n2011\t6 to 15\tObservation\t \t\n2012\t4 to 10\tIntravenous immunoglobulin G + prednisone + platelet transfusion\tIntracranial hemorrhage\t\n \t \tRomiplostim 8μg/kg to 10μg/kg\t \t\n2013\t12\tIntravenous immunoglobulin + prednisone + platelet transfusion\tIntracranial hemorrhage\t\nFive years after her initial intracranial hemorrhage, our patient had two more episodes of recurrent intracranial hemorrhage within the span of a year, at which time treatment with more aggressive cytotoxic chemotherapy was considered. A recent publication had reported the successful use of bortezomib in the treatment of a patient with refractory thrombotic thrombocytopenic purpura (TTP) in whom rituximab had been unsuccessful [2]. TTP has similar pathophysiology to ITP in that both disorders are antibody mediated. We therefore surmised that this agent may also have activity in refractory ITP, and treated our patient with bortezomib 1.3mg/m2 subcutaneously twice a week. Six weeks later, her platelet counts still ranged between 11,000 cells/mm3 and 20,000 cells/mm3.\n\nOur patient had received four out of 12 planned doses of bortezomib during this six weeks, primarily due to compliance issues. At this juncture, once-weekly intravenous rituximab (375mg/m2) was added to the regimen. Bortezomib was continued at the same dose twice weekly. Again, because of suboptimal compliance, she only received 10 out of 16 planned doses (Figure 1). There were no dose delays due to toxicity. This strategy was based on previously published data suggesting that these agents may be synergistic and that there may be a population of bortezomib-resistant B-cells that can be eliminated by the addition of rituximab [3,4]. Following this, our patient’s platelet count improved. Over the next three months, after some fluctuations, her platelet count normalized despite cessation of all therapy after six doses of rituximab. By this time, she had received a total of 14 subcutaneous injections of bortezomib (Figure 1). She did develop grade 1 neuropathy during the course of that treatment but otherwise tolerated it well. Her platelet count remained well above 100,000 cells/mm3 with the exception of three counts, one of which was below 40,000 cells/mm3, for 14 weeks of follow-up after the cessation of all therapy (Figure 1).\n\nFigure 1 Trend in platelet counts during treatment. The y-axis depicts platelet counts in thousands/mm3 and the timeline is plotted on the x-axis. The star indicates the time of the intracranial bleed. The dark bar shows the duration of bortezomib treatment and arrows indicate timing of the injections; the lighter bar shows the duration of rituximab treatment with arrows indicating the timing of the treatments.\n\nConclusion\nTo the best of our knowledge, this is the first report of the successful use of a combination of bortezomib and rituximab in a patient with highly refractory ITP. Our experience appears to be in line with the observations of Shortt et al. in the setting of another antibody-mediated disease, refractory TTP [2]. We believe our report strengthens the rationale for further study of this regimen in difficult cases of antibody-mediated autoimmune disorders such as TTP and ITP. It would also be an easier, less toxic alternative to conventional therapies in this setting, particularly with the anticipated availability in the near future of oral proteasome inhibitors that may have a lower risk of neuropathy as compared to bortezomib.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nITP: Immune thrombocytopenia; TTP: Thrombotic thrombocytopenic purpura.\n\nCompeting interests\nThe authors declare they have no competing interests.\n\nAuthors’ contributions\nAll authors analyzed and interpreted the patient data and contributed in writing the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nManuscript submission was funded by the James Graham Brown Cancer Center.\n==== Refs\nFierabracci A Proteasome inhibitors: a new perspective for treating autoimmune diseases Curr Drug Targets 2012 13 13 1665 1675 10.2174/138945012803530053 23092126 \nShortt J Oh DH Opat SS ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura N Engl J Med 2013 368 1 90 92 10.1056/NEJMc1213206 23281998 \nBil J Winiarska M Nowis D Bojarczuk K Dabrowska-Iwanicka A Basak GW Sułek K Jakobisiak M Golab J Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement dependent cytotoxicity Blood 2010 115 18 3745 3755 10.1182/blood-2009-09-244129 20200358 \nVerbrugge SE Al M Assaraf YG Niewerth D van Meerloo J Cloos J van der Veer M Scheffer GL Peters GJ Chan ET Anderl JL Kirk CJ Zweegman S Dijkmans BA Lems WF Scheper RJ de Gruijl TD Jansen G Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors Exp Hematol Oncol 2013 2 1 2 10.1186/2162-3619-2-2 23305345\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "8()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "19",
"pmc": null,
"pmid": "24428822",
"pubdate": "2014-01-15",
"publication_types": "D016428:Journal Article",
"references": "20200358;23092126;23281998;23305345",
"title": "A combination of bortezomib and rituximab yields a dramatic response in a woman with highly refractory immune thrombocytopenic purpura: a case report.",
"title_normalized": "a combination of bortezomib and rituximab yields a dramatic response in a woman with highly refractory immune thrombocytopenic purpura a case report"
} | [
{
"companynumb": "US-ROCHE-1336622",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "We commonly see patients presenting with either portal hypertensive gastropathy (PHG) or radiation gastritis. Radiation-induced hemorrhagic gastritis is an unusual lethal complication postradiation. Patients with preexisting PHG have very friable mucosa that can easily bleed after radiation for cancer treatment. There is an increased risk of bleeding with both entities present together. Our aim is to focus on treatment and possible prevention of gastrointestinal bleeding in patients with preexisting PHG undergoing radiation therapy for newly diagnosed cancer. Several therapies like prednisolone, argon plasma coagulation, laser coagulation have been proposed. There are no set guidelines for treatment. In these patients, if radiation therapy is indicated either for hepatic or gastrointestinal malignancy, it is suggested to premedicate with proton pump inhibitors or sucralfate. We describe a case of 73-year-old female who presented with upper gastrointestinal bleeding. She had liver cirrhosis secondary to nonalcoholic fatty liver disease and diagnosed with pancreatic cancer, for which she received chemoradiation. She was found to have both radiation gastritis and PHG with diffuse erythematous, edematous, congested mucosa with diffuse oozing blood in the antrum making it very challenging to treat.",
"affiliations": "Department of Internal Medicine, Staten Island University Hospital, New York, New York, USA.;Department of Gastroenterology, Staten Island University Hospital, New York, New York, USA.;Department of Internal Medicine, Staten Island University Hospital, New York, New York, USA.;Department of Gastroenterology, Staten Island University Hospital, New York, New York, USA.",
"authors": "Madala|Samragnyi|S|;Polavarapu|Abhishek|A|;Gurala|Dhineshreddy|D|;Gumaste|Vivek|V|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000516569",
"fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000516569\ncrg-0015-0513\nSingle Case\nUpper GI Bleeding Secondary to Radiation Gastritis in a Patient with Preexisting Portal Hypertensive Gastropathy\nMadala Samragnyi a *\nPolavarapu Abhishek b\nGurala Dhineshreddy a\nGumaste Vivek b\naDepartment of Internal Medicine, Staten Island University Hospital, New York, New York, USA\nbDepartment of Gastroenterology, Staten Island University Hospital, New York, New York, USA\n*Samragnyi Madala, smadala1@northwell.edu\nMay-Aug 2021\n11 6 2021\n11 6 2021\n15 2 513518\n5 2 2021\n19 3 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nWe commonly see patients presenting with either portal hypertensive gastropathy (PHG) or radiation gastritis. Radiation-induced hemorrhagic gastritis is an unusual lethal complication postradiation. Patients with preexisting PHG have very friable mucosa that can easily bleed after radiation for cancer treatment. There is an increased risk of bleeding with both entities present together. Our aim is to focus on treatment and possible prevention of gastrointestinal bleeding in patients with preexisting PHG undergoing radiation therapy for newly diagnosed cancer. Several therapies like prednisolone, argon plasma coagulation, laser coagulation have been proposed. There are no set guidelines for treatment. In these patients, if radiation therapy is indicated either for hepatic or gastrointestinal malignancy, it is suggested to premedicate with proton pump inhibitors or sucralfate. We describe a case of 73-year-old female who presented with upper gastrointestinal bleeding. She had liver cirrhosis secondary to nonalcoholic fatty liver disease and diagnosed with pancreatic cancer, for which she received chemoradiation. She was found to have both radiation gastritis and PHG with diffuse erythematous, edematous, congested mucosa with diffuse oozing blood in the antrum making it very challenging to treat.\n\nKeywords\n\nPortal hypertensive gastropathy\nRadiation-induced hemorrhagic gastritis\nLiver cirrhosis\n==== Body\npmcIntroduction\n\nRadiation-induced hemorrhagic gastritis is an unusual complication postradiation for gastrointestinal malignancies. Patients with cirrhosis can present with upper GI bleeding secondary to portal hypertensive gastropathy (PHG). We commonly see patients presenting with either PHG or with radiation-induced hemorrhagic gastritis. In our case, we noticed an increased risk of bleeding due to both entities present together. Our aim is to focus on treatment and possible prevention of gastrointestinal bleeding in patients with preexisting PHG undergoing radiation therapy for newly diagnosed cancer.\n\nCase Description\n\nWe have a 73-year-old female with past medical history of insulin-dependent diabetes mellitus, hypertension, liver cirrhosis secondary to nonalcoholic fatty liver disease, pancreatic cancer with liver metastasis diagnosed 8 months prior to presentation, completed chemoradiation therapy 3 months ago presented to the hospital with bright red blood in stool and 3 episodes of hematemesis quantified as a cupful each time starting on the day of presentation. Patient also complained of palpitations, lightheadedness, and chills for the past day. Vitals on admission showed blood pressure 90/50 mm Hg, heart rate 110 beats/min, afebrile, saturating 94% on room air. On abdominal examination mild tenderness in the mid epigastric region was present, positive bowel sounds, no distention, no guarding or rigidity. Rectal examination revealed bright red blood. Laboratory studies are mentioned in Table 1. Calculated MELD score was 9. Patient was adequately resuscitated with intravenous fluids, blood transfusion and started on pantoprazole and octreotide infusion. Emergent esophagogastroduodenoscopy (EGD) was done, results as below. Chronic liver disease workup is negative for viral hepatitis panel, autoimmune diseases. CT abdomen and pelvis with IV contrast showed pancreatic neck adenocarcinoma, cirrhosis of the liver with portal hypertension but no evidence of Hepatocellular carcinoma. US Doppler showed patent portal veins with normal directionality of flow, patent hepatic veins, and hepatic artery.\n\nPatient underwent EGD and colonoscopy at an outside hospital for similar complaints 2 weeks ago. EGD showed small varices, multiple bleeding distal gastric and duodenal vascular ectasias. Colonoscopy showed diffuse vascular ectasia in colon with flecks of blood but no active bleeding, so no intervention was performed. Liver biopsy showed steatohepatitis in the background of moderate steatosis, trichrome stain highlighting portal, and periportal fibrosis with bridging and vague nodule formation suggestive of cirrhosis.\n\nDuring hospitalization, the patient underwent series of endoscopies due to persistent bleeding. First EGD on day 1 of hospitalization showed nonbleeding grade 1, esophageal varices, PHG, portal hypertensive duodenopathy, diffuse active oozing noted in the distal stomach and duodenum not amenable to endoscopic techniques. Patient was continued on pantoprazole and octreotide infusion to complete a total of 5-day course of therapy. Patient was also started on nadolol for portal hypertension which made him hypotensive with a systolic blood pressure in 80 s in two instances due to which it had to be discontinued. Due to findings of PHG and duodenopathy on EGD with episodes of GI bleeding requiring transfusions and patient not tolerating nadolol, trans-jugular intrahepatic portosystemic shunt (TIPS) procedure was considered. As patient continued to have hematochezia, colonoscopy was performed on day 9, which showed 4 nonbleeding colonic angiectasias treated with argon plasma coagulation (APC), erythematous mucosa in transverse colon, nonbleeding rectal varices, and diverticulosis in ascending colon.\n\nPortal pressures measured by hepatic vein catheterization showed wedge hepatic venous pressure of 17 mm Hg, free hepatic venous pressure of 5 mm Hg, and hepatic venous pressure gradient of 12 mm Hg. Considering the pressures were not high enough, TIPS was not performed. It was also evident that patient had persistent bleeding from a secondary cause other than PHG. On day 15 of hospitalization, repeat EGD showed diffuse erythematous, edematous, congested mucosa with diffusely oozing blood in the antrum (Fig. 1) consistent with hemorrhagic gastritis. A small area in the antrum which was bleeding more than others was treated with APC. Hemostasis at that spot was achieved, but continuous oozing was present from other areas. Active oozing of blood was also noted in duodenal bulb, duodenal sweep, and second portion of duodenum consistent with hemorrhagic duodenopathy (Fig. 2). Due to the extent of involvement, decision was made to try medical management as endoscopic intervention is not amenable. Video capsule endoscopy showed diffuse oozing from stomach and duodenum with clots seen throughout the small bowel until approximately 2 h 30 min. There were no other lesions in rest of the small bowel and colon. Considering the timing of presentation after radiation therapy and EGD findings, this was believed to be likely secondary to radiation gastritis with overlying PHG. Patient was medically managed on sucralfate 4 times daily, subcutaneous octreotide injections twice daily, twice daily pantoprazole. Bleeding subsequently improved and patient had no significant bleeding in 3-month outpatient follow-up.\n\nDiscussion\n\nThe most common complications of portal hypertension leading to upper GI bleeding are Varices and PHG. Though varices are more commonly seen, it is not uncommon to see PHG. Like varices, PHG also develop as a result of increased resistance in the portal circulation [1]. Up to 65% of patients with cirrhosis and portal hypertension develop PHG [2]. While varices are seen more commonly in the lower esophagus and fundus of stomach, PHG is seen in the mucosa of antrum and body of the stomach. The stomach mucosa is edematous, very friable, and bleeds easily as a result of chronic congestion in PHG. Histologically, PHG can be seen as marked dilatation of capillaries and collecting venules in the gastric mucosa. Clinically patients present with overt or chronic upper GI bleeding due to oozing from the dilated capillaries. Bleeding is uncommon in mild stage PHG than in severe PHG. Approximately 65–90% have mild PHG whereas 10–25% may present as severe PHG [2]. Certain cytokines are known to play a role in the pathogenesis of PHG like TNF and VEGF. TNF upregulates nitric oxide (NO) synthase which increases NO production leading to capillary dilation. High levels of VEGF have also been found in PHG which can lead to increased angiogenesis [1]. Endoscopically, PHG can include several lesions like fine pink speckling, petechia, multiple bleeding spots, snake-like pattern, and cherry red spots [3]. Gastric mucosa is extremely susceptible to damage in PHG. The best treatment recommended so far are β-blockers and octreotide which reduce gastric blood flow. Endoscopic treatment has not been proven effective as the lesions are widespread. In patients not responding to medical therapy, TIPS must be considered [1].\n\nRadiation-induced hemorrhagic gastritis is an unusual lethal complication presenting 1–12-month postradiation with peak ulceration occurring within 1–2 months [4]. The severity of damage is directly related to the high total dose and high daily fraction of radiation used. Incidence of gastric ulcer occurs between 25 and 30% as the dose exceeds 45 Gy with risk of perforation when dose exceeds 60 Gy [5]. Damage to stomach mucosa is most commonly due to direct injury from radiation followed by vasculopathy which can progress to ischemia and ulceration. Histologically, mucosal edema, microscopic hemorrhages, and exudates with damage to parietal and chief cells can be seen [4]. Upper endoscopy should be performed 4–8 weeks after radiation therapy if symptoms of abdominal pain, nausea, vomiting, or GI bleeding are present [6]. Treatment with proton pump inhibitors, sucralfate must be initiated. There are no set guidelines for treatment and successful treatment can be very challenging. Hyperbaric oxygen has been tried in the past to increase neovascularization to help heal the ulcers [7]. Epsilon aminocaproic acid, a fibrinolytic inhibitor which acts by inhibiting plasminogen and antiplasmin activity has also been used [8]. Initial therapy with oral prednisolone [9] and rescue therapies like bevacizumab [10] have also been tried. Shukuwa et al. [11] described a case of hemorrhagic radiation gastritis after being treated for pancreatic cancer managed with APC successfully. In our patient, the mucosa was extensively involved that APC was ineffective in controlling the bleeding. After all the medical and endoscopic measures are exhausted, surgery with total gastrectomy will be the last resort for radiation injuries.\n\nChon et al. [4] has demonstrated that gastroduodenal complications were higher in patients receiving radiation therapy with preexisting PHG secondary to liver cirrhosis like our patient. Mucosa is very friable due to increased blood supply to the stomach from increased portal venous pressure gradient. Portal hypertensive gastropathy can be a complication of portal hypertension leading to upper GI bleeding in cirrhotic patients. In patients receiving radiation therapy for newly diagnosed liver or pancreatic cancer, preexisting PHG can make them more susceptible to hemorrhagic gastritis. There are no existing guidelines currently for appropriate treatment and successful control of bleeding can be very challenging due to extensive involvement. In these patients, if radiation therapy is indicated either for hepatic or gastrointestinal malignancy, it is suggested to premedicate with proton pump inhibitors, somatostatin analogues, or sucralfate to reduce the risk of radiation-induced hemorrhagic gastritis.\n\nStatement of Ethics\n\nAs per the institutional guidelines, review of medical records for publication of case reports of up to 3 patients is not considered human subjects research and does not require institutional review board review and approval. Written informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nConflict of Interest Statement\n\nThe authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.\n\nFunding Sources\n\nThis manuscript did not receive any funding.\n\nAuthor Contributions\n\nMadala S. drafted the manuscript. Polavarapu A. followed the patient while admitted to the hospital. Gurala D. edited the manuscript; Gumaste V. approved the final manuscript.\n\nFig. 1 Endoscopic image of antrum showing diffuse edematous, erythematous mucosa with angiectasias that are diffusely actively oozing blood.\n\nFig. 2 Endoscopic image of duodenum showing diffuse edematous, erythematous mucosa with angiectasias that are actively oozing blood.\n\nTable 1 Laboratory values on admission\n\n\tPatient data\tNormal range\t\nHematology\t\nWBC, K/µL\t1.33\t3.8–10.5\t\nHemoglobin, g/dL\t6.9\t11.5–15.5\t\nHematocrit, %\t21.6\t34.5–45.0\t\nPLT, K/µL\t71\t150–400\t\nBMP\t\nSodium, mmol/L\t143\t135–145\t\nPotassium, mmol/L\t4.0\t3.5–5.3\t\nBUN, mg/dL\t6.0\t7–23\t\nCreatinine, mg/dL\t0.6\t0.5–1.3\t\nCoagulation profile\t\nPT, s\t13.6\t9.8–13.1\t\nPTT, s\t28.8\t27.5–36.3\t\nINR\t1.22\t0.88–1.17\t\nLiver function tests\t\nTotal protein, g/dL\t4.6\t6–8.3\t\nAlbumin, g/dL\t2.7\t3.3–5\t\nTotal bilirubin, mg/dL\t0.4\t0.2–1.2\t\nALP, U/L\t61\t40–120\t\nAST, U/L\t31\t4–32\t\nALT, U/L\t32\t4–33\t\nWBC, white cell count; PLT, platelet count; BMP, basic metabolic profile; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; PT, prothrombin time; PTT, partial thromboplastin time.\n==== Refs\nReferences\n\n1 Wong F Portal hypertensive gastropathy Gastroenterol Hepatol 2007 3 (6) 428 73\n2 Piqué JM Portal hypertensive gastropathy Baillieres Clin Gastroenterol 1997 11 (2) 257 70 9395747\n3 Eleftheriadis E Portal hypertensive gastropathy a clinically significant puzzle Ann Gastroenterol 2001 14 (3) 196 204\n4 Chon YE Seong J Kim BK Cha J Kim SU Park JY Gastroduodenal complications after concurrent chemoradiation therapy in patients with hepatocellular carcinoma: endoscopic findings and risk factors Int J Radiat Oncol Biol Phys 2011 81 (5) 1343 51 20934268\n5 Sourati A Ameri A Malekzadeh M Radiation gastritis Acute side effects of radiation therapy 2017 Cham Springer\n6 Sangro B Martínez-Urbistondo D Bester L Bilbao JI Coldwell DM Flamen P Prevention and treatment of complications of selective internal radiation therapy: expert guidance and systematic review Hepatology 2017 66 (3) 969 82 28407278\n7 Kernstine KH Greensmith JE Johlin FC Funk GF De Armond DT Van Natta TL Hyperbaric oxygen treatment of hemorrhagic radiation-induced gastritis after esophagectomy Ann Thorac Surg 2005 80 (3) 1115 7 16122506\n8 Grover N Johnson A Aminocaproic acid used to control upper gastrointestinal bleeding in radiation gastritis Dig Dis Sci 1997 42 (5) 982 4 9149051\n9 Yun HG Kim HY Kim DY Lim YJ Successful treatment of intractable bleeding caused by radiation-induced hemorrhagic gastritis using oral prednisolone: a case report Cancer Res Treat 2015 47 (2) 334 8 25327495\n10 Maire F Muller N Lévy P First case of radiation-induced diffuse hemorrhagic gastritis successfully treated with intravenous bevazicumab Am J Gastroenterol 2017 112 (8) 1349 50 28766568\n11 Shukuwa K Kume K Yamasaki M Yoshikawa I Otsuki M Argon plasma coagulation therapy for a hemorrhagic radiation-induced gastritis in patient with pancreatic cancer Intern Med 2007 46 (13) 975 7 17603236\n\n",
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"issn_linking": "1662-0631",
"issue": "15(2)",
"journal": "Case reports in gastroenterology",
"keywords": "Liver cirrhosis; Portal hypertensive gastropathy; Radiation-induced hemorrhagic gastritis",
"medline_ta": "Case Rep Gastroenterol",
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"nlm_unique_id": "101474819",
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"pages": "513-518",
"pmc": null,
"pmid": "34616249",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "28766568;9395747;16122506;17603236;9149051;23329900;28407278;25327495;20934268",
"title": "Upper GI Bleeding Secondary to Radiation Gastritis in a Patient with Preexisting Portal Hypertensive Gastropathy.",
"title_normalized": "upper gi bleeding secondary to radiation gastritis in a patient with preexisting portal hypertensive gastropathy"
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"abstract": "This is the second reported case of minocycline-induced Sweet's syndrome (and the first such case to appear in the American literature). The syndrome developed in a 32-year-old man 10 days after minocycline therapy for acne was begun and resolved rapidly after discontinuation of the medication and start of oral prednisone therapy.",
"affiliations": "Department of Dermatology and Pathology, Jewish General Hospital, University of McGill, Montreal, Quebec, Canada.",
"authors": "Thibault|M J|MJ|;Billick|R C|RC|;Srolovitz|H|H|",
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"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000152:Acne Vulgaris; D000328:Adult; D003875:Drug Eruptions; D006801:Humans; D008297:Male; D008911:Minocycline; D016463:Sweet Syndrome",
"nlm_unique_id": "7907132",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced Sweet's syndrome.",
"title_normalized": "minocycline induced sweet s syndrome"
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"abstract": "Chemotherapy is associated with significant toxicity in elderly patients treated for hematological malignancies. Adequate tools to identify the best tailored treatment are essential.\n\n\n\nMedical charts of patients treated with adjusted chemotherapy for diffuse large B-cell lymphoma according to frailty status between August 1, 2013 and June 30, 2016 were included. Three groups were identified: fit, unfit, and frail patients.\n\n\n\nFifty-six patients with a median age of 70.5 years were analyzed. Adverse prognostic characteristics were more frequent than expected in the frail group, contributing to a worse outcome. The complete response (CR) rate for all patients was 61.2% (66.6%, 78.3%, and 40.0% for fit, unfit, and frail patients, respectively; P = .121). The 2-year overall survival (OS) for all patients was 78% (87%, 82%, and 59% for fit, unfit, and frail patients, respectively; P = .159) and the mean 2-year disease-free survival was 96% (87% for frail patients and 100% for unfit and fit patients; P = .287). Grade 3/4 hematologic toxicity was present in 83.3%, 65.2%, and 45% of fit, unfit, and frail patients, respectively. CR after therapy had a positive effect on OS, whereas ≥ 2 extranodal sites and febrile neutropenia had a negative effect.\n\n\n\nFrailty status assessment resulted in the identification of a group of unfit patients who had adequate tolerance to adjusted chemotherapy (R-choP; rituximab with cyclophosphamide, doxorubicin, and vincristine adjusted to 80% of the corresponding total doses in R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone]) with good results.",
"affiliations": "Hematology and Oncology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. Electronic address: isabel8411@hotmail.com.;Geriatric Medicine Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.;Red de Apoyo a la Investigación, CIC, Universidad Nacional Autónoma de México, Mexico City, Mexico.;Hematology and Oncology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.",
"authors": "Lastra-German|Isabel K|IK|;Navarrete-Reyes|Ana P|AP|;Mejía-Domínguez|Nancy R|NR|;Agreda-Vásquez|Gladys P|GP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2018.11.013",
"fulltext": null,
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"issn_linking": "2152-2669",
"issue": "19(2)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Fragility; Geriatric; Hematologic neoplasms; Latin America; Treatment",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000368:Aged; D005260:Female; D000073496:Frailty; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008800:Mexico",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e98-e106",
"pmc": null,
"pmid": "30545670",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adjusted Chemotherapy According to Frailty Status in Elderly Patients With Diffuse Large B-Cell Lymphoma: Experience From a Single Referral Center in Mexico City.",
"title_normalized": "adjusted chemotherapy according to frailty status in elderly patients with diffuse large b cell lymphoma experience from a single referral center in mexico city"
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"companynumb": "MX-JNJFOC-20190220088",
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"abstract": "OBJECTIVE\nSince there are only a few reports on pediatric systemic lupus erythematosus (pSLE) in Chinese populations, therefore we retrospectively report the clinical and immunological features as well as renal outcome in Chinese pSLE.\n\n\nMETHODS\nPatients diagnosed with pSLE at Shanghai Children's Medical Center between 2001 and 2016 were evaluated and clinical data were retrospectively collected.\n\n\nRESULTS\nA total of 102 pSLE patients were analyzed. Renal disorder including proteinuria (81.37%) and hematuria (65.69%) were most commonly identified. Class IV was the most common finding on renal biopsy. In lupus nephritis (LN), 67.21%, 78.0%, 86.0% and 94.55% achieved complete remission within 6, 12, 18 and 24 months, respectively. Furthermore, 16.67% of LN patients suffered at least one renal flare. Antinuclear antibodies were detected in nearly all patients (97.62%), followed by anti-double-stranded DNA (anti-dsDNA) antibodies (70.0%) and anti-Sjögren's syndrome A (anti-SSA) antibodies (60.64%). Oral corticosteroid (93.14%) and mycophenolate mofetil (64.71%) was used in the majority of patients. Infection (32.35%) was the main side effect caused by the medications.\n\n\nCONCLUSIONS\nOur population-based pSLE cohort indicated that compared to other international cohorts, there was a higher prevalence of LN in Chinese pSLE. Proteinuria was the most frequent manifestation both at disease onset and during the entire clinical course. Class IV LN was the dominant renal pathological type. Nevertheless, there was a favorable renal remission rate and relatively low incidence of renal flare in our cohort. Apart from antinuclear antibodies and anti-dsDNA antibodies, anti-SSA antibodies were most frequently detected. Infection was the leading complication caused by the medications.",
"affiliations": "Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology and Rheumatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.",
"authors": "Zhang|Chen-Xing|CX|;Cai|Li|L|;Zhou|Zheng-Yu|ZY|;Mao|You-Ying|YY|;Huang|Hua|H|;Yin|Lei|L|;Chen|Tong-Xin|TX|https://orcid.org/0000-0001-6000-3471;Zhou|Wei|W|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000974:Antibodies, Antinuclear; D015415:Biomarkers; C035356:SS-A antibodies; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13547",
"fulltext": null,
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"issn_linking": "1756-1841",
"issue": "22(6)",
"journal": "International journal of rheumatic diseases",
"keywords": "infection; lupus nephritis; pediatric systemic lupus erythematosus; renal outcome",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D017668:Age of Onset; D000974:Antibodies, Antinuclear; D015415:Biomarkers; D002648:Child; D002681:China; D005260:Female; D006417:Hematuria; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008297:Male; D009173:Mycophenolic Acid; D009894:Opportunistic Infections; D015995:Prevalence; D011507:Proteinuria; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "1070-1076",
"pmc": null,
"pmid": "30957986",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical manifestations, immunological features and prognosis of Chinese pediatric systemic lupus erythematosus: A single-center study.",
"title_normalized": "clinical manifestations immunological features and prognosis of chinese pediatric systemic lupus erythematosus a single center study"
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"companynumb": "CN-ROCHE-2358454",
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"activesubstancename": "CYCLOPHOSPHAMIDE"
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"abstract": "The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.",
"affiliations": "Pediatric Hematology and HSCT Department, Santa Creu and Sant Pau Hospital, Autonomous University, Barcelona, Spain. Electronic address: lsisinni@santpau.cat.;Hematology Department, La Paz University Hospital, Madrid, Spain.;Hematology Department, La Paz University Hospital, Madrid, Spain.;Cellular Therapy Unit, Cord Blood Bank, Centre Frederic Duran i Jordà, Barcelona, Spain.;Pediatric Hemato-Oncology, La Paz University Hospital, Madrid, Spain.;Hematological Malignancies H12O. Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain.;Pediatric HSCT Department, Sant Joan de Déu Hospital, Barcelona, Spain.;Pediatric Hemato-Oncology, La Paz University Hospital, Madrid, Spain.;Immunology Department, Hospital del Mar Medical Research Institute, Barcelona, Spain.;Pediatric HSCT Department, Hospital Vall d'Hebron, Barcelona, Spain.;Pediatric Hematology and HSCT Department, Santa Creu and Sant Pau Hospital, Autonomous University, Barcelona, Spain.;Immunology Department, La Paz University Hospital, Madrid, Spain.;Immunology Department, La Paz University Hospital, Madrid, Spain.;Cellular Therapy Unit, Cord Blood Bank, Centre Frederic Duran i Jordà, Barcelona, Spain.;Pediatric Hematology and HSCT Department, Santa Creu and Sant Pau Hospital, Autonomous University, Barcelona, Spain.;Pediatric HSCT Department, Hospital Vall d'Hebron, Barcelona, Spain.;Institute of Medical and Molecular Genetics, La Paz University Hospital, IdiPAZ, Madrid, Spain.;Pediatric Hemato-Oncology, La Paz University Hospital, Madrid, Spain.",
"authors": "Sisinni|Luisa|L|;Gasior|Mercedes|M|;de Paz|Raquel|R|;Querol|Sergio|S|;Bueno|David|D|;Fernández|Lucia|L|;Marsal|Julia|J|;Sastre|Ana|A|;Gimeno|Ramon|R|;Alonso|Laura|L|;Badell|Isabel|I|;López-Granados|Eduardo|E|;Torres|Juan|J|;Medina|Laura|L|;Torrent|Montserrat|M|;Diaz de Heredia|Cristina|C|;Escudero|Adela|A|;Pérez-Martínez|Antonio|A|",
"chemical_list": null,
"country": "United States",
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"issue": "24(11)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Encephalitis; Haploidentical transplantation; Human herpesvirus-6",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018792:Encephalitis, Viral; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D015654:Herpesvirus 6, Human; D006801:Humans; D015994:Incidence; D008297:Male; D013601:T-Lymphocytes; D019172:Transplantation Conditioning",
"nlm_unique_id": "9600628",
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"publication_types": "D016428:Journal Article",
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"title": "Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell-Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients.",
"title_normalized": "unexpected high incidence of human herpesvirus 6 encephalitis after naive t cell depleted graft of haploidentical stem cell transplantation in pediatric patients"
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"abstract": "Colchicine overdose is uncommon but potentially life threatening. Due to its serious adverse systemic effects, overdose must be recognized and treated. We report a case of an 18-year-old female who ingested 18 mg (~0.4 mg/kg) of colchicine in a suicide attempt. The patient's clinical manifestations included abdominal cramps, vomiting, pancytopenia, hypocholesterolemia, and rhabdomyolysis. Two unique manifestations of toxicity in this patient were profound and persistent, severe hypertriglyceridemia and electrolyte imbalance, mainly hypophosphatemia, with no other evident cause except the colchicine intoxication. Following intensive supportive treatment, including ventilator support, N-acetylcysteine, granulocyte colony stimulating factor, electrolyte repletion, and zinc supplementation, the patient made a complete recovery. Colchicine intoxication is a severe, life-threatening situation that should be followed closely in intensive care units. Severe changes in body functions can rapidly develop, as previously described in the literature. To our knowledge, this extremely elevated triglyceride level has never been reported without the administration of propofol, and requires further evaluation.",
"affiliations": "Intensive Care Unit, Rabin Medical Center, Petah-Tikva.;Sackler School of Medicine NY/American Program, Tel-Aviv University, Tel Aviv.;Clinical Pharmacy, Herzliya Medical Center, Herzliya.;Intensive Care Unit, Rabin Medical Center, Petah-Tikva.;Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.",
"authors": "Lev|Shaul|S|;Snyder|David|D|;Azran|Carmil|C|;Zolotarsky|Victor|V|;Dahan|Arik|A|",
"chemical_list": "D003078:Colchicine",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/DDDT.S140574",
"fulltext": "\n==== Front\nDrug Des Devel TherDrug Des Devel TherDrug Design, Development and TherapyDrug Design, Development and Therapy1177-8881Dove Medical Press 10.2147/DDDT.S140574dddt-11-3321Case ReportSevere hypertriglyceridemia and colchicine intoxication following suicide attempt Lev Shaul 1Snyder David 2Azran Carmil 3Zolotarsky Victor 1Dahan Arik 4\n1 Intensive Care Unit, Rabin Medical Center, Petah-Tikva\n2 Sackler School of Medicine NY/American Program, Tel-Aviv University, Tel Aviv\n3 Clinical Pharmacy, Herzliya Medical Center, Herzliya\n4 Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, IsraelCorrespondence: Arik Dahan, Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, Beer-Sheva 84105, Israel, Tel +972 8 647 9483, Fax +972 8 647 9303, Email arikd@bgu.ac.il2017 22 11 2017 11 3321 3324 © 2017 Lev et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Colchicine overdose is uncommon but potentially life threatening. Due to its serious adverse systemic effects, overdose must be recognized and treated. We report a case of an 18-year-old female who ingested 18 mg (~0.4 mg/kg) of colchicine in a suicide attempt. The patient’s clinical manifestations included abdominal cramps, vomiting, pancytopenia, hypocholesterolemia, and rhabdomyolysis. Two unique manifestations of toxicity in this patient were profound and persistent, severe hypertriglyceridemia and electrolyte imbalance, mainly hypophosphatemia, with no other evident cause except the colchicine intoxication. Following intensive supportive treatment, including ventilator support, N-acetylcysteine, granulocyte colony stimulating factor, electrolyte repletion, and zinc supplementation, the patient made a complete recovery. Colchicine intoxication is a severe, life-threatening situation that should be followed closely in intensive care units. Severe changes in body functions can rapidly develop, as previously described in the literature. To our knowledge, this extremely elevated triglyceride level has never been reported without the administration of propofol, and requires further evaluation.\n\nKeywords\ncolchicineintoxicationhypophosphatemiahypertriglyceridemia\n==== Body\nIntroduction\nA previously healthy 18-year-old female was admitted to our intensive care unit (ICU) after being transferred from a different hospital due to ingestion of approximately 30 tablets of colchicine (18 mg) 3 days prior.\n\nColchicine is a neutral and lipophilic alkaloid from the plant Colchicum autumnale and is a microtubule polymerization inhibitor. It is primarily used to treat acute gout as well as familial Mediterranean fever. It has been used in the treatment of gouty arthritis for centuries. Adverse effects of colchicine use are characterized by “crampy” abdominal pain, diarrhea, nausea, vomiting, headaches, and fatigue. Colchicine toxicity has been characterized by cytopenias (especially thrombocytopenia), electrolyte imbalance (especially hypophosphatemia and hypozincemia), and elevated creatinine phosphokinase (CPK).\n\nAt the time of admission (3rd day post-ingestion), she was alert and oriented but had suffered from vomiting and diarrhea for more than 2 days. She experienced mid-epigastric pain with intermittent bilious vomiting. The patient also presented with hepatic disturbances and metabolic acidosis. The results of a complete evaluation for infectious disease were negative.\n\nHer vital signs were unremarkable except for a pulse of 143 beats/minute and shortness of breath. There was mild abdominal distension but bowel sounds were normal. Written informed consent for the case details to be published was provided by the patient.\n\nDiagnostic assessment\nElectrocardiogram was unremarkable. She presented with elevated partial thromboplastin time, international normalized ratio of 52 sec and 2.4 respectively. Her platelet count was 100,000/mL and her fibrinogen was 205 mg/dL.\n\nPlasma electrolytes on admission (3rd day post-ingestion) were significant for mildly decreased phosphorous of 2.1 mg/dL, potassium 3.18 mEq/L, magnesium 1.39 mg/dL, and corrected calcium of 7.16 mg/dL. Despite receiving extensive electrolyte supplementation since the day of admission, persistent, severe electrolyte imbalances persisted and were difficult to control. Her electrolyte measurements included magnesium ranging from 1.39 mg/dL to 1.76 mg/dL and potassium ranging from 2.7 mg/dL to 3.49 mg/dL. The most profound electrolyte disturbance was hypophosphatemia reaching as low as 0.7 mg/dL on day 8. Rhabdomyolysis was diagnosed by elevated CPK levels up to 8,500 units/L and the urine tested positive for myoglobin (Figure 1).\n\nOn admission (3rd day post-ingestion) she also had an elevated triglyceride level of 816 mg/dL which later reached a peak of 1,273 mg/dL on day 10. This was accompanied by HDL levels ranging from 7 mg/dL to 13.7 mg/dL on day 4 and day 10, respectively.\n\nTherapeutic intervention\nOn arrival, she was given n-acetylcysteine (NAC) based on a previous case report describing successful NAC treatment in colchicine intoxication.1 Her paracetamol level was undetectable. No change in her condition was noted post-treatment.\n\nThe patient developed pancytopenia on her 4th day post-ingestion which resolved on day 9 under granulocyte colony stimulating factor treatment.2–5 Absolute neutrophil count was 8,100/mL and reached nadir 300/mL on day 6. Hemoglobin nadir 7.8 g/dL was on day 8. Platelets nadir was on day 7 with a level of 20,000/mL. Mean platelet volume of the patient was 6.8 fL on admission indicating bone marrow failure. On day 5 the patient exhibited mucosal damage and bleeding mainly in the mouth and eyes. On day 5 she received the granulocyte colony stimulating factor (filgrastim) treatment. Since high-grade fever had developed on day 4, she was treated with piperacillin/tazobactam. Platelet transfusions were given on day 7 when the absolute number decreased below 20,000/mL. On day 8 there was an improvement in her counts.\n\nOn day 6 post-ingestion she developed respiratory distress and hypoxemia accompanied by bilateral pulmonary infiltrates, compatible with the diagnosis of acute lung injury (ALI), which was treated with non-invasive mechanical ventilation and negative fluid balance. The ALI resolved on day 9.\n\nThe patient was also treated with intravenous multivitamins and trace elements with oral zinc supplementation to avoid hypozincemia.\n\nFollow-up and outcomes\nFourteen days post-ingestion the patient was transferred back to the referring hospital in a good condition. Figure 2 shows the changes, over time, of CPK and phosphorus and their return to acceptable levels.\n\nDiscussion\nColchicine is a neutral and lipophilic alkaloid. An overdose of colchicine inhibits cell division by fixing the intracellular tubule and arresting polymerization into microtubules; thus, mitosis and transport systems within the cells are disrupted. Tissues that are most susceptible to anti-mitotic effects are tissues with high division index, like mucosal surfaces, skin, and bone marrow.3 Additionally, oxidative stress-induced cellular damage by colchicine was evident in the improvement seen upon treatment with NAC. Our patient displayed many signs of endothelial and mucosal damage including conjunctival bleeding, diarrhea, disseminated intravascular coagulation (DIC), and ALI. First symptoms of acute toxicity occur within the first 24 hours of ingestion and include nausea, vomiting, diarrhea, anorexia, and abdominal pain. Multi-organ failure usually develops 24 to 72 hours after ingestion. Bone marrow suppression, hemolytic anemia, liver damage, renal failure, respiratory distress syndrome, arrhythmias, rhabdomyolysis, neuromuscular disturbances, and DIC can also develop. Delayed presentation is associated with a poor prognosis.9\n\nElevated triglyceride levels have been previously reported by others,6 but were attributed to propofol infusion syndrome. However, in our patient, propofol was not administered. We hypothesize that the high level of triglycerides was partly due to intense inflammatory response and a decrease in lipase activity. The low HDL levels and high CRP levels support the inflammatory concept. However, the triglycerides level continued to rise despite resolution of other symptoms and increase in HDL level, implying that inflammation by itself is not enough to explain such severe hypertriglyceridemia. Moreover, after oral ingestion, the mean half-life of colchicine is 9 to 16 hours. It is rapidly absorbed from the gastrointestinal tract after ingestion and undergoes significant first-pass hepatic metabolism. Since the triglyceride levels continued to elevate 10 days after oral ingestion, it is highly unlikely that the effect was pharmacological. To our knowledge no direct or indirect effects of colchicine in terms of apolipoprotein metabolism have been described.\n\nThe patient required massive doses of phosphate supplementations due to an unknown mechanism, but it was probably related to cellular redistribution, like that seen in re-feeding syndrome. The intensity of the phosphate drop was overwhelming and exceeded our protocol of 18 mmol to 21 mmol of potassium phosphate. The rhabdomyolysis that was present preceded the nadir in phosphate level and was most likely not the cause of it.\n\nThe patient was also treated with zinc supplementation due to hypozincemia which is very common in critically ill patients.7 In addition, the rationale of avoiding hypozincemia was based on an animal study indicating severe mucosal injury when colchicine is given in animals with zinc deficiency.8 This could be related to the crucial role of zinc in the function of the microtubule.\n\nConclusion\nColchicine intoxication is a severe, life-threatening situation that should be followed closely in ICUs. Severe changes in body functions can develop rapidly. This patient displayed some unique characteristics with severe bone marrow suppression and profound hypophosphatemia requiring intensive electrolyte repletion. To our knowledge, the extremely high triglyceride level has never been reported without the administration of propofol, and requires further evaluation.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Time-course of patient’s laboratory findings and symptoms.\n\nNotes: Elevated CPK (>180 units/L); neutropenia (neutrophil count <1,000 mL); thrombocytopenia (platelets <100,000/mL); fever (temp >38.1°C); hypophosphatemia (phosphorus <2.5 mg/dL); coagulopathy (INR >1.7); respiratory distress (RR >20/min, PaO2/FiO2 <200).\n\nAbbreviations: CPK, creatinine phosphokinase; INR, international normalized ratio; RR, respiratory rate.\n\nFigure 2 Phosphorus levels and CPK levels over time.\n\nAbbreviation: CPK, creatinine phosphokinase.\n==== Refs\nReferences\n1 Ioulia I Lan J Chin C Werb R Levin A Massive colchicine overdose with recovery Case Rep Nephrol Urol 2012 2 1 20 24 23197951 \n2 Harris R Marx G Gillet M Kark A Arunanthy S Colchicine-induced bone marrow suppression: treatment with granulocyte colony-stimulating factor J Emerg Med 2000 18 4 435 440 10802421 \n3 Harris R Gillet M Colchicine poisoning-overview and new directions Emerg Med 1988 10 161 167 \n4 Critchley JA Critchley LA Yeung EA Young RP Young RJ Chan TY Goh VK Granulocyte colony-stimulating factor in the treatment of colchicine poisoning Hum Exp Toxicol 1997 16 4 229 232 9154449 \n5 Grossmann A Lenox J Deisher TA Ren HP Humes JM Kaushansky K Sprugel KH Synergistic effects of thrombopoietin and granulocyte-stimulating factor on neutrophil recovery in myelosuppressed mice Blood 1996 88 9 3363 3370 8896401 \n6 Montiel V Huberlant V Vincent MF Bonbled F Hantson P Multiple organ failure after an overdose of less than 0.4 mg/kg of colchicine: role of coingestants and drugs during intensive care management Clin Toxicol (Phila) 2010 48 8 845 848 20969505 \n7 Besecker BY Exline MC Hollyfield J Phillips G Disilvestro RA Wewers MD Knoell DL A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission Am J Clin Nutr 2011 93 6 1356 1364 21525204 \n8 Dinsdale D Williams RB The enhancement by dietary zinc deficiency of the susceptibility of the rat duodenum to colchicine Br J Nutr 1977 37 1 135 142 191056 \n9 Finkelstein Y Aks SE Hutson JR Colchicine poisoning: the dark side of an ancient drug Clin Toxicol (Phila) 2010 48 5 407 414 20586571\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-8881",
"issue": "11()",
"journal": "Drug design, development and therapy",
"keywords": "colchicine; hypertriglyceridemia; hypophosphatemia; intoxication",
"medline_ta": "Drug Des Devel Ther",
"mesh_terms": "D000293:Adolescent; D003078:Colchicine; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia; D012720:Severity of Illness Index; D013406:Suicide, Attempted",
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"pages": "3321-3324",
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"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "191056;10802421;20969505;8896401;21525204;20586571;9154449;23197951",
"title": "Severe hypertriglyceridemia and colchicine intoxication following suicide attempt.",
"title_normalized": "severe hypertriglyceridemia and colchicine intoxication following suicide attempt"
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"abstract": "BACKGROUND\nMultiple myeloma (MM) is the second most frequent hematologic malignancy after lymphoma, contributing to approximately 10% of all hematologic malignancies. The prognosis of patients with MM is impacted by the heterogeneity of the disease, with worse outcomes reported in patients classified as International Staging System stage III, those with high-risk cytogenetics and elevated serum lactate dehydrogenase, and among patients who are elderly and have comorbidities. Previous studies have demonstrated an association between the presence of lung disease and worse outcomes; however, this impact in a real-world setting is not well understood.\n\n\nMETHODS\nThis retrospective, observational, cohort study included data from the nationwide US Optum® de-identified electronic health record (EHR) database from January 1, 2006, to December 31, 2019. MM patients with asthma or chronic obstructive pulmonary disease (COPD) were compared with MM patients without asthma or COPD for time to next treatment and overall survival using one-sided log-rank tests stratified by age and multivariable Cox proportional hazard models.\n\n\nRESULTS\nAmong 5186 patients with MM, approximately 15% had an asthma or COPD diagnosis (asthma/COPD) at baseline. The most commonly observed comorbidities among all MM patients and among those MM patients with asthma/COPD were cardiovascular disease, diabetes, and renal impairment. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD. Overall survival from first-line therapy was significantly worse among patients with COPD, with numerically worse overall survival from second-line therapy.\n\n\nCONCLUSIONS\nThese real-world data suggest that patients with asthma or COPD do not experience a shorter time interval to next treatment, but have significantly worse overall survival from start of first-line therapy and numerically worse survival from the start of later lines. Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients.",
"affiliations": ", 50 Binney Street, Cambridge, MA, 02142, USA. megan.rice@sanofi.com.;, 50 Binney Street, Cambridge, MA, 02142, USA.;, 50 Binney Street, Cambridge, MA, 02142, USA.",
"authors": "Rice|Megan S|MS|;Naeger|Sarah|S|;Singh|Erin|E|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40487-021-00146-4",
"fulltext": "\n==== Front\nOncol Ther\nOncol Ther\nOncology and Therapy\n2366-1070\n2366-1089\nSpringer Healthcare Cheshire\n\n33728584\n146\n10.1007/s40487-021-00146-4\nOriginal Research\nReal-World Treatment Patterns and Outcomes Among Multiple Myeloma Patients with Asthma and COPD in the United States\nRice Megan S. megan.rice@sanofi.com\n\nNaeger Sarah\nSingh Erin\n50 Binney Street, Cambridge, MA 02142 USA\n17 3 2021\n17 3 2021\n6 2021\n9 1 195212\n26 1 2021\n26 2 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.\nIntroduction\n\nMultiple myeloma (MM) is the second most frequent hematologic malignancy after lymphoma, contributing to approximately 10% of all hematologic malignancies. The prognosis of patients with MM is impacted by the heterogeneity of the disease, with worse outcomes reported in patients classified as International Staging System stage III, those with high-risk cytogenetics and elevated serum lactate dehydrogenase, and among patients who are elderly and have comorbidities. Previous studies have demonstrated an association between the presence of lung disease and worse outcomes; however, this impact in a real-world setting is not well understood.\n\nMethods\n\nThis retrospective, observational, cohort study included data from the nationwide US Optum® de-identified electronic health record (EHR) database from January 1, 2006, to December 31, 2019. MM patients with asthma or chronic obstructive pulmonary disease (COPD) were compared with MM patients without asthma or COPD for time to next treatment and overall survival using one-sided log-rank tests stratified by age and multivariable Cox proportional hazard models.\n\nResults\n\nAmong 5186 patients with MM, approximately 15% had an asthma or COPD diagnosis (asthma/COPD) at baseline. The most commonly observed comorbidities among all MM patients and among those MM patients with asthma/COPD were cardiovascular disease, diabetes, and renal impairment. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD. Overall survival from first-line therapy was significantly worse among patients with COPD, with numerically worse overall survival from second-line therapy.\n\nConclusion\n\nThese real-world data suggest that patients with asthma or COPD do not experience a shorter time interval to next treatment, but have significantly worse overall survival from start of first-line therapy and numerically worse survival from the start of later lines. Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients.\n\nKeywords\n\nAsthma\nCOPD\nMultiple myeloma\nReal-world evidence\nhttp://dx.doi.org/10.13039/100004339 Sanofi issue-copyright-statement© The Author(s) 2021\n==== Body\nKey Summary Points\n\nWhy carry out this study?\t\nComorbidities are known to impact outcomes in patients with multiple myeloma, but many patients with pulmonary disease are excluded from clinical trials; therefore, not much is known about this subgroup of patients.\t\nPrevious results have demonstrated an association between the presence of lung disease and worse outcomes; however, this impact in a real-world setting is not well understood.\t\nThe objective of the current study was to assess the prevalence of asthma and chronic obstructive pulmonary disease (COPD) in a real-world patient population with multiple myeloma, and to describe treatment patterns in patients with/without asthma/COPD, and time to next treatment and overall survival in patients with asthma/COPD.\t\nWhat was learned from the study?\t\nThese real-world data suggest that patients with asthma or COPD experience prolonged time to next treatment from first to second line, but have significantly worse overall survival from start of first-line therapy and numerically worse survival from the start of later lines of therapy.\t\nFuture investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients.\t\n\nDigital Features\n\nThis article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.14113682.\n\nIntroduction\n\nMultiple myeloma (MM) is the second most frequent hematologic malignancy after lymphoma, contributing to 1% of all cancers and approximately 10% of all hematologic malignancies [1, 2]. Despite the introduction of targeted therapies and combination regimens, patients with MM continue to experience multiple relapses and/or become refractory to treatment [3].\n\nThe prognosis of patients with MM has been shown to be impacted by the heterogeneity of the disease, with prognostic factors categorized by burden of disease, tumor biology, host factors, and depth of response to therapy [4]. Worse outcomes have been reported in patients classified as International Staging System stage III, those with high-risk cytogenetics and elevated serum lactate dehydrogenase, and among patients who are elderly and have comorbidities. Treatment decision-making may require consideration of preexisting comorbidities and organ dysfunction, which have been associated with an increased risk of treatment- and disease-related complications that contribute to high levels of mortality earlier in the treatment continuum.\n\nIn ICARIA-MM, a recent phase 3 study of isatuximab, an anti-CD38 monoclonal antibody that has been approved in combination with pomalidomide and dexamethasone in the United States, the European Union, Japan, and other countries for the treatment of adult patients with relapsed/refractory MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI) [5–9], approximately 10% of patients had a previous history of asthma or chronic obstructive pulmonary disorder (COPD) [10]. However, previous MM studies investigating other molecules have used COPD/pulmonary disease as an exclusion criterion (e.g., POLLUX; ELOQUENT-2 [if uncontrolled]; CASTOR; CANDOR; MAIA; CASSIOPEIA) [11–16]. As a result, little is known from randomized controlled trials about treatment patterns and outcomes in MM patients with respiratory comorbidities. Although some retrospective studies have demonstrated an association between the presence of lung disease and worse outcome [17], and an independent association has been reported between pulmonary function abnormalities and worse outcome in patients with MM [18], the real-world impact of preexisting lung disease is not well understood.\n\nTherefore, the objective of the current study was to assess the prevalence of asthma and COPD in a real-world patient population with MM, and to describe treatment patterns, time to next treatment, and overall survival in MM patients by asthma/COPD status.\n\nMethods\n\nThis retrospective, observational, cohort study included data from the nationwide US Optum® de-identified electronic health record (EHR) database. The dataset includes all data collected from January 1, 2006, to December 31, 2019. The dataset is statistically deidentified under the Expert Determination method consistent with the Health Insurance Portability and Accountability Act and managed according to Optum’s customer data use agreements. This article is based on previously collected data and does not contain any studies with human participants or animals performed by any of the authors.\n\nInclusion Criteria\n\nInclusion and exclusion criteria are described in Table 1. In this study, patients were included if they had ≥ 2 medical records with a diagnosis of MM at least 30 days apart but no more than 365 days apart. The first of these two medical records was considered the diagnosis date. Patients were aged ≥ 18 years as of the first observed treatment for MM. Patients had ≥ 1 medical record for a medical service with a procedure code or a prescription for an MM treatment, including immunomodulatory drugs (i.e., thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (PIs; i.e., bortezomib, carfilzomib, ixazomib), histone deacetylase inhibitors (i.e., panobinostat), monoclonal antibodies (i.e., daratumumab, elotuzumab, isatuximab), chemotherapy (i.e., bendamustine, cisplatin, cyclophosphamide, doxorubicin, etoposide, liposomal doxorubicin, melphalan), or other treatments (i.e., selinexor, an inhibitor of nuclear export). Patients were included if they initiated the first MM treatment ≤ 1 month prior to or any time after the MM diagnosis date, and if they initiated first-line therapy for first observed treatment for MM on or after January 1, 2012. Patients were enrolled in an integrated delivery network and must have had at least one medical activity within 12 months prior to the index date (date of initiation of the line of therapy) and at least one medical activity within 2 months after the index date.Table 1 Analysis population\n\n\tn\t% Remaining\t\nInclusion criteria\t\t\t\n Patients with ≥ 2 medical records with a diagnosis for MM at least 30 days apart but no more than 365 days apart\t45,663\t–\t\n Patients with ≥ 1 medical record with a procedure code or a prescription fill for an MM treatment at anytime\t21,324\t47%\t\n Patients who were initiated on the first MM treatment within 1 month prior to or any time after the first observed diagnosis for MM\t20,177\t95%\t\n Patients with their first observed MM treatment (defined as the index date) on or after 2012\t16,784\t83%\t\n Patients aged ≥ 18 years as of the first observed MM treatment\t16,779\t100%\t\n Patient enrolled in an integrated delivery network (IDN)\t10,939\t65%\t\nExclusion criteria\t\t\t\n Patients with an indicator of enrollment in a clinical trial on or after first observed treatment for MM\t10,244\t94%\t\n Patients with ≥ 2 medical records on different days with a diagnosis for a blood cancer other than MM anytime\t9354\t91%\t\n Patients with a diagnosis for neoplasms of unspecified behavior (ICD-9-CM: 239; ICD-10-CM: D49) on or after the first observed MM diagnosis\t8732\t93%\t\n Patients with ≥ 2 medical records with a diagnosis for malignant neoplasm within 2 years prior to the index date\t6468\t74%\t\n Patient with an indicator of SCT any time prior to the index date\t5997\t93%\t\n Patients with ≥ 1 medical record with a diagnosis for relapse/remission MM (ICD-9-CM: 203.01 or 203.02; ICD-10-CM: C90.01 or C90.02) any time prior to the index date\t5186\t86%\t\nMM multiple myeloma, SCT stem cell transplant\n\nExclusion Criteria\n\nPatients were excluded if any of the following criteria were met: an indicator of enrollment in a clinical trial on or after the first observed treatment for MM, ≥ 2 medical records on different days with a diagnosis for a blood cancer other than MM at any time, ≥ 1 medical record with a diagnosis for neoplasm of unspecified nature on or after the first observed treatment for MM, ≥ 2 medical records with a diagnosis for malignant neoplasm ≤ 2 years prior to the first observed treatment for MM, an indicator of stem cell transplant (SCT) prior to the first observed treatment for MM, ≥ 1 medical record with a diagnosis for relapsed MM or MM in remission prior to the first observed treatment for MM, or first-line treatment with melphalan or doxorubicin (with or without corticosteroids) before an indicator of SCT.\n\nOutcome Definitions\n\nFor time to next treatment, an event was defined as the start of the subsequent line of therapy, which was the date of the first occurrence of (a) treatment switch, (b) treatment add-on, (c) resumption of MM treatment (old or new regimen) after a treatment discontinuation (a drop of all therapeutic agents of the treatment regimen for > 90 days), or (d) death. For overall survival, an event was defined as death.\n\nSubgroups\n\nTo be included in the asthma group, patients had ≥ 1 medical record with a diagnosis for asthma during the 12-month baseline period prior to initiating treatment. To be included in the COPD group, patients had ≥ 1 medical record with a diagnosis for COPD during the 12-month baseline period prior to initiating treatment. To be included in the asthma or COPD group, patients had ≥ 1 medical record with a diagnosis for asthma or COPD during the 12-month baseline period prior to initiating treatment.\n\nStatistical Analysis\n\nPatient characteristics were summarized by line of therapy for the first four lines of therapy and replicated separately among the following subgroups: (a) patients with COPD, (b) patients without COPD, (c) patients with asthma, (d) patients without asthma, (e) patients with either asthma or COPD (asthma/COPD), and (f) patients with neither asthma nor COPD. Mean, standard deviation, and median are presented for continuous variables, and the frequency and percentage are presented for categorical variables.\n\nFor time-to-next-treatment analyses, patients were observed from the line of therapy initiation to start of the subsequent line of therapy. Patients without a subsequent line of therapy were censored at the earliest of death, the date of their last medical activity, or the end of the study period. For overall survival analyses, patients were observed from the line of therapy initiation to date of death, or patients without an observed date of death were censored at the end of the study period or the date of last medical activity.\n\nPatients with asthma, COPD, or asthma/COPD were compared with patients without asthma, COPD, or asthma/COPD for time to next treatment and overall survival using a one-sided log-rank test stratified by age. Cox proportional hazard models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for time to next treatment and overall survival, adjusted for age, sex, race, geographic region, insurance type, and Quan–Charlson comorbidity index (QCCI).\n\nResults\n\nPatient Characteristics\n\nA total of 5186 patients with MM were included in the analysis (Table 2). Of these patients, 10.1% (n = 524) had a COPD diagnosis at baseline, 7.2% (n = 373) had an asthma diagnosis at baseline, and 15.4% (n = 799) had a diagnosis of asthma or COPD at baseline. The most commonly observed comorbidities among all MM patients and among those MM patients with asthma/COPD included cardiovascular disease, diabetes, and renal impairment. Both patients with asthma or COPD and patients without asthma or COPD had a median age of 69 years, and similar proportions were observed across the age categories.Table 2 Patient characteristics\n\n\tFirst line\t\nAll\n(N = 5186)\tCOPD\n(n = 524)\tNo COPD\n(n = 4662)\tAsthma\n(n = 373)\tNo asthma\n(n = 4813)\tCOPD or asthma\n(n = 799)\tNeither COPD nor asthma\n(n = 4387)\t\nAt the index datea\t\t\t\t\t\t\t\t\n Age (years)\t\n Mean (SD)\t68.4 (11.0)\t70.2 (9.8)\t68.2 (11.1)\t67.6 (10.2)\t68.5 (11.0)\t69.2 (10.0)\t68.2 (11.1)\t\n Median\t69\t70\t69\t68\t69\t69\t69\t\n Age categories, n (%)\t\n < 50\t267 (5)\t7 (1)\t260 (6)\t17 (5)\t250 (5)\t21 (3)\t246 (6)\t\n 50–54\t258 (5)\t18 (3)\t240 (5)\t19 (5)\t239 (5)\t34 (4)\t224 (5)\t\n 55–59\t488 (9)\t49 (9)\t439 (9)\t40 (11)\t448 (9)\t75 (9)\t413 (9)\t\n 60–64\t814 (16)\t78 (15)\t736 (16)\t62 (17)\t752 (16)\t122 (15)\t692 (16)\t\n 65–69\t833 (16)\t92 (18)\t741 (16)\t75 (20)\t758 (16)\t150 (19)\t683 (16)\t\n 70–74\t814 (16)\t88 (17)\t726 (16)\t57 (15)\t757 (16)\t133 (17)\t681 (16)\t\n 75–79\t775 (15)\t86 (16)\t689 (15)\t57 (15)\t718 (15)\t127 (16)\t648 (15)\t\n 80–84\t709 (14)\t74 (14)\t635 (14)\t31 (8)\t678 (14)\t95 (12)\t614 (14)\t\n ≥ 85\t228 (4)\t32 (6)\t196 (4)\t15 (4)\t213 (4)\t42 (5)\t186 (4)\t\n Race, n (%)\t\n Caucasian\t3953 (76)\t399 (76)\t3554 (76)\t258 (69)\t3695 (77)\t590 (74)\t3363 (77)\t\n African American\t903 (17)\t105 (20)\t798 (17)\t90 (24)\t813 (17)\t167 (21)\t736 (17)\t\n Asian\t55 (1)\t1 (0)\t54 (1)\t5 (1)\t50 (1)\t6 (1)\t49 (1)\t\n Other/unknown\t275 (5)\t19 (4)\t256 (5)\t20 (5)\t255 (5)\t36 (5)\t239 (5)\t\n Ethnicity, n (%)\t\n Hispanic\t201 (4)\t15 (3)\t186 (4)\t18 (5)\t183 (4)\t33 (4)\t168 (4)\t\n Non-Hispanic\t4725 (91)\t486 (93)\t4239 (91)\t337 (90)\t4388 (91)\t730 (91)\t3995 (91)\t\n Unknown\t260 (5)\t23 (4)\t237 (5)\t18 (5)\t242 (5)\t36 (5)\t224 (5)\t\n Sex, n (%)\t\n Female\t2456 (47)\t239 (46)\t2217 (48)\t206 (55)\t2250 (47)\t396 (50)\t2060 (47)\t\n Male\t2724 (53)\t285 (54)\t2439 (52)\t166 (45)\t2558 (53)\t402 (50)\t2322 (53)\t\n Unknown\t6 (0)\t\t6 (0)\t1 (0)\t5 (0)\t1 (0)\t5 (0)\t\n Region of residence, n (%)\t\n Northeast\t708 (14)\t63 (12)\t645 (14)\t49 (13)\t659 (14)\t96 (12)\t612 (14)\t\n Midwest\t2808 (54)\t310 (59)\t2498 (54)\t229 (61)\t2579 (54)\t472 (59)\t2336 (53)\t\n South\t1147 (22)\t99 (19)\t1048 (22)\t64 (17)\t1083 (23)\t152 (19)\t995 (23)\t\n West\t414 (8)\t41 (8)\t373 (8)\t23 (6)\t391 (8)\t61 (8)\t353 (8)\t\n Other/unknown\t109 (2)\t11 (2)\t98 (2)\t8 (2)\t101 (2)\t18 (2)\t91 (2)\t\n Calendar year, n (%)\t\n 2012\t453 (8.74)\t37 (7.06)\t416 (8.92)\t19 (5.09)\t434 (9.02)\t52 (6.51)\t401 (9.14)\t\n 2013\t570 (10.99)\t52 (9.92)\t518 (11.11)\t34 (9.12)\t536 (11.14)\t79 (9.89)\t491 (11.19)\t\n 2014\t658 (12.69)\t67 (12.79)\t591 (12.68)\t49 (13.14)\t609 (12.65)\t107 (13.39)\t551 (12.56)\t\n 2015\t707 (13.63)\t68 (12.98)\t639 (13.71)\t41 (10.99)\t666 (13.84)\t99 (12.39)\t608 (13.86)\t\n 2016\t772 (14.89)\t72 (13.74)\t700 (15.02)\t70 (18.77)\t702 (14.59)\t118 (14.77)\t654 (14.91)\t\n 2017\t768 (14.81)\t94 (17.94)\t674 (14.46)\t67 (17.96)\t701 (14.56)\t141 (17.65)\t627 (14.29)\t\n 2018\t646 (12.46)\t72 (13.74)\t574 (12.31)\t50 (13.40)\t596 (12.38)\t108 (13.52)\t538 (12.26)\t\n 2019\t612 (11.80)\t62 (11.83)\t550 (11.80)\t43 (11.53)\t569 (11.82)\t95 (11.89)\t517 (11.78)\t\n Time from MM diagnosis to treatment line initiation (months)\t\n Mean (SD)\t9.1 (17.2)\t6.9 (13.8)\t9.4 (16.5)\t7.3 (14.8)\t9.3 (17.4)\t7.2 (14.7)\t9.5 (17.6)\t\n Insurance type, n (%)\t\n Commercial\t1630 (31)\t117 (22)\t1513 (32)\t128 (34)\t1502 (31)\t223 (28)\t1407 (32)\t\n Medicare\t2755 (53)\t314 (60)\t2441 (52)\t186 (50)\t2569 (53)\t449 (56)\t2306 (53)\t\n Medicaid\t220 (4)\t38 (7)\t182 (4)\t27 (7)\t193 (4)\t51 (6)\t169 (4)\t\n Other payor type\t83 (2)\t8 (2)\t75 (2)\t2 (1)\t81 (2)\t10 (1)\t73 (2)\t\n Uninsured\t64 (1)\t8 (2)\t56 (1)\t7 (2)\t57 (1)\t12 (2)\t52 (1)\t\n Unknown\t275 (5)\t32 (6)\t243 (5)\t19 (5)\t256 (5)\t45 (6)\t230 (5)\t\n Missing\t159 (3)\t7 (1)\t152 (3)\t4 (1)\t155 (3)\t9 (1)\t150 (3)\t\n Integrated patient, n (%)\t\n Yes\t1320 (25)\t125 (24)\t1195 (26)\t119 (32)\t1201 (25)\t215 (27)\t1105 (25)\t\n No\t3866 (75)\t399 (76)\t3467 (74)\t254 (68)\t3612 (75)\t584 (73)\t3282 (75)\t\nDuring the baseline periodb\t\n Quan–Charlson comorbidity index (excluding MM)\t\n Mean (SD)\t2.7 (3.1)\t5.2 (3.2)\t2.4 (3.0)\t4.7 (3.2)\t2.6 (3.1)\t5 (3.2)\t2.3 (3.0)\t\n Comorbidities, n (%)\t\n Anemia\t751 (14)\t115 (22)\t636 (14)\t79 (21)\t672 (14)\t166 (21)\t585 (13)\t\n Cardiovascular disease\t2659 (51)\t386 (74)\t2273 (49)\t279 (75)\t2380 (49)\t582 (73)\t2077 (47)\t\n Diabetes\t1094 (21)\t175 (33)\t919 (20)\t136 (36)\t958 (20)\t271 (34)\t823 (19)\t\n Hypercalcemia\t648 (12)\t74 (14)\t574 (12)\t55 (15)\t593 (12)\t123 (15)\t525 (12)\t\n Peripheral neuropathy\t357 (7)\t58 (11)\t299 (6)\t29 (8)\t328 (7)\t81 (10)\t276 (6)\t\n Renal impairment\t1363 (26)\t215 (41)\t1148 (25)\t134 (36)\t1229 (26)\t303 (38)\t1060 (24)\t\n Skeletal-related events\t878 (17)\t130 (25)\t748 (16)\t75 (20)\t803 (17)\t185 (23)\t693 (16)\t\n Thrombocytopenia\t546 (11)\t87 (17)\t459 (10)\t54 (14)\t492 (10)\t122 (15)\t424 (10)\t\nMM multiple myeloma, SD standard deviation\n\naIndex date was defined as the start for the treatment line\n\nbBaseline period was defined as the 12-month period prior to each treatment start date, excluding the index date\n\nThe second-line analysis included 2386 patients (161 [6.7%] with asthma and 184 [7.7%] with COPD). The third-line analysis included 1064 patients (68 [6.4%] with asthma and 78 [7.3%] with COPD). The fourth-line analysis included 474 patients (33 [7.0%] with asthma and 28 [5.9%] with COPD).\n\nA description of asthma/COPD and MM treatments are shown in Tables 3 and 4, respectively. The most common treatments for patients with asthma/COPD were systemic corticosteroids (76.7%, asthma; 72.7%, COPD), oral corticosteroids (70.5%, asthma; 70.0%, COPD), and short-acting beta agonists (56.6%, asthma; 55.7%, COPD) (Table 3).Table 3 Description of asthma and COPD treatments\n\n\tFirst line\t\nAsthma\tCOPD\t\nn = 373\tn = 524\t\nAsthma + COPD treatments, n (%)\t\t\t\n SABA (Y/N)\t211 (56.6)\t292 (55.7)\t\n LABA (Y/N)\t18 (4.8)\t32 (6.1)\t\n ICS (Y/N)\t31 (8.3)\t33 (6.3)\t\n ICS dose low\t0\t2 (0.4)\t\n ICS dose medium\t26 (7.0)\t27 (5.2)\t\n ICS dose high\t7 (1.9)\t8 (1.5)\t\n Leukotriene modifiers (Y/N)\t53 (14.2)\t31 (5.9)\t\n Theophylline (Y/N)\t3 (0.8)\t6 (1.1)\t\n Tiotropium (Y/N)\t26 (7.0)\t69 (13.2)\t\n OCS use (Y/N)\t263 (70.5)\t367 (70.0)\t\n Systemic corticosteroids (Y/N)\t286 (76.7)\t381 (72.7)\t\n Controller medication\t131 (35.1)\t171 (32.6)\t\n 1 type of controller mediation (Y/N)\t91 (24.4)\t119 (22.7)\t\n 2 types of controller medications (Y/N)\t32 (8.6)\t44 (8.4)\t\n ≥ 3 types of controller medications (Y/N)\t8 (2.1)\t8 (1.5)\t\n ICS only\t3 (0.8)\t1 (0.2)\t\n ICS + SABA\t10 (2.7)\t14 (2.7)\t\n ICS + LABA\t98 (26.3)\t126 (24.0)\t\n Triple or more therapy\t13 (3.5)\t16 (3.1)\t\nCOPD specific\t\t\t\n LAMA (Y/N)\t61 (16.4)\t129 (24.6)\t\n LAMA + LABA (Y/N)\t5 (1.3)\t9 (1.7)\t\n Long-term oxygen use (Y/N)\t1 (0.3)\t8 (1.5)\t\n Systematic antibiotics (Y/N)\t217 (58.2)\t303 (57.8)\t\nICS inhaled corticosteroid, LABA long-acting beta agonist, LAMA long-acting muscarinic antagonist, OCS oral corticosteroid, SABA short-acting beta agonist, Y/N yes or no response\n\nTable 4 Description of multiple myeloma treatments\n\n\tFirst line\t\n\tAll\n(N = 5186)\tCOPD\n(n = 524)\tAsthma\n(n = 373)\tCOPD or asthma\n(n = 799)\tNeither COPD nor asthma (n = 4387)\t\nType of treatment, n (%)\t\t\t\t\t\t\n IMiDs\t3071 (59.22)\t288 (54.96)\t223 (59.79)\t460 (57.57)\t2611 (59.52)\t\n Thalidomide\t173 (3.34)\t18 (3.44)\t16 (4.29)\t28 (3.50)\t145 (3.31)\t\n Lenalidomide\t2803 (54.05)\t258 (49.24)\t204 (54.69)\t417 (52.19)\t2386 (54.39)\t\n Pomalidomide\t126 (2.43)\t17 (3.24)\t5 (1.34)\t21 (2.63)\t105 (2.39)\t\n PIs\t2871 (55.36)\t305 (58.21)\t213 (57.10)\t457 (57.20)\t2414 (55.03)\t\n Bortezomib\t2684 (51.75)\t299 (57.06)\t205 (54.96)\t445 (55.69)\t2239 (51.04)\t\n Carfilzomib\t164 (3.16)\t4 (0.76)\t10 (2.68)\t13 (1.63)\t151 (3.44)\t\n Ixazomib\t61 (1.18)\t3 (0.57)\t2 (0.54)\t4 (0.50)\t57 (1.30)\t\n HDAC inhibitors\t1 (0.02)\t1 (0.19)\t0 (0)\t1 (0.13)\t0 (0)\t\n Panobinostat\t1 (0.02)\t1 (0.19)\t0 (0)\t1 (0.13)\t0 (0)\t\n Monoclonal antibodies\t111 (2.14)\t9 (1.72)\t4 (1.07)\t11 (1.38)\t100 (2.28)\t\n Daratumumab\t101 (1.95)\t9 (1.72)\t4 (1.07)\t11 (1.38)\t90 (2.05)\t\n Elotuzumab\t11 (0.21)\t0 (0)\t0 (0)\t0 (0)\t11 (0.25)\t\n Isatuximab\t\t\t\t\t\t\n Chemotherapy\t1188 (22.91)\t114 (21.76)\t101 (27.08)\t184 (23.03)\t1004 (22.89)\t\n Bendamustine\t10 (0.19)\t1 (0.19)\t1 (0.27)\t1 (0.13)\t9 (0.21)\t\n Cisplatin\t63 (1.21)\t6 (1.15)\t4 (1.07)\t8 (1.00)\t55 (1.25)\t\n Cyclophosphamide\t1051 (20.27)\t107 (20.42)\t90 (24.13)\t169 (21.15)\t882 (20.10)\t\n Doxorubicin\t126 (2.43)\t8 (1.53)\t9 (2.41)\t16 (2.00)\t110 (2.51)\t\n Etoposide\t74 (1.43)\t5 (0.95)\t5 (1.34)\t9 (1.13)\t65 (1.48)\t\n Liposomal doxorubicin\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\n Melphalan\t129 (2.49)\t7 (1.34)\t9 (2.41)\t13 (1.63)\t116 (2.64)\t\nTop 10 treatment regimens (mono or combination therapy), n (%)\t\t\t\t\t\t\n 1\tLenalidomide, 1657 (32.0)\tLenalidomide, 160 (30.5)\tLenalidomide, 116 (31.1)\tLenalidomide, 250 (31.3)\tLenalidomide, 1407 (32.1)\t\n 2\tBortezomib, 1041 (20.1)\tBortezomib, 136 (26.0)\tLenalidomide, bortezomib, 67 (18.0)\tBortezomib, 180 (22.5)\tBortezomib, 861 (19.6)\t\n 3\tLenalidomide, bortezomib, 831 (16.0)\tLenalidomide, bortezomib, 77 (14.7)\tBortezomib, 65 (17.4)\tLenalidomide, bortezomib, 131 (16.4)\tLenalidomide, bortezomib, 700 (16.0)\t\n 4\tBortezomib, cyclophosphamide, 516 (9.9)\tBortezomib, cyclophosphamide, 61 (11.6)\tBortezomib, cyclophosphamide, 48 (12.9)\tBortezomib, cyclophosphamide, 92 (11.5)\tBortezomib, cyclophosphamide, 424 (9.7)\t\n 5\tCyclophosphamide, 243 (4.7)\tCyclophosphamide, 19 (3.6)\tCyclophosphamide, 19 (5.1)\tCyclophosphamide, 35 (4.4)\tCyclophosphamide, 208 (4.7)\t\n 6\tPomalidomide, 81 (1.6)\tPomalidomide, 12 (2.3)\tThalidomide, 6 (1.6)\tPomalidomide, 15 (1.9)\tPomalidomide, 66 (1.5)\t\n 7\tThalidomide, 65 (1.3)\tThalidomide, 8 (1.5)\tBortezomib, cyclophosphamide, lenalidomide, 6 (1.6)\tThalidomide, 11 (1.4)\tCarfilzomib, 57 (1.3)\t\n 8\tLenalidomide, bortezomib, cyclophosphamide, 65 (1.3)\tBortezomib, cyclophosphamide, lenalidomide, 8 (1.5)\tLenalidomide, bortezomib, cyclophosphamide, 5 (1.3)\tBortezomib, cyclophosphamide, lenalidomide, 11 (1.4)\tLenalidomide, bortezomib, cyclophosphamide, 56 (1.3)\t\n 9\tMelphalan, 62 (1.2)\tLenalidomide, bortezomib, cyclophosphamide, 5 (1.0)\tMelphalan, 5 (1.3)\tLenalidomide, bortezomib, cyclophosphamide, 9 (1.1)\tMelphalan, 55 (1.3)\t\n 10\tCarfilzomib, 60 (1.2)\tMelphalan, 4 (0.8)\tLenalidomide, carfilzomib, 3 (0.8)\tMelphalan, 7 (0.9)\tThalidomide, 54 (1.2)\t\nStem cell transplant (SCT)\t\t\t\t\t\t\n Yes\t319 (6.2)\t14 (2.7)\t18 (4.8)\t30 (3.8)\t289 (6.6)\t\n No\t4867 (93.8)\t510 (97.3)\t355 (95.2)\t769 (96.2)\t4098 (93.4)\t\nMaintenance therapy, n (%)\t186 (3.59)\t13 (2.48)\t14 (3.75)\t24 (3.00)\t162 (3.69)\t\n Bortezomib\t23 (0.44)\t1 (0.19)\t3 (0.80)\t4 (0.50)\t19 (0.43)\t\n Lenalidomide\t156 (3.01)\t12 (2.29)\t10 (2.68)\t19 (2.38)\t137 (3.12)\t\n Thalidomide\t7 (0.13)\t0 (0)\t1 (0.27)\t1 (0.13)\t6 (0.14)\t\nCombination therapy, n (%)\t\t\t\t\t\t\n 2-agent combination\t1614 (31.12)\t151 (28.82)\t127 (34.05)\t245 (30.66)\t1369 (31.21)\t\n 3-agent combination\t189 (3.64)\t20 (3.82)\t21 (5.63)\t34 (4.26)\t155 (3.53)\t\n 4-agent combination\t27 (0.52)\t2 (0.38)\t1 (0.27)\t3 (0.38)\t24 (0.55)\t\n ≥ 5-agent combination\t63 (1.21)\t4 (0.76)\t4 (1.07)\t7 (0.88)\t56 (1.28)\t\nTop 10 therapies by agent, n (%)\t\t\t\t\t\t\n 1\tLenalidomide, 2803 (54.05)\tBortezomib, 299 (57.06)\tBortezomib, 205 (54.96)\tBortezomib, 445 (55.69)\tLenalidomide, 2386 (54.39)\t\n 2\tBortezomib, 2684 (51.75)\tLenalidomide, 258 (49.24)\tLenalidomide, 204 (54.69)\tLenalidomide, 417 (52.19)\tBortezomib, 2239 (51.04)\t\n 3\tCyclophosphamide, 1051 (20.27)\tCyclophosphamide, 107 (20.42)\tCyclophosphamide, 90 (24.13)\tCyclophosphamide, 169 (21.15)\tCyclophosphamide, 882 (20.10)\t\n 4\tThalidomide, 173 (3.34)\tThalidomide, 18 (3.44)\tThalidomide, 16 (4.29)\tThalidomide, 28 (3.50)\tCarfilzomib, 151 (3.44)\t\n 5\tCarfilzomib, 164 (3.16)\tPomalidomide, 17 (3.24)\tCarfilzomib, 10 (2.68)\tPomalidomide, 21 (2.63)\tThalidomide, 145 (3.31)\t\n 6\tMelphalan, 129 (2.49)\tDaratumumab, 9 (1.72)\tDoxorubicin, 9 (2.41)\tDoxorubicin, 16 (2.00)\tMelphalan, 116 (2.64)\t\n 7\tPomalidomide, 126 (2.43)\tDoxorubicin, 8 (1.53)\tMelphalan, 9 (2.41)\tCarfilzomib, 13 (1.63)\tDoxorubicin, 110 (2.51)\t\n 8\tDoxorubicin, 126 (2.43)\tMelphalan, 7 (1.34)\tPomalidomide, 5 (1.34)\tMelphalan, 13 (1.63)\tPomalidomide, 105 (2.39)\t\n 9\tDaratumumab, 101 (1.95)\tCisplatin, 6 (1.15)\tEtoposide, 5 (1.34)\tDaratumumab, 11 (1.38)\tDaratumumab, 90 (2.05)\t\n 10\tEtoposide, 74 (1.43)\tEtoposide, 5 (0.95)\tCisplatin, 4 (1.07)\tEtoposide, 9 (1.13)\tEtoposide, 65 (1.48)\t\nTop 5 therapies by type, n (%)\t\t\t\t\t\t\n 1\tIMiDs, 3102 (59.81)\tPIs, 306 (58.40)\tIMiDs, 225 (60.32)\tIMiDs, 466 (58.32)\tIMiDs, 2636 (60.09)\t\n 2\tPIs, 2909 (56.09)\tIMiDs, 293 (55.92)\tPIs, 217 (58.18)\tPIs, 462 (57.82)\tPIs, 2447 (55.78)\t\n 3\tChemotherapy, 1453 (28.02)\tChemotherapy, 134 (25.57)\tChemotherapy, 118 (31.64)\tChemotherapy, 216 (27.03)\tChemotherapy, 1237 (28.20)\t\n 4\tMonoclonal antibodies, 112 (2.16)\tMonoclonal antibodies, 9 (1.72)\tMonoclonal antibodies, 4 (1.07)\tMonoclonal antibodies, 11 (1.38)\tMonoclonal antibodies, 101 (2.30)\t\n 5\tHDAC inhibitors, 1 (0.02)\tHDAC inhibitors, 1 (0.19)\t\tHDAC inhibitors, 1 (0.13)\t\t\nCharacteristics at the end of line of therapy, n (%)\t\t\t\t\t\t\n Treatment augmentation (add-on)\t300 (5.78)\t25 (4.77)\t24 (6.43)\t44 (5.51)\t256 (5.84)\t\n Treatment switch\t813 (15.68)\t60 (11.45)\t51 (13.67)\t103 (12.89)\t710 (16.18)\t\n Treatment discontinuation\t1214 (23.41)\t96 (18.32)\t84 (22.52)\t166 (20.78)\t1048 (23.89)\t\n SCT\t59 (1.14)\t3 (0.57)\t2 (0.54)\t5 (0.63)\t54 (1.23)\t\n Death\t120 (2.31)\t22 (4.20)\t15 (4.02)\t30 (3.75)\t90 (2.05)\t\n Censored\t\t\t\t\t\t\n Last date of medical activity\t720 (13.88)\t69 (13.17)\t52 (13.94)\t105 (13.14)\t615 (14.02)\t\n End of data availability\t1960 (37.79)\t249 (47.52)\t145 (38.87)\t346 (43.30)\t1614 (36.79)\t\nCOPD chronic obstructive pulmonary disease, HDAC histone deacetylase, IMiDs immunomodulatory drugs, PI proteasome inhibitor\n\nApproximately half of patients received first-line anti-myeloma treatment with bortezomib or lenalidomide (Table 4). Overall, 31.1% of patients received a two-agent combination. Evidence for receipt of SCT was low across the groups, particularly for patients with COPD. Steroids were assumed to be present in treatment lines due to concerns about adequate capture of steroid use.\n\nTime to Next Treatment\n\nFirst to Second Line\n\nThe median time to next treatment for patients with COPD was significantly longer compared with patients with no COPD (27.56 vs. 22.10 months; adjusted HR 0.71; 95% CI 0.61–0.83; p = 0.04; Fig. 1a). There was no significant difference in time to next treatment between patients with asthma and patients without asthma (25.83 vs. 22.56 months; adjusted HR 0.88; 95% CI 0.74–1.04). The median time to next treatment for patients with asthma or COPD was significantly longer compared with patients with no asthma nor COPD (25.83 vs. 22.38 months; adjusted HR 0.80; 95% CI 0.70–0.90).Fig. 1 Time to next treatment. Kaplan–Meier analyses were used to estimate time to next treatment from first to second line (a), second to third line (b), and third to fourth line (c). Patients were observed from the line of therapy initiation (index date) to the subsequent line of therapy initiation (event; earliest of second-line index date or date of death), or the observation period of patients without a subsequent line of therapy was censored at the end of follow-up (censoring; i.e., first event end of data availability, and end of continuous medical activity). Patients at risk were defined as the total number of patients who were still observed (no prior event and no censoring) at the specific time period (i.e., patients without the study event prior to that time point and who were still followed)\n\nSecond to Third Line\n\nNo significant differences in time to third-line treatment were observed in patients with/without COPD (18.93 vs. 18.66 months; HR 1.07; 95% CI 0.85–1.35), with/without asthma (19.03 vs. 18.66 months; HR 0.93; 95% CI 0.73–1.20), or with/without asthma or COPD (18.66 vs. 18.70 months; HR 1.02; 95% CI 0.85–1.22; Fig. 1b).\n\nThird to Fourth Line\n\nNo significant differences in time to fourth-line treatment were observed in patients with/without asthma (15.90 vs. 14.46 months; HR 1.02; 95% CI 0.71–1.46), with/without COPD (15.73 vs. 14.46 months; HR 0.96; 95% CI 0.65–1.42), or with/without asthma or COPD (15.90 vs. 14.26 months; HR 0.98; 95% CI 0.74–1.30; Fig. 1c).\n\nOverall Survival\n\nOverall Survival: Line 1\n\nOverall survival from the start of first-line therapy was significantly worse among patients with COPD compared with patients without COPD (38.8 vs. 67.9 months; adjusted HR 1.30; 95% CI 1.12–1.51; p < 0.005; Fig. 2). No significant differences in overall survival from first-line therapy were observed in patients with/without asthma (73.3 vs. 60.9 months; adjusted HR 0.90; 95% CI 0.75–1.10), or with/without asthma or COPD (45.03 vs. 66.86 months; adjusted HR 1.11; 95% CI 0.98–1.27).Fig. 2 Overall survival. Kaplan–Meier analyses were used to estimate overall survival. Patients were observed from the line of therapy initiation to death (event), or the observation period of patients without a subsequent line of therapy was censored at the end of follow-up (censoring; i.e., first event end of data availability, and end of continuous medical activity). Patients at risk were defined as the total number of patients who were still observed (no prior event and no censoring) at the specific time period (i.e., patients without the study event prior to that time point and who were still followed)\n\nOverall Survival: Line 2\n\nMM patients with COPD had worse overall survival from the start of second-line therapy compared with patients without COPD (35.70 vs. 49.86 months); however, this difference was not statistically significant in multivariable adjusted models (adjusted HR 1.26; 95% CI 0.98–1.61). No significant differences in overall survival were observed for MM patients with/without asthma (63.66 vs. 48.13 months; adjusted HR 1.01; 95% CI 0.76–1.35), or with/without asthma or COPD (39.56 vs. 48.96 months; adjusted HR 1.15; 95% CI 0.94–1.41). Similarly, numerically worse overall survival was observed from the start of third- and fourth-line therapy among MM patients with COPD (data not shown).\n\nDiscussion\n\nIn this study of patients with MM from the Optum EHR database, approximately 15% had a previous asthma or COPD diagnosis. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD or a diagnosis of asthma or COPD. Overall survival from start of first-line therapy was significantly worse among MM patients with COPD; numerically worse overall survival was observed from the start of lines 2–4.\n\nIn the current study of 5186 patients with MM, 15% of patients had an asthma or COPD diagnosis. This is similar to the proportion of patients in the ICARIA-MM study who had asthma or COPD (~ 10%) [10]. In ICARIA-MM, asthma and COPD were not used as exclusion criteria. Previous MM studies have used COPD/pulmonary disease as an exclusion criterion (e.g., POLLUX; ELOQUENT-2 [if uncontrolled]; CASTOR; CANDOR; MAIA; CASSIOPEIA) [11–16]. Asthma and COPD were used as exclusion criteria in these studies due to concern for bronchial hyperreactivity, infusion reactions, and need for additional pre- and post-medications [19]. Because of this, there are limited data in patients with MM and COPD who have been treated with monoclonal antibodies to date.\n\nBased on the assessment of MM treatments in the current study, real-world monoclonal antibody use is not reported frequently to date, lagging behind treatment guidelines [20]. Within the small number of patients who received monoclonal antibody treatment, there was a trend towards more use in patients without asthma/COPD (2.28%) than with asthma/COPD (1.38%), suggesting that there may be some reluctance to treat due to concern for bronchial hyperreactivity, infusion reactions, and to paucity of data due to exclusion of patients from clinical trials [11–16, 19].\n\nExtending time to next treatment can frequently be a main objective of MM therapy and can also be interpreted as a measure of delayed progression [21]. Based on the lack of significant differences in time to next treatment between patients with and without COPD or asthma, the comorbidity of COPD or asthma does not automatically portend a worse prognosis, and these patients should be considered for inclusion in future clinical trials. In fact, patients with COPD exhibited a significantly longer time from first- to second-line therapy compared with patients without COPD. These results provide real-world data that may help inform clinical decisions related to therapies for MM patients with asthma and COPD.\n\nIn the current study, overall survival from first-line therapy was significantly worse among patients with COPD, and numerical differences were observed in the second through fourth line; however, we had limited power to detect significant differences in later treatment lines due to the fact that the number of patients with COPD decreased from 524 patients in line 1 to 28 patients in line 4. Results from a recent study also demonstrated significantly worse overall survival among patients with obstructive pulmonary defects [18]. The presence of peak expiratory flow and/or carbon monoxide diffusion capacity < 65% of predicted were independent prognostic factors of survival in the study. These pulmonary function parameters were not explored in the current study, however, providing areas of interest for additional real-world studies.\n\nIn the current study, higher proportions of patients with asthma/COPD had diabetes and cardiovascular and renal comorbidities compared with patients without asthma/COPD. Therefore, the discrepancy between the observed prolonged time to next treatment in early treatment lines and decreased overall survival for patients with COPD may be linked to decreased receipt of later-line treatment and more associated comorbidities.\n\nPrevious studies have reported preexisting moderate or severe pulmonary disease to be a negative predictor of survival among patients with MM in a Swedish registry-based population [22], and an association between higher all-cause and myeloma-specific mortality and previous chronic pulmonary disease, independent of age [17].\n\nInterestingly, numerically longer survival was observed in patients with asthma in lines 2 and 3 and in patients with COPD/asthma in line 3 of the current study. It is possible that a proportion of patients in the groups without a history of asthma or COPD had abnormal lung function, which may only be identified during spirometry testing [23, 24]. Additional studies are needed to better understand the relationship between preexisting pulmonary comorbidities and survival among patients with MM.\n\nThis study has some limitations. Patients were classified as having asthma and/or COPD based on the presence of at least one medical record with a diagnosis of asthma/COPD in the 12-month period prior to the index date, which may have resulted in some misclassification. As with all observational studies, there is the potential for unmeasured or residual confounding, though we adjusted for several potential confounders, including age and QCCI. However, other factors, such as smoking status, were not accounted for, which may explain some of the differences in overall survival between subgroups. Additionally, the lower number of patients included in each subsequent line of therapy resulted in reduced power, limiting our ability to detect differences in outcomes between subgroups. Strengths of the study include the inclusion of real-world data on MM patients with asthma or COPD, which increases the available information on this patient subgroup. These data provide longer-term treatment and outcomes information that may be used to inform future studies on MM patients with pulmonary comorbidities.\n\nConclusions\n\nAmong 5186 patients with MM, approximately 15% had an asthma or COPD diagnosis at baseline. The most commonly observed comorbidities among all patients were cardiovascular disease, diabetes, and renal impairment, which were even higher among those with asthma or COPD. Time from first- to second-line treatment was significantly longer for patients with a diagnosis of COPD. Overall survival from start of first-line therapy was significantly worse among patients with COPD, with numerically worse overall survival in subsequent lines. These data suggest that patients with COPD do not experience a shorter time interval to next treatment, but they may exhibit worse overall survival from the start of first-line therapy. Future investigations with larger datasets may improve the understanding of the influence of individual treatments on outcomes in these patients with multiple myeloma and pulmonary comorbidities.\n\nAcknowledgements\n\nFunding\n\nSponsorship for this study and Rapid Service Fee were funded by Sanofi (Cambridge, MA, USA).\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published\n\nAuthorship Contributions\n\nAll authors contributed to the interpretation of the data and were involved in the process of writing and reviewing this manuscript. All authors take complete responsibility for the integrity of the data and accuracy of the data analysis. The authors acknowledge medical writing assistance from Erin Burns-Tidmore, PhD, of Elevate Medical Affairs, contracted by Sanofi Genzyme for publication support services. The authors acknowledge programming support from Meriem Garsaa, of Quinten, contracted by Sanofi Genzyme for analytic support services.\n\nDisclosures\n\nMegan S. Rice is employed by Sanofi and may hold stock and/or stock options in the company. Sarah Naeger is employed by Sanofi and may hold stock and/or stock options in the company. Erin Singh is employed by Sanofi and may hold stock and/or stock options in the company.\n\nCompliance with Ethics Guidelines\n\nThis article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.\n\nData Availability\n\nThe datasets generated during and/or analyzed during the current study are from the US Optum® de-identified electronic health record database housed in DARWIN, https://www.optum.com/business/solutions/government/federal/data-analytics-federal/clinical-data.html#.\n==== Refs\nReferences\n\n1. Kazandjian D Multiple myeloma epidemiology and survival: a unique malignancy Semin Oncol 2016 43 6 676 681 10.1053/j.seminoncol.2016.11.004 28061985\n2. Rajkumar SV Kumar S Multiple myeloma: diagnosis and treatment Mayo Clin Proc 2016 91 1 101 119 10.1016/j.mayocp.2015.11.007 26763514\n3. Rajkumar SV Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management Am J Hematol 2016 91 7 719 734 10.1002/ajh.24402 27291302\n4. Biran N Jagannath S Chari A Risk stratification in multiple myeloma, part 1: characterization of high-risk disease Clin Adv Hematol Oncol 2013 11 8 489 503 24518420\n5. Sanofi-Aventis U.S LLC. Sarclisa (isatuximab-irfc). Sanofi-Aventis U.S LLC. Bridgewater, NJ. 2020. http://products.sanofi.us/Sarclisa/sarclisa.pdf. Accessed 2 Mar 2020.\n6. Sarclisa® 100 mg/500 mg IV infusion approved for relapsed or refractory myeloma 2020 [press release]. Tokyo, Japan: Sanofi Japan. 2020. https://www.sanofi.co.jp/-/media/Project/One-Sanofi-Web/Websites/Asia-Pacific/Sanofi-JP/Home/press-releases/PDF/2020/200629-02.pdf?la=ja. Accessed 23 Jul 2020.\n7. European Commission approves Sarclisa® (isatuximab) for adults with relapsed and refractory multiple myeloma [press release]. Paris, France: Sanofi France. 2020. https://www.sanofi.com/en/media-room/press-releases/2020/2020-06-02-12-47-38. Accessed 2 Jun 2020.\n8. FDA approves Sarclisa (isatuximab-ifrc) for patients with relapsed refractory multiple myeloma [press release]. 2020. https://www.sanofi.com/en/media-room/press-releases/2020/2020-03-02-19-51-16. Accessed 26 Oct 2020.\n9. Sarclisa® (isatuximab) registration certificate in the Russian Federation. 2020. http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=c754e935-ad28-4c1d-a643-0564811a2a00&t. Accessed 27 Aug 2020.\n10. Attal M Richardson PG Rajkumar SV Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study Lancet 2019 394 10214 2096 2107 10.1016/S0140-6736(19)32556-5 31735560\n11. Dimopoulos MA Oriol A Nahi H Daratumumab, lenalidomide, and dexamethasone for multiple myeloma N Engl J Med 2016 375 14 1319 1331 10.1056/NEJMoa1607751 27705267\n12. Lonial S Dimopoulos M Palumbo A Elotuzumab therapy for relapsed or refractory multiple myeloma N Engl J Med 2015 373 7 621 631 10.1056/NEJMoa1505654 26035255\n13. Palumbo A Chanan-Khan A Weisel K Daratumumab, bortezomib, and dexamethasone for multiple myeloma N Engl J Med 2016 375 8 754 766 10.1056/NEJMoa1606038 27557302\n14. Dimopoulos M Quach H Mateos MV Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study Lancet 2020 396 10245 186 197 10.1016/S0140-6736(20)30734-0 32682484\n15. Facon T Kumar S Plesner T Daratumumab plus lenalidomide and dexamethasone for untreated myeloma N Engl J Med 2019 380 22 2104 2115 10.1056/NEJMoa1817249 31141632\n16. Moreau P Attal M Hulin C Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study Lancet 2019 394 10192 29 38 10.1016/S0140-6736(19)31240-1 31171419\n17. Mohammadi M Cao Y Glimelius I Bottai M Eloranta S Smedby KE The impact of comorbid disease history on all-cause and cancer-specific mortality in myeloid leukemia and myeloma—a Swedish population-based study BMC Cancer 2015 15 850 10.1186/s12885-015-1857-x 26537111\n18. Trakada G Kastritis E Gavriatopoulou M Pulmonary function abnormalities are common in patients with multiple myeloma and are independently associated with worse outcome Ann Hematol 2019 98 6 1427 1434 10.1007/s00277-019-03641-x 30834954\n19. Janssen Biotech. Darzalex (daratumumab). Janssen Biotech. 2020. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf. Accessed 10 Nov 2020.\n20. Mikhael J Ismaila N Cheung MC Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline J Clin Oncol 2019 37 14 1228 1263 10.1200/JCO.18.02096 30932732\n21. Song X Cong Z Wilson K Real-world treatment patterns, comorbidities, and disease-related complications in patients with multiple myeloma in the United States Curr Med Res Opin 2016 32 1 95 103 10.1185/03007995.2015.1105202 26488820\n22. Kleber M Ihorst G Gross B Validation of the Freiburg Comorbidity Index in 466 multiple myeloma patients and combination with the international staging system are highly predictive for outcome Clin Lymphoma Myeloma Leuk 2013 13 5 541 551 10.1016/j.clml.2013.03.013 23810244\n23. Vogelmeier CF Criner GJ Martinez FJ Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary Respirology 2017 22 3 575 601 10.1111/resp.13012 28150362\n24. Mathers CD Loncar D Projections of global mortality and burden of disease from 2002 to 2030 PLoS Med 2006 3 11 e442 10.1371/journal.pmed.0030442 17132052\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2366-1089",
"issue": "9(1)",
"journal": "Oncology and therapy",
"keywords": "Asthma; COPD; Multiple myeloma; Real-world evidence",
"medline_ta": "Oncol Ther",
"mesh_terms": null,
"nlm_unique_id": "101677510",
"other_id": null,
"pages": "195-212",
"pmc": null,
"pmid": "33728584",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "26488820;24518420;28061985;30932732;27291302;28150362;23810244;27557302;31171419;31735560;31141632;17132052;26035255;26763514;27705267;32682484;30834954;26537111",
"title": "Real-World Treatment Patterns and Outcomes Among Multiple Myeloma Patients with Asthma and COPD in the United States.",
"title_normalized": "real world treatment patterns and outcomes among multiple myeloma patients with asthma and copd in the united states"
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"companynumb": "US-AMGEN-USASP2021128111",
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"abstract": "73-year-old man with ulcerative colitis was diagnosed with Campylobacter jejuni prosthetic knee infection. No preceding gastrointestinal illness was reported. Joint aspirate and operative cultures were negative; however, blood cultures were positive for Campylobacter jejuni. The role of ulcerative colitis in inducing bacteremia and subsequent prosthetic joint infection is discussed.",
"affiliations": "Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.;Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.;Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.",
"authors": "Ali|Sehar|S|;Siddiqui|Budder|B|;Lawal|Folake|F|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00920",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30228-6\n10.1016/j.idcr.2020.e00920\ne00920\nArticle\nCampylobacter jejuni prosthetic joint infection in an ulcerative colitis patient in the absence of gastrointestinal symptoms\nAli Sehar Siddiqui Budder Lawal Folake jfkidowu@gmail.com⁎ Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA\n⁎ Corresponding author at: 1120 15thSt, AE- 3024, Augusta, 30912, Georgia. jfkidowu@gmail.com\n30 7 2020 \n2020 \n30 7 2020 \n22 e0092023 6 2020 18 7 2020 18 7 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).73-year-old man with ulcerative colitis was diagnosed with Campylobacter jejuni prosthetic knee infection. No preceding gastrointestinal illness was reported. Joint aspirate and operative cultures were negative; however, blood cultures were positive for Campylobacter jejuni. The role of ulcerative colitis in inducing bacteremia and subsequent prosthetic joint infection is discussed.\n\nKeywords\nProsthetic joint infectionCampylobacter jejuniSeptic arthritisBacteremia\n==== Body\nIntroduction\nCampylobacter jejuni is most commonly known as a foodborne pathogen that causes about 1.5 million illnesses each year in the United States [1]. Gastroenteritis generally occurs following the consumption of contaminated undercooked meat, particularly poultry [1]. This illness is self-limited and does not usually require antibacterial treatment. While gastroenteritis is a common manifestation of Campylobacter species infection, subsequent bacteremia and joint space infections are uncommon. Here we describe a case of Campylobacter jejuni prosthetic joint infection following bacteremia in a patient with ulcerative colitis that presented without any associated intestinal symptoms.\n\nCase report\nA 73-year-old man with a prosthetic right knee joint presented to the emergency room with sudden onset of right knee pain, redness, and swelling. He reported a history of atrial fibrillation, ulcerative colitis, prostate cancer, and hypertension. His medications included apixaban, mesalamine, 6-mercaptopurine, leuprolide, lisinopril, metoprolol, and rosuvastatin. He also had extensive history of right knee surgery including a right total knee arthroplasty in 2007, a lysis of adhesions in 2012, and two manipulations under anesthesia, one of which was complicated by wound dehiscence. At that time, he underwent irrigation and debridement and was started on five weeks of antibacterial therapy, though cultures were negative. Since then, the patient reported that he has had mild knee stiffness.\n\nHowever, on the morning of admission, the patient described difficulty with range of motion of the right knee and an inability to ambulate. He denied trauma or inciting event, stating that he was able to ambulate well the previous day. He denied a history of gout, subjective fever, chills, cough, nausea, vomiting, or diarrhea. The patient was retired and lived at home with his wife. He denied contact with animals and reported no recent travel. He reported eats cooked meat at home and at restaurants regularly, although he did not feel he had eaten anything out of the ordinary.\n\nOn physical examination, the patient was febrile with a temperature of 39.2 °C, with heart rate of 81 bpm and blood pressure of 136/78 mmHg. There was swelling of the right lower extremity from the ankle to the mid-thigh. His right knee was markedly warmer than his left and was tender to palpation with a limited range of motion. There was no rash, erythema, or obvious signs of trauma noted. Knee radiographs were taken and showed osteolysis surrounding both the femoral and tibial implants as well as a moderate joint effusion. An arthrocentesis of the right knee yielded 30 mL of bloody purulent fluid that was sent for analysis and culture. Preliminary studies of joint aspirate showed 212,000 red blood cells/μL, 35,100 white blood cells/mm3 with 97 % segmented neutrophils, with the absence of crystals. Initial laboratory assessment demonstrated a complete blood count and comprehensive metabolic panel that were at baseline. However, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated at 61 mm/hr and 1.741 mg/dL, respectively. Gram stain of the joint aspirate was negative with moderate neutrophils. Bacterial cultures of aspirate yielded no organisms. Although this synovial fluid analysis may have represented an inflammatory arthritis, the history of prosthetic right knee joint with multiple surgeries made the diagnosis most consistent with septic arthritis until proven otherwise. Therefore, the patient was started on empiric intravenous (IV) vancomycin dosed to trough of 15–20 μg/mL and cefepime 2 g IV every 8 h.\n\nOn hospital day five, 1 of the 4 admission blood cultures were positive for Campylobacter jejuni. With this result, vancomycin and cefepime were discontinued and the patient was started on ertapenem 1 g IV every 24 h. He then underwent explantation of the right total knee arthroplasty with placement of a vancomycin and tobramycin saturated spacer. During the procedure, cloudy sanguineous material was noted along with loose hardware. Two periprosthetic tissue samples were sent for aerobic, anaerobic, and fungal cultures as well as gram stain. However, these samples returned with negative results. Repeat blood cultures after five days of treatment with vancomycin/cefepime and two days of ertapenem also returned with negative results. Transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) were scheduled to rule out endocarditis in the setting of bacteremia, however the patient was unable to tolerate the TEE after the TTE was unremarkable for endocarditis. The blood culture report was finalized without antibacterial susceptibility data and patient was discharged with instructions to continue ertapenem 1 g IV for a duration of 6 weeks. This allowed for broad coverage of most organisms other than methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas, as recurrent prosthetic joint infections are commonly polymicrobial [2].\n\nAfter completing six weeks of IV ertapenem, the patient had decreased swelling of his knee. However, he continued to complain of persistent limitation with range of motion. Full extension of his right knee was limited by 10 degrees and flexion was less than 45 degrees. His ESR and CRP had declined to 27 mm/hr and 1.444 mg/dL, respectively. Due to the persistence of his symptoms after treatment with IV ertapenem, the patient was placed on oral moxifloxacin 400 mg daily and amoxicillin-clavulanate 875 mg twice daily for 8 weeks. At the end of this course, he had improvement of his knee flexion to 70–80 degrees with minimal swelling. His ESR and CRP had decreased to 12 mm/hr and 0.388 mg/dL, respectively. To ensure his infection was cleared, the patient agreed with orthopedic surgery to keep the spacer, an all-poly tibial and femoral implant, while he considered his options for total knee arthroplasty.\n\nDiscussion\nCampylobacter bacteremia associated with prosthetic joint infection (PJI) as seen in our patient are very rare extraintestinal manifestations of infection [3]. To our knowledge, less than twenty-five cases of Campylobacter PJI have been reported worldwide [[4], [5], [6], [7], [8]]. Of these cases, most have been associated with Campylobacter fetus, while only three have been associated with Campylobacter jejuni [[4], [5], [6], [7]]. Initial infection with Campylobacter species commonly presents as acute gastroenteritis [1]. However, some studies have found that a sizable portion (up to 45.5 %) of patients with Campylobacter bacteremia did not present with intestinal symptoms such as watery diarrhea and abdominal pain [3]. Additionally, five cases of Campylobacter PJI have been reported with no preceding diarrheal illness like in our patient [5]. Campylobacter bacteremia is more frequently seen in immunocompromised patients with the most common source of blood stream infection being intrabdominal [3,4]. Transient bacteremia as a result of gastrointestinal translocation is a well understood phenomenon, even in healthy individuals. However, in immunosuppressed patients and those with compromise of the intestinal barrier, sepsis is more likely to ensue [9]. Furthermore, once bacteria enter the bloodstream, they are more likely to infect sites of prosthesis due to biofilm formation [10]. Therefore, we reason that the Campylobacter jejuni easily translocated this already immunosuppressed patient’s impaired gut mucosa due to his ulcerative colitis and seeded his prosthetic knee joint, resulting in PJI [11].\n\nAs Campylobacter species are slow growing fastidious organisms, isolation from our patient’s joint fluid and periprosthetic tissue samples proved to be difficult. Campylobacter species require 72−96 hours of incubation to be isolated from stool samples and can take even longer from blood samples [12]. As Campylobacter jejuni is a thermophilic organism, it grows best at 42 °C [12]. Growth of Campylobacter jejuni also improves under microaerophilic conditions and with the use of Mueller Hinton broth and agar [8,13]. Another method of isolating Campylobacter species includes the usage of real-time PCR assay on sonicated fluid [12]. In our patient’s case, notification of the microbiology laboratory to use targeted culture media and incubation conditions may have yielded a positive joint fluid or periprosthetic tissue sample, given the high clinical suspicion of Campylobacter PJI. However, even with strategies to optimize yield, sensitivity of culturing this organism remains to be 39–70 % [14]. Furthermore, 7–50 % of PJI cases have yielded negative culture results [14].\n\nThis case illustrates a unique association between immunosuppression and chronic intestinal inflammation with Campylobacter bacteremia leading to PJI. With this case, we also demonstrate that Campylobacter jejuni sepsis may not present as it does classically with gastrointestinal symptoms. Finally, this case further underscores the criticality of communication between the clinician and microbiologist in identifying an uncommon pathogen.\n==== Refs\nReferences\n1 Centers for Disease Control and Prevention Campylobacter (campylobacteriosis). Centers for disease control and prevention Atlanta, GA. Retrieved from 2019 https://www.cdc.gov/campylobacter \n2 Namdari S. Nicholson T. Abboud J. Comparative study of cultures and next-generation sequencing in the diagnosis of shoulder prosthetic joint infections J Shoulder Elbow Surg 28 1 2019 1 8 30551780 \n3 Fernández-Cruz A. Muñoz P. Mohedano R. Campylobacter bacteremia: clinical characteristics, incidence, and outcome over 23 years Medicine (Baltimore) 89 5 2010 319 330 20827109 \n4 Zamora-López M.J. Álvarez-García P. García-Campello M. Prosthetic hip joint infection caused by Campylobacter fetus: a case report and literature review Rev Esp Quimioter 31 1 2018 53 57 29390600 \n5 Vasoo S. Schwab J.J. Cunningham S.A. Campylobacter prosthetic joint infection J Clin Microbiol 52 5 2014 1771 1774 24523462 \n6 Peterson M.C. Farr R.W. Castiglia M. Prosthetic hip infection and bacteremia due to Campylobacter jejuni in a patient with AIDS Clin Infect Dis 16 3 1993 439 440 8452956 \n7 Prendki V. Marmor S. Zeller V. Lhotellier L. Mégraud F. Desplaces N. Campylobacter infection after prosthetic joint surgery Scand J Infect Dis 45 9 2013 706 710 23808718 \n8 Yao J.D. Ng H.M. Campbell I. Prosthetic hip joint infection due to Campylobacter fetus J Clin Microbiol 31 12 1993 3323 3324 8308129 \n9 Vaishnavi C. Translocation of gut flora and its role in sepsis Indian J Med Microbiol 31 4 2013 334 342 24064638 \n10 Tande A.J. Patel R. Prosthetic joint infection Clin Microbiol Rev 27 2 2014 302 345 24696437 \n11 Gardiner K.R. Anderson N.H. Rowlands B.J. Barbul A. Colitis and colonic mucosal barrier dysfunction Gut 37 4 1995 530 535 7489941 \n12 Allos B.M. Campylobacter jejuni Infections: update on emerging issues and trends Clin Infect Dis 32 8 2001 1201 1206 11283810 \n13 Davis L. DiRita V. Growth and laboratory maintenance of Campylobacter jejuni Curr Protoc Microbiol 2008 Chapter 8:Unit 8A.1.1-8A.1.7 \n14 Goswami K. Parvizi J. Culture-negative periprosthetic joint infection: is there a diagnostic role for next-generation sequencing? Expert Rev Mol Diagn 20 3 2019 269 272 31858850\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "22()",
"journal": "IDCases",
"keywords": "Bacteremia; Campylobacter jejuni; Prosthetic joint infection; Septic arthritis",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00920",
"pmc": null,
"pmid": "32793417",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "23808718;8452956;24696437;7489941;20827109;29390600;31858850;11283810;24523462;24064638;18729058;8308129;30551780",
"title": "Campylobacter jejuni prosthetic joint infection in an ulcerative colitis patient in the absence of gastrointestinal symptoms.",
"title_normalized": "campylobacter jejuni prosthetic joint infection in an ulcerative colitis patient in the absence of gastrointestinal symptoms"
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"abstract": "The optimal therapy to achieve higher rates of survival in pediatric relapsed/refractory acute leukemia (AL) is still unknown. In developing countries, it is difficult to obtain some of the recent drugs for optimal therapy and mostly well-known drugs proven to be effective are used. We assessed the efficacy of the combination of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG regimen) with or without idarubicin (IDA) in children with relapsed/refractory acute lymphoblastic leukemia and acute myeloid leukemia.\n\n\n\nBetween September 2007 and May 2015, 18 children with refractory/relapsed AL attending our center, treated with a FLAG regimen with or without IDA, were included. The primary end point was the remission status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after hematopoietic stem cell transplantation (HSCT).\n\n\n\nComplete remission (CR) was achieved in 7 patients (38.8%) after the first cycle, and at the end of the second cycle the total number of patients in CR was 8 (42.1%). All patients in CR underwent HSCT. The CR rate in patients who had IDA in combination therapy was 28.6%, and it was 50% in patients treated without IDA (p=0.36). Mean survival duration in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months), and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in nontransplanted patients. Five of them (27.7%) were still alive at the end of the study and in CR. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months).\n\n\n\nFLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with relapsed/refractory AL and can be recommended as therapeutic options prior to HSCT in developing countries.",
"affiliations": "Dokuz Eylül University Faculty of Medicine, Department of Pediatric Hematology, İzmir, Turkey Phone: +90 505 5252163 E-mail: sebnemyilmaz14@yahoo.com",
"authors": "Yılmaz Bengoa|Şebnem|Ş|;Ataseven|Eda|E|;Kızmazoğlu|Deniz|D|;Demir Yenigürbüz|Fatma|F|;Erdem|Melek|M|;Ören|Hale|H|",
"chemical_list": null,
"country": "Turkey",
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"doi": "10.4274/Tjh.2015.0411",
"fulltext": "\n==== Front\nTurk J HaematolTurk J HaematolTJHTurkish Journal of Hematology1300-77771308-5263Galenos Publishing 2709514410.4274/tjh.2015.04111960Research ArticleFLAG Regimen with or without Idarubicin in Children with Relapsed/Refractory Acute Leukemia: Experience from a Turkish Pediatric Hematology Center Nüks/Refrakter Akut Lösemili Çocuklarda İdarubisin Eklenerek veya Eklenmeden FLAG Tedavisi: Bir Türk Pediatrik Hematoloji Merkezi Deneyimi Yılmaz Bengoa Şebnem 1*Ataseven Eda 1Kızmazoğlu Deniz 1Demir Yenigürbüz Fatma 1Erdem Melek 1Ören Hale 1\n1 \nDokuz Eylül University Faculty of Medicine, Department of Pediatric Hematology, İzmir, Turkey\n* Address for Correspondence: Dokuz Eylül University Faculty of Medicine, Department of Pediatric Hematology, İzmir, Turkey GSM: +90 505 5252163 E-mail: sebnemyilmaz14@yahoo.com3 2017 1 3 2017 34 1 46 51 30 11 2015 25 12 2015 © Copyright 2017 by Turkish Society of Hematology\n\nTurkish Journal of Hematology published by Galenos Publishing House.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Objective:\nThe optimal therapy to achieve higher rates of survival in pediatric relapsed/refractory acute leukemia (AL) is still unknown. In developing countries, it is difficult to obtain some of the recent drugs for optimal therapy and mostly well-known drugs proven to be effective are used. We assessed the efficacy of the combination of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG regimen) with or without idarubicin (IDA) in children with relapsed/refractory acute lymphoblastic leukemia and acute myeloid leukemia.\n\nMaterials and Methods:\nBetween September 2007 and May 2015, 18 children with refractory/relapsed AL attending our center, treated with a FLAG regimen with or without IDA, were included. The primary end point was the remission status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after hematopoietic stem cell transplantation (HSCT).\n\nResults:\nComplete remission (CR) was achieved in 7 patients (38.8%) after the first cycle, and at the end of the second cycle the total number of patients in CR was 8 (42.1%). All patients in CR underwent HSCT. The CR rate in patients who had IDA in combination therapy was 28.6%, and it was 50% in patients treated without IDA (p=0.36). Mean survival duration in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months), and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in nontransplanted patients. Five of them (27.7%) were still alive at the end of the study and in CR. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months).\n\nConclusion:\nFLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with relapsed/refractory AL and can be recommended as therapeutic options prior to HSCT in developing countries.\n\nAmaç:\nNüks/refrakter akut lösemili (AL) çocuklarda daha yüksek sağkalımı sağlayabilecek en uygun tedavi yaklaşımı halen bilinmemektedir. Gelişmekte olan ülkelerde bu hasta grubunda etkin olduğu iyi bilinen ve yakın zamanda geliştirilmiş bazı ilaçlara ulaşımda güçlük yaşanmaktadır. Biz relaps/refrakter akut lenfoblastik lösemili ve akut miyeloid lösemili çocuklarda idarubisin (İDA) eklenmiş veya eklenmemiş, fludarabin, yüksek doz sitarabin ve granülosit koloni stimüle edici faktör (FLAG tedavisi) kombinasyonunun etkinliğini değerlendirdik.\n\nGereç ve Yöntemler:\nÇalışmaya Eylül 2007 ve Mayıs 2015 arasında merkezimizde izlenen, İDA eklenmiş veya eklenmemiş FLAG tedavisi verilen, 18 relaps/refrakter AL’li çocuk dahil edilmiştir. Birincil sonlanım noktası kemoterapi sonrası alınan kemik iliği örneğinin remisyon durumu ve ikinci sonlanım noktası ise hematopoetik kök hücre nakli (HKHN) sonrası sağkalım süresi olarak belirlenmiştir.\n\nBulgular:\nÇocukların yedisinde (%38,8) ilk siklus, toplam olarak sekizinde (%42,1) ise ikinci siklus sonrasında tam remisyon (TR) elde edildi. TR’deki tüm hastalara HKHN yapıldı. Kombinasyon tedavisine IDA eklenmiş olan hastalarda TR oranı %28,6, İDA eklenmemiş olanlarda %50 idi (p=0,36). HKHN yapılmış hastalarda ortalama sağkalım süresi 24,7±20,8 ay (minimum-maksimum: 2-70, medyan: 25 ay), yapılmamış olanlarda 2,7±1,64 ay (minimum-maksimum: 0-5, medyan: 3 ay) idi. Bu hastaların beşi (%27,7) halen sağ ve TR’dedir. Yaşayan hastaların median izlem süresi 33 ay (minimum-maksimum: 25-70 ay) idi.\n\nSonuç:\nIDA eklenmiş veya eklenmemiş FLAG tedavisi nüks/refrakter AL’li çocukların %27,7’sinde 24 aydan daha uzun süreli sağkalım sağlamıştır ve gelişmekte olan ülkelerde HKHN öncesi tedavi seçeneği olarak önerilebilir.\n\nRelapsed/refractory leukemiaFLAG regimenChemotherapychildhood\n==== Body\nINTRODUCTION\nDespite the improved prognosis in pediatric acute leukemias (ALs), survival rates are low for patients with relapsed or refractory disease [1,2]. Treatment approaches for these patients are not uniform. Effective reinduction regimens are needed and it has been shown that hematopoietic stem cell transplantation (HSCT) can offer long survival times [2,3]. In developing countries, it is difficult to obtain some of the more recent drugs for optimal therapy, and mostly well-known drugs proven to be effective are used. Regimens with the combination of fludarabine (FL), cytarabine, idarubicin (IDA), and granulocyte colony-stimulating factor (G-CSF) have been widely used for poor-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and relapsed or refractory acute lymphoblastic leukemia (ALL) in adults [4,5]. Pediatric series of AL cases with poor prognosis treated with these regimens are limited in the literature [6,7,8,9].\n\nFL, a fluorinated purine analog, and high-dose cytarabine are effective in the treatment of ALs [10]. The combination of FL with cytarabine appears to have a synergistic effect. A positive correlation has been found between the intracellular level of the active metabolite of cytarabine, Ara-C 5’-triphosphate (Ara-CTP), and remission rates. FL triphosphate, the active metabolite of FL, inhibits ribonucleotide reductase and increases intracellular Ara-CTP. Administration of fludarabine prior to cytarabine may enhance the clinical efficacy of cytarabine [11]. IDA has also been added to the combination to increase the antileukemic effect [6,7,8,9]. G-CSF prior to FL may increase the efficacy of chemotherapy by increasing the fraction of leukemic cells in the S-phase [12].\n\nThe combination regimen of FL, high-dose cytarabine, and G-CSF (FLAG) with or without IDA has been used in relapsed/refractory acute AML and ALL patients since 2007 in our clinic. Our aim was to evaluate the rate of complete remission (CR) and duration of survival after HSCT with this regimen.\n\nMATERIALS AND METHODS\nPatients\nBetween September 2007 and May 2015, 18 children (15 boys and 3 girls) with refractory/relapsed AL attending our center were treated with a FLAG regimen with or without IDA. The median age at treatment was 12 years (minimum-maximum: 9 months to 17 years). Ten patients had a diagnosis of ALL (6 precursor B-cell and 4 T-cell ALL) and 8 had AML (2 AML-M2, 2 AML-M4, 1 AML-M5, 2 secondary AML, and 1 myeloid sarcoma). Of the 10 children with ALL, 3 cases were primary refractory, 3 first-relapsed, and 4 second-relapsed (all of them were refractory to the ALL relapse protocol), while of the 8 children with AML, 5 cases were first-relapsed and 3 primary refractory. One patient with myeloid sarcoma received the FLAG regimen after his first relapse, underwent allogeneic HSCT, relapsed 20 months after transplantation, and received the second course of the FLAG regimen.\n\nAt the time of treatment 13 patients had isolated bone marrow infiltration, 3 had isolated extramedullary disease, and 3 had combined disease. The extramedullary disease site was the central nervous system in 4 patients, testis in 1 patient, and lymph node in 1 patient.\n\nAll parents signed written informed consent forms before the start of the regimens.\n\nTreatment\nFludarabine at 30 mg/m2/day was administered intravenously over 30 min and cytarabine at 2 g/m2/day was administered intravenously over 3 h starting 3.5 h after completing the fludarabine infusion for 4 consecutive days (days 1-4). IDA was given at 12 mg/m2/day by a 1-h infusion for 3 consecutive days (days 2-4) starting 1 h before the cytarabine infusion [7]. G-CSF was given at 200 or 400 µg/m2/day from day 0 to the first day of absolute neutrophil count (ANC) of >1000/µL in 10 patients, while it was started 48 h after completion of treatment in 8 patients.\n\nNineteen courses and 30 cycles were administered to 18 patients. In 9 courses 1 cycle, in 9 courses 2 cycles, and in 1 course 3 cycles of treatment regimen were administered. Detailed information is given in Table 1.\n\nIDA was not given to the previously heavily treated 12 patients to decrease the rate of cardiotoxicity. If CR could not be achieved after the first cycle, then IDA was added to the FLAG regimen.\n\nAll patients routinely received trimethoprim/sulfamethoxazole and antifungal prophylaxis. Patients with response to treatment underwent allogeneic HSCT if they had an eligible donor.\n\nThe toxicity of the regimen was assessed according to the Common Toxicity Criteria of the World Health Organization [13].\n\nAssessment of Response\nBone marrow examination was performed when ANC was >1000/µL or at day 30 after chemotherapy. CR was defined as the absence of physical signs of leukemia, no extramedullary blasts, no blasts in peripheral blood, <5% blasts in bone marrow (BM) with evidence of normal hematopoiesis, and no blasts in the cerebrospinal fluid. Partial remission (PR) was defined as marrow blasts between 5% and 25%. Aplasia was defined as blasts <5% in BM or peripheral blood, no extramedullary blasts, no evidence of hematopoietic regeneration, and no regeneration in peripheral blood count [14].\n\nThe primary end point was status of the bone marrow sampled after the first/second course of chemotherapy. The second end point was the duration of survival after HSCT.\n\nDuration of survival was calculated from the start of the treatment regimen up to the last follow-up or mortality.\n\nStatistical Analysis\nSPSS 15.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Analytical characteristics were given as percentage, mean and SD, or median. Data were analyzed for statistically significant differences using the Mann-Whitney U test and the chi-square test. Group differences with p<0.05 were considered to be statistically significant. Duration of survival and time of follow-up were calculated with descriptive statistics. With a total of only 18 cases the use of further statistical methods was limited.\n\nRESULTS\nTreatment Response\nThirty cycles were administered in 18 patients. Age, sex, diagnosis, remission duration before relapses, treatment regimen and response, remission duration after treatment regimen, and duration of survival/outcome of patients are shown in Table 1. After the first cycle, CR was achieved in 7 (38.8%) patients, PR was achieved in 1 (5.3%), remission was not observed in 5 (26.3%), and aplasia was found in 3 (15.7%). Two patients could not be evaluated for response because of early death after the first FLAG treatment. After the second cycle, one nonresponder achieved CR. CR rate in patients who did not receive G-CSF starting with the chemotherapy was 50% and CR rate in patients who received G-CSF with the beginning of chemotherapy was 36.4%; the difference was not significant (p=0.563). CR rate in patients who had IDA in the combination therapy was 28.6% and CR rate was 50% in patients treated without IDA (p=0.360). There was no difference in CR rate according to the duration of remission before the treatment (p=0.770).\n\nToxicity\nAll children had severe myelosuppression and were intensively supported with blood products. The median time of neutrophil recovery (>500/µL) was 24 days (minimum-maximum: 15-45), and that of platelet recovery (>20,000/µL) was 20 days (minimum-maximum: 15-73). Febrile neutropenia (FN) occurred after 26 (86.6%) cycles of regimens. FN was observed after 6 (85.7%) cycles with additional IDA and after 20 (87%) cycles without IDA. There was no difference in FN rate according to additional IDA (p=0.677). Most patients developed grade 3-4 mucositis. Seven children had transient mild hepatotoxicity (36.8%). There was no serious cardiotoxicity. Two patients (11.1%) had documented infections (blood cultures showed Escherichia coli and a yeast-like organism in 1 patient, and Klebsiella pneumoniae in 1 patient). Two patients, a primary refractory T-cell ALL patient and a relapsed AML patient with documented infection, died before the time of remission evaluation. Two patients (11.1%) had pulmonary invasive fungal infection.\n\nDuration of Survival\nAll patients in CR and one patient with AML secondary to MDS who had aplasia after the regimen, in total 9 (50%) patients, underwent subsequent allogeneic HSCT. Four patients were transplanted from matched sibling donors, 2 from matched unrelated donors, and 3 from haploidentical donors. Four patients died after HSCT; in 3 patients, the cause of death was infection. The fourth patient (case 18) relapsed after HSCT and had a second course with 3 cycles of FLAG; he was in remission after the first 2 cycles but relapsed after the third cycle and died.\n\nMean duration of survival in transplanted patients was 24.7±20.8 months (minimum-maximum: 2-70, median: 25 months) and it was 2.7±1.64 months (minimum-maximum: 0-5, median: 3 months) in the nontransplanted patients.\n\nAs a result, 5 (27.7%) patients who underwent HSCT are still alive and in CR. Two patients underwent allogeneic HSCT from their siblings, 2 underwent allogeneic HSCT from unrelated matched donors, and 1 underwent haploidentical HSCT from his mother. The median time of follow-up for these patients was 33 months (minimum-maximum: 25-70 months). Three were AML (one case secondary to MDS) and 2 were ALL patients.\n\nDISCUSSION\nThe treatment of children with relapsed or refractory AL is still challenging. Regimens containing FL and high-dose cytarabine with or without IDA have been used in this patient group, and the first results were published in 1996 [6]. In our study, the CR rate after 2 cycles was 42.1% (most of these patients were in CR after the first cycle), all of these patients could proceed to HSCT, and 27.7% survived. Fleischhack et al. reported a CR rate of 73.9% in patients with poor-prognosis AML; 47.8% underwent HSCT and 39.1% remained in CR [7]. In the study conducted by McCarthy et al., in a group of ALL, AML, and biphenotypic AL patients using the FLAG regimen the CR rate was 70%; 68.4% of the patients underwent HSCT and 36.8% were alive at the end of the study [15]. Tavil et al. from Turkey presented the results of 25 relapsed/refractory AL patients. The CR rate was 60%, 49% of their patients could proceed to HSCT, and 20% survived [8]. Yalman et al., also from Turkey, reported a CR rate of only 17.6% in 17 poor-prognosis AL patients; 2 underwent HSCT and only 1 child with a previous HSCT survived after donor lymphocyte infusion [9].\n\nThe CR rate in our patients who had IDA in combination therapy was 28.6% and it was 50% in patients treated without IDA; the difference was not statistically significant. Patients who received IDA-FLAG were mostly those who had refractory disease. This might be the reason for the lower response rate.\n\nAll of our patients experienced severe myelosuppression, FN developed after 86.6% of the cycles, and 2 patients (11.1%) died early with infection, shortly after chemotherapy (15th and 17th days). The addition of IDA to the FLAG regimen did not change the risk of FN. Invasive fungal infection was observed in a total of 3 patients (16.6%). The reported toxicity of these regimens is similar to rates reported in the literature [8,15].\n\nIn some recent studies, it was demonstrated that with the addition of agents like liposomal forms of daunorubicin and doxorubicin instead of IDA to treatment regimens containing FL and high-dose cytarabine, CR can be achieved in higher rates with less systemic toxicity in children with refractory/relapsed AL [16,17]. In developing countries such as Turkey, liposomal forms of these anthracyclines are not available and cannot be used due to economic reasons.\n\nBecause of the increased use of unrelated and haploidentical donors nowadays, even when a suitable family donor is lacking, the chance of transplantation with alternative stem cell sources in a short time after CR is better. Therefore, achieving CR in poor-prognosis AL with effective treatment regimens may result in better outcomes. Five of our patients achieved a CR of >24 months after HSCT.\n\nThe role of G-CSF in the management of relapsed/refractory AL has been tested widely and remains controversial [18]. Most of the trials demonstrated a modest reduction in the duration, but not the depth, of neutropenia [16,18,19]. The effects of G-CSF on duration of survival, incidence of severe infection, and duration of hospitalization are variable, but in developing countries, the death rates due to FN are higher than in developed countries, and G-CSF given with chemotherapy or after chemotherapy is still common. Even though a trend towards an increased incidence of relapses with G-CSF treatment in children with AML that overexpress the differentiation-defective G-CSFR isoform IV has been reported, the number of these cases is very low and G-CSF continues to be a part of the FLAG regimen [16,20]. We used G-CSF in all of our patients since the FN risk is high in our clinic. We did not find any statistically significant difference in CR rate whether we started G-CSF at day 0 or after completion of chemotherapy.\n\nCONCLUSION\nIn conclusion, FLAG regimens with or without IDA produced a CR of >24 months in 27.7% of children with refractory/relapsed AL and can be recommended as a therapeutic option prior to HSCT with appropriate supportive measurements in developing countries.\n\nEthics\n\nEthics Committee Approval: The study was a retrospective analysis, and we used data from hospital records; Informed Consent: All parents signed written informed consent forms before the start of the regimens.\n\nAuthorship Contributions\n\nConcept: Şebnem Yılmaz Bengoa, Hale Ören; Design: Şebnem Yılmaz Bengoa; Data Collection or Processing: Şebnem Yılmaz Bengoa, Eda Ataseven, Deniz Kızmazoğlu, Fatma Demir Yenigürbüz, Melek Erdem; Analysis or Interpretation: Şebnem Yılmaz Bengoa, Hale Ören; Literature Search: Şebnem Yılmaz Bengoa; Writing: Şebnem Yılmaz Bengoa, Hale Ören.\n\nConflict of Interest: The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n\nTable 1 Patient characteristics, treatment regimen, response to treatment, duration of survival, and outcome.\n==== Refs\nReferences\n1 Stahnke K Ritter J Schellong G Beck JD Kabisch H Lampert F Creutzig U Treatment of recurrence of acute myeloid leukemia in childhood. A retrospective analysis of recurrence in the AML-BFM-83 study Klin Padiatr 1992 204 253 257 1518261 \n2 Einsiedel HG von Stackelberg A Hartmann R Fengler R Schrappe M Janka-Schaub G Mann G Hählen K Göbel U Klingebiel T Ludwig WD Henze G Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87 J Clin Oncol 2005 23 7942 7950 16258094 \n3 Sander A Zimmermann M Dworzak M Fleischhack G von Neuhoff C Reinhardt D Kaspers GJ Creutzig U Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials Leukemia 2010 24 1422 1428 20535146 \n4 Virchis A Koh M Rankin P Mehta A Potter M Hoffbrand AV Prentice HG Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes Br J Haematol 2004 124 26 32 14675405 \n5 Yavuz S Paydas S Disel U Sahin B IDA-FLAG regimen for the therapy of primary refractory and relapse acute leukemia: a single-center experience Am J Ther 2006 13 389 393 16988532 \n6 Fleischhack G Graf N Hasan C Ackermann M Breu H Zernikow B Bode U IDA-FLAG (idarubicin, fludarabine, high dosage cytarabine and G-CSF)--an effective therapy regimen in treatment of recurrent acute myelocytic leukemia in children and adolescents. Initial results of a pilot study Klin Padiatr 1996 208 229 235 8926688 \n7 Fleischhack G Hasan C Graf N Mann G Bode U IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial Br J Haematol 1998 102 647 655 9722289 \n8 Tavil B Aytac S Balci YI Unal S Kuskonmaz B Yetgin S Gurgey A Tuncer M Gumruk F Uckan D Cetin M Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) for the treatment of children with poor-prognosis acute leukemia: the Hacettepe experience Pediatr Hematol Oncol 2010 27 517 528 20677923 \n9 Yalman N Sarper N Devecioğlu O Anak S Eryilmaz E Can M Yenilmez H Ağaoğlu L Gedikoğlu G Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of relapsed or poor risk childhood acute leukemia Turk J Pediatr 2000 42 198 204 11105617 \n10 Keating MJ O’Brien S Robertson LE Kantarjian H Dimopoulos M McLaughlin P Cabanillas F Gregoire V Li YY Gandhi V Estey E Plunkett W The expanding role of fludarabine in hematologic malignancies Leuk Lymphoma 1994 14 11 16 \n11 Gandhi V Estey E Keating MJ Plunkett W Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy J Clin Oncol 1993 11 116 124 8418222 \n12 Tosi P Visani G Ottaviani E Manfori S Zinzani PL Tura S Fludarabine + Ara-C + G-CSF: cytotoxic effect and induction of apoptosis on fresh acute myeloid leukemia cells Leukemia 1994 8 2076 2082 7528855 \n13 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 National Cancer Institute [Internet] Available online at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf \n14 Redner A Lanzkowsky P Leukemias Manual of Pediatric Hematology and Oncology, 5th ed New York Academic Press 2011 \n15 McCarthy AJ Pitcher LA Hann IM Oakhill A FLAG (fludarabine, high-dose cytarabine, and G-CSF) for refractory and high-risk relapsed acute leukemia in children Med Pediatr Oncol 1999 32 411 415 10358698 \n16 Kaspers GJ Zimmermann M Reinhardt D Gibson BE Tamminga RY Aleinikova O Armendariz H Dworzak M Ha SY Hasle H Hovi L Maschan A Bertrand Y Leverger GG Razzouk BI Rizzari C Smisek P Smith O Stark B Creutzig U Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group J Clin Oncol 2013 31 599 607 23319696 \n17 Quarello P Berger M Rivetti E Galletto C Masetti R Manicone R Barisone E Pession A Fagioli F FLAG-liposomal doxorubicin (Myocet) regimen for refractory or relapsed acute leukemia pediatric patients J Pediatr Hematol Oncol 2012 34 208 216 22395219 \n18 Milligan DW Wheatley K Littlewood T Craig JI Burnett AK NCRI Haematological Oncology Clinical Studies Group Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial Blood 2006 107 4614 4622 16484584 \n19 Usuki K Urabe A Masaoka T Ohno R Mizoguchi H Hamajima N Miyazaki T Niitsu Y Yoshida Y Miura A Shibata A Abe T Miura Y Ikeda Y Nomura T Nagao T Saitou H Shirakawa S Ohkuma M Matsuda T Nakamura T Horiuchi A Kuramoto A Kimura I Irino S Niho Y Takatsuki K Tomonaga M Uchino H Takaku F Gran AML Study Group Efficacy of granulocyte colony-stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study Br J Haematol 2002 116 103 112 11841402 \n20 Ehlers S Herbst C Zimmermann M Scharn N Germeshausen M von Neuhoff N Zwaan CM Reinhardt K Hollink IH Klusmann JH Lehrnbecher T Roettgers S Stary J Dworzak M Welte K Creutzig U Reinhardt D Granulocyte colony-stimulating factor (G-CSF) treatment of childhood acute myeloid leukemias that overexpress the differentiation-defective G-CSF receptor isoform IV is associated with a higher incidence of relapse J Clin Oncol 2010 28 2591 2597 20406937\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1300-7777",
"issue": "34(1)",
"journal": "Turkish journal of haematology : official journal of Turkish Society of Haematology",
"keywords": null,
"medline_ta": "Turk J Haematol",
"mesh_terms": null,
"nlm_unique_id": "9606065",
"other_id": null,
"pages": "46-51",
"pmc": null,
"pmid": "27095144",
"pubdate": "2017-03-01",
"publication_types": "D016428:Journal Article",
"references": "7528855;14675405;9722289;20535146;11841402;1518261;7533576;16988532;16484584;22395219;23319696;8926688;16258094;20677923;20406937;11105617;10358698;8418222",
"title": "FLAG Regimen with or without Idarubicin in Children with Relapsed/Refractory Acute Leukemia: Experience from a Turkish Pediatric Hematology Center.",
"title_normalized": "flag regimen with or without idarubicin in children with relapsed refractory acute leukemia experience from a turkish pediatric hematology center"
} | [
{
"companynumb": "TR-MYLANLABS-2017M1026300",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nTo evaluate the frequency of adverse events (AEs) across 4 treatment conditions in the Child/Adolescent Anxiety Multimodal Study (CAMS), and to compare the frequency of AEs between children and adolescents.\n\n\nMETHODS\nParticipants ages 7 to 17 years (mean = 10.7 years) meeting the DSM-IV criteria for 1 or more of the following disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia were randomized (2:2:2:1) to cognitive-behavioral therapy (CBT, n = 139), sertraline (SRT, n = 133), a combination of both (COMB, n = 140), or pill placebo (PBO, n = 76). Data on AEs were collected via a standardized inquiry method plus a self-report Physical Symptom Checklist (PSC).\n\n\nRESULTS\nThere were no differences between the double-blinded conditions (SRT versus PBO) for total physical and psychiatric AEs or any individual physical or psychiatric AEs. The rates of total physical AEs were greater in the SRT-alone treatment condition when compared to CBT (p < .01) and COMB (p < .01). Moreover, those who received SRT alone reported higher rates of several physical AEs when compared to COMB and CBT. The rate of total psychiatric AEs was higher in children (≤12 years) across all arms (31.7% versus 23.1%, p < .05). Total PSC scores decreased over time, with no significant differences between treatment groups.\n\n\nCONCLUSIONS\nThe results support the tolerability/safety of selective serotonin reuptake inhibitor (SSRI) treatment for anxiety disorders even after adjusting for the number of reporting opportunities, leading to no differences in overall rates of AEs. Few differences occurred on specific items. Additional monitoring of psychiatric AEs is recommended in children (≤12 years). Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov; NCT00052078.",
"affiliations": "Columbia University Medical Center (CUMC)/New York State Psychiatric Institute, New York. Electronic address: rynnm@nyspi.columbia.edu.;Weill Cornell Medical College and New York Presbyterian Hospital, New York.;Duke University Medical Center, Durham, NC.;Western Psychiatric Institute and Clinic-University of Pittsburgh Medical Center, Pittsburgh.;Division of Services and Intervention Research at the National Institute of Mental Health (NIMH), Bethesda, MD.;University of Illinois at Urbana-Champaign.;Temple University, Philadelphia.;University of California, Los Angeles (UCLA) Semel Institute for Neuroscience and Human Behavior.;Columbia University Medical Center (CUMC)/New York State Psychiatric Institute, New York.;University of California, Los Angeles (UCLA) Semel Institute for Neuroscience and Human Behavior.;Johns Hopkins University School of Medicine, Baltimore, MD.;Johns Hopkins University School of Medicine, Baltimore, MD.;Baystate Medical Center, Springfield, MA.;Duke University Medical Center, Durham, NC.;Western Psychiatric Institute and Clinic-University of Pittsburgh Medical Center, Pittsburgh.;Duke University Medical Center, Durham, NC.;Western Psychiatric Institute and Clinic-University of Pittsburgh Medical Center, Pittsburgh.",
"authors": "Rynn|Moira A|MA|;Walkup|John T|JT|;Compton|Scott N|SN|;Sakolsky|Dara J|DJ|;Sherrill|Joel T|JT|;Shen|Sa|S|;Kendall|Philip C|PC|;McCracken|James|J|;Albano|Anne Marie|AM|;Piacentini|John|J|;Riddle|Mark A|MA|;Keeton|Courtney|C|;Waslick|Bruce|B|;Chrisman|Allan|A|;Iyengar|Satish|S|;March|John S|JS|;Birmaher|Boris|B|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-8567",
"issue": "54(3)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": "adverse events; anxiety; selective serotonin reuptake inhibitors",
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D000293:Adolescent; D001010:Anxiety, Separation; D002648:Child; D015928:Cognitive Behavioral Therapy; D003131:Combined Modality Therapy; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D010698:Phobic Disorders; D011569:Psychiatric Status Rating Scales; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "180-90",
"pmc": null,
"pmid": "25721183",
"pubdate": "2015-03",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "20051130;10697062;12014783;20206470;15315995;19716988;18507848;15065961;16171696;9435761;12649628;12941675;15266189;10674193;18752117;22801001;15507582;16553536;17440145;15502598;19588367;18974308;11323729;22233250;16321730;9842950;21225851;15564818",
"title": "Child/Adolescent anxiety multimodal study: evaluating safety.",
"title_normalized": "child adolescent anxiety multimodal study evaluating safety"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US02170",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nThere are limited data on the risk of non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC) among thiopurine-treated patients with ulcerative colitis (UC). Our aim was to investigate the risk while on, by cumulative years, and after stopping thiopurine therapy.\n\n\nMETHODS\nNationwide data were obtained from the Veterans Affairs (VA) health-care system during 2001-2011. We performed a retrospective cohort study evaluating patients with UC. Cox regression was used to investigate the association between thiopurines use and time to NMSC while adjusting for demographics, ultraviolet radiation exposure, and VA visiting frequency. A matched nested case-control study was conducted to investigate the association between thiopurine use and MSC.\n\n\nRESULTS\nWe included 14,527 patients with UC in the analysis, with a median follow-up of 8.1 years. A total of 3,346 (23%) patients used thiopurines for a median duration of 1.6 years. We identified 421 NMSC and 45 MSC cases. The adjusted hazard ratios of developing NMSC while on and after stopping thiopurines were 2.1 (P<0.0001) and 0.7 (P=0.07), respectively, as compared with unexposed patients. The incidence rate of NMSC among those who never used thiopurines was 3.7 compared with 5.8, 7.9, 8.3, 7.8, and 13.6 per 1,000 person-years for the 1st, 2nd, 3th, 4th, and 5th year of thiopurine use, respectively. No statistically significant association was observed between thiopurine use and MSC, odds ratio 0.8 (P=0.6).\n\n\nCONCLUSIONS\nIn this predominantly white male nationwide cohort, there was a twofold increase in the risk of NMSC while on thiopurines. The incidence rate of NMSC significantly increased with subsequent years of cumulative exposure to thiopurines. Stopping thiopurines reduced the risk of NMSC to pre-exposure levels irrespective of the prior exposure duration.",
"affiliations": "1] Section of Gastroenterology, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, USA [2] Department of Medicine, University of Florida, Gainesville, Florida, USA.;Department of Epidemiology, School of Public Health, Louisiana State University Health Science Center, New Orleans, Louisiana, USA.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;The Philadelphia VA Medical Center, Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman school of Medicine, Philadelphia, Pennsylvania, USA.;1] Section of Gastroenterology, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, USA [2] The Philadelphia VA Medical Center, Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman school of Medicine, Philadelphia, Pennsylvania, USA.",
"authors": "Abbas|Ali M|AM|;Almukhtar|Rawaa M|RM|;Loftus|Edward V|EV|;Lichtenstein|Gary R|GR|;Khan|Nabeel|N|",
"chemical_list": "D000963:Antimetabolites; D015122:Mercaptopurine",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2014.298",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "109(11)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000368:Aged; D000963:Antimetabolites; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008545:Melanoma; D015122:Mercaptopurine; D008875:Middle Aged; D012044:Regression Analysis; D012189:Retrospective Studies; D012306:Risk; D012878:Skin Neoplasms; D014481:United States; D014728:Veterans",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1781-93",
"pmc": null,
"pmid": "25244964",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk of melanoma and non-melanoma skin cancer in ulcerative colitis patients treated with thiopurines: a nationwide retrospective cohort.",
"title_normalized": "risk of melanoma and non melanoma skin cancer in ulcerative colitis patients treated with thiopurines a nationwide retrospective cohort"
} | [
{
"companynumb": "US-JNJFOC-20150303004",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSynthetic antithyroid drugs are often used in the treatment of hyperthyroidism, regardless of aetiology. They may cause various side effects, including the development of anti-neutrophil cytoplasmic antibodies (ANCA), ANCA-associated vasculitis, and neutrophilic dermatoses. Propylthiouracil (PTU) is the antithyroid drug most frequently implicated in ANCA-associated diseases specifically involving anti-myeloperoxidase ANCA (MPO-ANCA). To our knowledge, there are no clinical reports describing the association of pyoderma gangrenosum (PG) and anti-proteinase3-ANCA (PR3-ANCA) induced by PTU, with ANCA levels decreasing after antithyroid drug withdrawal.\n\n\nMETHODS\nA 68-year-old woman was treated with propylthiouracil (PTU) for toxic multinodular goitre. She presented necrotic ulceration of the lower abdomen. The patient's history, physical examination, and bacteriological and histological samples led to a diagnosis of pyoderma gangrenosum. This pyoderma involved ANCA with antigenic specificity for proteinase 3. Withdrawal of PTU and a short course of corticosteroids and cyclosporine resulted in rapid and complete resolution of the pyoderma gangrenosum as well as a decrease in ANCA. No relapse was observed one year after cessation of treatment.\n\n\nCONCLUSIONS\nWe report a case of PG associated with PR3-ANCA induced by PTU, without any demonstrable vasculitis.",
"affiliations": "Département de dermatologie, grand hôpital de Charleroi (GHDC), Grand'Rue 3, 6000 Charleroi, Belgique. Electronic address: alisoncoster@hotmail.com.;Département d'anatomie pathologique, institut de pathologie et de génétique (IPG), 25, avenue Georges-Lemaître, 6041 Gosselies, Belgique.;Département de médecine interne, grand hôpital de Charleroi (GHDC), Grand'Rue 3, 6000 Charleroi, Belgique.;Département de médecine interne, grand hôpital de Charleroi (GHDC), Grand'Rue 3, 6000 Charleroi, Belgique.;Département de dermatologie, grand hôpital de Charleroi (GHDC), Grand'Rue 3, 6000 Charleroi, Belgique.",
"authors": "Coster|A|A|;Dargent|J-L|JL|;de Visscher|N|N|;Levecque|P|P|;Roquet-Gravy|P-P|PP|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D015415:Biomarkers; D003879:Dermatologic Agents; D005938:Glucocorticoids; D011441:Propylthiouracil; D016572:Cyclosporine",
"country": "France",
"delete": false,
"doi": "10.1016/j.annder.2017.01.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "144(5)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": "ANCA anti-protéinase 3 (PR3-ANCA); Anti-neutrophil cytoplasmic antibody (ANCA); Anticorps anti-cytoplasme des neutrophiles (ANCA); Propylthiouracil; Propylthiouracile; Proteinase3-ANCA (PR3-ANCA); Pyoderma gangrenosum",
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D000005:Abdomen; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D015415:Biomarkers; D016572:Cyclosporine; D003879:Dermatologic Agents; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006980:Hyperthyroidism; D011441:Propylthiouracil; D017511:Pyoderma Gangrenosum; D016896:Treatment Outcome",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "368-373",
"pmc": null,
"pmid": "28291538",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pyoderma gangrenosum associated with anti-proteinase 3 antineutrophil cytoplasmic antibodies (PR3-ANCA) induced by propylthiouracil.",
"title_normalized": "pyoderma gangrenosum associated with anti proteinase 3 antineutrophil cytoplasmic antibodies pr3 anca induced by propylthiouracil"
} | [
{
"companynumb": "AU-ENDO PHARMACEUTICALS INC-2017-003308",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPYLTHIOURACIL"
},
"drugaddit... |
{
"abstract": "Metreleptin, a recombinant methionyl -human -leptin, was approved to treat patients with generalized lipodystrophy (GL) in February 2014. However, leptin therapy has been associated with the development of lymphoma. We present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with Acquired Generalized Lipodystrophy (AGL) during the following year after a clinical remission of her lymphoma without receiving leptin therapy.\nA 33-year-old woman with a diagnosis of stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, underwent chemotherapy. Shortly after completion therapy, she had a relapse and required more chemotherapy with complete response, followed by allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides, loss of fat tissue from her entire body and diagnosis of diabetes. Constellation of these findings led to the diagnosis of AGL in 2013. Her leptin level was low at 3.4 ng/mL (182 pmol/mL). She is currently not receiving any treatment with Metreleptin for her AGL.\nCausal association between exogenous leptin therapy and T-cell lymphoma still remains unclear. We hereby present a case of a young woman who was diagnosed with AGL after going into remission from T-cell lymphoma and who has never been treated with Metreleptin. Steroid therapy and chemotherapy might have masked the diagnosis of AGL in this patient. We believe that patients can develop these 2 conditions independent of each other.",
"affiliations": "1Division of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan and Brehm Center for Diabetes, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105 USA.;2Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI USA.;1Division of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan and Brehm Center for Diabetes, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105 USA.;1Division of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan and Brehm Center for Diabetes, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105 USA.;1Division of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan and Brehm Center for Diabetes, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105 USA.;1Division of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan and Brehm Center for Diabetes, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105 USA.;1Division of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan and Brehm Center for Diabetes, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105 USA.",
"authors": "Esfandiari|Nazanene H|NH|;Rubenfire|Melvyn|M|;Neidert|Adam H|AH|;Hench|Rita|R|;Eldin|Abdelwahab Jalal|AJ|;Meral|Rasimcan|R|;Oral|Elif A|EA|0000-0002-9171-1144",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40842-019-0076-9",
"fulltext": "\n==== Front\nClin Diabetes EndocrinolClin Diabetes EndocrinolClinical Diabetes and Endocrinology2055-8260BioMed Central London 7610.1186/s40842-019-0076-9Case ReportDiagnosis of acquired generalized lipodystrophy in a single patient with T-cell lymphoma and no exposure to Metreleptin Esfandiari Nazanene H. nazanene@med.umich.edu 1Rubenfire Melvyn mrubenfi@med.umich.edu 2Neidert Adam H. aneidert@med.umich.edu 1Hench Rita rhench@med.umich.edu 1Eldin Abdelwahab Jalal eldin@med.umich.edu 1Meral Rasimcan meralr@med.umich.edu 1http://orcid.org/0000-0002-9171-1144Oral Elif A. (734) 615-7271eliforal@med.umich.edu 11 0000000086837370grid.214458.eDivision of Metabolism Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan and Brehm Center for Diabetes, 1000 Wall Street, Room 5313, Ann Arbor, MI 48105 USA 2 0000000086837370grid.214458.eDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI USA 14 3 2019 14 3 2019 2019 5 420 8 2018 29 1 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\nMetreleptin, a recombinant methionyl -human -leptin, was approved to treat patients with generalized lipodystrophy (GL) in February 2014. However, leptin therapy has been associated with the development of lymphoma. We present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with Acquired Generalized Lipodystrophy (AGL) during the following year after a clinical remission of her lymphoma without receiving leptin therapy.\n\nCase presentation\nA 33-year-old woman with a diagnosis of stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, underwent chemotherapy. Shortly after completion therapy, she had a relapse and required more chemotherapy with complete response, followed by allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides, loss of fat tissue from her entire body and diagnosis of diabetes. Constellation of these findings led to the diagnosis of AGL in 2013. Her leptin level was low at 3.4 ng/mL (182 pmol/mL). She is currently not receiving any treatment with Metreleptin for her AGL.\n\nConclusions\nCausal association between exogenous leptin therapy and T-cell lymphoma still remains unclear. We hereby present a case of a young woman who was diagnosed with AGL after going into remission from T-cell lymphoma and who has never been treated with Metreleptin. Steroid therapy and chemotherapy might have masked the diagnosis of AGL in this patient. We believe that patients can develop these 2 conditions independent of each other.\n\nKeywords\nT-cell lymphomaAcquired generalized lipodystrophyInsulin resistanceDiabetesLeptinhttp://dx.doi.org/10.13039/100000002National Institutes of HealthR01 DK088114Oral Elif A. University of MichiganLipodystrophy FundOral Elif A. issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nLipodystrophy is a rare disorder characterized by selective loss or absence of adipose tissue with leptin deficiency, ectopic lipid deposition, and severe metabolic abnormalities [1]. Lipodystrophy can be congenital or acquired and its distribution can be generalized or partial [2–4]. Metreleptin, a recombinant methionyl-human-leptin, was approved to treat generalized lipodystrophy in February 2014 [5]. Patients with acquired generalized lipodystrophy (AGL) present with loss of adipose tissue, hypertriglyceridemia, severe insulin resistance leading to diabetes and hepatic steatosis [3, 4]. Leptin therapy will improve many of the metabolic conditions in patients with AGL [6, 7]. Many patients with AGL have abnormal immune function and can even develop immunologic malignancies such as T-cell lymphoma [8].\n\nSince a few patients with AGL developed T-cell lymphomas after being exposed to Metreleptin for some time, the FDA placed a black box warning to monitor for lymphomas and immune abnormalities while on Metreleptin even though a causal association between drug exposure and the development of the T-cell lymphoma was not established. In this report, we present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with AGL during the following year after a clinical remission of her lymphoma. She has never received Metreleptin therapy. We believe that this report will add to the evidence that T-cell lymphoma and AGL may develop in the same patient independent of the use of Metreleptin or exogenous leptin therapy.\n\nCase presentation\nA 33-year-old woman without a significant past medical history, was diagnosed with stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, complicated by hemophagocytic lymphohistiocytosis. She completed 6 cycles of CHOEP regimen (cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone) in December 2011. Shortly after completion of the therapy, she relapsed and received multiple salvage regimens including gemcitabine/oxaliplatin, bexarotene/dexamethasone and pralatrexate. She was then initiated on ESHAP regimen; a combination of the chemotherapeutic drugs etoposide, methylprednisolone, a high-dose cytarabine and cisplatin in April 2012, achieving complete response; followed by an allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides (230 mg/dL [2.60 mmol/L] (normal range < 150 mg/dL [1.69 mmol/L]) in 2011, and 613 mg/dL [6.93 mmol/L] in 2013) and loss of fat tissue from her entire body with accompanying muscular prominence. She was also diagnosed with diabetes in 12/2013. Constellation of these findings led to the diagnosis of AGL in 2013.\n\nAt her visit in our clinic, her BMI was 24.4 kg/m2. Her leptin level was low at 3.4 ng/mL (182 pmol/mL) (a level of < 4 ng/mL [215 pmol/mL] is accepted as low for women with BMI < 25 kg/m2 despite a wider range provided by some reference labs). Upon obtaining a detailed history, and reviewing her old pictures, it was confirmed that the onset of body fat loss occurred prior to her T-cell lymphoma diagnosis. She also endorsed complaints of hyperphagia and a marked increase in her appetite. Current clinical endocrine problems outside of diabetes and dyslipidemia include increased appetite and hyperphagia, lack of menses and a generalized pain syndrome likely attributable to small fiber neuropathy due to hypertriglyceridemia [9]. Table 1 summarizes her laboratory findings since the diagnosis until her last visit in our clinic. Figure 1 panels a-d show her pictures; before diagnosis (a), at diagnosis of T-cell lymphoma(b), during chemotherapy (c) and after chemotherapy (d).Table 1 Laboratory data from our case\n\nYear\tGlucose\nmg/dL (mmol/L)\tA1C\n% (mmol/mol)\tTriglycerides\nmg/dL (mmol/L)\tCreatinine\nmg/dL (μmol/L)\t24-H urine protein\t\n2011\t82 (4.55)\t230 (2.60)\t0.4 (35.4)\t0.61a\t\n2012\t114 (6.33)\t416 (4.70)\t0.8 (70.7)\t\n2013\t114 (6.33)\t6.1 (43)\t466 (5.27)\n613 (6.93)\t1.1 (97.2)\t\n2014\t115 (6.38)\t6.4 (46)\t1027 (11.6)\n2577 (29.1)\t0.9 (79.6)\t< 5b\t\n2015\t201 (11.2)\t5.9 (41)\n7.2 (55)\t1372 (15.5)\n776 (8.77)\t1.05 (92.8)\t283b\t\n2016\t201 (11.2)\t6.2 (44)\n6.9 (52)\t478 (5.40)\n1392 (15.7)\n3615 (40.9)\t1.0 (88.4)\t\n2017\t146 (8.10)\t1604 (18.1)\n740 (8.36)\t1.06 (93.7)\t\n2018\t103 (5.72)\t7.7 (61)\t4380 (49.5)\n336 (3.80)\t1.05 (92.8)\t\nA1C: hemoglobin A1C\n\naand b: reference range for 24-h urine protein in our lab (0–0.15 g/24 h) and in an outside lab (42–225 mg/24 h), respectively\n\nFig. 1 Development of Physical Features of Lipodystrophy. Panel (a) shows the patient before the diagnosis of T-cell lymphoma and does not show convincing evidence for generalized lipodystrophy. Physical transformations are shown in panel (b) during the diagnosis of the T-cell lymphoma, suggesting that she may have already developed features of lipodystrophy at least around her face and neck. Panel (c) shows her appearance during chemotherapy and panel (d) is after the chemotherapy. Currently (4 years after the completion of therapy) patient’s appearance is like the picture as shown in (b) suggesting that the chemotherapy and steroid use temporarily masked the diagnosis of lipodystrophy and were able to modify the physical appearance\n\n\n\nAt her most recent visit, she was doing well and is in remission for T cell Lymphoma. A “fat shadow” [10] representation from her DXA scan (panel a) and her new clinical pictures (panels b-e) are presented in Fig. 2. For her metabolic complications of her AGL, she is currently not being treated with Metreleptin and this possibility is still under discussion. She is on multiple medications to treat her diabetes, high triglycerides and has been trying to limit her food intake.Fig. 2 Clinical Examination of Fat Distribution. Panel (a) show the “Fat Shadow” obtained from Dual X-ray Energy absorbtiometry (DXA) scan as described previously in Reference [10]. The fat shadow shows minimally retained fat around the neck and axilla, but loss of fat in a generalized fashion though not totally absent from the body. Close-up pictures taken in clinic setting demonstrate fat loss in the face and trunk (b), back (c), buttock and back of the legs (d), and forearms and legs (e). The absence of fat from the face together with the entire abdomen, trunk and extremities favor the diagnosis of generalized lipodystrophy as opposed to partial lipodystrophy. Neck fat is preserved, but not excessive. Mons pubis fat was not increased\n\n\n\nDiscussion and conclusions\nSeveral cases of T-cell lymphomas after Metreleptin exposure in patients with AGL have been described and led to a black box warning for the approval of Metreleptin in the United States. Over the past several years, there have been several case reports of AGL patients presenting with T-cell lymphomas who have never received leptin therapy. Given the rarity of the AGL, documentation of cases with T-cell lymphoma in the absence of Metreleptin therapy is quite important to provide the evidence base needed to provide assurance that Metreleptin is not playing a causal role in the development of the T-cell lymphomas. Our current report describes a unique case of a patient who developed adult onset AGL (which is quite rare), and who got diagnosed with the AGL after the remission of her T-cell lymphoma. It is important to underscore that this is distinctive than cases of children developing partial lipodystrophy who have undergone hematopoietic stem cell transplantation during childhood [11].\n\nLymphomas, particularly peripheral T-cell lymphomas (PTCL), have been noted in AGL [12, 13]. Brown et al. reported 5 cases of AGL and lymphoma [12]. The coexistence of AGL and lymphoma likely relates to an underlying autoimmune preponderance. Autoimmune diseases can occur commonly in patients with AGL [8, 12, 14, 15], including both organ-specific autoimmunity (e.g. type 1 diabetes, autoimmune hepatitis) and systemic autoimmune diseases (e.g. juvenile dermatomyositis) [12].\n\nLymphoma can be considered a systemic feature of AGL instead of an association with lipodystrophy per se given that other forms of lipodystrophy have not been associated with an increased risk of lymphomas [12]. Furthermore, it appears that patients with AGL are at an increased risk of the development of T-cell lymphomas, especially (PTCL), which is a heterogeneous and generally aggressive disorder. It is thought to be related to acquired lipodystrophy, as a subtype of PTCL localizes to the subcutaneous fat, termed subcutaneous panniculitis-like T-cell lymphoma. Panniculitis may be the presenting feature of AGL, as in the patient with AGL and PTCL reported by Yiannias and colleagues [16]. The clinical assessment of the potential role of Metreleptin in contributing to development and/or progression of lymphoma is limited by the lack of long term, controlled studies. Three out of 17 patients with AGL (18%) developed T-cell lymphoma within the NIH cohort [5], an incidence significantly higher than what is observed in the general population (approximately 2 per 100,000) [17].\n\nAnother interesting case of PTCL subsequently complicated by AGL has been described by Aslam et al. [18]. Misra and Garg proposed three classification types for AGL based on the etiology and pathological mechanisms: type 1 represents AGL associated with panniculitis; type 2 represents AGL with accompanying autoimmune diseases, and type 3 represents idiopathic AGL [8]. Aslam et al. felt that their patient developed AGL and likely represented an overlap of both the type 2 and 3 varieties [18]. The classification of AGL is likely not to be as simple, and there are newer case reports that may change or challenge these earlier classifications.\n\nThe time course of the development of AGL was interesting in our case. One possibility is that our patient started to develop AGL while she was going through the diagnosis of her T cell lymphoma as she had panniculitis related T-cell lymphoma. Her treatment with chemotherapy and steroids may have been a contributing factor in her clinical presentation. Steroids might have also masked the features of AGL until the remission of T cell lymphoma and discontinuation of steroids.\n\nIn conclusion, there are several clinical lessons from our case. First, development of extensive panniculitis in an adult patient who is losing body fat should raise suspicion of for both T-cell lymphoma and AGL. These patients should be vigilantly monitored for the development of metabolic complications over time. Finally, the association of T-cell lymphoma with known panniculitis within the setting of AGL may be expected and is not likely impacted by Metreleptin therapy.\n\nAbbreviations\nAGLAcquired generalized lipodystrophy\n\nGLGeneralized lipodystrophy\n\nPTCLPeripheral T-cell lymphoma\n\nThe authors thank the patient for letting us to report her unique case and sharing her pictures.\n\nFunding\nDr. Oral was partially supported by R01 DK088114. The work was supported by generous gifts to the Lipodystrophy Fund at the University of Michigan made by the Sopha family, Ionis Pharmaceuticals and the White Point Foundation of Turkey. These funding sources had no interference in the study design or direction.\n\nDr. Oral also received grant support from and served as an advisor to Amylin Pharmaceuticals LLC, Bristol-Myers-Squibb, AstraZeneca in the past. She is currently receiving grant support from Gemphire Therapeutics, Aegerion Pharmaceuticals, Ionis Pharmaceuticals and Akcea Therapeutics and serving as an advisor to Aegerion Pharmaceuticals, Akcea Therapeutics and Regeneron Pharmaceuticals. Dr. Oral recently completed grant support from GI Dynamics.\n\nAvailability of data and materials\nThe datasets analyzed during this study are included in this published article.\n\nAuthors’ contributions\nNHE gathered the data and wrote the manuscript. MR evaluated the patient in lipid clinic, reviewed and edited the manuscript. AHN, AJE and RH provided help in contacting the patient to get her pictures and obtained the written consent form, reviewed and edited the manuscript. RM helped in making her pictures appropriate for this manuscript, reviewed and edited the manuscript. EAO evaluated the patient, confirmed the diagnosis of lipodystrophy (currently follows the patient), reviewed and edited the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThere is no Ethics approval and consent to participate as this is a single case report.\n\nConsent for publication\nPatient has given us written consent for publication.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Chan JL Lutz K Cochran E Huang W Peters Y Weyer C Clinical effects of long-term metreleptin treatment in patients with lipodystrophy Endocr Pract 2011 17 6 922 932 10.4158/EP11229.OR 22068254 \n2. Handelsman Y Oral EA Bloomgarden ZT Brown RJ Chan JL Einhorn D The clinical approach to the detection of lipodystrophy - an AACE consensus statement Endocr Pract 2013 19 1 107 116 10.4158/endp.19.1.v767575m65p5mr06 23435042 \n3. Chan JL Oral EA Clinical classification and treatment of congenital and acquired lipodystrophy Endocr Pract 2010 16 2 310 323 10.4158/EP09154.RA 20061300 \n4. Garg A Clinical review#: lipodystrophies: genetic and acquired body fat disorders J Clin Endocrinol Metab 2011 96 11 3313 3325 10.1210/jc.2011-1159 21865368 \n5. Golden J. The Endocrinologic and Metabolic Drugs Advisory Committee Meeting Briefing Document BLA 125390 Myalept (metreleptin for injection) FDA.gov archive-it.org: Food and Drug Administration Center for Drug Evaluation and Research; 2013 [Available from: https://wayback.archive-it.org/7993/20170405215819/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM377928.pdf.\n6. Oral EA Simha V Ruiz E Andewelt A Premkumar A Snell P Leptin-replacement therapy for lipodystrophy N Engl J Med 2002 346 8 570 578 10.1056/NEJMoa012437 11856796 \n7. Rodriguez AJ Mastronardi CA Paz-Filho GJ New advances in the treatment of generalized lipodystrophy: role of metreleptin Ther Clin Risk Manag 2015 11 1391 1400 26396524 \n8. Misra A Garg A Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature Medicine (Baltimore) 2003 82 2 129 146 10.1097/00005792-200303000-00007 12640189 \n9. Wiggin TD Sullivan KA Pop-Busui R Amato A Sima AA Feldman EL Elevated triglycerides correlate with progression of diabetic neuropathy Diabetes 2009 58 7 1634 1640 10.2337/db08-1771 19411614 \n10. Meral R Ryan BJ Malandrino N Jalal A Neidert AH Muniyappa R \"fat shadows\" from DXA for the qualitative assessment of lipodystrophy: when a picture is worth a thousand numbers Diabetes Care 2018 41 10 2255 2258 10.2337/dc18-0978 30237235 \n11. Adachi M Oto Y Muroya K Hanakawa J Asakura Y Goto H Partial lipodystrophy in patients who have undergone hematopoietic stem cell transplantation during childhood: an institutional cross-sectional survey Clin Pediatr Endocrinol 2017 26 2 99 108 10.1297/cpe.26.99 28458462 \n12. Brown RJ Chan JL Jaffe ES Cochran E DePaoli AM Gautier JF Lymphoma in acquired generalized lipodystrophy Leuk Lymphoma 2016 57 1 45 50 10.3109/10428194.2015.1040015 25864863 \n13. Brown RJ Araujo-Vilar D Cheung PT Dunger D Garg A Jack M The diagnosis and Management of Lipodystrophy Syndromes: a multi-society practice guideline J Clin Endocrinol Metab 2016 101 12 4500 4511 10.1210/jc.2016-2466 27710244 \n14. Savage DB Semple RK Clatworthy MR Lyons PA Morgan BP Cochran EK Complement abnormalities in acquired lipodystrophy revisited J Clin Endocrinol Metab 2009 94 1 10 16 10.1210/jc.2008-1703 18854390 \n15. Garg A Acquired and inherited lipodystrophies N Engl J Med 2004 350 12 1220 1234 10.1056/NEJMra025261 15028826 \n16. Yiannias JA DiCaudo DJ Maskin E Peripheral T-cell lymphoma presenting as lipoatrophy and nodules Int J Dermatol 2006 45 12 1415 1419 10.1111/j.1365-4632.2006.02888.x 17184242 \n17. Wang SS Vose JM Foss F Epidemiology and prognosis of T-cell lymphoma T-cell lymphomas 2013 Totowa, NJ Humana Press 25 39 \n18. Aslam A Savage DB Coulson IH Acquired generalized lipodystrophy associated with peripheral T cell lymphoma with cutaneous infiltration Int J Dermatol 2015 54 7 827 829 10.1111/ijd.12185 24168394\n\n",
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"keywords": "Acquired generalized lipodystrophy; Diabetes; Insulin resistance; Leptin; T-cell lymphoma",
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"title": "Diagnosis of acquired generalized lipodystrophy in a single patient with T-cell lymphoma and no exposure to Metreleptin.",
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"abstract": "The combined squamous cell carcinoma (SCC) with neuroendocrine (atypical carcinoid (AC)) tumor is extremely rare in the head and neck. We present here the first case of SCC with AC arising in the floor of the mouth of 65-year-old man. The tumor is comprised of two components of SCC and AC in the biopsy specimen. Neuroendocrine tumor component was classified as AC from the punctate necrosis and 2-10>/10 HPF. Immunohistochemical staining was HMW-CK/34B (+) and P63 (+) in SCC and synaptophysin (+) and CD56 (+) in AC. The pathological diagnosis of SCC with AC was made from both the morphological and immunological exam. Concurrent chemoradiotherapy was performed with radiotherapy 70.2 Gy and chemotherapy of CDDP and VP-16. Although the treatment effect was complete response both of primary tumor and of neck metastases, the recurrence of the primary tumor was after 6 months. Bilateral modified radical neck dissection and tumor resection of the floor of the mouth with reconstructive surgery of anterior lateral thigh free flap were performed. Although the primary and neck tumor did not recur, the multiple lung metastases and mediastinum lymph node metastases occurred at 6 months after surgery.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.",
"authors": "Yamagata|Kenji|K|0000-0001-7231-7478;Terada|Kazuhiro|K|;Uchida|Fumihiko|F|;Kanno|Naomi|N|;Hasegawa|Shogo|S|0000-0002-2708-6073;Yanagawa|Toru|T|;Bukawa|Hiroki|H|",
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"doi": "10.1155/2016/7532805",
"fulltext": "\n==== Front\nCase Rep DentCase Rep DentCRIDCase Reports in Dentistry2090-64472090-6455Hindawi Publishing Corporation 2811617810.1155/2016/7532805Case ReportA Case of Primary Combined Squamous Cell Carcinoma with Neuroendocrine (Atypical Carcinoid) Tumor in the Floor of the Mouth http://orcid.org/0000-0001-7231-7478Yamagata Kenji \n*\nTerada Kazuhiro Uchida Fumihiko Kanno Naomi http://orcid.org/0000-0002-2708-6073Hasegawa Shogo Yanagawa Toru Bukawa Hiroki Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan*Kenji Yamagata: y-kenji@md.tsukuba.ac.jpAcademic Editor: Giuseppe Colella\n\n2016 27 12 2016 2016 75328058 8 2016 21 11 2016 Copyright © 2016 Kenji Yamagata et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The combined squamous cell carcinoma (SCC) with neuroendocrine (atypical carcinoid (AC)) tumor is extremely rare in the head and neck. We present here the first case of SCC with AC arising in the floor of the mouth of 65-year-old man. The tumor is comprised of two components of SCC and AC in the biopsy specimen. Neuroendocrine tumor component was classified as AC from the punctate necrosis and 2–10>/10 HPF. Immunohistochemical staining was HMW-CK/34B (+) and P63 (+) in SCC and synaptophysin (+) and CD56 (+) in AC. The pathological diagnosis of SCC with AC was made from both the morphological and immunological exam. Concurrent chemoradiotherapy was performed with radiotherapy 70.2 Gy and chemotherapy of CDDP and VP-16. Although the treatment effect was complete response both of primary tumor and of neck metastases, the recurrence of the primary tumor was after 6 months. Bilateral modified radical neck dissection and tumor resection of the floor of the mouth with reconstructive surgery of anterior lateral thigh free flap were performed. Although the primary and neck tumor did not recur, the multiple lung metastases and mediastinum lymph node metastases occurred at 6 months after surgery.\n==== Body\n1. Introduction \nNeuroendocrine neoplasms are a heterogeneous group of tumors that vary from benign to highly malignant. WHO (2005) classified neuroendocrine tumor (NET) of the larynx into 4 types: (1) typical carcinoid, (2) atypical carcinoid (AC), (3) small cell carcinoma, neuroendocrine type, and (4) combined small cell carcinoma, neuroendocrine type, with non-small cell carcinoma [1]. The AC (synonyms of malignant carcinoid, moderately differentiated neuroendocrine carcinoma, and large cell neuroendocrine carcinoma) is the most frequent, constituting 54% of all NET in this site, followed by the small cell carcinoma, neuroendocrine type (34%), paraganglioma (9%), and the typical carcinoid (3%) [1]. Although the NET is a tumor that occurs particularly in the lung and larynx, oral cavity is a rare site for a primary NET [2]. Recently, neuroendocrine differentiation has also been found in some tumors not considered to be of neuroendocrine origin, including squamous cell carcinoma (SCC) of the lung and esophagus [3, 4]. The occurrence and possible role of NET in the head and neck SCC have not yet been analyzed. Combined-type SCC and AC instances in the head and neck area were reported only in 3 cases and very rare [5–7]. We report here the fast case of the combined SCC with AC of the floor of the mouth.\n\n2. Case Report\nA 65-year-old Japanese man referred to the Department of Oral and Maxillofacial Surgery, University of Tsukuba Hospital, complaining of pain in the floor of the mouth for one month. His medical history revealed diabetes mellitus, hypertension, chronic pancreatitis, reflux esophagitis, and iron deficiency anemia. His face was symmetrical and there was no trismus. The regional lymph nodes were swollen multiply in both sides from level I to level II. Intraoral examination shows relatively well defined elastic hard mass with necrotic ulcer in the right to left floor of the mouth, which measures approximately 36 × 33 mm (Figure 1).\n\nT2 weighted MRI showed a sequence that shows a 29 × 23 × 22 mm heterogeneous high signal mass in the floor of mouth (Figure 2). Bilateral multiple neck lymph node metastases are depicted in MRI. The level Ia LNs are swollen in 16 mm and 7 mm, right level Ib LNs are swollen in 23 mm and 13 mm, left level Ib LN is swollen in 5 mm, and left level IIa LN is swollen in 37 mm (Figure 3). The 18F-fluorodeoxy-glucose positron-emission tomography combined with computed tomography (18F-FDG PET/CT) revealed FDG uptake in the floor of the mouth mass measuring 28 × 13 mm with the SUV max 10.4 and bilateral multiple LNs.\n\nThe incisional biopsy was performed from floor of the mouth under local anesthesia. Microscopically, the tumor consisted of two components of SCC and AC. SCC consisted of nonkeratic dysplastic squamous cells proliferated with apoptosis and mitosis. The cells change larger and have high N/C rate and chromatin, a lot of mitosis and karyolysises are seen in component of NET. The punctate necrosis was observed and 2–10>/10 HPF. The NET component was classified as AC (Figures 4(a)–4(c)). Immunohistochemical staining was synaptophysin (+), CD56 (+), and chromogranin A (−) in AC and HMW-CK/34B (+) and P63 (+) in SCC. There was no transitional part between SCC and AC (Figures 5(a) and 5(b)). From these findings pathological diagnosis of SCC with AC in the floor of the mouth was made.\n\nConcurrent chemoradiotherapy was performed with radiotherapy 70.2 Gy and chemotherapy of CDDP and VP-16 for 4 times under the consideration of unresectable neck metastases. Chemotherapy regimen was day 1: CDDP 70 mg/m2 + VP-16 100 mg/m2, day 2: VP-16 100 mg/m2, and day 3: VP-16 100 mg/m2. The highest side effects according to CTCAE ver. 4.0 were leukocytopenia (G4), anemia (G3), and thrombocytopenia (G3). The aspiration pneumonia occurred during pancytopenia after second chemotherapy. The leukocyte counts recovered on administrating of G-CSF and aspiration pneumonia was improved with the administration of antibiotics. The treatment effect was complete response both of primary tumor and of neck metastases.\n\nThe recurrence of the primary site occurred 6 months from the end of chemoradiotherapy with a diagnosis of primary site biopsy (Figure 6). The volume of lymph node metastases was decreased and changed to resectable. Bilateral modified radical neck dissection and tumor resection of the floor of the mouth with reconstructive surgery of anterior lateral thigh (ALT) free flap were performed under general anesthesia. The pathological diagnosis was SCC without AC in the primary site (Figure 7). There were no metastases in the specimen of neck lymph nodes. Although the primary and neck tumor did not recur, the multiple lung metastases and mediastinum lymph node metastases were diagnosed with FDG PET at 6 months after surgery (Figure 8). The patient received best supportive care with chemotherapy of paclitaxel and cetuximab.\n\n3. Discussion\nNETs represent a rare, heterogeneous subset in the laryngeal malignancies and are classified into distinct groups and ranging from benign to highly malignant. The oral cavity is a rare site of a primary NET and only 12 cases were reported [2]. Neuroendocrine differentiation has recently been reported in SCC of the lung and esophagus. The occurrence and possible role of neuroendocrine differentiation in the head and neck SCC have not yet been analyzed [8]. It has been hypothesized that tumor cells with neuroendocrine characterization may produce peptides to stimulate tumor growth via autocrine or paracrine mechanisms [4]. Three previously reported SCC with AC of head and neck cases were larynx, maxillary sinus, and upper gingiva [5–7]. The present case was the first report represented on the floor of the mouth with a composite tumor consisting of SCC and AC. Although the composite tumor consisted of combined SCC and small cell carcinoma was reported sometimes, to our knowledge, our case is the fourth to document a composite tumor including AC [5, 7].\n\nA capacity for multidirectional differentiation could arise from pluripotent stem cells. SCC and AC could have arisen from pluripotent cells that differentiated along two distinct paths or the AC could have differentiated secondarily from cells arising in SCC [5, 9]. Another hypothesis is that AC derived from pluripotential indifferent cells of either the squamous epithelium or the minor salivary gland [10]. In the present case, there was no transitional part between SCC and AC in the biopsy specimen, suggested to arise from pluripotent cells that differentiated along two distinct paths.\n\nImmunohistochemically, NET frequently expresses chromogranin A, synaptophysin, and CD56. The tumor cells of NET component are positive for synaptophysin and CD56 in our case. The SCC component was negative for synaptophysin and CD56 and positive for HMW-CK/34B and P63. Nisman et al. reported neuroendocrine differentiation in SCC was associated with poor prognosis [3]. On the other hand, chromogranin A and synaptophysin expression were reported not to associate with advanced disease stage and not to affect patient survival [8]. More cases of this tumor need to accumulate to clarify biological behavior and prognosis.\n\nThe AC most occur in supraglottic submucosal in the sixth- and seventh-decade males (M : F, 3 : 1). The rate of metastases was reported 66.7% and the 5-year survival 46% [10]. There was no evidence for the treatment of head and neck AC. The primary treatment is reported to be the surgery and the radiotherapy, with rare response in the chemotherapy [10]. However, AC is reported to be relatively resistant to chemotherapy and radiation therapy [11], and there is no proven optimal therapy for metastatic unresectable AC. Although surgical resection is usually recommended, patients did respond to radiotherapy and chemotherapy, suggesting a combined approach may be indicated in the larynx AC [12]. It was reported that the treatment of primary neoplasms consisting of more than one histological type is tailored to the most histologically aggressive tumor [7]. In our case, the clinical stage was advanced with bilateral multiple neck lymph node metastasis and the chemoradiotherapy was selected because of unresectable and aggressive tumor feature.\n\nTreatment regimens showing efficacy in pulmonary carcinoid were reported to include octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR)), etoposide (VP-16) + platinum (23% RR, 69% DCR), and temozolomide-based therapies (14% RR, 57% DCR) [13]. The regimen for our case was selected as etoposide + platinum, because platinum is standard regimen for SCC and both effective for SCC and effective for AC. Fortunately the chemotherapy with CDDP and VP-16 and radiotherapy were effective and achieved complete response. The side effect for CDDP and VP-16 of grade 4 leukocytopenia occurred after chemotherapy and the aspiration pneumonia occurred during pancytopenia. This chemotherapy was tolerable because the leukocyte counts recovered on administrating of G-CSF and aspiration pneumonia was improved with antibiotics.\n\nAlthough the treatment effect was complete response, the recurrence of the primary site occurred 6 months from the end of chemoradiotherapy. The resected primary tumor was SCC without AC, and there were no tumors in the lymph nodes. In the reported combined SCC and AC of the lung, intermediate-grade AC is considered as less aggressive than SCC. The rapid disease progression was suggested that SCC component contributes to the metastasis [14]. In the present case, the component of AC suggested to metastasize to the lymph nodes and to be sensitive to chemoradiotherapy. The component of SCC in primary site was not sensitive for chemoradiotherapy and recurred.\n\nWe experienced the first case of SCC with AC of the floor of mouth. More cases of this tumor need to accumulate to clarify biological behavior, treatment, and prognosis. Moreover the occurrence and possible role of SCC with AC have not yet been analyzed, and further research will be desired in the future.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Intraoral examination shows relatively well defined elastic hard mass with ulcer in the left floor of the mouth, which measures approximately 36 × 33 mm.\n\nFigure 2 T2 weighted MRI sequence shows a 29 × 23 × 22 mm heterogeneous high signal mass in the floor of mouth.\n\nFigure 3 Bilateral multiple neck lymph node metastases are shown. The level Ia LNs are swollen in 16 mm and 7 mm, right level Ib LNs are swollen in 23 mm and 13 mm, left level Ib LN is swollen in 5 mm, and left level IIa LN is swollen in 37 mm.\n\nFigure 4 (a) The histopathology of biopsy specimen (HE ×40). The square of straight line was comprised of SCC, and dotted line was comprised of AC. Microscopically, the tumor consists of two components of SCC and AC. (b) The component of SCC. Nonkeratic dysplastic squamous cells proliferated with apoptosis and mitosis. (c) The component of AC. The cells change in a larger way and have high N/C rate and chromatin, a lot of mitosis and karyolysises are seen. A punctate necrosis is observed in the tumor nest, and the rosette structures are observed.\n\nFigure 5 (a) Immunohistochemical staining shows that the tumor cells are positive for synaptophysin and CD56 in SCC. (b) Immunohistochemical staining shows that the tumor cells are positive for HMW-CK/34B and P63 in SCC.\n\nFigure 6 Intraoral examination 6 months after chemoradiotherapy shows small ulcer in the left floor of the mouth.\n\nFigure 7 The histopathology of recurred resected specimen (HE ×40, ×100). Microscopically, the resected tumor of floor of mouth was SCC.\n\nFigure 8 Lung metastasis and mediastinum lymph node metastases are depicted in the PET-CT.\n==== Refs\n1 Barnes L. Tumours of the Hypopharynx, Larynx, and Trachea: Neuroendocrine Tumors 2005 Lyon, France IARC Press \n2 Wu B.-Z. Gao Y. Yi B. Primary neuroendocrine carcinoma in oral cavity: two case reports and review of the literature Journal of Oral and Maxillofacial Surgery 2014 72 3 633 644 10.1016/j.joms.2013.08.020 2-s2.0-84893859899 24215661 \n3 Nisman B. Heching N. Biran H. Barak V. Peretz T. The prognostic significance of circulating neuroendocrine markers chromogranin A, pro-gastrin-releasing peptide and neuron-specific enolase in patients with advanced non-small-cell lung cancer Tumor Biology 2006 27 1 8 16 10.1159/000090151 2-s2.0-29244489499 16340245 \n4 Yuan A. Liu J. Liu Y. Cui G. Chromogranin a-positive tumor cells in human esophageal squamous cell carcinomas Pathology and Oncology Research 2007 13 4 321 325 10.1007/bf02940311 2-s2.0-39649092932 18158567 \n5 Mochizuki Y. Omura K. Sakamoto K. A case of primary combined neuroendocrine carcinoma with squamous cell carcinoma in the upper gingiva Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2010 109 4 e34 e39 10.1016/j.tripleo.2009.12.018 2-s2.0-77949647226 \n6 Franchi A. Rocchetta D. Palomba A. Innocenti D. R. D. Castiglione F. Spinelli G. Primary combined neuroendocrine and squamous cell carcinoma of the maxillary sinus: report of a case with immunohistochemical and molecular characterization Head and Neck Pathology 2015 9 1 107 113 10.1007/s12105-013-0513-5 2-s2.0-84948975935 24327102 \n7 Davies-Husband C. R. Montgomery P. Premachandra D. Hellquist H. Primary, combined, atypical carcinoid and squamous cell carcinoma of the larynx: a new variety of composite tumour Journal of Laryngology and Otology 2010 124 2 226 229 10.1017/s0022215109991228 2-s2.0-77949774599 19930775 \n8 Schartinger V. H. Falkeis C. Laimer K. Neuroendocrine differentiation in head and neck squamous cell carcinoma Journal of Laryngology and Otology 2012 126 12 1261 1270 10.1017/S0022215112002265 2-s2.0-84877156560 23050666 23050666 \n9 Cho K.-J. Jang J.-J. Lee S.-S. Zo J.-I. Basaloid squamous carcinoma of the oesophagus: a distinct neoplasm with multipotential differentiation Histopathology 2000 36 4 331 340 10.1046/j.1365-2559.2000.00851.x 2-s2.0-0034031637 10759947 \n10 Ferlito A. Devaney K. O. Rinaldo A. Neuroendocrine neoplasms of the larynx: advances in identification, understanding, and management Oral Oncology 2006 42 8 770 788 10.1016/j.oraloncology.2006.01.002 2-s2.0-33748111106 16815077 \n11 Hage R. de la Rivière A. B. Seldenrijk C. A. van den Bosch J. M. M. Update in pulmonary carcinoid tumors: a review article Annals of Surgical Oncology 2003 10 6 697 704 10.1245/aso.2003.09.019 2-s2.0-0141872354 12839856 \n12 Gillenwater A. Lewin J. Roberts D. El-Naggar A. Moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the larynx: a clinically aggressive tumor Laryngoscope 2005 115 7 1191 1195 10.1097/01.mlg.0000166179.40750.1b 2-s2.0-21844463059 15995505 \n13 Chong C. R. Wirth L. J. Nishino M. Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors Lung Cancer 2014 86 2 241 246 10.1016/j.lungcan.2014.08.012 2-s2.0-84908399268 25218177 \n14 Okazaki M. Sano Y. Soga Y. Combined atypical carcinoid tumour and squamous cell carcinoma of the lung Internal Medicine 2015 54 11 1385 1388 10.2169/internalmedicine.54.3846 2-s2.0-84939495796 26027992 26027992\n\n",
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"title": "A Case of Primary Combined Squamous Cell Carcinoma with Neuroendocrine (Atypical Carcinoid) Tumor in the Floor of the Mouth.",
"title_normalized": "a case of primary combined squamous cell carcinoma with neuroendocrine atypical carcinoid tumor in the floor of the mouth"
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"abstract": "The use of daptomycin (DAP) in septic pulmonary emboli (SPE) remains controversial. We analyzed 29 cases of MRSA bacteremia complicated by SPE treated with DAP (n = 14) or DAP-ceftaroline fosamil (CPT; n = 15). Initial treatment with DAP monotherapy was found to have a success rate comparable with DAP-CPT (71% vs. 80%; p = 0.68).",
"affiliations": "Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA.;Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA.;Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA.;Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA. m.rybak@wayne.edu.",
"authors": "Morrisette|Taylor|T|https://orcid.org/0000-0002-1094-043X;Lagnf|Abdalhamid M|AM|;Alosaimy|Sara|S|;Rybak|Michael J|MJ|",
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"keywords": "Daptomycin; Methicillin-resistant Staphylococcus aureus; Septic pulmonary emboli",
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"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002511:Cephalosporins; D015331:Cohort Studies; D017576:Daptomycin; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D016896:Treatment Outcome",
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"title": "A comparison of daptomycin alone and in combination with ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bacteremia complicated by septic pulmonary emboli.",
"title_normalized": "a comparison of daptomycin alone and in combination with ceftaroline fosamil for methicillin resistant staphylococcus aureus bacteremia complicated by septic pulmonary emboli"
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"abstract": "Cytarabine is a pyrimidine analogue that is used for the treatment of acute myeloid leukemia at different doses. Standard doses of cytarabine are used for induction therapy, while high doses are used for post-remission (consolidation) and relapsed/refractory treatment. One of the major side effects of its high doses is acute cerebellar toxicity occurring in 10 to 25% of patients. We report a case that developed this side effect after receiving two doses of high-dose cytarabine. The patient's symptoms improved after withholding the drug. Thereafter, the patient tolerated treatment continuation with lower doses.",
"affiliations": "Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.;Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.;Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.;Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.",
"authors": "Rahmani|Hamid|H|https://orcid.org/0000-0001-5814-9703;Radmehr|Mojan|M|;Hadjibabaie|Molouk|M|;Solduzian|Mohammad|M|",
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"keywords": "Acute leukemia; cerebellar toxicity; high-dose cytarabine",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002531:Cerebellum; D003561:Cytarabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D012074:Remission Induction; D055815:Young Adult",
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"title": "Acute cerebellar toxicity induced by high dose of cytarabine (HiDAC): A case report.",
"title_normalized": "acute cerebellar toxicity induced by high dose of cytarabine hidac a case report"
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"abstract": "An 86-year-old man with paroxysmal atrial fibrillation on flecainide, a class IC antiarrhythmic, presented with cardiac arrest. The patient had extremely wide QRS complexes with inconsistent pacemaker capture on electrocardiography. Due to cardiac failure and renal failure, the patient developed progressive flecainide toxicity, which led to pacemaker failure, and ultimately, death. (Level of Difficulty: Beginner.).",
"affiliations": "Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.;Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.",
"authors": "Rivner|Harold|H|;Lambrakos|Litsa K|LK|",
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"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)31427-3\n10.1016/j.jaccas.2020.11.030\nMini-Focus Issue: Electrophysiology\nCase Report: Clinical Case\nFlecainide Toxicity Leading to Loss of Pacemaker Capture and Cardiac Arrest\nRivner Harold MD\nLambrakos Litsa K. MD llambrakos@med.miami.edu\n@DrLitsaL\n∗\nCardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA\n∗ Address for correspondence: Dr. Litsa K. Lambrakos, Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, 400 NW 12 Avenue, Suite 4062, Miami, Florida 33136, USA. llambrakos@med.miami.edu@DrLitsaL\n27 1 2021\n4 2021\n27 1 2021\n3 4 586590\n29 6 2020\n2 11 2020\n24 11 2020\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAn 86-year-old man with paroxysmal atrial fibrillation on flecainide, a class IC antiarrhythmic, presented with cardiac arrest. The patient had extremely wide QRS complexes with inconsistent pacemaker capture on electrocardiography. Due to cardiac failure and renal failure, the patient developed progressive flecainide toxicity, which led to pacemaker failure, and ultimately, death. (Level of Difficulty: Beginner.)\n\nCentral Illustration\n\nKey Words\n\natrial fibrillation\ncardiac pacemaker\ncomplication\nAbbreviations and Acronyms\n\nAF, atrial fibrillation\nECG, electrocardiography\nHF, heart failure\nLVH, left ventricular hypertrophy\n==== Body\nHistory of Presentation\n\nAn 86-year-old man presented to the hospital after cardiac arrest. On the morning of the arrest, the patient collapsed while walking to the bathroom. Emergency medical services were called; they reportedly found the patient with pulseless electrical activity. Return of spontaneous circulation was achieved, and the patient was brought to the emergency department. Upon arrival, the patient arrested again with return of circulation after resuscitation.Learning Objectives\n\n• To illustrate the mechanism by which flecainide slows phase 0 of the fast sodium channel, which leads to decreased conduction velocity of the conduction system with widening of the QRS and increased repolarization times.\n\n• To recognize the toxic effects of flecainide and its contraindications in patients with HF. and structural heart disease.\n\n• To understand that renal failure increases the half-life of flecainide dramatically, and therefore, a high index of suspicion for flecainide toxicity is needed in the setting of renal failure and a wide QRS.\n\n• To recognize that immediate actions are needed to support patients while awaiting reversal of flecainide toxicity to prevent hemodynamic collapse and death.\n\nPast Medical History\n\nThe patient’s medical history included paroxysmal atrial fibrillation (AF), left ventricular hypertrophy (LVH) with a reported normal ejection fraction, and complete atrioventricular block; he had an Abbott/St. Jude Medical (Minneapolis, Minnesota) dual-chamber pacemaker. He had been started on flecainide 100 mg twice daily for his AF in the weeks preceding his admission. This was later increased to 150 mg due to an increased burden of paroxysmal AF. Concurrently, he developed heart failure (HF) symptoms that required escalating doses of furosemide.\n\nDifferential Diagnosis\n\nThe patient’s differential diagnosis for his pacemaker malfunction included medication toxicity, lead dislodgement, electrolyte abnormalities, and ischemia in the setting of known worsening HF. Due to his history, a probable inciting cause was flecainide toxicity.\n\nThe differential diagnosis for his arrest included bradycardia, negative inotropy, decreased cardiac output from dyssynchrony and HF, arrhythmia, or a combination of the preceding.\n\nInitial Investigation\n\nThe initial physical examination was significant for an unresponsive man on mechanical ventilation. As per emergency room documentation, initial heart rate after resuscitation was approximately 30 beats/min, with a mean arterial pressure of 60 mm Hg. Cardiac auscultation revealed a slow but regular rhythm with normal S1 and S2 without significant murmurs or gallops. Electrocardiography (ECG) revealed a wide complex rhythm (QRS duration ∼320 ms) with intermittent capture of his pacemaker spikes (2:1 ventricular capture). The ventricular rate by ECG was approximately 40 beats/min (Figure 1A). The patient’s pacemaker interrogation revealed programming of DDDR 70 with increased ventricular thresholds from a baseline of 1 V at 0.4 ms to 1.75 V at 0.4 ms. This threshold was performed several hours after initial resuscitation. Ventricular outputs were 2.5 V at 0.4 ms but increased at the time of interrogation to 4 V to provide a 2:1 safety margin. There were clear episodes of loss of reliable ventricular and atrial capture that seemed to correlate temporally to the presumed time of the patient’s arrest (Figure 2). These events were incidentally captured as automatic mode switching events because of lack of capture and oversensing in the atrial channel. Thus, we did not know the nadir ventricular rate during arrest. No ventricular arrhythmias were detected. The initial lactic acid on admission was 6.4 with a pH of 7.05 and bicarbonate of 20 mmol/l; he subsequently developed acute renal failure. His initial flecainide level was elevated to 2.44 μg/ml, which was more than twice the upper limit of normal (0.99 μg/ml). Echocardiography after resuscitation showed an ejection fraction of 20% to 25% with marked asymmetric LVH, with a measured interventricular septum of 1.8 cm (Figure 3). Marked mechanical ventricular dyssynchrony was present (Video 1). Coronary angiography showed no evidence of obstructive coronary artery disease.Figure 1 Electrocardiograms\n\n(A) Electrocardiogram after resuscitations shows very wide QRS (∼320 ms) with intermittent capture. The ventricular rate is 40 beats/min. (B) Electrocardiogram the next day shows underlying atrial flutter with ventricular paced rhythm. There is narrowing of QRS (200 ms) from admission and return of consistent ventricular capture.\n\nFigure 2 Device Interrogation From Around the Time of Event\n\nDevice interrogation from around the time of event shows loss of consistent ventricular capture (asterisk).\n\nFigure 3 Echocardiogram After Arrest\n\nThe parasternal long-axis view of the left ventricle shows marked asymmetric left ventricular hypertrophy. The interventricular septum measures 1.8 cm.\n\nManagement and Interventions\n\nThe patient was treated with a sodium bicarbonate infusion, and the pacemaker’s pacing output was increased to 4 V with return of consistent capture. Within 24 h, the patient had a ventricular paced rhythm with a narrowing of his QRS duration to approximately 200 ms (Figure 1B), and the ventricular pacing thresholds returned to baseline.\n\nDiscussion\n\nThis case report illustrated the multiple cardiovascular effects of flecainide toxicity that could affect device therapy. When the patient first presented with loss of capture, the initial reflex was to search for an intrinsic malfunction of his pacemaker. However, there were no issues with the pacemaker’s placement or programming. Instead, flecainide toxicity had produced a dose-dependent decrease in intracardiac conduction, increased ventricular refractoriness, and had consequently affected the ability of the pacemaker to capture both the atrial and ventricular channels (1). The acute changes of the QRS and QTc width associated with pacemaker loss of capture were consistent with the acute flecainide toxicity confirmed by serum levels.\n\nFlecainide is a Class IC antiarrhythmic that slows phase 0 of the fast sodium channel, which leads to decreased conduction velocity of the conduction system and myocardial electrical propagation (2). Specifically, its high affinity for open-state sodium channels with slow unbinding from these channels in diastole leads to prolonged ventricular refractoriness (3). Furthermore, it inhibits the rapid phase of the delayed rectifier potassium current (IKr), which leads to prolongation of ventricular action potentials (3). Therefore, toxic levels can lead to an extremely wide QRS and QTc, as seen in our patient. These decreased conduction times, with corresponding widening of the paced QRS morphology and increased refractoriness, resulted in intermittent capture. With standard programming, the timing of the pacing spike fell in a refractory period after the wide preceding ventricular paced complex. In addition, flecainide can increase the capture threshold of pacemakers by up to 200% (4), which leads to loss of capture with a correlation between the degree of QRS widening and the increase in pacing thresholds.\n\nFlecainide has also been associated with increased dyssynchrony with decreased cardiac output in an animal model with baseline left bundle branch block (5). Furthermore, it has a known negative inotropic effect (6). Due to these effects and the increased mortality seen in the CAST (Cardiac Arrhythmia Suppression Trial) (7), current guidelines recommend that the drug be avoided in patients with structural heart disease or coronary artery disease (8).\n\nToxicity can be amplified by renal failure due to the marked prolongation in the half-life of the drug (9). Congestive HF and ischemia also promote sodium channel blockade by flecainide (1). Our patient had worsening HF before admission and developed acute renal failure.\n\nIn light of this, the cause of this patient’s cardiac arrest was likely multifactorial―bradycardia with loss of consistent capture, marked ventricular dyssynchrony, and negative cardiac inotropy against the backdrop of worsening HF likely triggered and accelerated by the high flecainide levels.\n\nA high index of suspicion for toxicity is needed in patients with a device who have cardiac and metabolic disturbances on flecainide to preempt sequela of toxicity. Because flecainide is poorly dialyzable, therapies such as activated charcoal, intravenous sodium bicarbonate infusion, intravenous fat emulsion, increased pacing outputs, and mechanical support need to be initiated quickly to support the patient until the conduction system normalizes (2).\n\nFollow-up\n\nWe were able to support the patient with increased pacing outputs until the conduction abnormalities caused by his flecainide toxicity were successfully reversed after sodium bicarbonate infusion. Unfortunately, the patient had already sustained anoxic brain injury, and care was withdrawn.\n\nConclusions\n\nThis case demonstrated the importance of approaching the interpretation of device therapies and programming algorithms with an understanding of the dramatic effect of antiarrhythmic medications on intrinsic conduction properties and refractoriness. Although flecainide has an overall favorable safety profile in patients with AF, caution must be taken in patients at risk for structural heart disease and avoided all together in patients, such as our older adult man, with risk for HF with LVH and a pacemaker. Moreover, under circumstances promoting toxicity, flecainide can cause major conduction abnormalities at the cellular level, culminating in inconsistent pacemaker capture and worsening hemodynamics. In pacemaker-dependent patients, this can have devastating consequences.\n\nFUNDING SUPPORT AND Author Disclosures\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nSupplemental Video 1\n\nEchocardiogram after Cardiac Arrest. The echocardiogram shows reduced ejection fraction and marked ventricular dyssynchrony.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n\nAppendix\n\nFor a supplemental video, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Aliot E. Capucci A. Crijns H.J. Goette A. Tamargo J. Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation Europace 13 2011 161 173 21138930\n2 Valentino M.A. Panakos A. Ragupathi L. Williams J. Pavri B.B. Flecainide toxicity: a case report and systematic review of its electrocardiographic patterns and management Cardiovasc Toxicol 17 2017 260 266 27435408\n3 Andrikopoulos G.K. Pastromas S. Tzeis S. Flecainide: current status and perspectives in arrhythmia management World J Cardiol 7 2015 76 85 25717355\n4 Hellestrand K.J. Burnett P.J. Milne J.R. Effect of the antiarrhythmic agent flecainide acetate on acute and chronic pacing thresholds Pacing Clin Electrophysiol 6 1983 892 899 6195608\n5 van Middendorp L.B. Strik M. Houthuizen P. Electrophysiological and haemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts Europace 16 2014 1249 1256 24481779\n6 Hoffmeister H.M. Hepp A. Seipel L. Negative inotropic effect of class-I-antiarrhythmic drugs: comparison of flecainide with disopyramide and quinidine Eur Heart J 8 1987 1126 1132 3119341\n7 Echt D.S. Liebson P.R. Mitchell L.B. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial N Engl J Med 324 1991 781 788 1900101\n8 Brandes A. Deirdre A. Lebeau J.-P. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) Eur Heart J 42 2021 373 498 32860505\n9 Williams A.J. McQuinn R.L. Walls J. Pharmacokinetics of flecainide acetate in patients with severe renal impairment Clin Pharmacol Ther 43 1988 449 455 3128417\n\n",
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"issue": "3(4)",
"journal": "JACC. Case reports",
"keywords": "AF, atrial fibrillation; ECG, electrocardiography; HF, heart failure; LVH, left ventricular hypertrophy; atrial fibrillation; cardiac pacemaker; complication",
"medline_ta": "JACC Case Rep",
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"nlm_unique_id": "101757292",
"other_id": null,
"pages": "586-590",
"pmc": null,
"pmid": "34317582",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "6195608;3119341;3128417;21138930;1900101;32860505;27435408;24481779;25717355",
"title": "Flecainide Toxicity Leading to Loss of Pacemaker Capture and Cardiac Arrest.",
"title_normalized": "flecainide toxicity leading to loss of pacemaker capture and cardiac arrest"
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"abstract": "Alice in Wonderland Syndrome (AIWS) is characterized by a rare constellation of perceptual disturbances including distorted body image, metamorphopsia, and visual hallucinations. In this report, we relate a unique case of AIWS in a woman with a right temporo-parietal cavernoma. AIWS in this patient may be secondary to epileptiform activity associated with the cavernoma and improved with anti-epileptic treatment.",
"affiliations": "Department of Neurology and Neurosciences, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ, 07101-1709, USA. philipmi@njms.rutgers.edu.;Department of Neurology and Neurosciences, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ, 07101-1709, USA.;Department of Neurology and Neurosciences, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ, 07101-1709, USA.;Department of Radiology, Rutgers-New Jersey Medical School, Newark, NJ, 07101-1709, USA.;Department of Neurology and Neurosciences, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ, 07101-1709, USA.",
"authors": "Philip|Michelle|M|;Kornitzer|Jeffery|J|;Marks|David|D|;Lee|Huey-Jen|HJ|;Souayah|Nizar|N|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
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"fulltext": null,
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"issn_linking": "1931-7557",
"issue": "9(4)",
"journal": "Brain imaging and behavior",
"keywords": "Alice in Wonderland Syndrome; Cavernoma; Epilepsy; Hallucinations",
"medline_ta": "Brain Imaging Behav",
"mesh_terms": "D000328:Adult; D062026:Alice in Wonderland Syndrome; D000927:Anticonvulsants; D004569:Electroencephalography; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System; D006801:Humans; D008279:Magnetic Resonance Imaging; D010296:Parietal Lobe; D011247:Pregnancy; D011248:Pregnancy Complications; D013702:Temporal Lobe",
"nlm_unique_id": "101300405",
"other_id": null,
"pages": "910-2",
"pmc": null,
"pmid": "25663031",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Alice in Wonderland Syndrome associated with a temporo-parietal cavernoma.",
"title_normalized": "alice in wonderland syndrome associated with a temporo parietal cavernoma"
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"abstract": "Multiple myeloma (MM) is a slow-growing malignancy characterized by a low proliferation rate of plasma cells and a relatively rare incidence of tumour lysis syndrome (TLS). Three myeloma patients developed TLS following cytotoxic therapy (two after radiation treatment) that was associated with an abrupt increase of serum free light chains (FLC). All three patients demonstrated extramedullary plasmacytomas that exhibited aggressive features compared to the original myeloma. The findings suggested that an abrupt liberation (rather than slow secretion) of FLC from myeloma cells may trigger a fulminant cast nephropathy and present an unrecognized risk factor and potentially aggravating component of TLS.",
"affiliations": "Oncology Division, Kaiser Permanente San Jose Medical Center, San Jose, CA, USA.;Pathology/Immunohistopathology, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA.;Pathology/Immunohistopathology, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA.",
"authors": "Yavorkovsky|Leonid L|LL|0000-0002-8712-1141;Jing|Wen|W|;Baker|Robin|R|",
"chemical_list": "D007147:Immunoglobulin Light Chains; D009363:Neoplasm Proteins",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.16231",
"fulltext": null,
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"issn_linking": "0007-1048",
"issue": "188(5)",
"journal": "British journal of haematology",
"keywords": "complication; neoplasm; paraprotein; plasma cells",
"medline_ta": "Br J Haematol",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains; D008297:Male; D009101:Multiple Myeloma; D009363:Neoplasm Proteins; D012307:Risk Factors; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "732-735",
"pmc": null,
"pmid": "31573682",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An upsurge of the serum free light chains as a possible missing link in tumour lysis syndrome in multiple myeloma.",
"title_normalized": "an upsurge of the serum free light chains as a possible missing link in tumour lysis syndrome in multiple myeloma"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-01549",
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{
"abstract": "OBJECTIVE\nThis study aimed to assess the diagnostic ramifications of vascular occlusion of the ocular vein and artery as a first thrombotic event associated with factor V Leiden (FVL) and/or prothrombin gene (PTG) heterozygosity.\n\n\nMETHODS\nPatients with ocular vein (n=191) and artery (n=74) occlusion, free of cardioembolic etiologies, were sequentially referred from vitreoretinal specialists for measurement of thrombophilia-hypofibrinolysis and compared to 110 healthy normal controls.\n\n\nRESULTS\nOf the 265 patients, 29 (11%; 17 women, 12 men) of all referred ocular vascular occlusion (OVO) cases were found to be heterozygous for FVL and/or PTG, including 16 with FVL, 12 with PTG, and 1 with both. Of the 29 cases, 16 had central retinal vein occlusion (CRVO), 2 branch retinal vein occlusion (BRVO), 5 nonarteritic anterior ischemic optic neuropathy (NA-AION), 3 retinal artery occlusion (RAO), 2 amaurosis fugax (AF), and 1 had both CRVO and RAO. Of the 16 FVL cases, 15 (94%) had OVO as a first thrombotic event without prior deep venous thrombosis (DVT) or pulmonary embolism (PE); 6 (38%) also had other thrombotic events, including recurrent miscarriage, osteonecrosis, ischemic stroke, and/or ischemic colitis; and 5 (31%) had immediate family members with previous venous thromboembolism (VTE). Of the 12 PTG cases, 9 (75%) had OVO as a first thrombotic event, 5 (42%) experienced VTE other than DVT or PE, and 6 (50%) had immediate family members with VTE. In one patient with both FVL and PTG, DVT occurred before BRVO. Of the 17 women with FVL and/or PTG mutations, 7 (41%) experienced ≥1 miscarriage, 6 (35%) were on estrogen therapy, and 1 (6%) was on clomiphene.\n\n\nCONCLUSIONS\nOf the 265 patients with OVO, 29 (11%) had FVL and/or PTG, and 83% of these 29 cases presented with OVO as their first thrombotic event. By diagnosing thrombophilia as an etiology for OVO, the ophthalmologist opens a window to family screening and preventive therapy.",
"affiliations": "Internal Medicine Residency Program, The Jewish Hospital-Mercy Health, Cincinnati, Ohio, USA.;Cholesterol, Metabolism, and Thrombosis Center, The Jewish Hospital-Mercy Health, Cincinnati, Ohio, USA ; Mercy Health Physicians, Mercy Health, Cincinnati, Ohio, USA.;Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA ; Cincinnati Eye Institute, Cincinnati, Ohio, USA.;Cholesterol, Metabolism, and Thrombosis Center, The Jewish Hospital-Mercy Health, Cincinnati, Ohio, USA.;Cholesterol, Metabolism, and Thrombosis Center, The Jewish Hospital-Mercy Health, Cincinnati, Ohio, USA.;Cholesterol, Metabolism, and Thrombosis Center, The Jewish Hospital-Mercy Health, Cincinnati, Ohio, USA.",
"authors": "Schockman|Samantha|S|;Glueck|Charles J|CJ|;Hutchins|Robert K|RK|;Patel|Jaykumar|J|;Shah|Parth|P|;Wang|Ping|P|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OPTH.S80714",
"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S80714opth-9-591Original ResearchDiagnostic ramifications of ocular vascular occlusion as a first thrombotic event associated with factor V Leiden and prothrombin gene heterozygosity Schockman Samantha 1Glueck Charles J 23Hutchins Robert K 45Patel Jaykumar 2Shah Parth 2Wang Ping 21 Internal Medicine Residency Program, The Jewish Hospital-Mercy Health, Cincinnati, Ohio, USA2 Cholesterol, Metabolism, and Thrombosis Center, The Jewish Hospital-Mercy Health, Cincinnati, Ohio, USA3 Mercy Health Physicians, Mercy Health, Cincinnati, Ohio, USA4 Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA5 Cincinnati Eye Institute, Cincinnati, Ohio, USACorrespondence: Samantha Schockman, Cholesterol, Metabolism, and Thrombosis Center, Jewish Hospital of Cincinnati, 2135 Dana Avenue, Cincinnati, OH 45207, USA, Tel +1 513 309 2285, Fax +1 513 924 8273, Email samantha.schockman@gmail.com2015 03 4 2015 9 591 600 © 2015 Schockman et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Aim\nThis study aimed to assess the diagnostic ramifications of vascular occlusion of the ocular vein and artery as a first thrombotic event associated with factor V Leiden (FVL) and/or prothrombin gene (PTG) heterozygosity.\n\nMethods\nPatients with ocular vein (n=191) and artery (n=74) occlusion, free of cardioembolic etiologies, were sequentially referred from vitreoretinal specialists for measurement of thrombophilia-hypofibrinolysis and compared to 110 healthy normal controls.\n\nResults\nOf the 265 patients, 29 (11%; 17 women, 12 men) of all referred ocular vascular occlusion (OVO) cases were found to be heterozygous for FVL and/or PTG, including 16 with FVL, 12 with PTG, and 1 with both. Of the 29 cases, 16 had central retinal vein occlusion (CRVO), 2 branch retinal vein occlusion (BRVO), 5 nonarteritic anterior ischemic optic neuropathy (NA-AION), 3 retinal artery occlusion (RAO), 2 amaurosis fugax (AF), and 1 had both CRVO and RAO. Of the 16 FVL cases, 15 (94%) had OVO as a first thrombotic event without prior deep venous thrombosis (DVT) or pulmonary embolism (PE); 6 (38%) also had other thrombotic events, including recurrent miscarriage, osteonecrosis, ischemic stroke, and/or ischemic colitis; and 5 (31%) had immediate family members with previous venous thromboembolism (VTE). Of the 12 PTG cases, 9 (75%) had OVO as a first thrombotic event, 5 (42%) experienced VTE other than DVT or PE, and 6 (50%) had immediate family members with VTE. In one patient with both FVL and PTG, DVT occurred before BRVO. Of the 17 women with FVL and/or PTG mutations, 7 (41%) experienced ≥1 miscarriage, 6 (35%) were on estrogen therapy, and 1 (6%) was on clomiphene.\n\nConclusion\nOf the 265 patients with OVO, 29 (11%) had FVL and/or PTG, and 83% of these 29 cases presented with OVO as their first thrombotic event. By diagnosing thrombophilia as an etiology for OVO, the ophthalmologist opens a window to family screening and preventive therapy.\n\nKeywords\nfactor V Leidenprothrombin gene mutationocular vascular occlusionretinal vein occlusionretinal artery occlusionanterior ischemic optic neuropathy\n==== Body\nIntroduction\nRetinal vein occlusions (RVOs), retinal artery occlusions (RAOs), and ciliary artery occlusions causing optic nerve infarction or anterior ischemic optic neuropathy (AION) are well-recognized vascular ischemic events that affect the posterior segment of the eye. RVO is widely prevalent,1–4 with 5.20 cases per 1,000 people (95% confidence interval [CI]: 4.40–5.99) in the USA, Europe, Asia, and Australia as in 2010, suggesting that roughly 16 million people may have this disorder.4 AION is less common, with a median age of 62 and a mean annual incidence rate of 2.3 per 100,000 people for nonarteritic AION (NA-AION) and 0.36 per 100,000 people for arteritic AION (A-AION).5 Central retinal artery occlusion (CRAO), which causes retinal infarction, is slightly rarer, estimated to be 1 in 100,000 people and roughly 1 in 10,000 outpatient visits, but it may result in severe vision loss in up to 80% of patients.6\n\nThe presentation of ocular vascular occlusion (OVO), including RAO, RVO or AION, is widely variable and may range from an incidental finding in asymptomatic patients to partial visual field loss, diminished or absent central vision, or diminished or complete loss of vision resulting from either one or a combination of the following: optic nerve infarction, retinal infarction, macular edema, macular ischemia, and/or neovascular glaucoma.7,8 Because OVO has the potential for such devastating complications, including permanent vision loss, it is important to identify the etiology of the patient’s OVO to implement the appropriate treatment and to provide available prophylactic measures to prevent subsequent contralateral ocular and/or systemic thrombotic events.\n\nRecognized risk factors for OVO are categorized as systemic or local. Systemic factors include hyperviscosity, myeloproliferative disorders, retro-orbital mass effect, and vasculitis such as Behcet’s disease.7,9 A common local finding predisposing to OVO is open-angle glaucoma. Glaucoma decreases venous outflow through increased intraocular pressure, thus creating vascular stasis and increased risk of occlusion, in accordance with Virchow’s triad.10–13 When commonly recognized etiologies are ruled out, other risk factors for OVO must be assessed, including cardiovascular13–23 and hypercoagulable state9,24,25 risk factors.\n\nThe most recognized, but neither sensitive nor specific, cardiovascular risk factors for OVO include age, history of smoking, hypertension, hyperlipidemia, diabetes mellitus, and atherosclerosis.13–23 More recently, however, there has been increased focus on the pathoetiologic role of thrombophilia in OVO. In the absence of a cardioembolic etiology for OVO, thrombophilia is a common, major cause of ocular thrombotic events.9,24 In particular, thrombophilia should be carefully assessed in younger patients, <65 years old, or in patients with a personal or family history of thrombosis.25\n\nThrombophilia can be heritable – such as in hyperhomocysteinemia, factor V Leiden (FVL) mutation, prothrombin (PTG) G20210A mutation, antithrombin III deficiency, protein C deficiency, or protein S deficiency – or acquired, particularly the lupus anticoagulant found in antiphospholipid syndrome. Of the thrombophilias that are risk factors for OVO,7,16,20,21,24,26–37 hyperhomocysteinemia is the most likely to cause OVO7,20,24,32–37 and is a recognized risk factor for systemic vascular thrombosis, including ischemic heart disease and deep venous thrombosis (DVT).38,39 In addition to hyperhomocysteinemia, FVL and PTG heterozygosity result in a systemic hypercoagulable state and are major risk factors for large-vein thrombosis, and thus their role in OVO deserves careful attention.32,40–43\n\nThe FVL mutation involves a G-A substitution at nucleotide 1691 on the factor V gene, resulting in a procoagulant state caused by factor V’s resistance to inactivation by protein C.28,44 This is one of the commonest familial thrombophilias, witĥ ~5% of Caucasian populations being heterozygous for the mutation.45 Multiple studies, including case–control studies and a meta-analysis,21,24,26–28 have shown a significant increase in the prevalence of FVL in patients with OVO.\n\nThe PTG mutation is a G-A transition at nucleotide 20210 of the factor II gene and is associated with increased plasma prothrombin, resulting in a procoagulant state.42 Similar to FVL, the PTG mutation has a high-level carrier prevalence of 1%–4% and is more common among people of Caucasian descent.46 In addition, the PTG mutation, similar to the FVL mutation, is associated with venous thromboembolism (VTE),40,47,48 and recent literature has illustrated its significant role in mediating OVO.28,49\n\nThrombophilia and its role in OVO have received more attention in recent years, particularly in younger patients and in patients without an obvious cardiac, carotid, or embolic etiology. Particularly in Caucasian populations, the FVL and PTG mutations are some of the most frequent thrombophilic contributors to the development of VTE.40,47,50,51 Although the ophthalmologic literature has primarily focused on the pathophysiologic role that these thrombophilias play in ocular vascular thrombosis,8,16,18,21,22,25,30,36 it has not focused on the likelihood that the ocular thrombotic event is the patient’s first thrombotic event when associated with FVL and/or PTG, directing attention to familial thrombophilias in the kindred and prevention of subsequent thrombi in the proband and family. In the current study, our specific aim was to identify OVOs as first thrombotic events facilitated by FVL and/or PTG heterozygosity and to review the role that these heritable thrombophilias play in subsequent treatment, prophylaxis, and ramifications for patient and kindred.\n\nMethods\nThe study was approved by the Jewish Hospital Institutional Review Board (ID 12-03). Informed consent was obtained from patients after the nature of the study was fully explained.\n\nAfter NA-AION, branch or central retinal vein occlusion (BRVO, CRVO), RAO, or amaurosis fugax (AF) was diagnosed, 283 patients (172 with CRVO, 19 BRVO, 32 RAO, 41 AF, and 19 NA-AION) were sequentially referred from 1993 to 2015 by vitreoretinal specialists at the Cincinnati Eye Institute to our outpatient thrombosis research center. The diagnoses were established by complete ophthalmological evaluations during which the patients’ histories, visual deficits, and fundus abnormalities were ascertained and found to be typical of the ischemic events.\n\nPatients with NA-AION exhibited segmental edema of the optic nerve head in eyes with little or no preexisting optic nerve cupping. Eyes with RVOs showed dilation of retinal veins (all veins if a CRVO was present and less than all veins if a BRVO was found) associated with intraretinal hemorrhages, retinal edema, and cotton wool spots limited in area by the drainage bed of the affected veins. Eyes with RAOs demonstrated retinal arterial narrowing, segmentation of the arterial blood column in some cases, and whitening of the retina due to opacification and thickening of the inner retina. In the case of a CRAO, a cherry red spot was seen in the macula. The fundus features of acute OVOs are stereotypical to the degree that confirmatory testing may not be necessary. Fluorescein angiography and optical coherence tomography were performed to corroborate the diagnosis depending on the preference of the referring ophthalmologist. In the cases of AION, measurements of erythrocyte sedimentation rates and C-reactive protein levels helped in the elimination of giant cell arteritis as the cause.\n\nAll 92 patients referred with ocular arterial disease (NA-AION, RAO, and AF) underwent carotid ultrasound and cardiac echocardiogram studies, and 18 were not entered into our analysis cohort because of documented arterial emboli. Excepting these 18 excluded arterial cases, the analysis cohort was prospectively evaluated in the sequence of their referral and included 265 cases (163 women and 102 men), 191 with ocular venous occlusion and 74 with ocular arterial occlusion.\n\nThe analysis cohort was divided into patients with venous (low-pressure, low-velocity) occlusion, including BRVO and CRVO, and those with arterial (high-pressure and high-velocity) occlusion, including NA-AION, RAO, and AF.\n\nAt the patients’ initial visit at our center, a detailed history was taken and physical examination was conducted. In particular, presence of hypertension, diabetes mellitus, and hyperlipidemia; reproductive history and pregnancy outcomes; and previous episodes of VTE, DVT, and/or pulmonary embolism (PE) were noted. In addition, the patients’ use of tobacco or hormonal therapy, as well as family history of thrombosis, was obtained. Lastly, the patients’ visual status was assessed at the time of the ocular event and at each subsequent visit with the retinal specialist.\n\nAt the initial visit, atherosclerotic risk factors were measured, serologic coagulation assays were done, and polymerase chain reaction (PCR) analyses for thrombophilia and hypofibrinolysis were performed. Atherosclerotic risk factors measured included age, body mass index, smoking history, blood pressure, hemoglobin A1c, glucose, homocysteine, and levels of triglycerides and cholesterol, including HDL and LDL cholesterol.24\n\nPCR measures52 were used to measure G1691A factor V Leiden, G20210A prothrombin, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations, and the plasminogen activator inhibitor-1 4G/4G mutation. In addition, serologic measures of thrombophilia53 were used, including measurement of anticardiolipin antibodies immunoglobulin G (IgG) and IgM (ACLA IgM), antigenic protein C, total and free protein S, antithrombin III, lupus anticoagulant, factors VIII and XI, and homocysteine. All PCR and serologic measures were done as previously described.24\n\nHealthy normal controls (n=110) were hospital employees, documented by interview and physical examination to be free of acute and chronic disease, including any history or evidence of OVO.\n\nStatistical methods\nAll statistical analyses were performed using SAS V9.4 (SAS institute Inc, Cary, NC, USA).\n\nCases were compared to controls by Fisher’s exact test.\n\nSample size was estimated based on observed data of this report. To detect the difference of 50% having at least one of the seven thrombophilias in cases versus 20% in controls, there should be at least 39 subjects in each group for significance level 0.05 with power 80%.\n\nResults\nCentral and branch retinal vein occlusion\nOf the 191 RVO cases, 172 (90%) had CRVO and 19 (10%) BRVO; there were 116 (61%) women and 75 (39%) men (mean age ± standard deviation [SD]: 57±15 years; median age: 57 years).\n\nAs displayed in Figure 1, the 191 RVO cases differed from controls in terms of low free protein S (9% vs 2%, respectively; P=0.04), high homocysteine (23% vs 5%, respectively; P<0.0001), high factor VIII (18% vs 7%, respectively; P=0.01), and ACLA IgM (10% vs 2%, respectively; P=0.007). Assessing the number of abnormalities in the seven thrombophilias (FVL, PTG, free protein S, homocysteine, factor VIII, factor XI, and ACLA IgM), 50% of the 191 RVO cases had ≥1 thrombophilic abnormality vs 19% of normal controls (P<0.0001, Figure 1). The difference between patients with RVO vs controls in comparing ≥1 abnormality of FVL and PTG mutations was not statistically significant (Figure 1).\n\nRetinal artery occlusion\nThe 74 cases with RAO included 23 with CRAO, 32 AF, and 19 NA-AION, including 47 (64%) women and 27 (36%) men, with mean age ± SD of 54±16 (median: 55 years). As displayed in Figure 2, the 74 RAO cases differed from controls for ≥1 abnormality of FVL and PTG mutations (15% vs 5%, respectively; P=0.03). They also differed in having high levels of homocysteine (18% vs 5%, respectively; P=0.005) and factor VIII (21% vs 7%, respectively; P=0.009), as well as being marginally different in the low levels of free protein S (9% vs 2%, respectively; P=0.07). Assessing the number of abnormalities in the seven thrombophilias (FVL, PTG, free protein S, homocysteine, factor VIII, factor XI, and ACLA IgM), 49% of the 74 RAO cases had ≥1 thrombophilic abnormality vs 19% of normal controls (P<0.0001).\n\nTaken together, of the 265 patients with OVO (191 venous, 74 arterial), 29 (11%) had mutations of FVL, PTG, or both vs 5 (4.5%) of the 110 healthy normal controls (P=0.07).\n\nFVL or PTG mutations\nTable 1 shows the 29 (11%) cases with heterozygosity of FVL, PTG, or both, among the total cohort of 265 OVO cases. Among these 29 patients with FVL, PTG, or both, the initial ocular vascular occlusive event occurred before the age of 60 years in 18 (62%) cases, before age 50 years in 10 cases (34%), and before age 40 years in 5 cases (17%). The median age at the time of OVO in these 29 cases was 56 years. Of the 16 cases with FVL heterozygosity, nine (56%) were female and seven (44%) were male (mean age ± SD: 51±13 years; median: 52 years).\n\nFifteen (94%) of the 16 cases with FVL had OVO as their first thrombotic event, defined by no previous DVT or PE, while 1 (6%) had a previous initial thrombotic event (DVT) (Table 1). Of the 16 FVL heterozygotes, 6 (38%) experienced other thrombotic events, defined as events likely resulting from a hypercoagulable state other than DVT or PE, including recurrent miscarriages, osteonecrosis, ischemic stroke, and/or ischemic colitis (Table 1). Five (31%) of the 16 FVL heterozygotes had an immediate family member with a history of thrombosis, including DVT and/or PE.\n\nAt last follow-up visit, 2 (13%) of the 16 cases with FVL had no remaining vision in the affected eye, 6 (38%) had residual vision loss, 5 (31%) returned to baseline vision, and 3 (19%) were lost to follow-up (Table 1).\n\nOf the 12 heterozygous PTG cases, 7 (58%) were female and 5 (42%) were male (mean age ± SD: 59±20 years; median: 61 years). Nine (75%) of the 12 cases had OVO as an initial thrombotic event, while 3 (25%) had a known previous thrombotic event (2 DVT, 1 DVT-PE) (Table 1). Five (42%) of the 12 cases experienced other thrombotic events, and 6 (50%) had an immediate family member with a history of thrombosis. At their last follow-up visit, four (33%) of the 12 cases heterozygous for PTG had no remaining vision in the affected eye, 6 (50%) had residual vision loss, 1 (8%) returned to baseline vision, and 1 (9%) was lost to follow-up (Table 1). One of the 12 PTG heterozygotes (#10) had an additional ocular event (CRVO) in the second eye and returned to baseline vision in that eye at her last follow-up (Table 1).\n\nOne case was heterozygous for both FVL and PTG mutations. She had BRVO with previous DVT and recurrent miscarriages. She had residual vision loss at last follow-up (Table 1).\n\nOf the 29 cases with OVO found to have FVL and/or PTG mutations, 24 (83%) had OVO as a first thrombotic event without prior DVT and/or PE, and 12 (41%) had other thrombotic events including miscarriage, osteonecrosis, ischemic stroke, and/or ischemic colitis. Of these 12 cases with prior thrombotic complications, 10 (83%) were female, 7 (70%) of whom had had previous miscarriages.\n\nSeventeen (59%) of 29 OVO cases with FVL and/or PTG mutation were females (Table 1). Of these 17 cases, 7 (41%) had experienced at least one miscarriage for previously unknown reasons, 6 (35%) were on estrogen hormone therapy at the time of the ocular event, and 1 (6%) was on clomiphene. One male patient with PTG heterozygosity (#3, Table 1) developed RVO 3 months after starting testosterone therapy.\n\nDiscussion\nThe ophthalmologist plays a critical role in the disposition and prognosis of patients who present with OVO, particularly when the OVO is the patient’s first thrombotic event. The most frequent pathoetiology for RAO and AF is largely embolic,54,55 which is frequently detectable in branch retinal artery occlusions but often cannot be detected via fundoscopy in ciliary artery occlusions, CRAOs, or AION. The 74 cases with RAO in the current study all had normal carotid and vertebral imaging and normal echocardiography, ruling out overt causes of thromboemboli. There is no easy way to rule out microscopic emboli as a cause of RAO, even when there is no detectable carotid or cardiac abnormality.\n\nWhile cardioembolic investigation is warranted, there are numerous other contributing etiologies for OVO that must be considered. All patients should have a thorough assessment for cardiovascular and atherosclerotic risk factors, including screening for age, smoking history, hypertension, hyperlipidemia, and diabetes mellitus, all of which have been shown to have a significant, albeit nonspecific and nonsensitive, association with the development of OVO.7,9–23,54–56\n\nSeveral reports,24,35,57 congruent with our current findings, have demonstrated the significant role of thrombophilia in the development of OVO and emphasize the importance of evaluating for thrombophilia in patients who present with OVO. In the current study, 49% of cases with arterial OVO and 50% with venous OVO had one or more of the seven major thrombophilias vs 19% of 110 healthy normal controls (P<0.0001). In cases of both venous and arterial occlusion, high levels of homocysteine and factor VIII were much more common than in healthy normal controls. Of the multiple thrombophilias, hyperhomocysteinemia has received the most attention as a risk factor for OVO,53 and the relationship between elevated levels of homocysteine and both large-vein thrombosis and OVO is well recognized.5,20,24,32–34,36–39 In addition to hyperhomocysteinemia, genetic mutations of FVL and PTG are major risk factors for large-vein thrombosis.32,40–43 Recent studies have found a high prevalence of FVL21,24,26–28 and PTG mutations58,59 in patients with OVO versus controls; however, some have not found the same.16,29,30–32\n\nAn ophthalmologist is in a unique position to diagnose familial and acquired thrombophilias in patients who present with a new OVO. This remains true even when the patient presents with no personal history of prior thrombosis. In the current study, 24 (83%) of 29 OVO patients found to have FVL and/or PTG mutations had no previous DVT, PE, and/or prior OVO. It is critical to diagnose these underlying, heritable thrombophilias in patients who present with OVO as a first thrombotic event to minimize local and systemic thrombotic morbidity and mortality, including significant vision loss. Approximately 7% of patients with RVO may have a contralateral OVO within 4 years,17 and the risk of visual impairment with OVO is evident in the current study, in which 6 (21%) of 29 cases with FVL and/or PTG heterozygosity had no remaining vision in the affected eye, and 13 (45%) had residual vision loss.\n\nIn addition, thrombophilia often causes potentially preventable VTE, DVT, PE,60 ischemic cerebral vascular accidents,61 osteonecrosis,62 and pregnancy loss.63 In our study, 12 (41%) of 29 OVO cases with an underlying FVL and/or PTG mutation had some form of VTE other than DVT and/or PE, such as miscarriage, osteonecrosis, ischemic stroke, and/or ischemic colitis. The risk of systemic thrombosis and OVO is particularly high if the patient is exposed to additional known prothrombotic risk factors, including estrogen or testosterone hormone therapy, pregnancy, surgery, immobilization, or smoking.27,40\n\nOf particular note, 7 (41%) of 17 female patients with FVL and/or PTG heterozygosity presenting with OVO shared a history of at least one unexplained miscarriage. Patients with increased exposure to estrogens, including hormone therapy or pregnancy, in combination with thrombophilia, are at a much higher risk of thrombosis. Six (35%) of 17 females in this study who developed OVO were on estrogen therapy, and 1 (6%) was on clomiphene. Case reports have suggested that clomiphene may predispose individuals to RVO, especially patients with underlying risk factors such as thrombophilia.64 Other studies have shown the miscarriage rate in patients with RVO to be 24%–28%, significantly greater compared to the national figure of 15.7%.24,53,65 These findings illustrate the importance of discovering a thrombophilic state for the patient and family to avoid unnecessary risk exposure, such as hormone therapy, and to allow for close monitoring during high-risk periods, including pregnancy.\n\nMost thrombophilic mutations, including FVL and PTG mutations, are autosomal dominant and highly penetrant. Diagnosing an underlying thrombophilia has important implications, not only for the patient, but for the patient’s family as well. Of the 29 OVO cases in this study with the FVL and/or PTG mutation, 11 (38%) had immediate family members with a history of DVT and/or PE. OVOs serve as a gateway for physicians to discover an undiagnosed heritable thrombophilia, with significant implications for the patient and his or her family including the need for treatment, familial screening, and education regarding the avoidance of additional thrombotic risk factors.\n\nIn patients who are young, have an unexpected OVO, and/or have a personal or family history of thrombosis, the physician may discover a hypercoagulable state if appropriately evaluated.20 One study found that up to 84% patients with OVO in which noncoagulation etiologies were ruled out were found to have thrombophilia.9 This finding is of major importance for the patient and the patient’s family to ensure that appropriate medical and lifestyle measures are taken to minimize morbidity and mortality.\n\nWhile elevated homocysteine53 and antiphospholipid syndrome66 have received the most attention regarding thrombophilias associated with OVO, our study demonstrates the importance of testing for the common and highly prothrombotic familial thrombophilias, FVL and PTG mutations, and illustrates how FVL and PTG heterozygosity may present with OVO as a first thrombotic event. It is important for the ophthalmologist to diagnose underlying coagulation disorders as both an etiology for OVO and as a window to family screening and preventive therapy for the family and the proband.\n\nAcknowledgments\nThis work was supported in part by the Lipoprotein Research Fund of the Jewish Hospital of Cincinnati.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Thrombophilia in 191 patients with ocular vein occlusion (19 branch, 172 central) compared to 110 healthy normal controls without ocular venous or arterial thrombi.\n\nNotes: The seven thrombophilias included FVL, PTG, free protein S, homocysteine, factor VIII, factor XI, and ACLA IgM.\n\nAbbreviations: FVL, factor V Leiden; PTG, prothrombin gene; free S, free protein S; ACLA IgM, anticardiolipin antibody immunoglobulin M.\n\nFigure 2 Thrombophilia in 74 patients with ocular arterial occlusion (23 with central retinal artery occlusion, 32 with amaurosis fugax, and 19 with nonarteritic anterior ischemic optic neuropathy) compared to 110 healthy normal controls without ocular venous or arterial thrombi.\n\nNotes: The seven thrombophilias included FVL, PTG, free protein S, homocysteine, factor VIII, factor XI, and ACLA IgM. 1Central retinal thrombosis (n=23), amaurosis fugax (n=32) and nonarteritic anterior isochemic optic neuropathy (n=19).\n\nAbbreviations: FVL, factor V Leiden; PTG, prothrombin gene; free S, free protein S; ACLA IgM, anticardiolipin antibody immunoglobulin M.\n\nTable 1 Characteristics of 29 patients with ocular vascular occlusion with FVL or PTG G20210A variant\n\nSerial number\tSex\tAge (years)\tType of occlusion\tFVL\tPTG\tFirst thrombotic event?#\tOther thrombotic events?$\tKnown family history of thrombosis?†\tVisual outcome in given eye?\tEstrogen/testosterone/clomiphene use?‡\t\nFVL\t\n 1\tMale\t33\tRAO\tYes\tNo\tYes\t\tNo\tDecreased\tNo\t\n 2\tMale\t72\tCRVO\tYes\tNo\tYes\t\tNo\tNo follow-up\tNo\t\n 3\tMale\t55\tCRVO\tYes\tNo\tNo (DVT)\t\tYes\tNo change\tNo\t\n 4\tMale\t64\tNA-AION\tYes\tNo\tYes\t\tNo\tDecreased\tNo\t\n 5\tMale\t50\tCRVO\tYes\tNo\tYes\t\tNo\tBlind\tNo\t\n 6\tMale\t41\tCRVO\tYes\tNo\tYes\t\tNo\tNo follow-up\tNo\t\n 7\tMale\t43\tCRVO\tYes\tNo\tYes\t\tNo\tNo follow-up\tNo\t\n 8\tFemale\t52\tAF\tYes\tNo\tYes\tMiscarriages\tYes\tNo change\tNo\t\n 9\tFemale\t68\tCRVO\tYes\tNo\tYes\tMiscarriages\tNo\tDecreased\tNo\t\n 10\tFemale\t38\tCRVO\tYes\tNo\tYes\tMiscarriages\tYes\tNo change\tClomiphene\t\n 11\tFemale\t69\tCRVO\tYes\tNo\tYes\tAVN, miscarriage\tNo\tBlind\tNo\t\n 12\tFemale\t52\tCRVO\tYes\tNo\tYes\t\tYes\tDecreased\tNo\t\n 13\tFemale\t60\tCRVO\tYes\tNo\tYes\t\tYes\tNo change\tEstrogen\t\n 14\tFemale\t54\tCRVO\tYes\tNo\tYes\t\tNo\tNo change\tEstrogen\t\n 15\tFemale\t45\tRAO\tYes\tNo\tYes\tMiscarriages\tNo\tDecreased\tNo\t\n 16\tFemale\t25\tCRVO\tYes\tNo\tYes\tMultifocal ON\tNo\tDecreased\tEstrogen\t\nPTG\t\n 1\tMale\t69\tNA-AION\tNo\tYes\tYes\tStroke\tYes\tDecreased\tNo\t\n 2\tMale\t68\tAF\tNo\tYes\tNo (DVT)\t\tYes\tBlind\tNo\t\n 3\tMale\t59\tCRVO\tNo\tYes\tYes\t\tNo\tDecreased\tTestosterone\t\n 4\tMale\t50\tNA-AION\tNo\tYes\tYes\tTIA\tYes\tNo change\tNo\t\n 5\tMale\t29\tRAO\tNo\tYes\tYes\t\tNo\tNo follow-up\tNo\t\n 6\tFemale\t63\tBRVO\tNo\tYes\tYes\t\tYes\tDecreased\tNo\t\n 7\tFemale\t58\tCRVO\tNo\tYes\tYes\t\tNo\tDecreased\tNo\t\n 8\tFemale\t82\tCRVO\tNo\tYes\tYes\t\tNo\tBlind\tNo\t\n 9\tFemale\t16\tCRVO\tNo\tYes\tYes\t\tYes\tDecreased\tNo\t\n 10§\tFemale\t77\n80\tRAO\nCRVO\tNo\tYes\tYes\tMiscarriages\tNo\tBlind\nNo change\tEstrogen\nEstrogen\t\n 11\tFemale\t75\tNA-AION\tNo\tYes\tNo (DVT)\tIschemic colitis\tNo\tDecreased\tEstrogen\t\n 12\tFemale\t56\tNA-AION\tNo\tYes\tNo (DVT-PE)\tAVN\tYes\tBlind\tNo\t\nFVL + PTG\t\n 1\tFemale\t73\tBRVO\tYes\tYes\tNo (DVT)\tMiscarriages\tNo\tDecreased\tNo\t\nNotes:\n\n# First thrombotic event in patient, defined as no previous DVT or PE.\n\n$ Other thrombotic events in patient, defined as events likely resulting from a hypercoagulable state other than DVT or PE, such as miscarriages, AVN, multifocal ON, stroke, or ischemic colitis.\n\n† Known family history of thrombosis, defined as an immediate family member with previous DVT or PE.\n\n‡ Use of estrogen, clomiphene, or testosterone therapy at the time of ocular event.\n\n§ One patient with PTG mutation with two separate ocular events, RAO at the age of 77 years in the left eye and RVO at the age of 80 years in the right eye.\n\nAbbreviations: AF, amaurosis fugax; AVN, avascular necrosis; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; DVT, deep venous thrombosis; FVL, factor V Leiden; NA-AION, nonarteritic anterior ischemic optic neuropathy; ON, osteonecrosis; PE, pulmonary embolism; PTG, prothrombin gene; RAO, retinal artery occlusion; RVO, retinal vein occlusion; TIA, transient ischemic attack.\n==== Refs\nReferences\n1 Cugati S Wang JJ Rochtchina E Mitchell P Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study Arch Ophthalmol 2006 124 726 732 16682596 \n2 David R Zangwill L Badarna M Yassur Y Epidemiology of retinal vein occlusion and its association with glaucoma and increased intraocular pressure Ophthalmologica 1988 197 69 74 3186211 \n3 Klein R Moss SE Meuer SM Klein BE The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study Arch Ophthalmol 2008 126 513 518 18413521 \n4 Rogers S McIntosh RL Cheung N International Eye Disease Consortium The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia Ophthalmology 2010 117 313 319 20022117 \n5 Johnson LN Arnold AC Incidence of nonarteritic and arteritic ischemic optic neuropathy: population-based study in the state of Missouri and Los Angeles County, California J Neuroophthalmol 1994 14 38 44 8032479 \n6 Varma DD Cugati S Lee AW Chen CS A review of central retinal artery occlusion: clinical presentation and management Eye 2013 27 688 697 23470793 \n7 Karia N Retinal vein occlusion: pathophysiology and treatment options Clin Ophthalmol 2010 4 809 816 20689798 \n8 Rehak M Wiedemann P Retinal vein thrombosis: pathogenesis and management J Thromb Haemost 2010 8 1886 1894 20492457 \n9 Bick RL Alfar H Goedecke C Thrombophilic causes of retinal vascular thrombosis: etiology and treatment outcomes Clin Appl Thromb Hemost 2002 8 315 318 12516681 \n10 Beaumont PE Kang HK Clinical characteristics of retinal venous occlusions occuring at different sites Br J Ophthalmol 2002 86 572 580 11973257 \n11 Hitchings RA Spaeth GL Chronic retinal vein occlusion in glaucoma Br J Ophthalmol 1976 60 694 699 1009041 \n12 Dryden RM Central retinal vein occlusions and chronic simple glaucoma Arch Ophthalmol 1965 73 659 663 14281983 \n13 Group EDC-CS Risk factors for central retinal vein occlusion Arch Ophthalmol 1996 114 545 554 8619763 \n14 Mohamed Q McIntosh RL Saw SM Wong TY Interventions for central retinal vein occlusion: an evidence-based systematic review Ophthalmology 2007 114 507 519 17324695 \n15 Stem MS Talwar N Comer GM Stein JD A longitudinal analysis of risk factors associated with central retinal vein occlusion Ophthalmology 2013 120 362 370 23177364 \n16 Weger M Renner W Pinter O Role of factor V Leiden and prothrombin 20210A in patients with retinal artery occlusion Eye (Lond) 2003 17 731 734 12928685 \n17 Hayreh SS Zimmerman B McCarthy MJ Podhajsky P Systemic diseases associated with various types of retinal vein occlusion Am J Ophthalmol 2001 131 61 77 11162981 \n18 Prisco D Marcucci R Bertini L Gori AM Cardiovascular and thrombophilic risk factors for central retinal vein occlusion Eur J Intern Med 2002 13 163 169 12020623 \n19 Recchia FM Brown GC Systemic disorders associated with retinal vascular occlusion Curr Opin Ophthalmol 2000 11 462 467 11141642 \n20 Backhouse O Parapia L Mahomed I Lee D Familial thrombophilia and retinal vein occlusion Eye (Lond) 2000 14 13 17 10755093 \n21 Rehak M Rehak J Müller M The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors Thromb Haemost 2008 99 925 929 18449423 \n22 Cheung N Klein R Wang JJ Traditional and novel cardiovascular risk factors for retinal vein occlusion: the multiethnic study of atherosclerosis Invest Ophthalmol Vis Sci 2008 49 4297 4302 18539932 \n23 O’Mahoney P Wong T Ray J Retinal vein occlusion and traditional risk factors for atherosclerosis Arch Ophthalmol 2008 126 692 699 18474782 \n24 Glueck CJ Wang P Hutchins R Petersen MR Golnik K Ocular vascular thrombotic events: central retinal vein and central retinal artery occlusions Clin Appl Thromb Hemost 2008 14 286 294 18160589 \n25 Yau JW Lee P Wong TY Best J Jenkins A Retinal vein occlusion: an approach to diagnosis, systemic risk factors and management Intern Med J 2008 38 904 910 19120547 \n26 Williamson TH Rumley A Lowe GD Blood viscosity, coagulation, and activated protein C resistance in central retinal vein occlusion: a population controlled study Br J Ophthalmol 1996 80 203 208 8703856 \n27 Larsson J Olafsdottir E Bauer B Activated protein C resistance in young adults with central retinal vein occlusion Br J Ophthalmol 1996 80 200 202 8703855 \n28 Ben-Ami R Zeltser D Leibowitz I Berliner SA Retinal artery occlusion in a patient with factor V Leiden and prothrombin G20210A mutations Blood Coagul Fibrinolysis 2002 13 57 59 11994569 \n29 Aras S Yilmaz G Alpas I Baltaci V Tayanç E Aydin P Retinal vein occlusion and factor V Leiden and prothrombin 20210 G: A mutations Eur J Ophthalmol 2001 11 351 355 11820306 \n30 Demirci FY Güney DB Akarçay K Prevalence of factor V Leiden in patients with retinal vein occlusion Acta Ophthalmol Scand 1999 77 631 633 10634553 \n31 Larsson J Hillarp A The prothrombin gene G20210A mutation and the platelet glycopprotein IIIa polymorphism PIA2 in patients with central retinal vein occlusion Thromb Res 1999 96 323 327 10593436 \n32 Janssen MCH den Heijer M Cruysberg JRM Wollersheim H Bredie SJH Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? J Thromb Haemost 2005 93 1021 1026 \n33 Fegan CD Central retinal vein occlusion and thrombophilia Eye (Lond) 2002 16 98 106 11913903 \n34 Turello M Pasca S Daminato R Retinal vein occlusion: evaluation of “classic” and “emerging” risk factors and treatment J Thromb Thrombolysis 2010 29 459 464 19669864 \n35 Sottilotta G Oriana V Latella C Role of hyperhomocystinemia in retinal vascular occlusive disease Clin Appl Thromb Hemost 2007 13 104 107 17164500 \n36 Cahill MT Stinnett SS Fekrat S Meta-analysis of plasma homocysteine, serum folate, serum vitamin B(12), and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease Am J Ophthalmol 2003 136 1136 1150 14644226 \n37 Biousse V Newman NJ Sternberg PJ Retinal vein occlusion and transient monocular visual loss associated with hyperhomocystinemia Am J Ophthalmol 1997 124 257 260 9262559 \n38 McCully KS Homocysteine and vascular disease Nat Med 1996 2 386 389 8597939 \n39 Wald DS Law M Morris JK Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis BMJ 2002 325 1202 12446535 \n40 Simsek E Yesilyurt A Pinarli F Eyerci N Ulus AT Combined genetic mutations have remarkable effect on deep venous thrombosis and/or pulmonary embolism occurence Gene 2013 536 171 176 24334115 \n41 Seligsohn U Lubetsky A Genetic susceptibility to venous thrombosis N Engl J Med 2001 344 1222 1231 11309638 \n42 Poort SR Rosendaal FR Reitsma PH Bertina RM A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis Blood 1996 88 3698 3703 8916933 \n43 Koster T Rosendaal FR de Ronde H Briët E Vandenbroucke JP Bertina RM Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study Lancet 1993 342 1503 1506 7902898 \n44 Bertina RM Koeleman BP Koster T Mutation in blood coagulation factor V associated with resistance to activated protein C Nature 1994 369 64 67 8164741 \n45 Ridker PM Miletich JP Hennekens CH Buring JE Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening JAMA 1997 277 1305 1307 9109469 \n46 Rosendaal FR Doggen CJ Zivelin A Geographic distribution of the 20210 G to A prothrombin variant Thromb Haemost 1998 79 706 708 9569177 \n47 Zhou X Qian W Li J Who are at risk for thromboembolism after arthroplasty? A systematic review and meta-analysis Thromb Res 2013 132 531 536 24074702 \n48 Tug E Aydin H Kaplan E Dogruer D Frequency of genetic mutations associated with thromboembolism in the Western Black Sea Region Intern Med 2011 50 17 21 21212568 \n49 Glueck CJ Wang P Ocular vascular thrombotic events: a diagnostic window to familial thrombophilia (compound factor V Leiden and prothrombin gene heterozygosity) and thrombosis Clin Appl Thromb Hemost 2009 15 12 18 18796459 \n50 Weingarz L Schwonberg J Schindewolf M Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry Br J Haematol 2013 163 655 665 24219332 \n51 de Jong PG Goddijn M Middeldorp S Testing for inherited thrombophilia in recurrent miscarriage Semin Reprod Med 2011 29 540 547 22161466 \n52 Glueck CJ Freiberg RA Wang P Heritable thrombophilia-hypofibrinolysis and osteonecrosis of the femoral head Clin Orthop Relat Res 2008 466 1034 1040 18350351 \n53 Glueck CJ Hutchins RK Jurantee J Khan Z Wang P Thrombophilia and retinal vascular occlusion Clin Ophthalmol 2012 6 1377 1384 22969282 \n54 Sharma S Naqvi A Sharma SM Cruess AF Brown GC Transthoracic echocardiographic findings in patients with acute retinal arterial obstruction. A retrospective review. Retinal Emboli of Cardiac Origin Group Arch Ophthalmol 1996 114 1189 1192 8859076 \n55 Sharma S The systemic evaluation of acute retinal artery occlusion Curr Opin Ophthalmol 1998 9 1 5 10182093 \n56 Salomon O Huna-Baron R Moisseiev J Thrombophilia as a cause for central and branch retinal artery occlusion in patients without an apparent embolic source Eye (Lond) 2001 15 511 514 11767028 \n57 Greiner K Hafner G Dick B Peetz D Prellwitz W Pfeiffer N Retinal vascular occlusion and deficiencies in the protein C pathway Am J Ophthalmol 1999 128 69 74 10482096 \n58 Kapur RK Mills LA Spitzer SG Hultin MB A prothrombin gene mutation is significantly associated with venous thrombosis Arterioscler Thromb Vasc Biol 1997 17 2875 2879 9409269 \n59 Gurgey A Haznedaroglu IC Egesel T Two common genetic thrombotic risk factors: factor V Leiden and prothrombin G20210A in adult Turkish patients with thrombosis Am J Hematol 2001 67 107 111 11343382 \n60 Rodeghiero F Tosetto A Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism Ann Intern Med 1999 130 643 650 10215560 \n61 Glueck CJ Fontaine RN Wang P Interaction of heritable and estrogen-induced thrombophilia: possible etiologies for ischemic optic neuropathy and ischemic stroke Thromb Haemost 2001 85 256 259 11246543 \n62 Glueck CJ Freiberg RA Fontaine RN Sieve-Smith L Wang P Anticoagulant therapy for osteonecrosis associated with heritable hypofibrinolysis and thrombophilia Expert Opin Investig Drugs 2001 10 1309 1316 \n63 Glueck CJ Pranikoff J Aregawi D The factor V Leiden mutation, high factor VIII, and high plasminogen activator inhibitor activity: etiologies for sporadic miscarriage Metabolism 2005 54 1345 1349 16154434 \n64 Viola MI Meyer D Kruger T Association between clomiphene citrate and visual disturbances with special emphasis on central retinal vein occlusion: a review Gynecol Obstet Invest 2010 71 73 76 21160153 \n65 Ventura SJ Mosher WD Curtin SC Abma JC Henshaw S Trends in pregnancies and pregnancy rates by outcome: estimates for the United States, 1976–1996 Vital Health Stat 21 2000 21 1 47 10740440 \n66 Yang P Kruh JN Foster CS Antiphospholipid antibody syndrome Curr Opin Ophthalmol 2012 23 528 532 23042148\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "9()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "anterior ischemic optic neuropathy; factor V Leiden; ocular vascular occlusion; prothrombin gene mutation; retinal artery occlusion; retinal vein occlusion",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "591-600",
"pmc": null,
"pmid": "25897198",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "9409269;10593436;18796459;7902898;18539932;22969282;11767028;11994569;24074702;23042148;11772253;10482096;11246543;11820306;10634553;17164500;18474782;21212568;10740440;23470793;8619763;10755093;11343382;10182093;3186211;11973257;14644226;10215560;11913903;12928685;12446535;9569177;8164741;24219332;18160589;12516681;18413521;22161466;1009041;20492457;21160153;15968383;18350351;19120547;12020623;16682596;16154434;9109469;8859076;8916933;11141642;14281983;9262559;11309638;11162981;24334115;20689798;8703855;23177364;18449423;8032479;19669864;20022117;8703856;8597939;17324695",
"title": "Diagnostic ramifications of ocular vascular occlusion as a first thrombotic event associated with factor V Leiden and prothrombin gene heterozygosity.",
"title_normalized": "diagnostic ramifications of ocular vascular occlusion as a first thrombotic event associated with factor v leiden and prothrombin gene heterozygosity"
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"abstract": "OBJECTIVE\nWe suspect that the life-threatening complication of metformin-associated lactic acidosis, solely due to drug accumulation following renal impairment, occurs more frequently than that previously reported and is not necessarily associated with other predisposing factors for lactic acidosis.\n\n\nMETHODS\nDuring a period of 13 months, at a tertiary referral centre, the incidence of lactic acidosis of any aetiology was 12.8% [67 of 524 total intensive care unit (ICU) admissions]. Metformin-associated lactic acidosis solely as the result of drug accumulation was diagnosed in 6% of all the patients suffering from lactic acidosis (4 of 67 patients).\n\n\nRESULTS\nThese patients presented with severe circulatory shock due to lactic acidosis. We could not identify any predisposing factor for lactic acidosis other than renal impairment. Intercurrent deterioration of diabetic nephropathy was suspected to be responsible for the accumulation of metformin followed by lactic acidosis, finally resulting in multiorgan failure. The diagnosis was supported by extensively elevated serum levels of metformin. Two patients died during ICU treatment.\n\n\nCONCLUSIONS\nOur data indicate that the incidence of metformin-associated lactic acidosis solely due to metformin accumulation is possible and underestimated. Symptoms of metformin-associated lactic acidosis are unspecific and physicians should be aware that metformin, if prescribed in patients with renal impairment, can cause fatal lactic acidosis due to drug accumulation.",
"affiliations": "Department of Cardiology, Pneumology, and Intensive Care Medicine, Ernst Moritz Arndt University, Greifswald, Germany. srunge@uni-greifswald.de",
"authors": "Runge|S|S|;Mayerle|J|J|;Warnke|C|C|;Robinson|D|D|;Roser|M|M|;Felix|S B|SB|;Friesecke|S|S|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1111/j.1463-1326.2006.00657.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-8902",
"issue": "10(1)",
"journal": "Diabetes, obesity & metabolism",
"keywords": null,
"medline_ta": "Diabetes Obes Metab",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D003928:Diabetic Nephropathies; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D051437:Renal Insufficiency",
"nlm_unique_id": "100883645",
"other_id": null,
"pages": "91-3",
"pmc": null,
"pmid": "18095950",
"pubdate": "2008-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Metformin-associated lactic acidosis in patients with renal impairment solely due to drug accumulation?",
"title_normalized": "metformin associated lactic acidosis in patients with renal impairment solely due to drug accumulation"
} | [
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"companynumb": "DE-BAUSCH-BL-2019-057090",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Despite the good prognosis in patients with transplant organs, limited evidence is available on how immunosuppressants affect pregnancy. The aim of this study was to determine whether immunosuppressant use affects the pregnancy outcome and to identify whether there is any need to change the immunosuppressant before the patient tries to conceive.\n\n\n\nThis retrospective cohort study included women with previous kidney transplantation history who visited the Department of Obstetrics and Gynecology for either infertility or antenatal care between January 2005 and May 2016. A total of 40 cases (36 women) met the inclusion criteria. Statistical analyses were performed using SAS version 9.4.\n\n\n\nThere were no differences in the immunosuppressant regimen between the pregnant and non-pregnant groups (never-pregnant+miscarriage) (P = 0.73). Individual immunosuppressant use was significantly different in terms of pregnancy outcome among the never-pregnant, miscarriage, and clinical pregnancy groups (azathioprine, P = 0.01; deflazacort, P < 0.0001). Only deflazacort use differed significantly between the clinical pregnancy and non-pregnant groups (P = 0.003). After adjusting for factors that may affect pregnancy outcome, deflazacort use remained significantly associated with a decreased odds ratio for clinical pregnancy (P = 0.02). Cox regression analysis also showed that deflazacort use was the only remaining factor that could hinder the success of clinical pregnancy (P = 0.03).\n\n\n\nOur study suggests that the type of immunosuppressive regimen may not affect the success of clinical pregnancy. However, deflazacort may decrease the possibility of clinical pregnancy in women with kidney transplant when they try to conceive.",
"affiliations": "Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.;Department of Transplant Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. tudeolseo@yuhs.ac.;Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.;Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. dr222@yuhs.ac.",
"authors": "Yun|Bo Hyon|BH|;Joo|Dong Jin|DJ|;Seo|Seok Kyo|SK|0000-0003-3404-0484;Cho|Si Hyun|SH|;Choi|Young Sik|YS|;Lee|Byung Seok|BS|",
"chemical_list": "D007166:Immunosuppressive Agents; D011282:Pregnenediones; C021988:deflazacort",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-019-1346-6",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 134610.1186/s12882-019-1346-6Research ArticleEffect of deflazacort on pregnancy outcome in kidney transplant patients: should we change the immunosuppressant before conception? Yun Bo Hyon garfieldzz@yuhs.ac 12Joo Dong Jin DJJOO@yuhs.ac 3http://orcid.org/0000-0003-3404-0484Seo Seok Kyo +82-2-2228-2230tudeolseo@yuhs.ac 12Cho Si Hyun sihyuncho@yuhs.ac 24Choi Young Sik YSCHOI08@yuhs.ac 12Lee Byung Seok +82-2-2228-2230dr222@yuhs.ac 121 0000 0004 0470 5454grid.15444.30Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722 Republic of Korea 2 0000 0004 0470 5454grid.15444.30Institute of Women’s Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea 3 0000 0004 0470 5454grid.15444.30Department of Transplant Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 4 0000 0004 0470 5454grid.15444.30Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 14 5 2019 14 5 2019 2019 20 16116 8 2018 18 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDespite the good prognosis in patients with transplant organs, limited evidence is available on how immunosuppressants affect pregnancy. The aim of this study was to determine whether immunosuppressant use affects the pregnancy outcome and to identify whether there is any need to change the immunosuppressant before the patient tries to conceive.\n\nMethods\nThis retrospective cohort study included women with previous kidney transplantation history who visited the Department of Obstetrics and Gynecology for either infertility or antenatal care between January 2005 and May 2016. A total of 40 cases (36 women) met the inclusion criteria. Statistical analyses were performed using SAS version 9.4.\n\nResults\nThere were no differences in the immunosuppressant regimen between the pregnant and non-pregnant groups (never-pregnant+miscarriage) (P = 0.73). Individual immunosuppressant use was significantly different in terms of pregnancy outcome among the never-pregnant, miscarriage, and clinical pregnancy groups (azathioprine, P = 0.01; deflazacort, P < 0.0001). Only deflazacort use differed significantly between the clinical pregnancy and non-pregnant groups (P = 0.003). After adjusting for factors that may affect pregnancy outcome, deflazacort use remained significantly associated with a decreased odds ratio for clinical pregnancy (P = 0.02). Cox regression analysis also showed that deflazacort use was the only remaining factor that could hinder the success of clinical pregnancy (P = 0.03).\n\nConclusions\nOur study suggests that the type of immunosuppressive regimen may not affect the success of clinical pregnancy. However, deflazacort may decrease the possibility of clinical pregnancy in women with kidney transplant when they try to conceive.\n\nKeywords\nKidney transplantImmunosuppressantPregnancyissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nSince the first successful kidney transplantation performed in 1954 by Dr. Joseph E. Murray, the number of people who live longer and healthier lives continues to increase each year. About 126,670 patients underwent organ transplantation in 2015 worldwide, with the kidney being the most commonly transplanted organ (84,347 cases), according to statistics from the Global Observatory on Donation and Transplantation (www.transplant-observatory.org). The first successful pregnancy after kidney transplantation was reported in 1956 [1] and the first pregnancy following in vitro fertilization-embryo transfer (IVF-ET) in a kidney transplant patient was in 1995 [2]. Extensive discussion has been conducted regarding the adequate conditions necessary before trying to conceive, such as stable blood pressure (BP), a normally functioning transplant organ, and infrequent graft rejections [3, 4]. For years, observations suggested that transplantation and immunosuppressant use may not interfere with the fertility of women [5], but may affect the pregnancy outcome such as intrauterine growth restriction and preeclampsia, leading to preterm delivery [6]. Given the effect of chronic disease and renal dysfunction, which may affect steroid hormone metabolism, infertility related to anovulation has been suggested as a possible infertility factor; however, after transplantation, the increase in ovulation resumption may lead to incidental pregnancy [5]. The number of patients trying to conceive is increasing, owing to improved prognosis and well-being after transplantation.\n\nHowever, there is a paucity of information on whether immunosuppressant use affects the achievement of pregnancy or the pregnancy outcome. When a kidney transplant patient considers pregnancy, certain immunosuppressants, such as mycophenolate mofetil, may be substituted because of their potential risk for fetal congenital orofacial anomalies and miscarriage; however, even this remains unclear as no distinct pattern of congenital anomalies has been identified as of yet [7]. The aim of this study was to determine whether immunosuppressant use affects the pregnancy outcomes of women with kidney transplants and to identify whether there is any need to change the immunosuppressant before the patient tries to conceive.\n\nMethods\nStudy population\nWomen with a history of kidney transplantation who visited the Department of Obstetrics and Gynecology for infertility or antenatal care from January 2005 to May 2016 in Severance Hospital, Yonsei University College of Medicine were included. Women who were pregnant before transplantation (n = 6), cases lost to follow-up (n = 2), and those who used certain immunosuppressants, such as sirolimus (n = 2) were excluded (Fig. 1). Finally, 40 cases (36 women) were included in this study: 18 cases of 18 infertile women who visited the infertility clinic (infertile group) and 22 cases of 18 pregnant women who visited the antenatal clinic (fertile group) after achieving successful conception within a year of trying to conceive. Prednisolone (Pred) was used as a first line steroid. Deflazacort (DFZ) was chosen instead of Pred in patients with diabetes, osteoporosis, and Cushing syndrome caused by prolonged use of corticosteroids.Fig. 1 Flow chart of participant inclusion in the study\n\n\n\nPrimary infertility was diagnosed in those who had tried to conceive for more than 1 year without contraception, and secondary infertility was diagnosed in those who had a previous history of pregnancy but failed to conceive for more than 1 year. The duration of attempted conception, cause of end-stage renal disease (ESRD), time since the transplantation, and whether the patient had graft rejection and hypertension were assessed through a retrospective chart review. The time of data collection for each factor, including the type of immunosuppressant medication, was within the month of the last menstruation in the clinical pregnancy and miscarriage groups or at the start of attempting conception in the never-pregnant group. The never-pregnant and miscarriage groups were merged into the non-pregnant group in analyses to compare with the clinical pregnancy group [8].\n\nMeasurements\nPatients’ BP was measured using an automated oscillometric measurement while seated with their arm at heart level. Hypertension was diagnosed if systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg, or antihypertensive medication was currently used. Blood samples were taken from the antecubital vein after at least 8 h of fasting. Blood tests commonly included blood urea nitrogen (BUN) and creatinine (Cr). Some patients who visited the infertility clinic underwent laboratory testing for hormones, including the follicle-stimulating hormone, luteinizing hormone, estradiol, and anti-Müllerian hormone. Renal function was assessed by estimated glomerular filtration rate (eGFR) [9, 10], using the following formula: Modification of Diet in Renal Disease (MDRD) 175 × Cr-1.154 × age-0.203 × 0.742.\n\nTo confirm the pregnancy, transvaginal ultrasonography was performed by experienced gynecologists using the available ultrasound systems (Accuvix V20 Prestige, Medison Co., Seoul, Korea; iU22, Philips Healthcare, WA, USA; and Voluson E8, GE Medical Systems, Zipf, Austria). Clinical pregnancy was defined as the presence of an intrauterine gestational sac with a pulsating fetal heartbeat detected by ultrasonography. Miscarriage was defined as confirmed intrauterine gestational sac without fetal heartbeat on ultrasonography.\n\nAll women with infertility underwent testing for tubal patency by hysterosalpingography and evaluation of pelvic anatomy by ultrasonography. Semen parameters were interpreted using the World Health Organization (2010) criteria [11]. The causes of infertility were unexplained infertility, male factor, tubal factor, decreased ovarian reserve, and endometriosis. The patients who visited the infertility clinic decided to proceed with intrauterine insemination (IUI; n = 5) or IVF-ET (n = 11) based on the cause of their infertility. Women with unexplained infertility in conjunction to irregular menstruation tried to conceive naturally using ovulation induction (n = 2).\n\nStatistical analysis\nData was analyzed using the SAS version 9.4 (SAS Institute, Cary, NC, USA). The Student t-test and one-way analysis of variance were used to compare the means for normally distributed continuous variables. The Mann-Whitney U-test and Kruskal-Wallis test were used to analyze non-parametrically distributed variables. The Fisher exact and chi-square tests were used to assess categorical variables. Univariate and multivariate logistic regression analyses were also performed. The logistic model included the factors that showed significance on the univariate analysis. Given the uneven distribution of the adjusting factors, the Firth-type bias-reduced logistic regression was used for adjustment. Multicollinearity, goodness of fit, and the predictive power of the logistic model were checked. Based on the logistic model, Cox’s regression analyses for clinical pregnancy and trial period of pregnancy were performed. A P-value < 0.05 was considered statistically significant.\n\nResults\nA total of 40 cases in 36 kidney transplant women were included in this study: 10 cases who had never been pregnant, 9 cases with miscarriage, and 21 cases with clinical pregnancy. One patient in the fertile group had three miscarriages. Two other patients in the fertile group each had one delivery and one miscarriage. Among the infertile women, 12 and 6 women had primary and secondary infertility, respectively. Of these women, 11 had an unexplained cause for infertility, 2 had infertility due to male factor, 4 had decreased ovarian reserve, and 1 had severe endometriosis (retaining duplicate causes). In the infertile group, 2, 4, and 12 women attempted pregnancy through natural conception, IUI, and IVF-ET, respectively. All women in the fertile group conceived naturally. Twenty-one cases of clinical pregnancy were achieved through natural conception in 15 women, IUI in 2 women, and IVF-ET in 2 women. The mean age of all participants was 33.8 ± 3.4 years. Mean duration of attempted conception was 17.6 ± 18.2 months and average time interval from the time of kidney transplant to the time they tried conceiving was 5.9 ± 4.1 years.\n\nTable 1 shows the patients’ baseline characteristics categorized by pregnancy outcome. The median age and BP were the lowest in the clinical pregnancy group, without a significant difference. Serum BUN level (17.2 mg/dL, P = 0.04) was low and eGFR (60.72, P = 0.02) was significantly high in the clinical pregnancy group compared to other groups. The proportion of patients with diabetes mellitus was significantly different among the groups, with two cases occuring in the never-pregnant group (P = 0.008). The graft rejection rate was significantly different among the three groups; the incidence of rejection was highest in the miscarriage group and lowest in the clinical pregnancy group (never-pregnant 30%, miscarriage 66.7%, clinical pregnancy 9.5%, P = 0.01). The cause of ESRD was predominantly nephrotic syndrome in the clinical pregnancy group (glomerulonephritis 42.9%, immunoglobulin A nephropathy 33.3%) and never-pregnant group (glomerulonephritis 40%, immunoglobulin A nephropathy 20%), while systemic lupus erythematous (SLE) (33.3%) was highest in the miscarriage group, but without significant difference among the groups (P = 0.13). Immunosuppressant use was analyzed in terms of the regimen and type of medication. The immunosuppressants analyzed were as follows: cyclosporine (CyA), tacrolimus (TAC), DFZ, Pred, azathioprine (AZT), and mycophenolate mofetil (MMF). The regimens were grouped as follows: CI + ST + AP, CI + ST, and CI + AP (CI, calcineurin inhibitor: CyA and TAC; ST, steroid: DFZ and Pred; AP, antiproliferative drug: AZT and MMF). Among the never-pregnant, miscarriage, and clinical pregnancy groups, the use of AZT (P = 0.01) and DFZ (P < 0.0001) was significantly different; however, there was no difference in the immunosuppressive regimen. None of the patients consumed DFZ on account of planning for pregnancy. All patients started DFZ directly following kidney transplantation as a substitute for Pred according to medical indications. There were only two patients with diabetes among the 36 women in our study.Table 1 Baseline characteristics of participants according to the pregnancy outcome\n\n\tNever-pregnant (n = 10)\tMiscarriage (n = 9)\tClinical pregnancy(n = 21)\tP value\t\nAge (years)\t34.5 (29–42)\t36 (30–39)\t33 (27–41)\t0.44\t\nDuration tried to concieve (months)\t44 (16–108)\t48 (6–96)\t22 (6–96)\t0.1\t\nYears since transplantation (years)\t4 (2–8)a\t7 (2–18)a\t5.5 (1–14)\t0.08\t\nSBP (mmHg)\t123 (113–144)\t135 (100–162)\t120 (100–145)\t0.44\t\nDBP (mmHg)\t80 (70–92)\t76 (60–96)\t72 (58–96)\t0.2\t\nSerum BUN (mg/dL)\t18.85 (8.4–34.4)\t25.4 (18.7–37.2)b\t17.2 (10.2–35.3)b\t0.04\t\neGFR\t55.08 (22–96.6)\t39 (9.0–76)b\t60.72 (37–89.7)b\t0.02\t\nHypertension\t\t\t\t0.59\t\n No\t4 (40%)\t2 (22.2%)\t5 (23.8%)\t\t\n Yes\t6 (60%)\t7 (77.8%)\t16 (76.2%)\t\t\nDiabetes melitus\t\t\t\t0.04\t\n No\t8 (80%)\t9 (100%)\t21 (100%)\t\t\n Yes\t2 (20%)\t0\t0\t\t\nGraft rejection\t\t\t\t0.01\t\n No\t7 (70%)\t3 (33.32%)\t19 (90.5%)\t\t\n Yes\t3 (30%)\t6 (66.7%)b\t2 (9.5%)b\t\t\nCause of ESRD\t\t\t\t0.13\t\n Unknown\t1 (10%)\t2 (22.2%)\t5 (25%)\t\t\n SLE\t1 (10%)\t3 (33.3%)\t0\t\t\n Glomerulonephritis\t4 (40%)\t2 (22.2%)\t9 (42.9%)\t\t\n Ig A nephropathy\t2 (20%)\t1 (11.1%)\t7 (33.3%)\t\t\n Congenital anomaly\t1 (10%)\t1 (11.1%)\t0\t\t\n Diabetes melitus\t1 (10%)\t0\t0\t\t\nImmunosuppressant regimen\t\t\t\t0.3\t\n CI\t1 (10%)\t2 (22.2%)\t6 (28.6%)\t\t\n CI + ST + AP\t6 (60%)\t1 (11.1%)\t5 (23.8%)\t\t\n CI + ST\t3 (30%)\t5 (55.6%)\t9 (42.9%)\t\t\n CI + AP\t0\t1 (11.1%)\t1 (4.8%)\t\t\nImmunosuppressant use\t\n CyA\t3 (30%)\t2 (22.2%)\t9 (45%)\t0.52\t\n TAC\t6 (60%)\t7 (77.8%)\t12 (57.1%)\t0.55\t\n DFZ\t9 (90%)\t1 (11.1%)\t2 (9.5%)\t< 0.0001\t\n Pred\t2 (20%)\t6 (66.7%)\t13 (61.9%)\t0.06\t\n Aza\t5 (50%)\t0\t2 (9.5%)\t0.01\t\n MMF\t2 (20%)\t2 (22.2%)\t4 (19%)\t0.98\t\nData are presented as the median (minimum to maximum). The P-values were obtained using the analysis of variance and the Kruskal-Wallis test for continuous variables, and the chi-square test was used for analyzing categorical variables. Post hoc analysis using the Tukey method was performed, which showed a significant difference between the non-pregnant group and the miscarriage groupa, and the miscarriage group and clinical pregnancy groupb\n\nNote: Duration, period of attempted conception; SBP, systolic blood pressure; DBP, diastolic blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease; SLE, systemic lupus erythematous; Ig, immunoglobulin; CI, calcineurin inhibitor; ST, steroid; AP; antiproliferative drug; CyA, cyclosporine; TAC, tacrolimus; DFZ, deflazacort; Pred, predinosolone; Aza, azathioprine; MMF, mycophenolate mofetil\n\n\n\nTable 2 presents a comparison of immunosuppressant use among never-pregnant, miscarriage, and clinical pregnancy groups. The clinical pregnancy group had no significant difference in the regimen used. Regarding each medication separately, DFZ use was significantly different between the non-pregnant and clinical pregnancy groups (52.6% vs. 9.5%, P = 0.003). Use of other immunosuppressants was similar between these two groups. We tried to determine whether there would be any difference if we grouped the patients according to the presence of a gestational sac on the ultrasonogram to either the implantation or the non-implantation group for failed pregnancies (data not shown). Steroid use remained significantly different between the two groups: DFZ use in non-implantation vs. implantation groups (88.9% vs. 12.9%, P < 0.0001); and Pred use in non-implantation vs. implantation groups (22.2% vs. 61.3%, P = 0.04). Additionally, AZT use was significantly different between the non-implantation and implantation groups (55.6% vs. 6.5%, P = 0.001). The immunosuppressive regimen was not different between the implantation and non-implantation groups. There were no significant differences in the method of conception between the non-pregnant and clinical pregnancy groups according to the immunosuppressant used, except for DFZ (P = 0.02, Table 3) and MMF (P = 0.02, Table 3).Table 2 Differences in immunosuppressant use and the pregnancy outcome\n\n\t\tNon-pregnant (n = 19)\tClinical pregnancy (n = 21)\tP value\t\n\t\t\t\t0.73\t\nRegimen\tCI\t3 (15.8%)\t6 (28.6%)\t\t\nCI + ST + AP\t7 (36.8%)\t5 (23.8%)\t\t\nCI + ST\t8 (42.1%)\t9 (42.9%)\t\t\nCI + AP\t1 (5.3%)\t1 (4.8%)\t\t\nImmunosuppressant use\tCyA\t5 (26.3%)\t9 (42.9%)\t0.27\t\n\tTAC\t13 (68.4%)\t12 (57.1%)\t0.46\t\n\tDFZ\t10 (52.6%)\t2 (9.5%)\t0.003\t\n\tPred\t8 (42.1%)\t13 (61.9%)\t0.21\t\n\tAza\t5 (26.3%)\t2 (9.5%)\t0.16\t\n\tMMF\t4 (21.1%)\t4 (19%)\t0.87\t\nNote: CI calcineurin inhibitor, ST steroid, AP antiproliferative drug, CyA cyclosporine, TAC tacrolimus, DFZ deflazacort, Pred predinosolone, Aza azathioprine, MMF mycophenolate mofetil\n\nTable 3 Differences in immunosuppressant use and the method of conception\n\n\t\tART (n = 6)\tNatural conception (n = 15)\tP value\t\n\t\t\t\t0.08\t\nRegimen\tCI\t1 (16.7%)\t5 (33.3%)\t\t\nCI + ST + AP\t3 (50%)\t2 (13.3%)\t\t\nCI + ST\t1 (16.7%)\t8 (53.3%)\t\t\nCI + AP\t1 (16.7%)\t0\t\t\nImmunosuppressant use\tCyA\t1 (16.7%)\t8 (53.3%)\t0.13\t\nTAC\t5 (83.3%)\t7 (46.7%)\t0.13\t\nDFZ\t2 (33.3%)\t0\t0.02\t\nPred\t3 (23.1%)\t10 (66.7%)\t0.48\t\nAza\t1 (16.7%)\t1 (16.7%)\t0.48\t\nMMF\t3 (50%)\t1 (6.7%)\t0.02\t\nNote: ART assisted reproductive techniques, CI calcineurin inhibitor, ST steroid, AP antiproliferative drug, CyA cyclosporine, TAC tacrolimus, DFZ deflazacort, Pred predinosolone, Aza azathioprine, MMF mycophenolate mofetil\n\n\n\nLastly, multivariate logistic models, using the Firth-type bias-reduced method, were utilized for some factors. The univariate analyses showed that the use of DFZ and whether the patient experienced graft rejection at the point of data collection were significantly different between the clinical pregnancy and non-pregnant groups (Table 4). After adjusting confounding factors, DFZ was the only significant immunosuppressant showing decreased odds to clinical pregnancy (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.01–0.68, P = 0.02, Table 5). To examine the hazard factors for clinical pregnancy, Cox regression models were used (Table 6). Before adjustment, whether the patient experienced graft rejection or not at the point of data collection was a significant hazardous factor of clinical pregnancy. On the multivariate Cox model, DFZ use was the only significant hazardous factor for clinical pregnancy (hazard ratio (HR) 0.17, 95% CI 0.03–0.86, P = 0.03, Table 6). When the total duration and cumulative dosage of DFZ used were included in the respective models, the longer duration hindered clinical pregnancy (HR 0.97, 95% CI 0.95–0.99, P = 0.04, Table 6). For the cases that used DFZ, the total duration of DFZ use was 57 months (median; 25–188 months, min-max) and its cumulative dose was 12,051 mg (median; 672–68,940 mg, min-max).Table 4 Unadjusted odds ratios of factors in clinical pregnancy\n\nFactors\tUnadjusted OR (95% CI)\tP value\t\nAge (years)\t0.87 (0.72–1.06)\t0.17\t\nDuration tried to conceive (months)\t0.98 (0.96–1.0)\t0.09\t\nYears since transplantation (years)\t0.94 (0.80–1.10)\t0.45\t\nHypertension\t1.48 (0.37–5.96)\t0.58\t\nSerum BUN (mg/dL)\t0.94 (0.87–1.03)\t0.19\t\neGFR\t1.03 (0.99–1.07)\t0.09\t\nGraft rejection\t0.12 (0.02–0.65)\t0.01\t\nDiabetes mellitus\t0.16 (0.004–7.09)\t0.35\t\nCause of ESRD\t\t\t\n Unknown\t1\t\t\n SLE\t0.07 (0.002–2.49)\t0.15\t\n Glomerulonephritis\t0.93 (0.16–5.38)\t0.94\t\n Ig A nephropathy\t1.36 (0.2–9.56)\t0.75\t\n Congenital anomaly\t0.13 (0.002–6.82)\t0.31\t\n Diabetes melitus\t0.16 (0.001–25.91)\t0.48\t\nUse of ART\t0.36 (0.1–1.33)\t0.13\t\nCyA\t2.1 (0.55–8.0)\t0.28\t\nTAC\t0.62 (0.17–2.25)\t0.46\t\nDFZ\t0.09 (0.02–0.53)\t0.007\t\nPred\t2.23 (0.63–7.93)\t0.21\t\nAza\t0.29 (0.05–1.75)\t0.18\t\nMMF\t0.88 (0.19–4.16)\t0.88\t\nNote: ART assisted reproductive techniques, SBP systolic blood pressure, DBP diastolic blood pressure, BUN blood urea nitrogen, eGFR estimated glomerular filtration rate, ESRD end stage renal disease, SLE systemic lupus erythematous, Ig immunoglobulin, CyA cyclosporine, TAC tacrolimus, DFZ deflazacort, Pred predinosolone, Aza azathioprine, MMF mycophenolate mofetil, OR odds ratio, CI confidence interval\n\nTable 5 Adjusted odds ratios of immunosuppressants in clinical pregnancy\n\nImmunosuppressant\tUnadjusted OR (95% CI)\tP value\tAdjusted OR (95% CI)\tP value\t\nCyA\t2.1 (0.55–8.0)\t0.28\t1.38 (0.22–8.89)\t0.73\t\nTAC\t0.62 (0.17–2.25)\t0.46\t0.84 (0.16–4.49)\t0.84\t\nDFZ\t0.09 (0.02–0.53)\t0.007\t0.06 (0.01–0.68)\t0.02\t\nPred\t2.23 (0.63–7.93)\t0.21\t2.8 (0.53–14.85)\t0.23\t\nAza\t0.29 (0.05–1.75)\t0.18\t0.48 (0.06–4.1)\t0.5\t\nMMF\t0.88 (0.19–4.16)\t0.88\t0.78 (0.14–4.39)\t0.78\t\nThe P-values were obtained using simple and multiple logistic regression analysis. The analysis was adjusted for age, estimated glomerular filtration rate, graft rejection after transplantation, diabetes mellitus, and use of assisted reproductive techniques. The logistic regression analysis was performed for each immunosuppressant, respectively\n\nNote: CyA, cyclosporine; TAC, tacrolimus; DFZ, deflazacort; Pred, predinosolone; Aza, azathioprine; MMF, mycophenolate mofetil; OR, odds ratio; CI, confidence interval\n\nTable 6 Adjusted hazard ratios of immunosuppressants for clinical pregnancy and duration\n\nImmunosuppressant\tUnadjusted HR (95% CI)\tP value\tAdjusted HR (95% CI)\tP value\t\nCyA\t0.89 (0.37–2.14)\t0.8\t0.33 (0.1–1.09)\t0.07\t\nTAC\t1.16 (0.49–2.79)\t0.73\t2.99 (0.92–9.72)\t0.07\t\nDFZ\t0.23 (0.05–0.99)\t0.05\t0.17 (0.03–0.86)\t0.03\t\nPred\t1.28 (0.53–3.11)\t0.59\t1.06 (0.42–2.72)\t0.9\t\nAza\t0.31 (0.07–1.34)\t0.12\t0.36 (0.08–1.77)\t0.21\t\nMMF\t0.57 (0.19–1.72)\t0.32\t0.61 (0.2–1.83)\t0.38\t\nCumulative dose of DFZ (mg)\t1.0\t0.11\t1.0\t0.14\t\nTotal duration of DFZ use (months)\t0.98 (0.95–1.0)\t0.06\t0.97 (0.95–1.0)\t0.04\t\nThe P-values were obtained using univariate and multivariate cox regression analyses. The analysis was adjusted for age, eGFR, graft rejection after transplantation, diabetes mellitus, and use of assisted reproductive techniques. The cox regression multivariate analysis was performed for each immunosuppressant, respectively\n\nNote: CyA cyclosporine, TAC tacrolimus, DFZ deflazacort, Pred predinosolone, Aza azathioprine, MMF mycophenolate mofetil, HR hazard ratio, CI confidence interval\n\n\n\nDiscussion\nConsidering the lack of knowledge in how immunosuppressants affect successful pregnancy, our study suggests a possible detrimental effect of DFZ for the first time. Until now, most studies on the adverse effects of immunosuppressants have focused on the development of diabetes or osteoporosis with their long-term use. Some studies have shown their impact on pregnancy complications and fetal outcome; but studies studying their impact on either fertility or pregnancy success are few. Our study suggests that the type of immunosuppressant regimen may not affect the success of clinical pregnancy; however, a certain medication-DFZ- may.\n\nIn our study, of the 40 cases, 17 cases were on CI and ST regimen (17/40, 42.5%), 12 on CI with ST and AP regimen (12/40, 30%), 9 on CI regimen only (9/40, 22.5%), and 2 on CI and AP regimens (2/40, 5%). Little is known on the effect of immunosuppressants on fertility. AZT was reported to show teratotoxicity in animal studies, but not in humans [12]. MMF is a reversible inhibitor of inosine monophosphate dehydrogenase, which blocks de novo purine synthesis and is thereby suggested as a category D drug in pregnancy. An increased risk of miscarriage and congenital orofacial malformations, especially microtia, is reported with MMF use [7]. CI acts by blocking cytokine secretion necessary for T-cell activation and proliferation. CyA and TAC are category C drugs in pregnancy that require strictly monitored serum levels. There has been no evidence of congenital anomaly development with these drugs; however, alteration of the immune response in neonates exposed to TAC in utero is possible [13]. Corticosteroids are mostly category B drugs in pregnancy that are associated with multiple maternal adverse effects [14]. Although the effect of Pred use is still unclear, it has been suggested that it enhances implantation rate in infertile women and decreases the risk of miscarriage in women with idiopathic recurrent pregnancy loss [15, 16]. The effect of Pred on uterine natural killer (NK) cells may be the key factor to its positive effect. Pred may inhibit uterine NK cells in the endometrium [16] and bind to the glucocorticoid receptor in the endometrium, which leads to an immunomodulating effect [17].\n\nDFZ is a heterocyclic corticosteroid, which is an oxazoline derivative of Pred. It was developed in the early 1980s [18] to treat patients with Duchenne muscular dystrophy [19] and is characterized by high efficacy and good tolerability because of its substantial lack of fluid retention and low interference with carbohydrate and phosphocalcium metabolisms [20]. Given DFZ’s excellent anti-inflammatory properties and good tolerability, it is preferred in patients with osteoporosis [21] or diabetes [22]. In our study, there were 2 patients with diabetes among those 12 patients who used DFZ. Although the number of patients using immunosuppressants is consistently increasing, little is known of their long-term effects during pregnancy. This may be because the indication for DFZ use was initially for patients with Duchenne muscular dystrophy who are less likely to attempt conception because of their underlying disease. As DFZ use is increasing in various fields of autoimmune diseases [23, 24], comparison to Pred has been done in terms of osteoporosis, cushinoid features, and body weight [25]. Our study is the first and only study, to our knowledge, showing adverse effects regarding fertility in those who use DFZ.\n\nSince the purpose of the study was to identify whether there is any need to change the immunosuppressant before trying to conceive, we generated logistic and Cox hazard models that focused on each immunosuppressant. To minimize the interaction among drugs and to focus on the effect of each immunosuppressant, multivariate models were constructed to include each immunosuppressant separately with the factors that showed significance on univariate analyses. DFZ showed significantly decreased odds for clinical pregnancy (OR 0.06, P = 0.02) and decreased possibility for achieving clinical pregnancy (HR 0.17, P = 0.03) after adjustment on multivariate models. Considering studies which suggest the positive effects of steroids on pregnancy, our result showing the possible detrimental effect of DFZ is unexpected. However, the possible harm of DFZ on conception may be explained by the difference between Pred and DFZ in inhibiting type 1 11ß-hydroxysteroid dehydrogenase (type 1 11ß-HSD) [26]. Type 1 11ß-HSD is an enzyme widely distributed throughout the central nervous system and peripheral tissues, and it is essential in hepatic and adipose tissue carbohydrate metabolism [27]. Decreased type 1 11ß-HSD expression was significantly associated with increased uterine NK cell density especially in the human endometrium [28]. Moreover, type 1 11ß-HSD has been identified as a key factor in decidualization of endometrial stromal cells [29]. The difference in the inhibiting ability of type 1 11ß-HSD may lead to a different expression of uterine NK cells and may affect the process of decidualization in the endometrium, resulting in a detrimental effect in implantation and successful pregnancy.\n\nIn the current study, renal function was better in the clinical pregnancy group than in the miscarriage group, exhibiting a significantly high eGFR and low serum BUN level (Table 1). However, the factors which may reflect graft function, such as eGFR and graft rejection, were not the ones with affected odds or hazard after adjustment for clinical pregnancy. Better kidney function with fewer graft rejection should be associated with better pregnancy prognosis, resulting in a lower possibility of miscarriage; however, our study did not prove this hypothesis. After discovering the possible detrimental effect of DFZ on clinical pregnancy, we additionally analyzed whether the duration or cumulative dosage of DFZ may further affect the clinical pregnancy. The total duration of DFZ use showed a possible hazardous impact (Table 6); however, the hazard was not found to be significant, probably because of the small number of cases included in this study. There were no cases of newly developed acute rejection during the period of trying to conceive.\n\nOur study was subject to several limitations. First, our study had a small number of patients and was of retrospective design. There may be a selective bias as kidney transplant patients who failed to conceive, but did not seek fertility treatment might be missed. However, as kidney transplant patients are usually very concerned about how their fertility is effected by their medication use, we believe that most would discuss infertility at length with their primary physician and seek further help if needed. Nonetheless, it may be unclear as to whether infertility in these patients is due to the immunosuppressant use or the fact that they did not seek fertility treatment. Secondly, as DFZ use was limited to certain diseases and countries, long-term reference data was unavailable. Finally, it is unclear as to how the immunosuppressants may interact with each other and whether they will negatively impact fertility. On the other hand, the strength of our study is that, for the first time, we showed a possible detrimental effect of DFZ in terms of implantation and success of pregnancy. To our knowledge, excluding the report demonstrating TAC as a basic immunosuppressive agent that achieved a high rate of successful pregnancy [30], this is the only study that investigated the effect of immunosuppressant use in fertility and pregnancy outcome.\n\nConclusions\nIn conclusion, DFZ may decrease the possibility of clinical pregnancy. The use and effect of immunosuppressants need to be evaluated more thoroughly in future studies. Before attempting pregnancy, modulating the immunosuppressant regimen may be required.\n\nAbbreviations\nAMHAnti-Müllerian hormone\n\nAPantiproliferative drug\n\nAZTazathioprine\n\nBPblood pressure\n\nBUNblood urea nitrogen\n\nCIcalcineurin Inhibitor\n\nCrcreatinine\n\nCyAcyclosporine\n\nDFZdeflazacort\n\nESRDend-stage renal disease\n\nIUIintrauterine insemination\n\nIVFin vitro fertilization\n\nMMFmycophenolate mofetil\n\nNKnatural killer\n\nPredprednisolone\n\nSLEsystemic lupus erythematous\n\nTACtacrolimus\n\nTVStransvaginal ultrasonography\n\ntype 1 11ß-HSDtype 1 11ß-hydroxysteroid dehydrogenase\n\nWe deeply appreciate Ms. HJ Shin, M.S. for statistical assistance.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe datasets generated and/or analyzed during the current study are not publicly available due [The whole data set used in this study is in the possession of Severance hospital, Yonsei University College of Medicine], but available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nBHY developed the idea for the paper, designed the study, analyzed the data, and wrote the manuscript; DJJ provided expert advice and contributed to the manuscript revision; YSC contributed to the interpretation of data, participated in study design, and provided patients of the study; SKS developed the idea for the paper, formulated the study design, and contributed analysis and interpretation of data; SC contributed interpretation of data and critical discussion; BSL formulated the study design, and provided patients of the study. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe study was approved by the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine (approval number: 4–2017-0454). The consent to participate was not required due to the retrospective nature of this study.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Murray JE Reid DE Harrison JH Merrill JP Successful pregnancies after human renal transplantation N Engl J Med 1963 269 341 343 13936776 \n2. Lockwood GM Ledger WL Barlow DH Successful pregnancy outcome in a renal transplant patient following in-vitro fertilization Hum Reprod 1995 10 6 1528 1530 7593529 \n3. Shah S Verma P Overview of pregnancy in renal transplant patients International journal of nephrology 2016 2016 4539342 28042483 \n4. Lopez LF Martinez CJ Castaneda DA Hernandez AC Perez HC Lozano E Pregnancy and kidney transplantation, triple hazard? Current concepts and algorithm for approach of preconception and perinatal care of the patient with kidney transplantation Transplant Proc 2014 46 9 3027 3031 25420815 \n5. Lessan-Pezeshki M Ghazizadeh S Khatami MR Mahdavi M Razeghi E Seifi S Ahmadi F Maziar S Fertility and contraceptive issues after kidney transplantation in women Transplant Proc 2004 36 5 1405 1406 15251344 \n6. Cardonick E Moritz M Armenti V Pregnancy in patients with organ transplantation: a review Obstet Gynecol Surv 2004 59 3 214 222 15105711 \n7. Mastrobattista JM Gomez-Lobo V Society for Maternal-Fetal M Pregnancy after solid organ transplantation Obstet Gynecol 2008 112 4 919 932 18827137 \n8. Maesawa Y Yamada H Deguchi M Ebina Y History of biochemical pregnancy was associated with the subsequent reproductive failure among women with recurrent spontaneous abortion Gynecol Endocrinol 2015 31 4 306 308 25539407 \n9. Sienko J Jasiczek A Paczek L Wyczalkowska-Tomasik A Kotowski M Nowacki A Sulikowski T Romanowski M Ostrowski M Evaluation of renal graft function based on standard mathematical formulas Ann Transplant 2014 19 452 455 25208483 \n10. Abouchacra S Chaaban A Hakim R Gebran N El-Jack H Rashid F Boobes Y Muhairi A Hussain Q Khan I Renal biomarkers for assessment of kidney function in renal transplant recipients: how do they compare? Int Urol Nephrol 2012 44 6 1871 1876 22639068 \n11. Tocci A Lucchini C WHO reference values for human semen Hum Reprod Update 2010 16 5 559 20542895 \n12. Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, Gulati R, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2005:69–83.\n13. Mak RH Hoffman HM Transplantation: outcomes of prenatal immunosuppression Nat Rev Nephrol 2015 11 7 390 391 25986424 \n14. Tedeschi SK Guan H Fine A Costenbader KH Bermas B Organ-specific systemic lupus erythematosus activity during pregnancy is associated with adverse pregnancy outcomes Clin Rheumatol 2016 35 7 1725 1732 27166627 \n15. Dan S Wei W Yichao S Hongbo C Shenmin Y Jiaxiong W Hong L Effect of prednisolone administration on patients with unexplained recurrent miscarriage and in routine intracytoplasmic sperm injection: a meta-analysis Am J Reprod Immunol 2015 74 1 89 97 25753479 \n16. Kemp MW Newnham JP Challis JG Jobe AH Stock SJ The clinical use of corticosteroids in pregnancy Hum Reprod Update 2016 22 2 240 259 26590298 \n17. Henderson TA Saunders PT Moffett-King A Groome NP Critchley HO Steroid receptor expression in uterine natural killer cells J Clin Endocrinol Metab 2003 88 1 440 449 12519888 \n18. Hahn BH Pletscher LS Muniain M Immunosuppressive effects of deflazacort - a new glucocorticoid with bone-sparing and carbohydrate-sparing properties: comparison with prednisone J Rheumatol 1981 8 5 783 790 6458701 \n19. Matthews E Brassington R Kuntzer T Jichi F Manzur AY Corticosteroids for the treatment of Duchenne muscular dystrophy Cochrane Database Syst Rev 2016 5 CD003725 \n20. Scudeletti M Castagnetta L Imbimbo B Puppo F Pierri I Indiveri F New glucocorticoids. Mechanisms of immunological activity at the cellular level and in the clinical setting Ann N Y Acad Sci 1990 595 368 382 1695828 \n21. Kim MS Kim YS Lim SK Kim SI Moon JI Park K Effect of deflazacort on bone mineral density in renal transplant recipients Transplant Proc 1998 30 7 3041 3042 9838340 \n22. Kim YS Kim MS Kim SI Lim SK Lee HY Han DS Park K Post-transplantation diabetes is better controlled after conversion from prednisone to deflazacort: a prospective trial in renal transplants Transpl Int 1997 10 3 197 201 9163859 \n23. Bakthavatchalam M Lai FHP Rong SS Ng DS Brelen ME Treatment of cystoid macular edema secondary to retinitis pigmentosa: a systematic review Surv Ophthalmol 2018 63 3 329 339 28987613 \n24. Shieh PB McIntosh J Jin F Souza M Elfring G Narayanan S Trifillis P Peltz SW McDonald CM Darras BT Deflazacort versus prednisone/prednisolone for maintaining motor function and delaying loss of ambulation: a post HOC analysis from the ACT DMD trial Muscle Nerve 2018 58 5 639 645 30028519 \n25. Ganapati A, Ravindran R, David T, Yadav B, Jeyaseelan V, Jeyaseelan L, Danda D. Head to head comparison of adverse effects and efficacy between high dose deflazacort and high dose prednisolone in systemic lupus erythematosus: a prospective cohort study. Lupus. 2018:961203317751854.\n26. Hult M Jörnvall H Oppermann UC Selective inhibition of human type 1 11beta-hydroxysteroid dehydrogenase by synthetic steroids and xenobiotics FEBS Lett 1998 441 1 25 28 9877158 \n27. Voice MW Seckl JR Edwards CR Chapman KE 11 beta-hydroxysteroid dehydrogenase type 1 expression in 2S FAZA hepatoma cells is hormonally regulated: a model system for the study of hepatic glucocorticoid metabolism Biochem J 1996 317 Pt 2 621 625 8713094 \n28. Kuroda K Venkatakrishnan R James S Sucurovic S Mulac-Jericevic B Lucas ES Takeda S Shmygol A Brosens JJ Quenby S Elevated periimplantation uterine natural killer cell density in human endometrium is associated with impaired corticosteroid signaling in decidualizing stromal cells J Clin Endocrinol Metab 2013 98 11 4429 4437 24025400 \n29. Kuroda K Venkatakrishnan R Salker MS Lucas ES Shaheen F Kuroda M Blanks A Christian M Quenby S Brosens JJ Induction of 11beta-HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells Mol Endocrinol 2013 27 2 192 202 23275455 \n30. Garcia-Donaire JA Acevedo M Gutierrez MJ Manzanera MJ Oliva E Gutierrez E Andres A Morales JM Tacrolimus as basic immunosuppression in pregnancy after renal transplantation. A single-center experience Transplant Proc 2005 37 9 3754 3755 16386528\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "20(1)",
"journal": "BMC nephrology",
"keywords": "Immunosuppressant; Kidney transplant; Pregnancy",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D015331:Cohort Studies; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D011247:Pregnancy; D011256:Pregnancy Outcome; D011282:Pregnenediones; D011295:Prenatal Care; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100967793",
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"pages": "161",
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"pmid": "31088388",
"pubdate": "2019-05-14",
"publication_types": "D016428:Journal Article",
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"title": "Effect of deflazacort on pregnancy outcome in kidney transplant patients: should we change the immunosuppressant before conception?",
"title_normalized": "effect of deflazacort on pregnancy outcome in kidney transplant patients should we change the immunosuppressant before conception"
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"activesubstancename": "DEFLAZACORT"
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"abstract": "Tramadol concentrations and analgesic effect are dependent on the CYP2D6 enzymatic activity. It is well known that some genetic polymorphisms are responsible for the variability in the expression of this enzyme and in the individual drug response. The detection of allelic variants described as non-functional can be useful to explain some circumstances of death in the study of post-mortem cases with tramadol. A Sanger sequencing methodology was developed for the detection of genetic variants that cause absent or reduced CYP2D6 activity, such as *3, *4, *6, *8, *10 and *12 alleles. This methodology, as well as the GC/MS method for the detection and quantification of tramadol and its main metabolites in blood samples was fully validated in accordance with international guidelines. Both methodologies were successfully applied to 100 post-mortem blood samples and the relation between toxicological and genetic results evaluated. Tramadol metabolism, expressed as its metabolites concentration ratio (N-desmethyltramadol/O-desmethyltramadol), has been shown to be correlated with the poor-metabolizer phenotype based on genetic characterization. It was also demonstrated the importance of enzyme inhibitors identification in toxicological analysis. According to our knowledge, this is the first study where a CYP2D6 sequencing methodology is validated and applied to post-mortem samples, in Portugal. The developed methodology allows the data collection of post-mortem cases, which is of primordial importance to enhance the application of these genetic tools to forensic toxicology and pathology.",
"affiliations": "National Institute of Legal Medicine and Forensic Sciences, Portugal. Electronic address: suzana.m.fonseca@inmlcf.mj.pt.;National Institute of Legal Medicine and Forensic Sciences, Portugal.;National Institute of Legal Medicine and Forensic Sciences, Portugal.;National Institute of Legal Medicine and Forensic Sciences, Portugal.;National Institute of Legal Medicine and Forensic Sciences, Portugal.;National Institute of Legal Medicine and Forensic Sciences, Portugal.;National Institute of Legal Medicine and Forensic Sciences, Portugal.",
"authors": "Fonseca|Suzana|S|;Amorim|António|A|;Costa|Heloísa Afonso|HA|;Franco|João|J|;Porto|Maria João|MJ|;Santos|Jorge Costa|JC|;Dias|Mário|M|",
"chemical_list": "D009294:Narcotics; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6",
"country": "Ireland",
"delete": false,
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"issn_linking": "0379-0738",
"issue": "265()",
"journal": "Forensic science international",
"keywords": "CYP2D6; Forensic toxicology; Pharmacogenetics; Poor metabolizers; Post-mortem; Tramadol",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019389:Cytochrome P-450 CYP2D6; D053593:Forensic Toxicology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009294:Narcotics; D010597:Pharmacogenetics; D011041:Poisoning; D020641:Polymorphism, Single Nucleotide; D011174:Portugal; D011180:Postmortem Changes; D014147:Tramadol",
"nlm_unique_id": "7902034",
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"pages": "153-9",
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"pmid": "26926096",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sequencing CYP2D6 for the detection of poor-metabolizers in post-mortem blood samples with tramadol.",
"title_normalized": "sequencing cyp2d6 for the detection of poor metabolizers in post mortem blood samples with tramadol"
} | [
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"abstract": "A 45-year-old woman presented to us in March 2019 with complaints of fever and right lower quadrant abdominal pain for 1 month. She had undergone renal transplantation in 2017 for end-stage renal disease and developed four episodes of urinary tract infection in the next 16 months post transplantation, which were treated based on culture reports. She was subsequently kept on long-term prophylaxis with trimethoprim and sulfamethoxazole. Her present laboratory parameters showed a normal blood picture and elevated creatinine. Urine culture grew Escherichia coli Non-contrast CT of the abdomen-pelvis revealed an endo-exophytic hyperdense mass in the graft kidney showing local infiltration and associated few regional lymph nodes. PET-CT revealed the soft-tissue mass and regional lymph nodes to be hypermetabolic, raising the possibility of lymphoma. However, biopsy showed features of malakoplakia. She was subsequently initiated on long-term antibiotic therapy and her immunosuppression decreased.",
"affiliations": "Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Radiology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India hiralal2007@yahoo.co.in.",
"authors": "Patel|Manas Ranjan|MR|;Thammishetti|Venkatesh|V|;Agarwal|Surabhi|S|;Lal|Hira|H|http://orcid.org/0000-0001-7957-635X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-244228",
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"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "malignant disease and immunosuppression; renal system; renal transplantation; urinary and genital tract disorders; urinary tract infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D008287:Malacoplakia; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D014552:Urinary Tract Infections",
"nlm_unique_id": "101526291",
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"pmid": "34400429",
"pubdate": "2021-08-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal graft malakoplakia masquerading post-transplant lymphoproliferative disorder.",
"title_normalized": "renal graft malakoplakia masquerading post transplant lymphoproliferative disorder"
} | [
{
"companynumb": "IN-STRIDES ARCOLAB LIMITED-2021SP028267",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"activesubstancename": "TACROLIMUS"
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"abstract": "The aims were to characterise paediatric medication errors and to identify the prevalence of known high-alert substances in these errors.\n\n\n\nAll paediatric drug-related incident reports and complaints nationally reported to the Health and Social Care Inspectorate in Sweden 2011-2017 regarding inpatients were characterised by context and modal details. In addition, drug use at a university hospital was matched to local incident reports. Drug substances were classified using three high-alert lists.\n\n\n\nOn a national level, there were 160 reports (2.5 per 10 000 patients) in which the three high-alert lists were found in different degrees (17/35/47%). Morphine (n = 12), vancomycin (n = 11) and potassium (n = 7) were most frequently involved. Eighty per cent of the reports concerned patients aged 0-6 years. Intravenous was the most common route of administration (66%). On a university hospital level, the prevalence of all types of drug incidents reports was 1.7% among all inpatients. The prevalence of local incident reports involving high-alert substances was almost double that of non-alert substances.\n\n\n\nExisting high-alert drug lists are relevant for paediatric inpatients. A higher awareness and usage of such lists among hospital staff prescribing, dispensing and administering drugs to children may have the potential to reduce medication errors.",
"affiliations": "Astrid Lindgren's Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.;Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.;Astrid Lindgren's Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.;Astrid Lindgren's Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Nydert|Per|P|0000-0002-8275-3625;Kumlien|Antonia|A|;Norman|Mikael|M|0000-0003-4191-3781;Lindemalm|Synnöve|S|",
"chemical_list": null,
"country": "Norway",
"delete": false,
"doi": "10.1111/apa.15273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-5253",
"issue": "109(12)",
"journal": "Acta paediatrica (Oslo, Norway : 1992)",
"keywords": "child; medication errors; paediatrics; patient safety; risk management",
"medline_ta": "Acta Paediatr",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007297:Inpatients; D008508:Medication Errors; D012308:Risk Management; D013548:Sweden",
"nlm_unique_id": "9205968",
"other_id": null,
"pages": "2810-2819",
"pmc": null,
"pmid": "32239536",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cross-sectional study identifying high-alert substances in medication error reporting among Swedish paediatric inpatients.",
"title_normalized": "cross sectional study identifying high alert substances in medication error reporting among swedish paediatric inpatients"
} | [
{
"companynumb": "SE-ALKEM LABORATORIES LIMITED-SE-ALKEM-2020-08934",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nAlthough serological tests are useful for identifying celiac disease, it is well established that a minority of celiacs are seronegative.\n\n\nOBJECTIVE\nTo define the prevalence and features of seronegative compared to seropositive celiac disease, and to establish whether celiac disease is a common cause of seronegative villous atrophy.\n\n\nMETHODS\nStarting from 810 celiac disease diagnoses, seronegative patients were retrospectively characterized for clinical, histological and laboratory findings.\n\n\nRESULTS\nOf the 810 patients, fourteen fulfilled the diagnostic criteria for seronegative celiac disease based on antibody negativity, villous atrophy, HLA-DQ2/-DQ8 positivity and clinical/histological improvement after gluten free diet. Compared to seropositive, seronegative celiac disease showed a significantly higher median age at diagnosis and a higher prevalence of classical phenotype (i.e., malabsorption), autoimmune disorders and severe villous atrophy. The most frequent diagnosis in the 31 cases with seronegative flat mucosa was celiac disease (45%), whereas other diagnoses were Giardiasis (20%), common variable immunodeficiency (16%) and autoimmune enteropathy (10%).\n\n\nCONCLUSIONS\nAlthough rare seronegative celiac disease can be regarded as the most frequent cause of seronegative villous atrophy being characterized by a high median age at diagnosis; a close association with malabsorption and flat mucosa; and a high prevalence of autoimmune disorders.",
"affiliations": "Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy.;Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy.;Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy.;Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy.;Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy.;Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy.;Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy.;Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Italy. Electronic address: roberto.degiorgio@unibo.it.",
"authors": "Volta|Umberto|U|;Caio|Giacomo|G|;Boschetti|Elisa|E|;Giancola|Fiorella|F|;Rhoden|Kerry J|KJ|;Ruggeri|Eugenio|E|;Paterini|Paola|P|;De Giorgio|Roberto|R|",
"chemical_list": "D001323:Autoantibodies; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "48(9)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Autoantibodies; Autoimmune disorders; Autoimmune enteropathy; Common variable immunodeficiency; Olmesartan; Seronegative celiac disease; Villous atrophy",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D001284:Atrophy; D001323:Autoantibodies; D002446:Celiac Disease; D017074:Common Variable Immunodeficiency; D055050:Diet, Gluten-Free; D005260:Female; D005873:Giardiasis; D006683:HLA-DQ Antigens; D006801:Humans; D007413:Intestinal Mucosa; D007558:Italy; D008297:Male; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune; D012189:Retrospective Studies; D016036:Seroepidemiologic Studies; D055815:Young Adult",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "1018-22",
"pmc": null,
"pmid": "27352981",
"pubdate": "2016-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Seronegative celiac disease: Shedding light on an obscure clinical entity.",
"title_normalized": "seronegative celiac disease shedding light on an obscure clinical entity"
} | [
{
"companynumb": "IT-DSJP-DSE-2016-123654",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLMESARTAN MEDOXOMIL"
},
"drugadditional": "3",... |
{
"abstract": "Lymphoid interstitial pneumonia (LIP) is categorized as a rare form of interstitial lung disease. Most cases are associated with autoimmune disease.\nA 78-year-old male with Crohn's disease, presented with progressive dyspnea and dry cough for few weeks. The pathology of transbronchial lung biopsy was compatible with LIP and positive cells on EBER in situ hybridization. Blood EBV viral load was 85,715 copies/mL, compatible with EBV-associated LIP. All immunosuppressive agents were discontinued, but unfortunately the patient died due to hospital-acquired infections. In addition, we reviewed all reported cases of EBV-associated LIP in literature.\nTo our knowledge, we report herein the first case of EBV-associated LIP in an IBD patient. We postulate that LIP was the consequence from EBV reactivation, probably due to immunosuppressive agents and/or IBD itself. The physician should aware of this disease when taking care of immunosuppressive patients who present with acute interstitial pneumonitis.",
"affiliations": "Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Pathology, Chulalongkorn University, Bangkok, Thailand.;Department of Pathology, Chulalongkorn University, Bangkok, Thailand.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.",
"authors": "Prasoppokakorn|Thaninee|T|;Assanasen|Thammathorn|T|;Chantranuwatana|Poonchavist|P|;Suankratay|Chusana|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101059",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30013-7\n10.1016/j.rmcr.2020.101059\n101059\nCase Report\nEBV-associated lymphoid interstitial pneumonia in IBD patient: Case report and literature review\nPrasoppokakorn Thaninee thanineeeve@gmail.coma Assanasen Thammathorn b Chantranuwatana Poonchavist b Suankratay Chusana csuankratay@gmail.comc∗ a Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand\nb Department of Pathology, Chulalongkorn University, Bangkok, Thailand\nc Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand\n∗ Corresponding author. csuankratay@gmail.com\n18 4 2020 \n2020 \n18 4 2020 \n30 1010596 1 2020 3 4 2020 11 4 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nLymphoid interstitial pneumonia (LIP) is categorized as a rare form of interstitial lung disease. Most cases are associated with autoimmune disease.\n\nCase report\nA 78-year-old male with Crohn's disease, presented with progressive dyspnea and dry cough for few weeks. The pathology of transbronchial lung biopsy was compatible with LIP and positive cells on EBER in situ hybridization. Blood EBV viral load was 85,715 copies/mL, compatible with EBV-associated LIP. All immunosuppressive agents were discontinued, but unfortunately the patient died due to hospital-acquired infections. In addition, we reviewed all reported cases of EBV-associated LIP in literature.\n\nConclusions\nTo our knowledge, we report herein the first case of EBV-associated LIP in an IBD patient. We postulate that LIP was the consequence from EBV reactivation, probably due to immunosuppressive agents and/or IBD itself. The physician should aware of this disease when taking care of immunosuppressive patients who present with acute interstitial pneumonitis.\n\nKeywords\nEpstein-barr virusEBV-Associated lymphoid interstitial pneumoniaPulmonary lymphoproliferative disorderInflammatory bowel disease\n==== Body\n1 Introduction\nLymphoid interstitial pneumonia (LIP) is categorized as a rare form of interstitial lung disease according to the classification of American Thoracic Society/European Respiratory Society [1]. The definite diagnosis requires both imagings and pathology. Chest computed tomogram reveals the presence of ground glass attenuation, centrilobular and subpleural nodules, and thickening of bronchovascular bundles. The pathologic are characterized by the presence of dense polyclonal interstitial lymphocytic infiltrates with widening interlobular and alveolar septa [2,3]. Most cases are associated with autoimmune disease or lymphoproliferative disorder [4].\n\nEBV, a double-stranded DNA virus, belongs to the Herpesviridae family [5]. EBV is able to cause latent infection, and reactivation occurs when infected individuals develop immunosuppressive state. Primary EBV infection causes infectious mononucleosis syndrome, and chronic infection/reactivation can cause lymphoma, and lymphoproliferative disorder including post transplant lymphoproliferative disease (LPD) [6]. In latent phase of infection, viral protein has the ability to transform mature B lymphocyte, resulting in uncontrolled its proliferation, as LPD [7].\n\nInflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, have been reported to be associated with LPD [8,9]. However, to date, there have been no reports of EBV-associated LIP in IBD patients.\n\n2 Case report\nA 78-year-old male was hospitalized at King Chulalongkorn Memorial Hospital, Thailand, due to progressive dyspnea, dry cough, and fever for few weeks; and acute confusion for 1 day. He was diagnosed with Crohn's disease 2 years prior to admission due to chronic abdominal pain with watery diarrhea, and colonoscopy revealed multiple ulcers at ileocecal valve and ascending colon with pathology compatible with Crohn's disease. He had received prednisolone, azathioprine, and mesalazine. Prednisolone was tapered down to 7.5 mg for maintenance clinical remission.\n\nTen weeks prior to admission, he was hospitalized due to hematochezia, and colonoscopy revealed multiple ulcers at terminal ileum, and ascending colon. The pathology exhibited severe colitis with negative results of owl's cells and CMV-infected cells on immunohistochemistry. However, his blood Cytomegalovirus (CMV) viral load was 595 copies/mL. A diagnosis of CMV colitis was made, and ganciclovir was given for 6 weeks to maintain undetectable viremia. Unfortunately one month prior to admission, he developed hematochezia again, colonoscopy revealed some healed ulcers at terminal ileum, and ascending colon despite new multiple clean-based ulcer at ileocaecal valve. The pathological exhibited moderate chronic active ileitis despite CMV viral load suppression. The diagnosis of active Crohn's disease was made, oral prednisolone of 60 mg/day and infliximab were then given in accompanying with azathioprine of 50 mg and mesalazine of 3000 mg.\n\nHis past medical history included hypertension, dyslipidemia, and old ischemic stroke.\n\nUpon admission, the patient had bitemporal throbbing headache and sudden onset of altered mentation, cranial computed tomogram (CT) revealed diffuse brain atrophy with small intraventricular hemorrhage in occipital horns of lateral ventricles without evidence of obvious aneurysm. Lumbar puncture revealed xanthochromic cerebrospinal fluid (CSF) with white blood cell (WBC) of 9 cells/μL, red blood cell (RBC) of 51,000 cells/μL, glucose of 51 mg/dL, protein of 48 mg/dL, and negative results of herpes simplex virus (HSV), varicella zoster virus (VZV), and CMV polymerase chain reaction (PCR). Chest X-ray showed bilateral interstitial infiltrates. Complete blood count analysis revealed hemoglobin (Hb) of 8.4 g/dL, WBC of 3460/μL (neutrophil 87.5%, lymphocyte 6.2%, monocyte 5.7%), and platelet of 138,000/μL. Peripheral blood smear exhibited moderate polychromasia and microspherocytes, and direct Coombs’ test was strongly positive, compatible with autoimmune hemolytic anemia (AIHA). Blood CMV and EBV viral loads were 21,709 and 85,715 copies/mL, respectively. There were negative CMV viral capsid antigen (VCA) IgM, positive CMV VCA IgG, negative EBV VCA IgM, positive EBV VCA IgG, and positive EBV nuclear antigen (EBNA) IgG in the serum. Bone marrow aspiration and biopsy showed hypocellularity, no abnormal cell infiltrates, and negative result of EBV-encoded RNA (EBER) in situ hybridization. A presumptive diagnosis of CMV syndrome was made, and intravenous ganciclovir was given. Nevertheless, during hospitalization, his clinical condition had gradually worsened and he finally developed acute respiratory failure requiring ventilator support. Chest CT revealed diffuse interstitial mixed with multifocal irregular consolidation infiltrates (Fig. 1). Bronchoscopy and bronchoalveolar lavage showing WBC of 139 cells/μL (neutrophils 53%). The pathology of transbronchial biopsy exhibited diffuse interstitial infiltrates with lymphocytes and plasma cells, without viral inclusion bodies. CMV immunohistochemistry was negative, but EBER in situ hybridization (ISH) exhibited 10 positive cells per total 100 lymphocytes by processing automated chromogenic ISH was performed using EBER Probe, known prediagnosed cases of EBER-positive cell were taken as positive controls, as well as nonneoplastic cells were taken as negative controls (Fig. 2). Two weeks after treatment, his blood CMV viral load was down to 214 copies/mL and eventually undetectable in three weeks course of ganciclovir, whereas EBV viral load was still 549,697 copies/mL. Hence, a final diagnosis of EBV-associated lymphocytic interstitial pneumonitis was made, and all immunosuppressive agents were discontinued. Unfortunately, the patient developed multiple hospital-acquired infections, including of Pneumocystis jiroveci pneumonia, pulmonary aspergillosis, and multidrug-resistant bacteria infection, and eventually expired 5 weeks after hospitalization.Fig. 1 Chest computed tomography revealed diffuse interstitial mixed with multifocal irregular consolidation infiltrates.\n\nFig. 1Fig. 2 Haematoxylin and eosin stain pathology of transbronchial biopsy (left) low power field revealed diffuse interstitial infiltrates with lymphocytes and plasma cells, and (right) high power field revealed florid lymphocytic interstitial infiltrates predominantly.\n\nFig. 2\n\n3 Discussion\nTo our knowledge, we reported the first case of EBV-associated LIP in an IBD patient. We postulate that LIP in our patient was the consequence from EBV reactivation, probably due to immunosuppressive state from immunosuppressive agents and/or IBD itself.\n\nLIP is a rare interstitial lung disease. It represents a nonspecific response to stimuli, and has been reported to be associated with systemic disorders including autoimmune, lymphoproliferative, and infectious diseases [2]. To date, there have been handful cases of EBV-associated LIP. Our case had both CT and pathological findings compatible with LIP. CT revealed diffuse interstitial mixed with multifocal irregular consolidation infiltrates, and the pathology exhibited diffuse interstitial infiltrates of lymphocytes and plasma cells. There were also 10 positive cells per total 100 lymphocytes on EBER in situ hybridization testing which are very high in comparison with normal individuals. In addition, blood EBV viral load was persistently high during the course of his illness. We postulate that LIP in our case should be in association with EBV infection. The immunopathogenesis of EBV-associated LIP has been proposed [4]. Chronic EBV infection can drive the proliferation and probably transformation of B lymphocytes in bronchus-associated lymphoid tissue which subsequently progresses to LIP [4]. Among normal individuals, EBV is in the latency phase of infection due to the host's immune surveillance against the virus. In contrast, latent EBV infection can be reactivated to become chronic infection leading to LPD in individuals with immunosuppressive state [5]. Notably, the prototype of pathogenesis in EBV-driven LPD is PTLD [10]. In our case, there had been many immunosuppressive agents. CMV colitis, one of the opportunistic infection, is the strong evidence that our case had immunosuppressive state.\n\nTo our knowledge, the association between EBV infection and AIHA has not been reported. We postulate that the development of AIHA in our case should be due to the dysregulation of host immune response driven by chronic EBV infection.\n\n4 Literature review\nWe reviewed all 16 patients with EBV-associated LIP published in English literature from 1986 to 2019 (Table 1 [[11], [12], [13], [14], [15], [16], [17], [18], [19], [20]]). There were 5 males and 11 females with the mean age of 39.9 ± 17.3 (range: 17–78) years; our patient was the oldest patient in the literature. There were 5 Asians and 11 Caucasians. Of 16 patients, AIDS was the most common comorbidity (5 patients, 31.2%), followed by post splenectomy (2, 12.5%), and heart/lung transplantation, bone marrow transplantation, systemic lupus erythematosus, Sjogen's syndrome, polymyositis, chronic active EBV disease, and Crohn's disease (1 each, 6.2%). Cough was the most common clinical presentation (10, 62.5%), followed by fever (8, 50.0%), dyspnea (3, 18.7%), pleurisy (2, 12.5%), and respiratory failure (1, 6.2%). The duration of symptoms ranged from 5 days to 18 months. Of 16 patients, tachypnea was the most common signs (9, 56.2%), followed by abnormal lung sounds (5, 31.2%), lymphadenopathy (4, 25.0%), hepatomegaly, splenomegaly, hepatosplenomegaly (2 each, 12.5%). Of 5 patients with abnormal lung sounds, crepitation was the most common signs (3, 60.0%), followed by wheezing and decreased breath sound (1 each, 20.0%). In addition, the findings from imagings either chest X-ray or computed tomogram, reticulonodular pattern was the most common infiltration (5, 31.2%), followed by interstitial pattern (4, 25.0%), consolidation (3, 18.7%), septal thickening (3, 18.7%), and pleural effusion (1, 6.2%). All 16 patients had bilateral lung infiltrates, predominantly at the lower lung zone (10, 62.5%). Regarding the pathology, of 13 patients, diffuse interstitial lymphocytic infiltrate was the common finding (12, 92.3%), followed by peribronchial infiltration (6, 46.1%), vasculitis (2, 15.4%), and granulomatous inflammation (1, 7.7%). Of 13 patients, EBER hybridization was positive in 3 (23.0%) patients including our patient. Regarding EBV serology, 1 (6.2%), 12 (75.0%), 0 (0%), and 12 (75.5%) patients had positive VCA IgM, VCA IgG, early antigen-diffuse component (EA-D) IgM, and EA-D IgG, respectively. From the evidence of EBV serology, EBV-associated LIP develops from EBV reactivation. Due to no specific antiviral treatment for EBV infection/disease, discontinuation or dose reduction of immunosuppressive agents was done in 1 (6.5%) patients. Four (25.0%) patients had received immunomodulating agent including corticosteroid, cyclophosphamide, rituximab, subcutaneous interferon alpha. Complications reported acute respiratory distress syndrome, pulmonary hypertension, and bacterial septicemia (1 each, 6.2%). Of 10 patients, there were complete resolution (5, 50%), partial resolution (2, 20.0%), and fatal outcome (3, 30.0%); 6 patients had unknown outcome (37.5%).Table 1 A summary of all 16 cases with EBV-associated lymphocytic interstitial pneumonitis reported from 1986 to 2019.\n\nTable 1Patient\tGender/age (year)\tRace\tOther medical problems\tClinical presentations\tDuration\tPhysical findings\tImaging/chest X-rays (CXR)/CT\tHistological finding\tAnti VCA IgM/IgG, anti EA-D IgM/IgG\tTreatment\tComplication\tOutcome\t\n1 [11] (1986)\tF/18\tCaucasian\tNone\tNonproductive cough, pleuritic chest pain\t5 days\tLymphadenopathy, splenomegaly\tCXR - Bilateral interstitial infiltrates of lower lungs\tNA\t1:160/1:40,960, 1:40/1:10,240\tIV acyclovir\tMild restrictive lung disease, pulmonary hypertension\tComplete resolution\t\n2 [11] (1986)\tF/17\tIndia\tNone\tFever, pharyngitis\t18 months\tSplenomegaly\tCXR - Bilateral patchy, nodular infiltrates\tInterstitial infiltrate of mature lymphocytes in interalveolar septa, no EBV by DNA hybridization\tNA/1:10,240, NA/1:>640\tIV acyclovir\tVitritis, Pseudomonas septicemia\tDied\t\n3 [12] (1992)\tM/33\tHaitian\tAIDS\tNonproductive cough\tNA\tTachypnea\tCXR - Bilateral diffuse reticulonodular infiltrates prominent at basal lungs\tDiffuse lymphocytic infiltrates in interstitium, peribronchial infiltration\t−/+, −/+\tNA\tNA\tNA\t\n4 [12] (1992)\tF/28\tHaitian\tAIDS\tNonproductive cough\tNA\tTachypnea\tCXR - Bilateral diffuse reticulonodular infiltrates prominent at basal lungs\tDiffuse lymphocytic infiltrates in interstitium, peribronchial infiltration, vasculitis\t−/+, −/+\tNA\tNA\tNA\t\n5 [12] (1992)\tF/36\tCaucasian\tAIDS\tNonproductive cough\tNA\tTachypnea\tCXR - Bilateral diffuse reticulonodular infiltrates prominent at basal lungs\tDiffuse lymphocytic infiltrates in interstitium, peribronchial infiltration\t−/+, −/+\tNA\tNA\tNA\t\n6 [12] (1992)\tM/35\tCaucasian\tAIDS\tNonproductive cough\tNA\tTachypnea\tCXR - Bilateral diffuse reticulonodular infiltrates prominent at basal lungs\tDiffuse lymphocytic infiltrates in interstitium, peribronchial infiltration\t−/+, −/+\tNA\tNA\tNA\t\n7 [12] (1992)\tF/48\tCaucasian\tAIDS\tNonproductive cough\tNA\tTachypnea\tCXR - Bilateral diffuse reticulonodular infiltrates prominent at basal lungs\tDiffuse lymphocytic infiltrates in interstitium, peribronchial infiltration\t−/+, −/+\tNA\tNA\tNA\t\n8 [13] (1998)\tF/39\tCaucasian\tHeart-lung transplant\tNA\tN\tNA\tCT - Multiple nodules and distributed consolidation, pleural and septal thickening\tPolyclonal LPD, perivascular lymphocytic infiltrate extends into interstitium of alveolar walls, atypical large lymphoid cells\tNA\tDecrease in imuunosuppression\tNA\tPartial resolution\t\n9 [14] (1999)\tM/65\tCaucasian\tChronic lymphocytic leukemia\tFever, nonproductive cough\tNA\tLymphadenopathy, hepatosplenomegaly\tCT - Diffuse interstitial pneumonia in both lungs\tIn situ hybridization disclosed EBV-encoded small RNA in lymphoma cells (Richter's syndrome)\tNA/1:2,560, NA/1:640\tChemotherapy\tNone\tDied\t\n10 [15] (2002)\tF/50\tKorean\tSLE, Sjogen's syndrome\tFever, dyspnea, cough, pleuritic chest pain\t20 days\tTachypnea, bibasilar crackling rales, hepatomegaly\tCXR - Bilateral consolidations in lower lungs, pleural effusion\tLymphoplasmacytic infiltrates in interstitial, pleura foaming reactive lymphoid follicles with germinal centers, multifocal areas of vasculitis\tNA\nIn situ hybridization of tissue positive Ab\tCorticosteroid cyclophosphamide\tNone\tComplete resolution\t\n11 [16] (2005)\tF/27\tCaucasian\tPost splenectomy\tFever, fatigue, nonproductive cough\t1 day\tUnremarkable\tCXR - Bilateral infiltration in lower lungs\tDiffuse nonspecific interstitial pneumonitis with poorly defined granulomatous inflammation\t<1:10/1:37,690, 1:20/1:40,960\tSupportive\tNone\tNA\t\n12 [17] (2007)\tM/53\tJapanese\tAML post bone marrow transplantation\tFever, fatigue\t14 days\tUnremarkable\tCT - Bilateral interstitial infiltration\tLarge lymphocytes infiltrate sub-bronchial lesion, in situ hybridization for EBER positive\tNA/1:1,280, NA/1:160\nPCR DNA 6800 copies/106 cells\tRituximab\tNone\tComplete resolution\t\n13 [18] (2009)\tF/62\tCaucasian\tPolymyositis\tDyspnea\t1 month\tTachypnea, crepitation middle lungs\tCT -Widespread marked ground glass opacity with intra and interlobular septal thickening\tNA\tNA detectable copy number 28,420/ml on quantitative PCR\tIV acyclovir\tNone\tComplete resolution\t\n14 [19] (2011)\tF/28\tKorean\tNone\tFever, flu-like symptoms\t21 days\tTachypnea, decrease breath sounds lower lungs, lymphadenopathy hepatosplenomegaly\tCT -Diffuse ground glass opacities in both lower lungs, pleural effusion, interlobular septal thickening\tSmall to large lymphocytes infiltrates in the alveolar septum and peribronchial interstitium, in situ hybridization for EBER positive\t−/+,−/+\nRT-PCR 946 copies/5μl\tSupportive\tNone\tComplete resolution\t\n15 [20] (2018)\tF/22\tCaucasian\tChronic active EBV disease, post splenectomy\tFever, productive cough, weakness\t1 month\tTachypnea, wheezing middle and lower lungs, lymphadenopathy hepatomegaly\tCT - Disseminated maculate infiltrates both lungs\tNA\t−/+, −/+\tSubcutaneous interferon alpha\tNone\tPartial resolution\t\n16 (our case, 2019)\tM/78\tThai\tCrohn's disease, CMV colitis\tFever, respiratory failure\t14 days\tTachypnea, coarse crepitation lower lungs\tCT - Diffuse multifocal irregular consolidation and ground glass opacities scattered in both lungs\tLarge amount of usual lung parenchymal cells, several foamy materials, without viral inclusion, in situ hybridization for EBER positive\tNA, viral load 549,697 copies/mL (log 5.74)\tIV acyclovir, supportive\tARDS\tDied\t\nVCA, viral capsid antigen; EA-D, early antigen-diffuse component; EBER, Epstein-Barr virus-encoded RNA; LPD, lymphoproliferative disease; AIDS, acquired immune deficiency syndrome; SLE, systemic lupus erythematosus; ARDS, acute respiratory distress syndrome; CT, computed tomography; IV, intravenous; NA, not applicable; F, female; M, male.\n\n\n\n5 Conclusions\nTo date, EBV has rarely been reported as a causative agent or an association of LIP. To our knowledge, we report the first case of EBV-associated LIP in an IBD patient. We postulate that LIP was the consequence from EBV reactivation probably due to immunosuppressive state from immunosuppressive agents and/or IBD itself. The physician should aware of EBV-associated LIP when taking care of immunosuppressive patients presenting with interstitial pneumonitis.\n\nFinancial disclosure\nNone declared.\n\nDeclaration of competing interest\nNone declared.\n==== Refs\nReferences\n1 Travis W.D. Costabel U. Hansell D.M. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias Am. J. Respir. Crit. Care Med. 188 6 2013 733 748 24032382 \n2 Panchabhai T.S. Farver C. Highland K.B. Lymphocytic interstitial pneumonia Clin. Chest Med. 37 3 2016 463 474 27514593 \n3 Cha S.I. Fessler M.B. Cool C.D. Lymphoid interstitial pneumonia: clinical features, associations and prognosis Eur. Respir. J. 28 2 2006 364 369 16571614 \n4 Swigris J.J. Berry G.J. Raffin T.A. Lymphoid interstitial pneumonia: a narrative review Chest 122 6 2002 2150 2164 12475860 \n5 Cohen J.I. Epstein-Barr virus infection N. Engl. J. Med. 343 7 2000 481 492 10944566 \n6 Jha Hem C. Pei Yonggang Erle S. Robertson Epstein-Barr virus: diseases linked to infection and transformation Front. Microbiol. 7 2016 1602 27826287 \n7 Lam G.Y. Halloran B.P. Peters A.C. Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: lesson from other inflammatory disorders World J. Gastrointest. Pathophysiol. 6 4 2015 181 192 26600976 \n8 Bernardes C. Russo P. Carvalho D. Lymphoproliferative disorders in inflammatory bowel disease patients: is it the drugs or the disease GE Port Gastroenterol 25 4 2018 175 178 \n9 Borie R. Wislez M. Antoine M. Lymphoproliferative disorders of the lung Respiration 94 2 2017 157 175 28609772 \n10 Dierickx D. Habermann T.M. Post-transplantation lymphoproliferative disorders in adults N. Engl. J. Med. 378 6 2018 549 562 29414277 \n11 Schooley R.T. Carey R.W. Miller G. Chronic Epstein-Barr virus infection associated with fever and interstitial pneumonitis. Clinical and serologic features and response to antiviral chemotherapy Ann. Intern. Med. 104 5 1986 636 643 3008616 \n12 Kramer M.R. Saldana M.J. Ramos M. High titers of Epstein-Barr virus antibodies in adult patients with lymphocytic interstitial pneumonitis associated with AIDS Respir. Med. 86 1 1992 49 52 1314403 \n13 Collins J. Müller N.L. Leung A.N. Epstein-Barr-virus-associated lymphoproliferative disease of the lung: CT and histologic findings Radiology 208 3 1998 749 759 9722856 \n14 Otsuka E. Miyazaki Y. Moriyama K. Epstain-Barr virus associated Richter's syndrome accompanied by interstitial pneumonia [Rinsho Ketsueki] The Japanese journal of clinical hematology 40 5 1999 402 407 10390889 \n15 Yum H.K. Kim E.S. Ok K.S. Lymphocytic interstitial pneumonitis associated with Epstein-Barr virus in systemic lupus erythematosus and Sjogren's syndrome. Complete remission with corticosteroid and cyclophosphamide Korean J Intern Med 17 3 2002 198 203 12298431 \n16 Marzouk K. Corate L. Saleh S. Epstein-Barr-virus-induced interstitial lung disease Curr. Opin. Pulm. Med. 11 5 2005 456 460 16093822 \n17 Kunitomi A. Arima N. Ishikawa T. Epstein-Barr virus-associated post-transplant lymphoproliferative disorders presented as intertstitial pneumonia; successful recovery with rituximab Haematologica 92 4 2007 e49 52 17562592 \n18 McManus T.E. Coyle P.V. Lawson J. Epstein-barr virus pneumonitis Ulster Med. J. 78 2 2009 137 138 19568452 \n19 Joo E.J. Ha Y.E. Jung D.S. An adult case of chronic active Epstein-Barr virus infection with interstitial pneumonitis Kor. J. Intern. Med. 26 4 2011 466 469 \n20 Rolinski J. Grywalska E. Pyzik A. Interferon alpha as antiviral therapy in chronic active Epstein-Barr virus disease with interstitial pneumonia – case report BMC Infect. Dis. 18 1 2018 190 29678144\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "30()",
"journal": "Respiratory medicine case reports",
"keywords": "EBV-Associated lymphoid interstitial pneumonia; Epstein-barr virus; Inflammatory bowel disease; Pulmonary lymphoproliferative disorder",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101059",
"pmc": null,
"pmid": "32373453",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29678144;16571614;3008616;12475860;27826287;27514593;29998162;28609772;10944566;26600976;9722856;29414277;12298431;10390889;17562592;1314403;16093822;24032382;22205850;19568452",
"title": "EBV-associated lymphoid interstitial pneumonia in IBD patient: Case report and literature review.",
"title_normalized": "ebv associated lymphoid interstitial pneumonia in ibd patient case report and literature review"
} | [
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"abstract": "5-Fluorouracil (5-FU), the mainstay of solid tumor chemotherapy over the past 40 years, induces grade III-IV toxicities in up to 15% of patients with polymorphisms in the dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), and methylenetetrahydrofolate reductase (MTHFR) genes. These toxicities include mucositis, neutropenia, nausea, diarrhea, myelosuppression, hand-foot syndrome, and rare ocular adverse effects. Here, we present the case of a female patient with rectal cancer who received 5-FU-based chemotherapy and developed grade III hand-foot syndrome and rare acute ocular adverse effects. Genetic analysis revealed that the patient had an 85T>C mutation in the DPYD gene resulting in a DPYD*9A allele. The clinical and molecular observations indicate that DPYD deficiency may be responsible for the severe ocular adverse effects observed in 5-FU-treated patients. Application of personalized therapy based on molecular testing should help clinicians provide the most effective chemotherapy agents and dose modifications for each patient, although further population-based pharmacogenetic trials for the 5-FU metabolism-related genes are necessary to minimize adverse effects and enhance clinical outcomes.",
"affiliations": "1Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey; 2Department of Clinical Oncology, Ataturk University, Erzurum, Turkey; and 3Department of Clinical Oncology, Dokuz Eylul University, Izmir; Turkey.",
"authors": "Baskin|Yasemin|Y|;Amirfallah|Arsalan|A|;Unal|Olcun Umit|OU|;Calibasi|Gizem|G|;Oztop|Ilhan|I|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e31829e8516",
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"issn_linking": "1075-2765",
"issue": "22(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000483:Alleles; D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005128:Eye Diseases; D005260:Female; D005472:Fluorouracil; D060831:Hand-Foot Syndrome; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010597:Pharmacogenetics; D012004:Rectal Neoplasms",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e36-9",
"pmc": null,
"pmid": "24434920",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dihydropyrimidine dehydrogenase 85T>C mutation is associated with ocular toxicity of 5-fluorouracil: a case report.",
"title_normalized": "dihydropyrimidine dehydrogenase 85t c mutation is associated with ocular toxicity of 5 fluorouracil a case report"
} | [
{
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{
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"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "A pregnant woman with a non-IgE-mediated penicillin allergy was treated for syphilis with doxycycline with resolution of infection and no evidence of adverse outcome for mother or infant.",
"affiliations": "University of New Mexico Health Sciences Center, Department of Internal Medicine University of New Mexico Health Sciences Center, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine University of Washington, Department of Internal Medicine, Division of Allergy and Infectious Disease.",
"authors": "Tillery|Kory A|KA|;Smiley|Sarah G|SG|;Thomas|Elaine|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/OLQ.0000000000001576",
"fulltext": null,
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"issue": null,
"journal": "Sexually transmitted diseases",
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"nlm_unique_id": "7705941",
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"pages": null,
"pmc": null,
"pmid": "34694273",
"pubdate": "2021-10-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of Syphilis with Doxycycline in a Pregnant Woman Unable to be Desensitized to Penicillin.",
"title_normalized": "treatment of syphilis with doxycycline in a pregnant woman unable to be desensitized to penicillin"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2022US108796",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditional": "4",
... |
{
"abstract": "We have reported a patient who had had renal transplantation for end-stage renal disease; she was treated for fever and presumed sepsis with intravenous tobramycin and vancomycin, with subsequent development of persistent fever, eosinophilia, and a maculopapular rash that progressed to linear bullae. Findings on skin biopsy were consistent with a diagnosis of toxic epidermal necrolysis. Sustained measurable serum concentrations of vancomycin, the temporal response to drug exposure, and the response to steroid therapy suggest vancomycin as the causative agent.",
"affiliations": "Department of Medicine, George Washington University Medical Center, Washington, DC 20037.",
"authors": "Hannah|B A|BA|;Kimmel|P L|PL|;Dosa|S|S|;Turner|M L|ML|",
"chemical_list": "D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1097/00007611-199006000-00035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-4348",
"issue": "83(6)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D000328:Adult; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D013262:Stevens-Johnson Syndrome; D013997:Time Factors; D014640:Vancomycin",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "720-2",
"pmc": null,
"pmid": "2356503",
"pubdate": "1990-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vancomycin-induced toxic epidermal necrolysis.",
"title_normalized": "vancomycin induced toxic epidermal necrolysis"
} | [
{
"companynumb": "US-BAXTER-2020BAX003215",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Low-molecular-weight heparin (LMWH) is a recommended anticoagulant for thromboprophylaxis after major orthopedic surgery. Dabigatran etexilate is an oral anticoagulant recognized as noninferior to LMWH. We aimed to assess the incidence of symptomatic venous thromboembolic events (VTEs) after discharge in patients who underwent joint replacement, using a hospital registry.\nPatients who underwent total knee and hip arthroplasty between September 2011 and March 2015 were selected. Subcutaneous enoxaparin (30 mg twice daily) was given during hospitalization. At discharge, patients received either enoxaparin 30 mg twice daily/40 mg once daily or dabigatran 220 mg/150 mg once daily. Patients were seen or called at 2, 6, and 12 weeks after surgery. Outcomes were the number of VTEs, including deep venous thrombosis, pulmonary embolism, and the number of major/minor bleeding events after discharge.\nAfter discharge, 1468 patients were prescribed enoxaparin and 904 dabigatran (1396 total knee arthroplasty and 976 total hip arthroplasty patients). Mean age was 66±10 years, and 60% were female. The cumulative incidence of VTEs during the 12-week follow-up was 0.7%. One patient sustained a VTE during the switch window. Seven patients sustained a pulmonary embolism (0.3%). There was no statistical difference between the total knee arthroplasty and total hip arthroplasty groups. The incidence of major and minor bleeding events during follow-up was 0.3% and 30.3%, respectively. These events had a higher incidence in the dabigatran group compared to the enoxaparin group after discharge (p<0.05), but not between knee and hip replacement groups for major bleeding events.\nA pharmaceutical prophylaxis protocol using LMWH and dabigatran during the post-discharge period resulted in low incidences of VTE and equivalence between treatments. However, the increased number of major and minor bleeding events in patients taking dabigatran is of concern regarding the safety and needs to be evaluated using analyses adjusted for risk factors.",
"affiliations": "Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada.;Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital Jean-Talon, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.;Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.",
"authors": "Senay|Andréa|A|;Trottier|Milanne|M|;Delisle|Josée|J|;Banica|Andreea|A|;Benoit|Benoit|B|;Laflamme|G Yves|GY|;Malo|Michel|M|;Nguyen|Hai|H|;Ranger|Pierre|P|;Fernandes|Julio C|JC|",
"chemical_list": "D000925:Anticoagulants; D000991:Antithrombins; D017984:Enoxaparin; D000069604:Dabigatran",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/VHRM.S150474",
"fulltext": "\n==== Front\nVasc Health Risk ManagVasc Health Risk ManagVascular Health and Risk ManagementVascular Health and Risk Management1176-63441178-2048Dove Medical Press 10.2147/VHRM.S150474vhrm-14-081Original ResearchIncidence of symptomatic venous thromboembolism in 2372 knee and hip replacement patients after discharge: data from a thromboprophylaxis registry in Montreal, Canada Senay Andréa 12Trottier Milanne 3Delisle Josée 24Banica Andreea 24Benoit Benoit 24Laflamme G Yves 24Malo Michel 24Nguyen Hai 4Ranger Pierre 24Fernandes Julio C 234\n1 Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada\n2 Department of Orthopaedic Surgery, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada\n3 Faculty of Medicine, Université de Montréal, Montréal, QC, Canada\n4 Department of Orthopaedic Surgery, Hôpital Jean-Talon, Montréal, QC, CanadaCorrespondence: Julio C Fernandes, Research Center, Office K3045, Hôpital du Sacré-Coeur de Montréal, 5400 bl. Gouin ouest, Montreal, H4J 1C5 QC, Canada, Tel +1 514 338 2222; ext 2050, Fax +1 514 338 3490, Email julio.c.fernandes@umontreal.ca2018 08 5 2018 14 81 89 © 2018 Senay et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nLow-molecular-weight heparin (LMWH) is a recommended anticoagulant for thromboprophylaxis after major orthopedic surgery. Dabigatran etexilate is an oral anticoagulant recognized as noninferior to LMWH. We aimed to assess the incidence of symptomatic venous thromboembolic events (VTEs) after discharge in patients who underwent joint replacement, using a hospital registry.\n\nPatients and methods\nPatients who underwent total knee and hip arthroplasty between September 2011 and March 2015 were selected. Subcutaneous enoxaparin (30 mg twice daily) was given during hospitalization. At discharge, patients received either enoxaparin 30 mg twice daily/40 mg once daily or dabigatran 220 mg/150 mg once daily. Patients were seen or called at 2, 6, and 12 weeks after surgery. Outcomes were the number of VTEs, including deep venous thrombosis, pulmonary embolism, and the number of major/minor bleeding events after discharge.\n\nResults\nAfter discharge, 1468 patients were prescribed enoxaparin and 904 dabigatran (1396 total knee arthroplasty and 976 total hip arthroplasty patients). Mean age was 66±10 years, and 60% were female. The cumulative incidence of VTEs during the 12-week follow-up was 0.7%. One patient sustained a VTE during the switch window. Seven patients sustained a pulmonary embolism (0.3%). There was no statistical difference between the total knee arthroplasty and total hip arthroplasty groups. The incidence of major and minor bleeding events during follow-up was 0.3% and 30.3%, respectively. These events had a higher incidence in the dabigatran group compared to the enoxaparin group after discharge (p<0.05), but not between knee and hip replacement groups for major bleeding events.\n\nConclusion\nA pharmaceutical prophylaxis protocol using LMWH and dabigatran during the post-discharge period resulted in low incidences of VTE and equivalence between treatments. However, the increased number of major and minor bleeding events in patients taking dabigatran is of concern regarding the safety and needs to be evaluated using analyses adjusted for risk factors.\n\nKeywords\narthroplastyprophylaxisenoxaparindabigatranvenous thromboembolismpulmonary embolism\n==== Body\nIntroduction\nVenous thromboembolic events (VTEs), a major health issue associated with significant mortality and morbidity, are a common complication following orthopedic surgeries, especially in total hip arthroplasty (THA) or total knee arthroplasty (TKA).1,2 A supplemental study of the ninth American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy and prevention of thrombosis derived estimates of nonfatal symptomatic VTE rates using contemporary populations under prophylaxis from several randomized clinical trials (RCTs). They estimated a baseline risk of symptomatic VTEs, without prophylaxis after major orthopedic surgery, at 4.3% (0–35 days after surgery).3 It is currently impossible to predict which patients will develop symptomatic VTE following major orthopedic surgery, hence the necessity for routine thromboprophylaxis.1 The efficacy of pharmacologic prophylaxis in reducing the risk of VTEs after THA and TKA is well proven and has been standardized for over 20 years.1,4\n\nThe 2012 ACCP guidelines on antithrombotic therapy and prevention of thrombosis advocate a minimum of 10–14 days of thromboprophylaxis after both THA and TKA.5 Given that many studies have demonstrated the importance of prolonged prophylaxis following major orthopedic surgery,3,6–8 the ACCP recommends extended prophylaxis for up to 35 days in patients undergoing THA. This also applies to patients undergoing TKA, but with a lower level of evidence. The standard recommended anticoagulant agent for thromboprophylaxis after THA or TKA, according to the ACCP and the American Academy of Orthopedic Surgeons guidelines, is low-molecular-weight heparin (LMWH).5,9,10 It has been shown to consistently reduce asymptomatic deep vein thrombosis (DVT) by 50%3 and to be more effective than low-dose unfractionated heparin, aspirin, and vitamin K antagonists in preventing VTEs, for both types of surgery.1,3,11–13 However, LMWH requires parenteral administration, which can be problematic for long-term thromboprophylaxis in the outpatient setting,14 negatively affecting patient compliance,15 while also requiring home visits by health professionals for up to 20% of patients, unable to perform self-injections.16\n\nDirect oral anticoagulants have been developed to facilitate prophylaxis and the treatment of VTEs.17 Among these, dabigatran etexilate, an oral direct thrombin inhibitor, has been approved in 75 countries, including Canada, but not the USA, for prophylactic use in high-risk orthopedic surgical patients.18 Data from large and well-designed RCTs found it to be at least noninferior to enoxaparin, the LMWH comparator, in preventing VTEs.7,19,20\n\nThere are ~1000 hip and knee arthroplasty procedures performed every year in our institution (Hôpital Jean-Talon, Montréal, QC, Canada). With the purpose of optimizing VTE prevention after orthopedic surgery and improving the quality of care, we aimed to evaluate the effectiveness and safety of post-discharge thromboprophylaxis up to 12 weeks after surgery as well as the treatment switch from subcutaneous enoxaparin to oral dabigatran at discharge.\n\nPatients and methods\nStudy design\nUsing hospital registry data on thromboprophylaxis, we conducted a retrospective observational study of patients who underwent THA or TKA. The registry was implemented at Hôpital Jean-Talon from September 2011 to March 2015. The registry was authorized by the director of professional services of Hôpital Jean-Talon, and the study protocol was approved by the ethics committee of the Centre Intégré Universitaire de Santé et de Services Sociaux Nord-de-l’Île-de-Montréal. Informed consent was waived because data collection was within an implemented best clinical practice thromboprophylaxis protocol and data were gathered in a registry.\n\nPatients were initially met at the preoperative clinic where thromboprophylaxis regimens, either enoxaparin or dabigatran etexilate, were explained and they were free to choose one or the other before discharge. However, given that dabigatran is not covered by local public insurance, only patients with private insurance, or those willing to pay, took the oral treatment. In Quebec, Canada, provincial public health insurance (Régie de l’assurance maladie du Québec) covers the drug expenses for every citizen not covered by private insurance.\n\nPatients\nAll patients 18 years or older undergoing THA or TKA were included in our thromboprophylaxis registry, with no exclusion criteria, in order to maximize recruitment. For the purpose of this study, only those patients who were prescribed subcutaneous enoxaparin or oral dabigatran etexilate after discharge were selected. Thus, patients following other therapies (warfarin, rivaroxaban, apixaban) after hospital discharge were not considered for analysis. As per the protocol, patients who sustain a VTE during hospitalization are prescribed therapeutic warfarin and were, therefore, excluded from the study.\n\nTreatment regimens/procedure\nAfter surgery, every patient was given 30 mg subcutaneous enoxaparin twice daily, starting 12 hours postoperatively. At the time of discharge, patients either continued subcutaneous enoxaparin 30 mg twice daily or 40 mg once daily, or received a prescription of prophylactic oral dabigatran etexilate 220 mg once daily or 150 mg once daily if creatinine clearance was between 30 and 50 mL/hour, as per product description.21,22 On the morning of discharge, all patients received a final dose of subcutaneous enoxaparin at the hospital. The next anticoagulant dose, whether enoxaparin or dabigatran, was given 12 hours later to ensure continued appropriate thromboprophylaxis. Patients followed the treatment for a total of 14–35 days depending on the prescribing orthopedic surgeon.\n\nPatients were followed over a 3-month period after the date of surgery. They were seen or contacted by phone at 2, 6, and 12 weeks after surgery. Collected data included age, gender, joint replaced, type of prophylaxis treatment, treatment length, patient-reported complications, VTE, and VTE history. Medical files of patients reporting a VTE were consulted to validate the event. Patients that switched from enoxaparin to dabigatran were asked specifically about the time window (2-3 days following discharge) to report the surge in VTE incidence.\n\nOutcome measures\nOne of the primary outcomes was the rate of symptomatic DVT and pulmonary embolism (PE) up to 12 weeks after surgery during the post-discharge period. The other primary outcome was the rate of VTE during the switch period for patients taking dabigatran. Clinically relevant VTEs included symptomatic proximal and distal DVT and symptomatic PE. Subsegmental PE was not excluded. Patients presenting clinical signs of DVT (swelling, pain, and/or rigidity of the limb) and/or PE (desaturation, dyspnea, tachycardia, hypo- or hypertension) were investigated with duplex Doppler ultrasound imaging and ventilation–perfusion scan/computed tomography angiography, respectively. If diagnosed, they were referred to Department of Internal Medicine for treatment.\n\nThe secondary outcomes were the incidence of major and minor bleeding events registered for patients after discharge during the follow-up period. Major and minor bleeding were defined according to accepted guidelines.23 Major bleeding referred to the following: fatal bleeding; clinically overt bleeding in excess, associated with ≥2 g/mL fall in hemoglobin and/or leading to transfusion of ≥2 units of packed cells or whole blood; symptomatic retroperitoneal, intracranial, intraocular, or intraspinal bleeding; and bleeding requiring treatment cessation and/or operation/hospitalization. Minor bleeding events excluded the events meeting the definition of major bleeding and included wound bleeding or discharge, spontaneous skin hematomas, spontaneous nose bleeding, spontaneous macroscopic hematuria, or blood in stools.\n\nStatistical analysis\nDemographic and clinical data were compared between TKA and THA patients as well as between patients taking enoxaparin and patients taking dabigatran after discharge using Pearson’s chi-squared/Fisher’s exact tests and independent samples Student’s t-test for categorical and continuous variables, respectively.\n\nThe total cumulative incidence of VTE, major bleeding events, and minor bleeding events after discharge were reported according to thromboprophylaxis and the joint replaced. Differences between groups were measured using absolute risk differences (ARD) with 95% CIs and Pearson’s chi-squared/Fisher’s exact tests. Statistical significance was declared when p≤0.05. All statistical analyses were completed using SPSS statistics software, version 23.0 (IBM Corporation, Armonyk, NY, USA, 2015).\n\nResults\nPatients\nBetween 2011 and 2015, 2921 patients underwent TKA or THA in our institution, with data on 2516 (86.1%) patients gathered in the registry. All 2516 received a regimen of enoxaparin thromboprophylaxis during inpatient stay. After discharge, 58.3% (n=1468) were prescribed subcutaneous enoxaparin, 35.9% (n=904) were prescribed oral dabigatran etexilate, and 5.7% (n=144) of patients were prescribed other treatments (warfarin, rivaroxaban, apixaban). After discharge, 1402 (95.5%) patients receiving enoxaparin and 870 (96.2%) receiving dabigatran were retained throughout the entire follow-up period (Figure 1). During inpatient stay, 35 VTEs (30 proximal DVT, 5 distal DVT, 23 DVT that evolved to a PE) were reported. These patients were prescribed therapeutic warfarin dosage. There was a higher number of VTEs in TKA (n=31) patients than in THA patients (n=4; p<0.01).\n\nBaseline characteristics\nTable 1 shows the characteristics of the entire cohort and those specific to the joint replaced. Overall, the mean age was 66 years and 60% of patients were female. Almost 90% of procedures were unilateral. A twice-daily dose of 30 or 40 mg once daily (mostly for THA) was equally prescribed among patients treated with enoxaparin, whereas most patients (83%) prescribed with dabigatran had a 220 mg dose once daily. TKA patients were older, with more female patients than THA patients, and there were more bilateral knee replacements than bilateral hip replacements. The number of postoperative transfusions was higher in TKA patients than in THA patients, with a total of 6% of all patients needing a transfusion. Overall, 26 deep infections (1.1%) necessitating debridement and washout were reported over 12 weeks, mostly in TKA patients (20/26 [76.9%]).\n\nPatient characteristics, according to thromboprophylaxis, are presented in Table 2. Patients prescribed enoxaparin after discharge were older, and ~60% of patients on either treatment regimen underwent a knee replacement. In both treatment expositions, the proportion of patients prescribed thromboprophylaxis for 35 days averaged 80%, the rest of treatment lengths neighboring 14 days. Almost 6% of patients reported previous DVT history and <1% reported previous PE history in both groups. The number of transfusions did not differ between treatments, but the number of deep infections was significantly higher in patients taking dabigatran (16/26). Regarding treatment lengths, there was no statistically significant differences in age, gender, whether the patient had a TKA or a THA and whether the patient was prescribed enoxaparin or dabigatran after discharge. There was a higher number of total symptomatic VTEs in patients treated for 35 days (n=7) than in those treated for 14 days (n=5, p=0.002), but no significant differences for subtypes of VTEs and major/minor bleeding events.\n\nPrimary outcomes\nDuring the 12 weeks post-discharge follow-up, the total incidence of symptomatic VTE was 0.7% (Table 3). These results were distributed as follows: 12 VTE (4 PE) at 2 weeks (0.53%), 3 VTE (2 PE) at 6 weeks (0.13%), and 1 VTE (1 PE) at 12 weeks (0.04%), with no statistical difference between patients taking enoxaparin and dabigatran.\n\nOne patient taking dabigatran sustained a VTE during the switch window (1 day after discharge, after 4 days of inpatient stay). This patient was a 72-year-old female who had undergone a TKA, with no history of VTE.\n\nMean time from surgery to post-discharge symptomatic VTE was 20.4 days, ranging from 5 to 84 days, with a mean time of 27.7 days for the dabigatran group and 14.7 days for the enoxaparin group. Mean time from surgery to post-discharge symptomatic VTE was 17.7 days for the TKA group and 23.9 days for the THA group. Mean time from surgery to post-discharge PE was 29.7 days, ranging from 9 to 84 days, with a mean time of 42.3 days for the dabigatran group and 20.3 days for the enoxaparin group. Mean time from surgery to post-discharge symptomatic PE was 36.7 days for the TKA group and 24.5 days for the THA group. No patient died. A PE was reported 110 days after surgery during a retrospective telephone follow-up for a patient who was not reached at 12 weeks (an 81-year-old woman anticoagulated for 35 days with dabigatran after discharge). This patient was not included in the 12-week follow-up analysis.\n\nTable 4 shows the primary and secondary outcomes for TKA and THA patients. There was no significant difference between knee and hip replacements in VTE incidence after hospital discharge.\n\nSecondary outcomes\nMajor bleeding\nDuring the follow-up period, the total incidence of major bleeding events was 0.3% (Table 3). There was a statistically significant increase in the number of major bleeding events in the dabigatran group (5 patients), compared to the enoxaparin group (1 patient). Among those taking dabigatran after discharge who suffered major bleeding, 2 were hospitalized 10 and 16 days after the arthroplasty for a hematoma related to dabigatran use. One of the patients that received dabigatran after discharge was hospitalized 10 days after joint replacement surgery for important vomiting and diarrhea with melena (dark black feces). Dabigatran was ceased during this second inpatient stay. Another one was hospitalized for digestive hemorrhage secondary to dabigatran use (16 days postoperatively), and the last one had to cease taking dabigatran because of significant wound bleeding 14 days after surgery (outpatient clinic). In the enoxaparin group, the only major bleeding event was that of a patient seen at the outpatient clinic 14 days after surgery with significant wound bleeding, where enoxaparin was ceased. There was no significant difference in the number of major bleeding events between TKA and THA patients (Table 4).\n\nMinor bleeding\nDuring the follow-up period, the total incidence of minor bleeding events was 30.3% (Table 3). The incidence of minor bleeding events was statistically significantly higher in patients taking dabigatran etexilate (33.1%) than in patients taking enoxaparin (28.5%). According to the ARD, for every 100 patients treated with dabigatran, 5 patients sustained a minor bleeding event compared to patients treated with enoxaparin. This association was more specific to hematuria and blood in stools. The most common minor bleeding events were hematomas and wound bleeding which generally occurred at 2 weeks after surgery (27%). The incidence of minor bleeding events was higher in patients with knee replacements than in patients with hip replacements, specifically for hematomas and wound bleeding (Table 4).\n\nDiscussion\nThese results show that thromboprophylaxis after joint arthroplasty, using subcutaneous enoxaparin or oral dabigatran etexilate, limited symptomatic VTE incidence after discharge to 0.7%. One DVT was reported during the switch window from enoxaparin to dabigatran after discharge. The overall incidence of major bleeding events post-discharge was of 0.3% and was higher in patients taking dabigatran, although the total number of events remained low. There was also a higher number of minor bleeding events in patients taking dabigatran compared to patients taking enoxaparin after discharge.\n\nDuring hospitalization, the VTE incidence rates of 2.2% after TKA and 0.4% after THA were similar to data reported in RCTs and observational studies (patients taking enoxaparin). There were also 8 (0.3%) potential critical bleeding events reported during inpatient stay. A meta-analysis of 47 studies performed by Januel et al reported that the pooled incidence rates of VTE for patients treated with LMWH were 1.4% (95% CI: 1.0%–1.8%) in TKA studies and 0.6% (95% CI: 0.4%–0.8%) in THA studies.24 VTE incidence after TKA was slightly higher in our registry, which could be explained by the inclusion of subsegmental PE in the efficacy outcome. Their meta-analysis also noted that the incidence rates of VTE in patients undergoing TKA are significantly heterogeneous.\n\nRegarding the primary effectiveness and safety outcomes, our study shows that there was no statistically significant difference between treatment groups in VTE incidence during the follow-up period. Our findings were consistent with those observed in 3 prospective Phase III RCTs comparing the efficacy and safety of dabigatran to enoxaparin in THA patients (RE-NOVATE) and TKA patients (RE-MOBILIZE and RE-MODEL).7,19,20 Pooled analysis of the 3 trials by Friedman et al demonstrated that dabigatran (220 or 150 mg) was equivalent to enoxaparin in decreasing the risk of major VTE and VTE-related mortality, as well as in terms of safety, given that each treatment had a similar bleeding profile.25\n\nThe switch period between enoxaparin and dabigatran could have led to 1 DVT event among the 904 patients in our study (0.1%). Ozler et al also compared switch-therapy modalities from enoxaparin to rivaroxaban or dabigatran, to an enoxaparin monotherapy for thromboprophylaxis, after THA and TKA, and found no DVT.26 Two other studies evaluated the outcomes of a VTE protocol when switching from LMWH to dabigatran, which showed promising results.27,28 However, all these studies had insufficient number of patients to extrapolate their findings to the general population, as opposed to this study, given the size of our patient sample.\n\nThe main reason for comparing a treatment switch instead of a dabigatran monotherapy to an enoxaparin monotherapy was that dabigatran was not included in the hospital thromboprophylaxis algorithm. Thus, patients who wanted to take the oral treatment were only able to do so after discharge. The choice of dabigatran over rivaroxaban was motivated by the higher incidence of bleeding complications and wound infections associated with the latter4 and the convenience of dabigatran over LMWH for the patient in an outpatient setting. However, the increase in major and minor bleeding events (hematuria/blood in stools), which could possibly influence the infection rate, has to be investigated and considered before further use of this oral anticoagulant for thromboprophylaxis after THA and TKA.\n\nThe total incidence of major bleeding events after discharge was 0.3% and was significantly higher in patients taking dabigatran than in patients taking enoxaparin (the risk of major bleeding event was 0.5% higher when dabigatran was received rather than enoxaparin). Pedersen et al found a 0.6% risk of readmission for major bleeding 3 months postoperatively in a cohort of >83,000 patients undergoing knee or hip replacements, where most patients used heparin as thromboprophylaxis. Their definition of major bleeding included intracranial bleeding, gastrointestinal bleeding, and urinary or pulmonary bleeding.29 RCTs comparing the therapies of interest did not report a difference in major bleeding event rates.25 A recent Cochrane review also reported a nonsignificant difference between the use of direct oral anticoagulants and heparin (odds ratio =1.11, 95% CI: 0.79–1.54).30 Consistent with the results of the previously mentioned studies, we did not find a difference in incidence of major bleeding events between TKA and THA patients. Therefore, our findings could be attributed to the study period chosen, the 3 months following surgery excluding inpatient stay, regardless of the length of treatment. In other studies, only the postoperative period was considered. Of our 2372 studied patients, 8 reported a major bleeding event during inpatient stay (n=2 were prescribed dabigatran after discharge, n=6 continued enoxaparin after discharge). If we add these results with those of the follow-up, we obtain the following ARD: −0.30 for 100 patients (95% CI: −0.97 to 0.36), similar to those of other studies. Nevertheless, the reported increase of major bleeding events during follow-up could indicate a risk when using dabigatran for extended prophylaxis.\n\nMinor bleeding post-discharge, although defined according to the same guidelines or as not fulfilling the criteria for major or clinically significant bleeding events,17,31,32 had a high incidence in this study (33.1% for dabigatran and 28.5% for enoxaparin) compared to that observed in other studies and in RCTs. This can be attributed to the high incidence of hematomas (22.9%) reported by patients, independently of their size and location. Indeed, except for the 2- and 6-week assessments when a majority of patients were met at the outpatient clinic or health community service center for a follow-up, most of the assessments were done over the phone. Despite nurses describing as thoroughly as possible injuries and symptoms, there was a high risk for patients to confuse a hematoma and an ecchymosis. Thus, this patient-reported outcome could be biased and overestimated. Our results show that dabigatran was associated with a significant increase in minor bleeding events, especially at 2 weeks after the surgery, where hematuria or blood in stools subtype of event was statistically significant for this group. Bloch et al found that the use of dabigatran led to an increase in wound leakage after total joint replacement, which resulted in a longer hospital stay.33 In another study comparing minor bleeding events when using either dabigatran or enoxaparin, a significant increase in serous discharge was found in the dabigatran group. Thus, delayed administration of dabigatran may prevent some wound leakage, but can still increase the risk of minor bleeding events compared to LMWH therapy.17\n\nThe main strength of this study was the minimal loss to follow-up, difficult to achieve given the size of our patient sample, which reduced the risk of selection bias. Nonetheless, there are several limitations to consider. As the risk for major bleeding events and VTEs is higher during the early postoperative period,3 and patients with VTE events during hospitalization were excluded, it should be noted that the risk for VTEs or major bleeding events over 3 months of follow-up is probably lower for this sample, which can impact external validity by underestimating risk. Generalizability is also compromised by the fact that most patients on dabigatran had private insurance. Furthermore, the treatment period was not clearly defined within the follow-up period. Thus, there was no distinction between VTEs and bleeding events that occurred during or after the treatment period. It would also have been relevant to check compliance between the treatment groups, given that oral anticoagulants are associated with better compliance. Although symptomatic VTE and PE were all included in the registry, it is possible that asymptomatic minor VTEs were not detected, leading to an underestimation of risk. Using patient-reported outcomes implies a possibility for information bias. Finally, this is a registry-based observational study limited by the possibility of confounding variables because of a lack of randomization.\n\nConclusion\nWe found a low incidence of VTE and major bleeding events after using either subcutaneous enoxaparin or oral dabigatran etexilate after inpatient stay for joint replacement. However, dabigatran was associated with a significant increase in major and minor bleeding events. Switching treatment from LMWH to oral anticoagulants is a safe way to achieve appropriate thromboprophylaxis after joint replacement surgery discharge.\n\nAcknowledgments\nThe authors would like to thank Ms. Kathleen Beaumont for her help with language format.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Flow diagram of the registry.\n\nNotes:\naEnoxaparin dose during hospitalization: 30 mg BID. bOther therapies prescribed at discharge included warfarin, rivaroxaban, or apixaban. cDabigatran dose, options after discharge: 220, 150 mg DIE. dEnoxaparin dose, options after discharge: 30 mg BID, 40 mg DIE. ePatients were either contacted by phone or seen at the outpatient orthopedic clinic.\n\nAbbreviations: BID, twice daily; DIE, once daily.\n\nTable 1 Patient characteristics specific to the joint replaced\n\nCharacteristics\tTotal (N=2372)\tTKA (n=1396)\tTHA (n=976)\t\nAge (years), mean (±SD)\t65.9 (10.4)\t66.5 (9.7)\t65.2 (11.3)*\t\nFemale, n (%)\t1431 (60.3)\t877 (62.8)\t554 (56.8)*\t\nUnilateral, n (%)\t2123 (89.5)\t1188 (85.1)\t935 (95.8)\t\nBilateral, n (%)\t249 (10.5)\t208 (14.9)\t41 (4.2)*\t\nEnoxaparin dosagea\t\t\t614\t\n 30 mg BID\t723 (49.3)\t416 (48.7)\t307 (50.0)\t\n 40 mg DIE\t651 (44.3)\t374 (43.8)\t277 (45.1)\t\nDabigatran dosageb\t\t\t\t\n 220 mg DIE\t751 (83.1)\t447 (82.5)\t304 (84.0)\t\n 150 mg DIE\t107 (11.8)\t63 (11.6)\t44 (12.1)\t\nOther dosage/missing data\t140 (5.9)\t96 (6.9)\t44 (4.5)\t\nPatients with PO transfusion(s), n (%)\t140 (5.9)\t95 (6.8)\t45 (4.6)*\t\nInfectionsc, n (%)\t26 (1.1)\t20 (1.4)\t6 (0.6)\t\nNotes:\n\na Denominator is 1468 for the total cohort, 854 for TKA, and 614 for THA.\n\nb Denominator is 904 for the total cohort, 542 for TKA, and 362 for THA.\n\nc Deep infections that required debridement and washout.\n\n* p-value <0.05 using Pearson’s chi-squared test or Fisher’s exact test, except for age (independent samples Students t-test).\n\nAbbreviations: BID, twice daily; DIE, once daily; PO, postoperative; THA, total hip arthroplasty; TKA, total knee arthroplasty.\n\nTable 2 Patient characteristics according to thromboprophylaxis after discharge\n\nCharacteristics\tDabigatran (n=904)\tEnoxaparin (n=1468)\tp-valuea\t\nAge (years), mean (±SD)\t64.1 (10.6)\t67.1 (10.1)\t<0.001\t\nFemale, n (%)\t534 (59.1)\t897 (61.1)\t0.326\t\nJoint replaced, n (%)\t\t\t\t\n Knee\t542 (60.0)\t854 (58.2)\t0.392\t\n Hip\t362 (40.0)\t614 (41.8)\t\t\nTreatment length (days), n (%)\t\t\t\t\n <14\t6 (0.7)\t9 (0.6)\t0.237\t\n 14\t109 (12.1)\t156 (10.6)\t\t\n 15–34\t10 (1.1)\t18 (1.2)\t\t\n 35\t736 (81.4)\t1218 (83.0)\t\t\n >35\t16 (1.8)\t12 (0.8)\t\t\n Missing data\t27 (3.0)\t55 (3.7)\t\t\nDVT history, n (%)b\t53 (5.9)\t95 (6.5)\t0.552\t\nPE history, n (%)\t4 (0.4)\t13 (0.9)\t0.214\t\nPatients with PO transfusion(s), n (%)\t62 (6.9)\t78 (5.3)\t0.121\t\nInfections,c n (%)\t16 (1.8)\t10 (0.7)\t0.013\t\nNotes:\n\na Pearson’s chi-squared test or Fisher’s exact test, except for age (independent samples Student’s t-test).\n\nb Ten patients with history of both DVT and PE.\n\nc Deep infections that required debridement and washout.\n\nAbbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; PO, postoperative.\n\nTable 3 Thromboprophylaxis efficacy and safety outcomes for patients prescribed dabigatran or enoxaparin after joint replacement and discharge\n\nOutcomes\tTotal, n(%) (N=2372)\tDabigatran, n(%) (n=904)\tEnoxaparin, n(%) (n=1468)\tAbsolute risk differencea (per 100 patients, 95% confidence intervals)\tp-valueb\t\nEfficacy outcomes\t\t\t\t\t\t\nAfter discharge\t\t\t\t\t\t\n Total symptomatic VTE\t16 (0.7)\t7 (0.8)\t9 (0.6)\t−0.16 (−0.87; 0.54)\t0.641\t\n Proximal DVT\t13 (0.6)\t6 (0.7)\t7 (0.5)\t−0.19 (−0.83; 0.45)\t0.559\t\n Distal DVT\t3 (0.1)\t1 (0.1)\t2 (0.1)\t*\t0.672\t\n Symptomatic PE\t7 (0.3)\t3 (0.3)\t4 (0.3)\t*\t0.543\t\nSafety outcomes\t\t\t\t\t\t\nAfter discharge\t\t\t\t\t\t\n Major bleeding events\t6 (0.3)\t5 (0.6)\t1 (0.1)\t−0.50 (−0.94; −0.07)\t0.033**\t\n Minor bleeding events\t688 (30.3)\t288 (33.1)\t400 (28.5)\t−4.57 (−8.46; −0.69)\t0.021**\t\n Hematomas\t521 (22.9)\t217 (24.9)\t304 (21.7)\t−3.26 (−6.81; 0.30)\t0.072\t\n Wound bleeding/discharge\t118 (5.2)\t53 (6.1)\t65 (4.6)\t−1.46 (−3.33; 0.42)\t0.129\t\n Nose bleeding\t69 (3.0)\t23 (2.6)\t46 (3.3)\t0.64 (−0.81; 2.09)\t0.389\t\n Hematuria or blood in stool\t62 (2.7)\t36 (4.1)\t26 (1.9)\t−2.28 (−3.66; −0.90)\t0.001**\t\nNotes: Denominators are the numbers at the last follow-up (12 months): 870 for dabigatran and 1402 for enoxaparin.\n\na Difference in VTE risk for patients prescribed dabigatran compared to patients prescribed enoxaparin after total joint replacement. A negative value means an increased risk for patients prescribed dabigatran compared to patients prescribed enoxaparin.\n\nb Pearson’s chi-squared test or Fisher’s exact test.\n\n* Numbers too small to obtain significant results.\n\n** Statistically significant with p-value of <0.05.\n\nAbbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolic event.\n\nTable 4 Thromboprophylaxis efficacy and safety outcomes after joint replacement and discharge between knee and hip replacements\n\nOutcomes\tTotal, n (%) N=2372\tTKA, n (%) N=1396\tTHA, n (%) N=976\tAbsolute risk differencea (per 100 patients, 95% CI)\tp-valueb\t\nEfficacy outcomes\t\t\t\t\t\t\nAfter discharge\t\t\t\t\t\t\n Total symptomatic VTE\t16 (0.7)\t9 (0.7)\t7 (0.7)\t0.06 (−0.65; 0.77)\t0.832\t\n Proximal DVT\t13 (0.6)\t7 (0.5)\t6 (0.6)\t0.10 (−0.53; 0.74)\t0.745\t\n Distal DVT\t3 (0.1)\t2 (0.1)\t1 (0.1)\t*\t1.000\t\n Symptomatic PE\t7 (0.3)\t3 (0.2)\t4 (0.4)\t*\t0.460\t\nSafety outcomes\t\t\t\t\t\t\nAfter discharge\t\t\t\t\t\t\n Major bleeding events\t6 (0.3)\t3 (0.2)\t3 (0.3)\t0.09 (−0.34; 0.52)\t0.699\t\n Minor bleeding events\t688 (30.3)\t437 (33.0)\t251 (26.5)\t−6.53 (−10.36; −2.70)\t0.001**\t\n Hematomas\t521 (22.9)\t323 (24.4)\t198 (20.9)\t−3.51 (−7.01; 0.00)\t0.050\t\n Wound bleeding/discharge\t118 (5.2)\t89 (6.7)\t29 (3.1)\t−3.66 (−5.51; −1.81)\t<0.001**\t\n Nose bleeding\t69 (3.0)\t43 (3.2)\t26 (2.7)\t−0.50 (−1.94; 0.93)\t0.489\t\n Hematuria or blood in stool\t62 (2.7)\t35 (2.6)\t27 (2.7)\t0.20 (−1.15; 1.56)\t0.768\t\nNotes: Denominators are the numbers at the last follow-up (12 months): 1324 for TKA and 948 for THA.\n\na Difference in VTE risk for patients with TKA compared to patients with THA. A negative value means an increased risk for TKA patients compared to THA patients.\n\nb Pearson’s Chi-squared test or Fischer’s exact test.\n\n* Numbers too small to obtain significant results.\n\n** Statistically significant with p-value of <0.05.\n\nAbbreviations: CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolic event.\n==== Refs\nReferences\n1 Geerts WH Bergqvist D Pineo GF Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008 133 6 Suppl 381s 453s 18574271 \n2 Markovic-Denic L Zivkovic K Lesic A Bumbasirevic V Dubljanin-Raspopovic E Bumbasirevic M Risk factors and distribution of symptomatic venous thromboembolism in total hip and knee replacements: prospective study In Orthop 2012 36 6 1299 1305 \n3 Falck-Ytter Y Francis CW Johanson NA Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012 141 2 Suppl e278S 325S 22315265 \n4 Jameson SS Bottle A Malviya A Muller SD Reed MR The impact of national guidelines for the prophylaxis of venous thromboembolism on the complications of arthroplasty of the lower limb J Bone Joint Surg Br 2010 92 1 123 129 20044690 \n5 Guyatt GH Akl EA Crowther M Gutterman DD Schuunemann HJ Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012 141 2 Suppl 7s 47s 22315257 \n6 Dahl OE Gudmundsen TE Pripp AH Aanesen JJ Clinical venous thromboembolism following joint surgery: effect of extended thromboprophylaxis on its annual frequency and postoperative pattern over 22 years Clin Appl Thromb Hemost 2014 20 2 117 123 24113492 \n7 Eriksson BI Dahl OE Rosencher N Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial J Thromb Haemost 2007 5 11 2178 2185 17764540 \n8 Warwick D Friedman RJ Agnelli G Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry J Bone Joint Surg Br 2007 89 6 799 807 17613508 \n9 Warwick D Prevention of venous thromboembolism in total knee and hip replacement Circulation 2012 125 17 2151 2155 22547755 \n10 Lieberman JR Heckmann N Venous thromboembolism prophylaxis in total hip arthroplasty and total knee arthroplasty patients: from guidelines to practice J Am Acad Orthop Surg 2017 25 12 789 798 29176502 \n11 Guyatt G Walter S Norman G Measuring change over time: assessing the usefulness of evaluative instruments J Chronic Dis 1987 40 2 171 178 3818871 \n12 Hull RD Pineo GF Francis C Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs. in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators Arch Intern Med 2000 160 14 2208 2215 10904465 \n13 Muntz J Thromboprophylaxis in orthopedic surgery: how long is long enough? Am J Orthop (Belle Mead, NJ) 2009 38 8 394 401 19809604 \n14 Friedman RJ Gallus A Gil-Garay E FitzGerald G Cushner F Practice patterns in the use of venous thromboembolism prophylaxis after total joint arthroplasty–insights from the Multinational Global Orthopaedic Registry (GLORY) Am J Orthop (Belle Mead, NJ) 2010 39 9 Suppl 14 21 21290027 \n15 Wilke T Patient preferences for an oral anticoagulant after major orthopedic surgery: results of a german survey Patient 2009 2 1 39 49 22273058 \n16 Fisher WD Impact of venous thromboembolism on clinical management and therapy after hip and knee arthroplasty Can J Surg 2011 54 5 344 351 21774881 \n17 Gombar C Horvath G Gality H Sisak K Toth K Comparison of minor bleeding complications using dabigatran or enoxaparin after cemented total hip arthroplasty Arch Orthop Trauma Surg 2014 134 4 449 457 24488447 \n18 Fanola CL Current and emerging strategies in the management of venous thromboembolism: benefit-risk assessment of dabigatran Vasc Health Risk Manag 2015 11 271 282 26064057 \n19 Eriksson BI Dahl OE Huo MH Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial Thromb Haemost 2011 105 4 721 729 21225098 \n20 Ginsberg JS Davidson BL Comp PC Oral thrombin inhibitor dabigatran etexilate vs. North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery J Arthroplasty 2009 24 1 1 9 \n21 Boehringer Ingelheim Canada Ltd Pradaxa product monograph. Dabigatran etexilate capsules 2016 Available from: https://www.boehringer-ingelheim.ca/sites/ca/files/documents/pradaxapmen.pdf Accessed June 15, 2017 \n22 Sanofi-aventis Canada Inc Lovenox product monograph. Enoxaparin sodium solution for injection 2013 Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.592.7577&rep=rep1&type=pdf Accessed June 15, 2017 \n23 The European Agency for the Evaluation of Medicinal Products Guideline on clinical investigation of medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk 2007 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143764.pdf Accessed June 15, 2017 \n24 Januel JM Chen G Ruffieux C Symptomatic in-hospital deep vein thrombosis and pulmonary embolism following hip and knee arthroplasty among patients receiving recommended prophylaxis: a systematic review JAMA 2012 307 3 294 303 22253396 \n25 Friedman RJ Dahl OE Rosencher N Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials Thromb Res 2010 126 3 175 182 20434759 \n26 Ozler T Ulucay C Onal A Altintas F Comparison of switch-therapy modalities (enoxaparin to rivaroxaban/dabigatran) and enoxaparin monotherapy after hip and knee replacement Acta Orthop Traumat Turc 2015 49 3 255 259 \n27 Subramanian P Kantharuban S Shilston S Pearce OJ A 12 month review of a modified protocol using low dose Dabigatran Etexilate in postoperative thromboembolic prophylaxis in joint replacement surgery Thromb J 2012 10 1 14 22916689 \n28 Wurnig C Clemens A Rauscher H Safety and efficacy of switching from low molecular weight heparin to dabigatran in patients undergoing elective total hip or knee replacement surgery Thromb J 2015 13 37 26612979 \n29 Pedersen AB Mehnert F Sorensen HT Emmeluth C Overgaard S Johnsen SP The risk of venous thromboembolism, myocardial infarction, stroke, major bleeding and death in patients undergoing total hip and knee replacement: a 15-year retrospective cohort study of routine clinical practice Bone Joint J 2014 96-b 4 479 485 24692614 \n30 Forster R Stewart M Anticoagulants (extended duration) for prevention of venous thromboembolism following total hip or knee replacement or hip fracture repair Cochrane Database Syst Rev 2016 3 CD004179 27027384 \n31 Eriksson BI Dahl OE Rosencher N Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials Thromb J 2015 13 36 26578849 \n32 Rosencher N Samama CM Feuring M Dabigatran etexilate for thromboprophylaxis in over 5000 hip or knee replacement patients in a real-world clinical setting Thromb J 2016 14 8 27042163 \n33 Bloch BV Patel V Best AJ Thromboprophylaxis with dabigatran leads to an increased incidence of wound leakage and an increased length of stay after total joint replacement Bone Joint J 2014 96-b 1 122 126\n\n",
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"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D000991:Antithrombins; D019644:Arthroplasty, Replacement, Hip; D019645:Arthroplasty, Replacement, Knee; D000069604:Dabigatran; D017984:Enoxaparin; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010351:Patient Discharge; D011655:Pulmonary Embolism; D011792:Quebec; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D054556:Venous Thromboembolism; D020246:Venous Thrombosis",
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"title": "Incidence of symptomatic venous thromboembolism in 2372 knee and hip replacement patients after discharge: data from a thromboprophylaxis registry in Montreal, Canada.",
"title_normalized": "incidence of symptomatic venous thromboembolism in 2372 knee and hip replacement patients after discharge data from a thromboprophylaxis registry in montreal canada"
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"abstract": "Hypersensitivity to proton pump inhibitors (PPI) is rare but potentially severe. An increase in hypersensitivity reactions to PPI is expected as these drugs are widely prescribed and some have become available over-the-counter. Allergy to PPI has to be considered in patients presenting anaphylaxis, late-type skin rashes, interstitial nephritis and other organ involvement suspicious to be drug-induced. Cross-reactivity between PPI is of concern, as they are closely related in structure. Skin prick- and intradermal testing are reliable tools to confirm immediate-type allergy to one PPI compound and search for safe alternatives. We review the literature on immediate and delayed hypersensitivity to these drugs.",
"affiliations": "Service d'allergologie et immunologie clinique, HUG, 1211 Geneve 14. marcel.bergmann@hcuge.ch",
"authors": "Bergmann|M|M|;Guignard|B|B|;Ribi|C|C|",
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"mesh_terms": "D000465:Algorithms; D004342:Drug Hypersensitivity; D006801:Humans; D015394:Molecular Structure; D054328:Proton Pump Inhibitors; D012882:Skin Tests",
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"references": null,
"title": "Hypersensitivity to proton pump inhibitors.",
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"abstract": "Ischemic stroke patients with active cancer are known to have poor clinical outcomes. However, the efficacy and safety of intravenous alteplase (IV t-PA) in this group are still unclear. In this study, we aimed to evaluate whether stroke patients with cancer had poor clinical outcomes after use of IV t-PA. We reviewed ischemic stroke patients with active cancer treated with isolated IV t-PA between April 2010 and March 2015 at three national university hospitals from the registry for ischemic stroke in Korea. The clinical outcomes of early neurological deterioration (END), hemorrhagic transformation, in-hospital mortality, 3-month modified Rankin scale (mRS), the National Institutes of Health Stroke Scale (NIHSS) discharge score, and duration of hospitalization were compared. We enrolled a total of 12 patients, and the cohort showed poor outcomes including 4 (33%) END events, 7 (58%) hemorrhagic transformations, 3 (25%) in-hospital mortality cases, and 7 (58%) poor mRS (3-6) scores. Additionally, the cryptogenic stroke group (n = 6) more frequently had high mRS scores (P = 0.043) as well as tendencies for frequent END events, hemorrhagic transformations, in-hospital mortality cases, and higher discharge NIHSS scores without statistical significance. In conclusion, ischemic stroke patients with active cancer, especially those with a cryptogenic mechanism, showed poor clinical outcomes after use of IV t-PA.",
"affiliations": "Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Neurology, Korea University Guro Hospital and Korea University College of Medicine, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Neurology, Korea University Guro Hospital and Korea University College of Medicine, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.",
"authors": "Nam|Ki-Woong|KW|0000-0001-7514-6264;Kim|Chi Kyung|CK|;Kim|Tae Jung|TJ|;An|Sang Joon|SJ|;Oh|Kyungmi|K|;Ko|Sang-Bae|SB|;Yoon|Byung-Woo|BW|0000-0002-8597-807X",
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"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi 10.1155/2017/4635829Research ArticleIntravenous Thrombolysis in Acute Ischemic Stroke with Active Cancer http://orcid.org/0000-0001-7514-6264Nam Ki-Woong \n1\nKim Chi Kyung \n2\nKim Tae Jung \n1\nAn Sang Joon \n1\nOh Kyungmi \n2\nKo Sang-Bae \n1\nhttp://orcid.org/0000-0002-8597-807XYoon Byung-Woo \n1\n\n*\n1Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea2Department of Neurology, Korea University Guro Hospital and Korea University College of Medicine, Seoul, Republic of Korea*Byung-Woo Yoon: bwyoon@snu.ac.krAcademic Editor: Gelin Xu\n\n2017 4 6 2017 2017 46358296 1 2017 18 4 2017 14 5 2017 Copyright © 2017 Ki-Woong Nam et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Ischemic stroke patients with active cancer are known to have poor clinical outcomes. However, the efficacy and safety of intravenous alteplase (IV t-PA) in this group are still unclear. In this study, we aimed to evaluate whether stroke patients with cancer had poor clinical outcomes after use of IV t-PA. We reviewed ischemic stroke patients with active cancer treated with isolated IV t-PA between April 2010 and March 2015 at three national university hospitals from the registry for ischemic stroke in Korea. The clinical outcomes of early neurological deterioration (END), hemorrhagic transformation, in-hospital mortality, 3-month modified Rankin scale (mRS), the National Institutes of Health Stroke Scale (NIHSS) discharge score, and duration of hospitalization were compared. We enrolled a total of 12 patients, and the cohort showed poor outcomes including 4 (33%) END events, 7 (58%) hemorrhagic transformations, 3 (25%) in-hospital mortality cases, and 7 (58%) poor mRS (3–6) scores. Additionally, the cryptogenic stroke group (n = 6) more frequently had high mRS scores (P = 0.043) as well as tendencies for frequent END events, hemorrhagic transformations, in-hospital mortality cases, and higher discharge NIHSS scores without statistical significance. In conclusion, ischemic stroke patients with active cancer, especially those with a cryptogenic mechanism, showed poor clinical outcomes after use of IV t-PA.\n==== Body\n1. Introduction\nIschemic stroke in cancer patients, with a frequent occurrence of up to 15%, has been recently studied [1]. These patients have complicated stroke mechanism by conventional stroke mechanisms (e.g., large-artery atherosclerosis, small-vessel disease, and cardioembolism) and cancer-specific mechanisms (e.g., hypercoagulability, tumor embolism, and nonbacterial thrombotic endocarditis) [2]. Previously, patients who experienced stroke with cryptogenic mechanism, who had no evidence of conventional mechanisms, were proven to be more closely related to those with stroke with cancer-specific mechanisms (especially hypercoagulability) and had poorer clinical outcomes [1, 3–9].\n\nIntravenous alteplase (IV t-PA) is a well-known treatment option to recover from poststroke disability during the acute period. However, its efficacy and safety in patients with active cancer have not been well addressed due to its complex stroke mechanisms [6]. With longer life-expectancy due to improved cancer treatments, we needed to assess the exact prognosis and identify the high-risk subset after use of IV t-PA in ischemic stroke patients with active cancer.\n\nIn this study, we evaluated whether ischemic stroke patients with active cancer had poor clinical outcomes after use of IV t-PA. In addition, we also aimed to evaluate the impact of stroke mechanisms (e.g., conventional versus cryptogenic mechanisms) on the clinical outcomes after use of IV t-PA.\n\n2. Methods\n2.1. Study Population\nWe retrospectively reviewed medical records from the consecutively enrolled stroke registry for ischemic stroke patients with active cancer who visited three national university hospitals (Seoul National University Hospital, Seoul National University Bundang Hospital, and Seoul Metropolitan Government-Seoul National University Boramae Medical Center) in Korea between April 2010 and March 2015. Active cancer was defined as any diagnosis, recurrence, metastasis, and progression of cancer within 6 months of enrollment [6]. Among the cases, we extracted the subpopulation that was treated with IV t-PA. Patients using both IV t-PA and intra-arterial thrombectomy were excluded as to evaluate the sole effects of IV t-PA for the study. In addition, we also excluded patients under the age of 18 years and those who had a hematologic malignancy or a primary intracranial tumor which are known to have different stroke mechanisms [6]. Finally, a total of 12 patients remained for the analysis (Figure 1). This study was approved by the institutional review board (IRB) of Seoul National University Hospital (H-1610-036-797) and designed according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.\n\n2.2. Clinical Assessment\nWe collected demographic, clinical, and cardiovascular risk factors, including the presence of hypertension, diabetes, hyperlipidemia, current smoking, use of alcohol, history of stroke, initial stroke severity, mechanisms of stroke, blood pressure (BP), initial antithrombotics taken, and dose of t-PA [3]. The initial stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) by well-trained neurologists. The mechanisms of stroke were classified using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. We, then, dichotomized the stroke mechanisms into conventional (large-artery atherosclerosis, small-vessel occlusion, and cardioembolism) and cryptogenic mechanisms [6]. BP was assessed for initial systolic BP and diastolic BP. Initial antithrombotics were divided into low-molecular weight heparin, warfarin, antiplatelet agent, and no treatment. Data regarding the patient's cancer were also assessed including cancer type, systemic or brain metastasis, and venous thromboembolism (e.g., deep-vein thrombosis, pulmonary embolism).\n\nWe assessed the clinical outcomes in variable aspects. We evaluated early neurological deterioration (END), hemorrhagic transformation, hospitalization duration, discharge NIHSS scores, in-hospital mortality events, and the 3-month modified Rankin scale (mRS) scores. END was defined as an increase of ≥1 in the motor NIHSS score or ≥2 in the total NIHSS score [3].\n\n2.3. Radiological Assessment\nAll patients underwent brain magnetic resonance imaging (MRI) within 4 hours of admission using a 3.0-Tesla MR scanner (Achieva 3.0 T; Philips, Eindhoven, Netherlands). We dichotomized the initial diffusion-weighted image lesion into single territory lesions and multiple territory lesions [7]. Laboratory results, including C-reactive protein, D-dimer, prothrombin time, and activated partial thromboplastin time were assessed within 24 hours of admission.\n\n2.4. Statistical Analysis\nAll statistical analyses were conducted using SPSS version 22 (IBM SPSS, Chicago, IL, USA). We presented continuous variables as the mean ± SD when data were normally distributed, while the others were presented as the median + interquartile range. Student's t-test or Mann–Whitney U test were used for continuous variables, and the chi-squared test or Fisher's exact test were used for categorical variables. All variables with P < 0.05 were considered significant in the statistical analyses.\n\n3. Results\nWe enrolled a total of 12 ischemic stroke patients with active cancer who were treated with IV t-PA (mean age of 69 years, visit time 1 [0.5–1.75] hours, median NIHSS scores 10 [7–19], Table 1). Among them, 6 patients were classified as having a conventional stroke mechanism, and the remaining with a cryptogenic mechanism. In clinical outcomes, the cohort had 4 (33%) END events, 7 (58%) hemorrhagic transformations, 3 (25%) in-hospital mortalities, and 7 (58%) poor mRS (3–6) scores. The duration of hospitalization was 12 [9–25] days.\n\nNone of the demographic, clinical, cardiovascular, laboratory, or radiological variables were significantly different between the conventional and the cryptogenic groups (Table 2). However, in clinical outcomes, the cryptogenic group had higher 3-month mRS scores (P = 0.043, Figure 2). The cryptogenic group also had a tendency of more frequent END events, hemorrhagic transformations, in-hospital mortality cases, and higher discharge NIHSS scores without statistical significance. Three in-hospital mortality cases occurred only in the cryptogenic group, and the causes of death were pneumonia aggravation, myocardial infarction, and stroke recurrence.\n\n4. Discussion\nIn this study, ischemic stroke patients with active cancer showed poor outcomes after use of IV-tPA. Furthermore, cryptogenic stroke mechanisms seemed to be related to poor outcomes.\n\nAccording to a previous study, ischemic stroke patients with cancer were proven to be as safe as noncancer patients in a large population study, showing 12% in-hospital mortality and 6% intracerebral hemorrhage cases [10]. However, this study included cancer-associated stroke with relatively heterogeneous traits (e.g., including hematologic malignancy, nonactive cancer with stably controlled states, treated by both IV-tPA and intra-arterial thrombectomy). Thus, the pure outcomes of cancer-associated stroke may be hard to interpret. Additionally, there have also been two case-series studies that reported on safety and hazardous events after use of t-PA in ischemic stroke with cancer [11, 12]. The cases that resulted in hazardous events occurred in patients with newly diagnosed cancer and high elevated D-dimer levels with nonbacterial thrombotic endocarditis, similar to our participants [11, 12]. In contrast, patients with fair outcomes were those with nonactive cancer status, defined as being stable after operation or in complete remission with regular treatment [12]. In this study, we attempted to collect data from patients with relatively homogenous cancer-related stroke, and these patients showed poorer outcomes than previous studies in variable clinical aspects (e.g., in-hospital mortality, hemorrhagic transformation, and END), although the 3-month mRS scores were not significantly different [13].\n\nAdditionally, the mechanisms of stroke in this group seemed to play a role in the clinical outcomes. Those with cryptogenic stroke showed more frequent END events, hemorrhagic transformation, in-hospital mortality, and a higher number of discharge NIHSS scores and 3-month mRS scores despite these patients having the same initial NIHSS scores as the other group. We already knew that cryptogenic stroke in cancer patients had a worse outcome than conventional stroke in the clinical outcomes of stroke [14]. However, the result of having worse clinical outcomes with cryptogenic stroke after use of t-PA is interesting. We hypothesize that having a more advanced cancer and an impaired coagulation cascade might play a role.\n\nThis study is the first report on clinical outcomes after using t-PA in homogeneous cancer-related stroke and the impact of the stroke mechanisms on clinical outcomes. However, there are some caveats to this study. This study was designed as a three-center, uncontrolled, retrospective study. A small sample size limited the statistical power, despite considering the difficulty of collecting homogenous traits of this group. There was also a possibility of selection bias as a result of the retrospective.\n\nIn conclusion, ischemic stroke patients with active cancer showed poor clinical outcomes after use of IV t-PA. As the cryptogenic group showed worse outcomes, a more careful observation of this group should be recommended.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\nKi-Woong Nam and Chi Kyung Kim contributed equally in this work.\n\nFigure 1 Patient selection for the study.\n\nFigure 2 Distributions of 3-month mRS scores between patients that experienced stroke with conventional and cryptogenic mechanisms. P for trend < 0.043 in linear-by-linear association.\n\nTable 1 Brief profile of participants in the study.\n\nNumber/sex/age, y\tCancer type\tt-PA dose\tInitial D-dimer\tMechanism\tInitial NIHSS\tEND\t3m mRS\tHemorrhagic transformation\tInitial treatment\t\n1/F/64\tLung\t0.9\t26.8\tCryptogenic\t20\tN\t5\tY\tEnoxaparin\t\n2/M/61\tPancreas\t0.9\t5.11\tCryptogenic\t7\tY\t6\tY\tEnoxaparin\t\n3/F/74\tPancreas\t0.9\t3.7\tCryptogenic\t13\tY\t6\tY\tNo treatment\t\n4/M/61\tLung\t0.6\t2.01\tCryptogenic\t7\tN\t0\tN\tEnoxaparin\t\n5/M/76\tLung\t0.6\t3.91\tCryptogenic\t15\tY\t6\tY\tNo treatment\t\n6/M/82\tGastric\t0.6\t20\tCryptogenic\t7\tN\t6\tY\tEnoxaparin\t\n7/M/70\tGastric\t0.9\t11.1\tCE\t7\tN\t1\tY\tWarfarin\t\n8/M/81\tColon\t0.6\t0.82\tLAD\t19\tY\t3\tY\tAntiplatelet\t\n9/M/64\tColon\t0.6\t0.73\tLAD\t3\tN\t0\tN\tAntiplatelet\t\n10/M/67\tLung\t0.6\t1.77\tLAD\t19\tN\t1\tN\tAntiplatelet\t\n11/F/56\tCervical\t0.6\t0.16\tLAD\t5\tN\t1\tN\tAntiplatelet\t\n12/F/76\tLung\t0.9\t8.28\tCE\t24\tN\t5\tY\tEnoxaparin\t\nTable 2 Baseline characteristics and clinical outcomes between conventional and cryptogenic stroke mechanisms.\n\n \tConventional\n(n = 6)\tCryptogenic\n(n = 6)\t\nP value\t\nTime delay to visit, h [IQR]\t1 [1-2]\t1 [0-1]\t0.624\t\nAge, y [SD]\t69 ± 9\t70 ± 9\t0.899\t\nSex, male %\t4 (67)\t4 (67)\t1.000\t\nHypertension, %\t3 (50)\t1 (17)\t0.545\t\nDiabetes, %\t2 (33)\t0 (0)\t0.455\t\nHyperlipidemia, %\t1 (17)\t2 (33)\t1.000\t\nCurrent smoking, %\t2 (33)\t1 (17)\t1.000\t\nAlcohol, %\t4 (67)\t1 (17)\t0.242\t\nHistory of stroke, %\t1 (17)\t0 (0)\t1.000\t\nVenous thrombosis, %\t0 (0)\t2 (33)\t0.455\t\nCancer type, %\t \t \t0.688\t\n Lung\t2 (33)\t3 (50)\t \t\n Gastric\t1 (17)\t1 (17)\t \t\n Colorectal\t2 (33)\t0 (0)\t \t\n Hepatobiliary\t0 (0)\t2 (33)\t \t\n Genitourinary\t1 (17)\t0 (0)\t \t\nSystemic metastasis, %\t1 (17)\t5 (83)\t0.080\t\nBrain metastasis, %\t0 (0)\t3 (50)\t0.182\t\nInitial NIHSS [IQR]\t13 [5–19]\t10 [7–15]\t0.935\t\nSBP, mmHg [SD]\t130 ± 27\t151 ± 28\t0.213\t\nDBP, mmHg [SD]\t77 ± 23\t84 ± 12\t0.479\t\nInitial antithrombotics, %\t \t \t0.476\t\n Low-molecular weight heparin\t1 (17)\t4 (67)\t \t\n Warfarin\t1 (17)\t0 (0)\t \t\n Antiplatelet agent\t4 (67)\t0 (0)\t \t\n No treatment\t0 (0)\t2 (33)\t \t\nIntravenous alteplase dose, %\t \t \t1.000\t\n 0.6 mg/kg\t4 (67)\t3 (50)\t \t\n 0.9 mg/kg\t2 (33)\t3 (50)\t \t\nInitial DWI lesion\t \t \t0.061\t\n Single territory\t6 (100)\t2 (33)\t \t\n Multiple territory\t0 (0)\t4 (67)\t \t\nD-dimer, µg/mL [IQR]\t1.30 [0.73–8.28]\t4.51 [3.70–20.0]\t0.109\t\nCRP, mg/dL [IQR]\t0.03 [0.03–0.11]\t2.79 [0.38–12.20]\t0.085\t\nPT, INR [SD]\t1.09 ± 0.05\t1.15 ± 0.20\t0.497\t\naPTT, sec [SD]\t34.1 ± 4.6\t31.5 ± 9.8\t0.578\t\nHospital stay, day [IQR]\t16 [9–28]\t12 [6–17]\t0.420\t\nDischarge NIHSS [IQR]\t4 [2–7]\t28 [8–42]\t0.063\t\nEarly neurological deterioration, %\t1 (17)\t3 (50)\t0.545\t\nHemorrhagic transformation, %\t2 (33)\t5 (83)\t0.242\t\nIn-hospital mortality, %\t0 (0)\t3 (50)\t0.182\t\n3m mRS, %\t \t \t0.043\t\n 0\t1 (17)\t1 (17)\t \t\n 1\t3 (50)\t0 (0)\t \t\n 2\t0 (0)\t0 (0)\t\t\n 3\t1 (17)\t0 (0)\t \t\n 4\t0 (0)\t0 (0)\t \t\n 5\t1 (17)\t1 (17)\t \t\n 6\t0 (0)\t4 (67)\t \t\nWe used Student's t-test or Mann–Whitney U test for continuous variables, while chi-square test or Fisher's exact test was used for categorical variables.\n==== Refs\n1 Nam K. Kim C. K. Kim T. J. Predictors of 30-day mortality and the risk of recurrent systemic thromboembolism in cancer patients suffering acute ischemic stroke PLOS ONE 2017 12 3 p. e0172793 10.1371/journal.pone.0172793 28282388 \n2 Lee A. Y. Cancer and thromboembolic disease: pathogenic mechanisms Cancer Treatment Reviews 2002 28 3 137 140 10.1016/s0305-7372(02)00044-0 2-s2.0-0036622936 12234564 \n3 Nam K. Kim C. K. Kim T. J. D-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer European Journal of Neurology 2017 24 1 205 211 10.1111/ene.13184 27766716 \n4 Kim S. J. Park J. H. Lee M.-J. Park Y. G. Ahn M.-J. Bang O. Y. Clues to occult cancer in patients with ischemic stroke PLoS ONE 2012 7 9 p. e44959 10.1371/journal.pone.0044959 2-s2.0-84866316312 22984594 \n5 Schwarzbach C. J. Schaefer A. Ebert A. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology Stroke 2012 43 11 3029 3034 10.1161/strokeaha.112.658625 22996958 \n6 Kim S. G. Hong J. M. Kim H. Y. Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea Stroke 2010 41 4 798 801 10.1161/strokeaha.109.571356 2-s2.0-77950225519 20150545 \n7 Bang O. Y. Seok J. M. Kim S. G. Ischemic stroke and cancer: stroke severely impacts cancer patients, while cancer increases the number of strokes Journal of Clinical Neurology 2011 7 2 53 59 10.3988/jcn.2011.7.2.53 2-s2.0-79960447824 21779292 \n8 Seok J. M. Kim S. G. Kim J. W. Coagulopathy and embolic signal in cancer patients with ischemic stroke Annals of Neurology 2010 68 2 213 219 2-s2.0-77955293003 20695014 \n9 Lee M. J. Chung J. Ahn M. Hypercoagulability and mortality of patients with stroke and active cancer: the OASIS-CANCER study Journal of Stroke 2017 19 1 77 87 10.5853/jos.2016.00570 28030894 \n10 Murthy S. B. Karanth S. Shah S. Thrombolysis for acute ischemic stroke in patients with cancer: a population study Stroke 2013 44 12 3573 3576 10.1161/STROKEAHA.113.003058 2-s2.0-84889241696 24065712 \n11 Yagi T. Takahashi K. Tanikawa M. Seki M. Abe T. Suzuki N. Fatal intracranial hemorrhage after intravenous thrombolytic therapy for acute ischemic stroke associated with cancer-related nonbacterial thrombotic endocarditis Journal of Stroke and Cerebrovascular Diseases 2014 23 8 e413 e416 2-s2.0-84908208056 10.1016/j.jstrokecerebrovasdis.2014.04.004 25126699 \n12 Casado-Naranjo I. Calle M. L. Falcón A. Intravenous thrombolysis for acute stroke in patients with cancer Journal of Neurology, Neurosurgery & Psychiatry 2010 207472 \n13 Hacke W. Donnan G. Fieschi C. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials The Lancet 2004 363 9411 768 774 10.1016/S0140-6736(04)15692-4 \n14 Navi B. B. Singer S. Merkler A. E. Cryptogenic subtype predicts reduced survival among cancer patients with ischemic stroke Stroke 2014 45 8 2292 2297 2-s2.0-84906101733 10.1161/STROKEAHA.114.005784 24994717\n\n",
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"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D056910:Republic of Korea; D012720:Severity of Illness Index; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
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"title": "Intravenous Thrombolysis in Acute Ischemic Stroke with Active Cancer.",
"title_normalized": "intravenous thrombolysis in acute ischemic stroke with active cancer"
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"abstract": "Botulinum toxin (Botox) injection into the lower esophageal sphincter (LES) has been used for the treatment of achlasia cardia since the 1990s. Currently it is indicated for patients who are not candidates for definitive therapy like Heller's myotomy or pneumatic dilation and in those who have recurrence of symptoms after definitive treatments. We present a case of severe anaphylaxix due to Botox. The purpose of this case is to highlight one of the under-reported adverse effects of Botox. Anaphylactic reactions to Botox are very rare with only one other case being reported and have not been emphasized enough to be widely known in clinical practice.",
"affiliations": "SUNY Upstate Medical University, Syracuse, NY 13202, USA. Electronic address: aggarwaa@upstate.edu.;SUNY Upstate Medical University, Syracuse, NY 13202, USA.;SUNY Upstate Medical University, Syracuse, NY 13202, USA.;SUNY Upstate Medical University, Syracuse, NY 13202, USA.;SUNY Upstate Medical University, Syracuse, NY 13202, USA.;SUNY Upstate Medical University, Syracuse, NY 13202, USA.",
"authors": "Aggarwal|Aakash|A|;Kaul|Viren|V|;Kaur|Gurmeen|G|;Banas|Emerald|E|;Sampath|Praveen|P|;Roy|Ajoy K|AK|",
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"abstract": "Ogilvie syndrome or intestinal pseudo-obstruction is a clinical syndrome characterized by autonomic imbalance affecting peristalsis of colon leading to obstructive signs and symptoms. The etiologies commonly implicated are drugs affecting the cholinergic system, narcotics, electrolyte imbalance, severe sepsis, cancer, major surgery, and renal and cardiac failure. Ogilvie syndrome secondary to chemotherapy is a very rare phenomenon with very few reports in the literature. Cisplatin-induced neuropathy has been reported to occur when the cumulative dose exceeds 360 mg/m<sup>2</sup>. It manifests predominantly as peripheral sensory neuropathy with autonomic neuropathy occurring very rarely in a subset of patients. All the reported cases to date who presented with autonomic dysfunction secondary to cisplatin also had peripheral sensory neuropathy. Herein, we report a case of metastatic nonseminomatous germ cell tumor treated with cisplatin based regimen, who presented with severe intestinal pseudo-obstruction when the cumulative dose exceeded 400 mg/m<sup>2</sup> without any other manifestation of neuropathy. To our knowledge this is the first such case reported in the literature.",
"affiliations": "Department of Translational Medicine and Therapeutics, Healthcare Global Enterprises Limited, Bangalore, India.;Department of Medical Oncology, Healthcare Global Enterprises Limited, Bangalore, India.;Department of Medical Oncology, Healthcare Global Enterprises Limited, Bangalore, India.;Department of Clinical Pharmacology, Healthcare Global Enterprises Limited, Bangalore, India.;Department of Medical Oncology, Healthcare Global Enterprises Limited, Bangalore, India.;Department of Radiology, Healthcare Global Enterprises Limited, Bangalore, India.;Department of Medical Oncology, Healthcare Global Enterprises Limited, Bangalore, India.",
"authors": "Varayathu|Hrishi|H|;Shah|Mansi Sandip|MS|;Sarathy|Vinu|V|;Thomas|Beulah Elsa|BE|;Munirathnam|Vinayak|V|;Shivalingappa|Shivakumar Swamy|SS|;Naik|Radheshyam|R|",
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"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000510045\ncro-0013-1171\nCase Report\nOgilvie Syndrome in a Refractory Germ Cell Tumor Treated with Vinblastine, Ifosfamide and Cisplatin Regimen\nVarayathu Hrishi a* Shah Mansi Sandip b Sarathy Vinu b Thomas Beulah Elsa c Munirathnam Vinayak b Shivalingappa Shivakumar Swamy d Naik Radheshyam b aDepartment of Translational Medicine and Therapeutics, Healthcare Global Enterprises Limited, Bangalore, India\nbDepartment of Medical Oncology, Healthcare Global Enterprises Limited, Bangalore, India\ncDepartment of Clinical Pharmacology, Healthcare Global Enterprises Limited, Bangalore, India\ndDepartment of Radiology, Healthcare Global Enterprises Limited, Bangalore, India\n*Hrishi Varayathu, Department of Translational Medicine and Therapeutics, Healthcare Global Enterprises Limited, Kalinga Rao Road, Bangalore 560027 (India), hrishivarayathu@gmail.com\nSep-Dec 2020 \n28 9 2020 \n28 9 2020 \n13 3 1171 1175\n6 7 2020 9 7 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Ogilvie syndrome or intestinal pseudo-obstruction is a clinical syndrome characterized by autonomic imbalance affecting peristalsis of colon leading to obstructive signs and symptoms. The etiologies commonly implicated are drugs affecting the cholinergic system, narcotics, electrolyte imbalance, severe sepsis, cancer, major surgery, and renal and cardiac failure. Ogilvie syndrome secondary to chemotherapy is a very rare phenomenon with very few reports in the literature. Cisplatin-induced neuropathy has been reported to occur when the cumulative dose exceeds 360 mg/m<sup>2</sup>. It manifests predominantly as peripheral sensory neuropathy with autonomic neuropathy occurring very rarely in a subset of patients. All the reported cases to date who presented with autonomic dysfunction secondary to cisplatin also had peripheral sensory neuropathy. Herein, we report a case of metastatic nonseminomatous germ cell tumor treated with cisplatin based regimen, who presented with severe intestinal pseudo-obstruction when the cumulative dose exceeded 400 mg/m<sup>2</sup> without any other manifestation of neuropathy. To our knowledge this is the first such case reported in the literature.\n\nKeywords\nDrug-induced Ogilvie syndromeAutonomic neuropathyPeripheral neuropathyCumulative toxicity\n==== Body\nBackground\nOgilvie syndrome or acute colonic pseudo-obstruction (ACPO) is a rare acquired disorder characterized by autonomic abnormalities affecting peristalsis of the colon. The imbalance in autonomic activity leading to excessive sympathetic stimulation of the colon and suppressed parasympathetic activity has been proposed as the mechanism for this syndrome. Drug-induced ACPO is very rare and has been reported with neuroleptic medications, anti-cholinergics, amphetamines, steroids, and narcotics. Cytotoxic chemotherapy such as vincristine, cisplatin and high-dose methotrexate are rarely reported as a cause of Ogilvie syndrome [1, 2, 3, 4, 5]. We report a patient with a germ cell tumor who manifested with Ogilvie syndrome after 1 cycle of second-line vinblastine, ifosfamide and cisplatin (VeIP) combination chemotherapy.\n\nCase Presentation\nA 43-year-old male patient diagnosed with non-seminomatous mixed germ cell tumor (yolk sac 80%, teratoma 8%, and embryonal 2%) categorized as good risk with pulmonary metastasis underwent orchidectomy and 4 cycles of adjuvant bleomycin + etoposide + cisplatin (BEP) regimen. The patient received a cumulative dose of 270 IU of bleomycin, 400 mg/m2of cisplatin, and 2 g/m2of etoposide after 4 cycles of BEP regimen. The patient developed bleomycin-induced grade 2 pulmonary toxicity after 270 IU; hence, bleomycin was omitted from the fourth cycle of chemotherapy. After 4 cycles of BEP regimen, CT scan showed residual disease in the lung. As the patient was not willing to undergo surgery, he was planned and received a second-line VeIP regimen (vinblastine 9 mg + cisplatin 100 mg/m2+ ifosfamide 6 g/m2). The patient did not have any clinical signs or symptoms of peripheral neuropathy, and audiometry was normal before initiation of VeIP. Three days after completion of first cycle of VeIP regimen, the patient presented with complaints of severe abdomen pain and constipation. X-ray erect abdomen showed grossly distended large bowel loops with fecal matter and normal bowel gas pattern (shown in Fig. 1). Blood investigations showed normal serum electrolytes and renal and hepatic function. Serum amylase and lipase levels were also within normal limits. There were no signs of active infection like fever or diarrhea, and blood counts were within normal limits. The patient was not on any medication known to cause paralytic ileus like anti-cholinergics, opioids or any anti-motility drugs. On physical examination, the patient had diffuse tenders distension of the abdomen with decreased bowel sounds. There was no evidence of free fluid on percussion. The patient was afebrile with a slightly elevated blood pressure of 154/90 mm Hg and had tachycardia with a heart rate of 122/min. All other vital signs were within normal limits. As the patient's abdominal pain was very severe (visual analogue scale 9/10) and did not respond to analgesics, a CT scan abdomen was done which showed extensive fecal loading in the caecum and ascending and transverse colon without any evidence of obstruction (Fig. 2). Per rectal examination was done which showed an empty rectum. The patient was treated with laxatives, enema and fentanyl infusion for severe pain. With the above supportive measures, the patient gradually recovered and was relieved of his constipation and pain 1 week after the first cycle of VeIP regimen.\n\nOutcome and Follow-Up\nChemotherapy with VeIP was discontinued, the and patient is planned for radiotherapy to residual lung lesions.\n\nDiscussion\nOgilvie syndrome or ACPO is a disorder of gastrointestinal motility due to autonomic imbalance or autonomic nerve dysfunction which is characterized by dilation of colon without any mechanical obstruction. The exact cause and underlying mechanism of Ogilvie syndrome is not fully understood. The disorder is most commonly associated with serious medical illness or surgical procedures. Medical conditions such as nonoperative trauma, infections, electrolyte imbalance, renal insufficiency, heart diseases, respiratory failure, cancer and surgeries including abdominal, orthopedic (especially total hip replacement), neurologic, urologic and cardiac surgeries have been reported to be associated with Ogilvie syndrome [3]. However, cytotoxic drug-induced ACPO is a very rare complication and is usually accompanied by concomitant peripheral neuropathies. Peripheral neuropathy is a common dose-limiting toxicity with various cytotoxic drugs including cisplatin and vinca alkaloids. The mechanism of chemotherapy-induced peripheral neuropathy is multifactorial and involves microtubule disruption, oxidative stress, mitochondrial damage, altered ion channel activity, myelin sheath damage, DNA damage, immunological processes and neuro-inflammation [6]. Peripheral neuropathies can impair sensory, motor and autonomic function either singly or in combination. Neuropathies associated with chemotherapy are dose dependent. As our patient received only one dose of vinblastine, which is known to have very low neurotoxic potential, we hypothesized that our case of ACPO was mainly due to cisplatin as patient had already received a cumulative dose of 400 mg/m2prior to second line therapy with VeIP. Krarup-Hansen et al. [7]reported that neuropathy occurs with cumulative dose >350 mg/m2of cisplatin which is greatly increased beyond cumulative doses of 500–600 mg/m2. Kurita et al. [8] reported that cisplatin-induced autonomic nervous dysfunction manifests after a patient has received cumulative dose sufficient enough to produce severe sensory neuropathy. Our patient developed ACPO after a cumulative cisplatin dose of 500 mg/m2without any evidence of sensory neuropathy. Abd Rahim and Fuang Ho et al. [2] reported a case of paralytic ileus 3 days after completion of cisplatin, which was similar to our case. Cases of Ogilvie syndrome reported in association with drugs have been mostly treated with para-sympathomimetic agents like neostigmine or spontaneously relieved as the drug effect wears off. In our case, patient gradually recovered 7 days after last dose of cisplatin. The patient most probably recovered as the effects of cisplatin gradually wore off.\n\nIn a nutshell, Ogilvie syndrome associated with cisplatin is extremely rare, and caution should be exercised especially when cumulative cisplatin dose exceeds 400 mg/m2. Concomitant use of other potentially neurotoxic drugs like vinca alkaloids may further accentuate this cytotoxicity.\n\nStatement of Ethics\nThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The subject has given his written informed consent to publish his case.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding has been received for the study.\n\nAuthor Contributions\nHrishi Varayathu: manuscript writer, design of the study, observation. Mansi Sandip Shah: treating oncologist. Vinu Sarathy: treating oncologist, observation. Beulah Elsa Thomas: manuscript writing, references, pharmacology inputs. Vinayak Munirathnam: treating oncologist. Shivakumar Swamy Shivalingappa: radiologist. Radheshyam Naik: consultant, proof reading, final approval.\n\nAcknowledgement\nWe acknowledge all the team members of Department of Medical Oncology Healthcare Global enterprises limited for sharing their knowledge and valuable inputs.\n\nFig. 1 Erect abdomen radiograph showing gaseous distension of the colon with significant amount of fecal matter in the right colon.\n\nFig. 2 Axial, coronal and sagittal CT images show the fecal-filled distended right-sided colon and cecum.\n==== Refs\nReferences\n1 Carraro F Rivetti E Romano E Fagioli F Two cases of paralitic ileus in onco-hematologic patients Pediatr Rep 2012 4 (1) e3 22690309 \n2 Case report An unusual case of cisplatin induced paralytic ileus | Rahim | Advances in Modern Oncology Research [Internet] [cited 2020 May 31]. Available from: http://www.advmodoncolres.sg/index.php/amor/article/view/159/162 \n3 Lee GE Lim G-Y Lee J-W Cho B Acute colonic pseudo-obstruction complicating chemotherapy in paediatric oncohaematological patients: clinical and imaging features \n4 Xie H Peereboom DM Ogilvie's syndrome during chemotherapy with high-dose methotrexate for primary CNS lymphoma J Clin Oncol 2012 Jul 20 [Cited 2020 May 31] 30 (21) e192 22711852 \n5 Pessôa FMC Bittencourt LK de Melo ASA Síndrome de Ogilvie após uso de vincristina: Achados tomográficos Radiologia Brasileira. Colegio Brasileiro de Radiologia 2017 Vol. 50 273 4 \n6 Zajaczkowska R Kocot-Kepska M Leppert W Wrzosek A Mika J Wordliczek J Molecular Sciences Mechanisms of Chemotherapy-Induced Peripheral Neuropathy 2019 [cited 2020 May 31] Available from: www.mdpi.com/journal/ijms \n7 Krarup-Hansen A Helweg-Larsen S Schmalbruch H Roth M Krarup C Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies | Brain | Oxford Academic [Internet] [cited 2020 May 31] Available from: https://academic.oup.com/brain/article/130/4/1076/275387 \n8 Kurita A Mochio S Hasunuma T Oka H Isogai Y Cisplatin-induced autonomic nervous dysfunction Journal of the Autonomic Nervous System 1995 Jan 3 50 (3) 372\n\n",
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"issn_linking": "1662-6575",
"issue": "13(3)",
"journal": "Case reports in oncology",
"keywords": "Autonomic neuropathy; Cumulative toxicity; Drug-induced Ogilvie syndrome; Peripheral neuropathy",
"medline_ta": "Case Rep Oncol",
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"pages": "1171-1175",
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"title": "Ogilvie Syndrome in a Refractory Germ Cell Tumor Treated with Vinblastine, Ifosfamide and Cisplatin Regimen.",
"title_normalized": "ogilvie syndrome in a refractory germ cell tumor treated with vinblastine ifosfamide and cisplatin regimen"
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{
"abstract": "OBJECTIVE\nTo report a case of optic neuritis with visual field defect associated with ibuprofen.\n\n\nMETHODS\nA 41-year-old white man developed blurred vision in his right eye and pain with eye and head movements that lasted 2 days after use of ibuprofen 400 mg 3 times daily during the preceding 3 weeks. Medical and family histories were negative for significant related disease. Ophthalmologic examination revealed a marked decrease in visual acuity to 20/200 in the right eye with quadrant visual field loss and absent responses in visual evoked potential (VEP). After discontinuation of the drug and treatment with high-dose intravenous methylprednisolone and subcutaneous low-molecular-weight heparin, the patient's vision improved to 20/70, the visual field defect vanished, and the VEP returned to almost normal values during a 1 year follow-up period. An objective causality assessment revealed that the adverse reaction was possibly related to ibuprofen.\n\n\nCONCLUSIONS\nOcular toxicity with blurred vision and centrocecal visual field defects have been rarely associated with long-term ibuprofen intake. We report a case of retrobulbar optic neuritis with quadrant visual field defect following short-term but regular ibuprofen intake. Although idiopathic optic neuritis cannot be completely ruled out, the absence of other risk factors and additional findings plus the improvement after discontinuation of the drug speak for isolated toxic optic neuritis of the right eye.\n\n\nCONCLUSIONS\nDrug toxicity is an important differential diagnosis in retrobulbar optic neuritis. Clinicians should be aware of the potential optic toxicity, even with short-term use of a drug, and perform a thorough medication history in every patient with visual disturbances without a clear cause.",
"affiliations": "Department of Ophthalmology, University of Regensburg, Germany. gamulescu@eye-regensburg.de",
"authors": "Gamulescu|Maria-A|MA|;Schalke|Berthold|B|;Schuierer|Gerhard|G|;Gabel|Veit-P|VP|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1G451",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "40(3)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005074:Evoked Potentials, Visual; D006801:Humans; D007052:Ibuprofen; D008297:Male; D008775:Methylprednisolone; D009902:Optic Neuritis; D014792:Visual Acuity; D014794:Visual Fields",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "571-3",
"pmc": null,
"pmid": "16507621",
"pubdate": "2006-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Optic neuritis with visual field defect--possible Ibuprofen-related toxicity.",
"title_normalized": "optic neuritis with visual field defect possible ibuprofen related toxicity"
} | [
{
"companynumb": "DE-DRREDDYS-GER/GER/18/0105746",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
... |
{
"abstract": "There have been several case reports of risperidone-associated dysphagia. Risperidone-induced bulbar palsy-like syndrome has not been previously described. We report on a 58-year-old gentleman with prior history of schizophrenia and remote chlorpromazine use with no history of extrapyramidal symptoms who experienced acute onset of dysphagia and facial diplegia with hyperprolactinemia while being treated with risperidone. To date there have been five reported cases of dysphagia associated with risperidone, occurring by such mechanisms as isolated pharyngeal dysfunction from pharyngeal constrictor palsy and dystonia, drug-induced parkinsonism, and acute dystonic reaction. These cases were associated either with initiation or up-titration of risperidone, with complete resolution of dysphagia after medication discontinuation or dose change. Our patient developed dysphagia within 2 weeks of taking risperidone and completely resolved 1 month after the medication was stopped. Unlike other reported cases, our patient also experienced symptomatic hyperprolactinemia, another known side effect of risperidone. Physicians should also be aware that risperidone can be associated with oropharyngeal dysphagia secondary to an acute bulbar palsy-like syndrome that places patients at increased risk of aspiration events and its associated morbidity and mortality.",
"affiliations": "Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA. jason.sico@va.gov",
"authors": "Sico|Jason Jonathon|JJ|;Patwa|Huned|H|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1007/s00455-010-9307-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-051X",
"issue": "26(3)",
"journal": "Dysphagia",
"keywords": null,
"medline_ta": "Dysphagia",
"mesh_terms": "D014150:Antipsychotic Agents; D003680:Deglutition Disorders; D006801:Humans; D006966:Hyperprolactinemia; D008297:Male; D008875:Middle Aged; D018967:Risperidone; D012559:Schizophrenia",
"nlm_unique_id": "8610856",
"other_id": null,
"pages": "340-3",
"pmc": null,
"pmid": "20922432",
"pubdate": "2011-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "17934560;17482029;7805424;15099239;15733025;17024549;17102565;14571332;16000684;11569473;18458730;17984854;842710",
"title": "Risperidone-induced bulbar palsy-like syndrome.",
"title_normalized": "risperidone induced bulbar palsy like syndrome"
} | [
{
"companynumb": "US-JNJFOC-20121210272",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nImmune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX; OMIM 304930) syndrome is a congenital syndrome characterized by autoimmune enteropathy, endocrinopathy, dermatitis, and other autoimmune phenomena. In the present work, we aimed to uncover the molecular basis of a distinct form of IPEX syndrome presenting at the edge of autoimmunity and severe allergy.\n\n\nMETHODS\nThe FOXP3 gene was sequenced, FOXP3 messenger RNA (mRNA) was quantified by real-time polymerase chain reaction (PCR), and protein expression in peripheral blood lymphocytes was analyzed by flow cytometry after intracellular staining. In coculture experiments (CD4(+)CD25(-) and CD4(+)CD25(+) cells), the functions of regulatory T cells were analyzed. Expression of interferon gamma and interleukin 2 and 4 mRNA within the inflamed intestinal mucosa was quantified by real-time PCR.\n\n\nRESULTS\nHere, we describe a distinct familial form of IPEX syndrome that combines autoimmune and allergic manifestations including severe enteropathy, food allergies, atopic dermatitis, hyper-IgE, and eosinophilia. We have identified a 1388-base pair deletion (g.del-6247_-4859) of the FOXP3 gene encompassing a portion of an upstream noncoding exon (exon -1) and the adjacent intron (intron -1). This deletion impairs mRNA splicing, resulting in accumulation of unspliced pre-mRNA and alternatively spliced mRNA. This causes low FOXP3 mRNA levels and markedly decreased protein expression in peripheral blood lymphocytes of affected patients. Numbers of CD4(+)CD25(+)FOXP3(+) regulatory T cells are extremely low, and the CD4(+)CD25(+) T cells that are present exhibit little regulatory function.\n\n\nCONCLUSIONS\nA new mutation within an upstream noncoding region of FOXP3 results in a variant of IPEX syndrome associating autoimmune and severe immunoallergic symptoms.",
"affiliations": "University of Washington & Children's Hospital, Department of Pediatrics, Division of Immunology, Rheumatology, & Infectious Diseases, Seattle, Washington, USA.",
"authors": "Torgerson|Troy R|TR|;Linane|Avriel|A|;Moes|Nicolette|N|;Anover|Stephanie|S|;Mateo|Véronique|V|;Rieux-Laucat|Frédéric|F|;Hermine|Olivier|O|;Vijay|Shashi|S|;Gambineri|Eleonora|E|;Cerf-Bensussan|Nadine|N|;Fischer|Alain|A|;Ochs|Hans D|HD|;Goulet|Olivier|O|;Ruemmele|Frank M|FM|",
"chemical_list": "D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2007.02.044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "132(5)",
"journal": "Gastroenterology",
"keywords": null,
"medline_ta": "Gastroenterology",
"mesh_terms": "D001483:Base Sequence; D015704:CD4 Antigens; D002648:Child; D002675:Child, Preschool; D004485:Eczema; D005260:Female; D005512:Food Hypersensitivity; D051858:Forkhead Transcription Factors; D017353:Gene Deletion; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit; D007410:Intestinal Diseases; D007413:Intestinal Mucosa; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D016884:Polyendocrinopathies, Autoimmune; D012333:RNA, Messenger; D050378:T-Lymphocytes, Regulatory; D053632:X-Linked Combined Immunodeficiency Diseases",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "1705-17",
"pmc": null,
"pmid": "17484868",
"pubdate": "2007-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene.",
"title_normalized": "severe food allergy as a variant of ipex syndrome caused by a deletion in a noncoding region of the foxp3 gene"
} | [
{
"companynumb": "US-PFIZER INC-2019246774",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALBUMIN HUMAN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study is to describe a possible association between unintentional secondary exogenous corticosteroid exposure and central serous chorioretinpathy (CSCR).\n\n\nMETHODS\nA retrospective review of three patients diagnosed with CSCR in one or both eyes and a history of possible unintentional secondary corticosteroid exposure. Clinical history, exam findings, optical coherence tomography, fluorescein angiography, and clinical course were reviewed.\n\n\nRESULTS\nThree patients, who did not use corticosteroids, reported suspected unintentional secondary corticosteroid exposure from living with family members or partners using dermatologic corticosteroid cream and/or inhalers frequently. Two of the three patients had a history of recurrent CSCR, one patient involving both eyes. After taking precautions to avoid secondary corticosteroid exposure, all three patients had complete resolution of CSCR without further recurrence during follow-up ranging from 2 to 4 years.\n\n\nCONCLUSIONS\nPatients with CSCR should be queried for both primary and possible unintentional secondary routes of corticosteroid exposure, which may contribute to this condition.",
"affiliations": "Department of Ophthalmology and Vision Science, University of California Davis Eye Center, Sacramento, CA, USA.;Department of Ophthalmology and Vision Science, University of California Davis Eye Center, Sacramento, CA, USA.;Department of Ophthalmology and Vision Science, University of California Davis Eye Center, Sacramento, CA, USA.",
"authors": "Thinda|S|S|;Lam|K|K|;Park|S S|SS|000000032559643X",
"chemical_list": "D000305:Adrenal Cortex Hormones; D003879:Dermatologic Agents",
"country": "England",
"delete": false,
"doi": "10.1038/eye.2014.328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0950-222X",
"issue": "29(4)",
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D056833:Central Serous Chorioretinopathy; D003879:Dermatologic Agents; D004781:Environmental Exposure; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "8703986",
"other_id": null,
"pages": "577-9",
"pmc": null,
"pmid": "25592121",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "11157885;12431693;15019370;15320828;3543522;3484371;20172062;20930852;23410821",
"title": "Unintentional secondary exogenous corticosteroid exposure and central serous chorioretinopathy.",
"title_normalized": "unintentional secondary exogenous corticosteroid exposure and central serous chorioretinopathy"
} | [
{
"companynumb": "US-TARO PHARMACEUTICALS USA.,INC-2016SUN00285",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drug... |
{
"abstract": "BACKGROUND\nAllogeneic haemopoietic stem cell transplant (Allo-HSCT) is a specialised and costly intervention, associated with significant morbidity and mortality. It is used to treat a broad range of paediatric conditions. South Africa (SA) is an upper middle-income country with limitations on healthcare spending. The role of paediatric Allo-HSCT in this setting is reviewed.\n\n\nOBJECTIVE\nTo review paediatric patients who underwent Allo-HSCT at the Groote Schuur Hospital/University of Cape Town Private Academic Hospital transplant unit in Cape Town, South Africa, and received post-transplant care at Red Cross War Memorial Children's Hospital, over the period January 2006 - December 2014 in respect of indications for the transplant, donor sources, conditioning regimens, treatment-related morbidity and overall survival (OS).\n\n\nMETHODS\nA retrospective analysis of patient records was performed and a database was created in Microsoft Access. Descriptive analyses of relevant demographic, clinical and laboratory data were performed. Summary statistics of demographic and clinical parameters were derived with Excel. OS was calculated from the date of transplant to the date of an event (death) or last follow-up using the Kaplan-Meier method in Statistica.\n\n\nRESULTS\nA total of 48 children received Allo-HSCT: 24 for haematological malignancies, 20 for non-oncological haematological conditions, 3 for immune disorders and 1 for adrenoleukodystrophy. There were 28 boys (median age 7.5 years) and 20 girls (8.5 years). There were 31 sibling matched peripheral-blood stem cell (PBSC) transplants and 1 maternal haploidentical PBSC transplant. Stem cells were mobilised from bone marrow into peripheral blood by administering granulocyte-colony stimulating factor to donors. PBSCs were harvested by apheresis. Eight patients received 10/10 HLA-matched grafts from unrelated donors. Six were PBSC grafts and 2 were bone marrow grafts. Three of the unrelated PBSC grafts were from SA donors. Eight transplants used umbilical cord blood from international registries. OS for patients with non-oncological disorders was 91.3% (median follow-up 3.9 years), while that for oncology patients was 56.8% (1.9 years). Two of the survivors developed chronic graft-versus-host disease.\n\n\nCONCLUSIONS\nOS for non-oncological conditions was excellent, while outcomes for oncological disorders were on par with those in high-income settings. Transplantation offers many patients the opportunity for long-term survival and has been shown to be both feasible and rewarding in a less well-resourced environment servicing an economically diverse population.",
"affiliations": "Haematology Oncology Service, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and Faculty of Health Sciences, University of Cape Town, South Africa. ann.vaneyssen@uct.ac.za.",
"authors": "Van Eyssen|A|A|;Novitsky|N|N|;De Wit|P|P|;Schlaphoff|T|T|;Thomas|V|V|;Pillay|D|D|;Hendricks|M|M|;Davidson|A|A|",
"chemical_list": null,
"country": "South Africa",
"delete": false,
"doi": "10.7196/SAMJ.2017.v107i3.11313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "107(3)",
"journal": "South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde",
"keywords": null,
"medline_ta": "S Afr Med J",
"mesh_terms": null,
"nlm_unique_id": "0404520",
"other_id": null,
"pages": "232-238",
"pmc": null,
"pmid": "28281429",
"pubdate": "2017-02-27",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Single-centre experience of allogeneic haemopoietic stem cell transplant in paediatric patients in Cape Town, South Africa.",
"title_normalized": "single centre experience of allogeneic haemopoietic stem cell transplant in paediatric patients in cape town south africa"
} | [
{
"companynumb": "PHHY2017ZA039257",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nSeveral cases of hearing loss induced by hydroxychloroquine have been reported in the literature but the role of hydroxychloroquine still remains debated.\n\n\nMETHODS\nWe report the first case, to our knowledge, of hearing loss induced by hydroxychloroquine with a positive re challenge in a woman treated for systemic lupus. An analysis of the French pharmacovigilance database allowed to identify 23 additional cases of hearing loss in patients treated with hydroxychloroquine and, among them, 8 had systemic lupus.\n\n\nCONCLUSIONS\nDespite an excellent tolerance and high efficacy-side effect ratio, this case report adds some evidence for an otoxicity of hydroxychloroquine.",
"affiliations": "Centre régional de pharmacovigilance de Lille, CHRU de Lille, 1, place de Verdun, 59045 Lille cedex, France.;Centre régional de pharmacovigilance de Lille, CHRU de Lille, 1, place de Verdun, 59045 Lille cedex, France. Electronic address: ma.auffret@gmail.com.;Centre régional de pharmacovigilance de Dijon, CHU de Dijon, 21079 Dijon cedex France.;Centre régional de pharmacovigilance de Toulouse, CHU de Toulouse, 31000 Toulouse France.;Service de médecine Interne, hôpital Claude-Huriez, CHRU de Lille, 59045 Lille cedex France.;Centre régional de pharmacovigilance de Lille, CHRU de Lille, 1, place de Verdun, 59045 Lille cedex, France.",
"authors": "Chatelet|J-N|JN|;Auffret|M|M|;Combret|S|S|;Bondon-Guitton|E|E|;Lambert|M|M|;Gautier|S|S|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2016.07.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "38(5)",
"journal": "La Revue de medecine interne",
"keywords": "Adverse drug reaction; Effet indésirable; Hearing loss; Hydroxychloroquine; Lupus; Perte d’audition; Surdité",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D016208:Databases, Factual; D005260:Female; D005602:France; D034381:Hearing Loss; D006801:Humans; D006886:Hydroxychloroquine; D008180:Lupus Erythematosus, Systemic; D060735:Pharmacovigilance",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "340-343",
"pmc": null,
"pmid": "27745936",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydroxychloroquine-induced hearing loss: First case of positive rechallenge and analysis of the French pharmacovigilance database.",
"title_normalized": "hydroxychloroquine induced hearing loss first case of positive rechallenge and analysis of the french pharmacovigilance database"
} | [
{
"companynumb": "FR-IPCA LABORATORIES LIMITED-IPC201702-000150",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},
... |
{
"abstract": "Recent case reports suggest a possible causal correlation between antecollis and pramipexole. Here, we report the case of a 62-year-old Italian man with a 2-year history of Parkinson's disease (PD) and cervical spondylosis for which he was treated with pramipexole. He developed severe neck rigidity immediately after an inguinal hernia operation but several months after introduction of pramipexole. He was initially treated with painkillers and physiotherapy with no significant improvement. His condition deteriorated presenting disproportionate rigidity between anterior and posterior neck muscles (antecollis) to the extent that normal activities were severely restricted. However, significant improvement occurred after the withdrawal of pramipexole. The patient undertook a second cycle of physiotherapy with remarkable results and returned to function normally in everyday life. This case report suggests that neurologists should be motivated to inform the scientific community about other possible cases in which an association between antecollis and pramipexole might operate in PD.",
"affiliations": "Anglia Ruskin University , Cambridge , UK.;FMSI Federazione Medico Sportiva Italiana, Medicina Sportiva , Livorno , Italy.;Centro di Fisioterapia FISIOS , Livorno , Italy.;Anglia Ruskin University , Cambridge , UK.",
"authors": "Filippi|Roberto|R|;Rasetti|Mario|M|;Lenzi|Marco|M|;Bright|Peter|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omu003",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omu003omu0031300Case ReportsPossible effects of pramipexole on neck muscles in a patient with Parkinson's disease Filippi Roberto 1*Rasetti Mario 2Lenzi Marco 3Bright Peter 11 Anglia Ruskin University, Cambridge, UK2 FMSI Federazione Medico Sportiva Italiana, Medicina Sportiva, Livorno, Italy3 Centro di Fisioterapia FISIOS, Livorno, Italy* Correspondence address. Department of Psychology, Faculty of Science and Technology, Anglia Ruskin University, East Road, CB1 1PT Cambridge, UK. Tel: +44 (0)1223 363271; E-mail: roberto.filippi@anglia.ac.uk4 2014 5 4 2014 2014 1 8 10 3 2 2014 28 2 2014 2 3 2014 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 20142014This 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 non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comRecent case reports suggest a possible causal correlation between antecollis and pramipexole. Here, we report the case of a 62-year-old Italian man with a 2-year history of Parkinson's disease (PD) and cervical spondylosis for which he was treated with pramipexole. He developed severe neck rigidity immediately after an inguinal hernia operation but several months after introduction of pramipexole. He was initially treated with painkillers and physiotherapy with no significant improvement. His condition deteriorated presenting disproportionate rigidity between anterior and posterior neck muscles (antecollis) to the extent that normal activities were severely restricted. However, significant improvement occurred after the withdrawal of pramipexole. The patient undertook a second cycle of physiotherapy with remarkable results and returned to function normally in everyday life. This case report suggests that neurologists should be motivated to inform the scientific community about other possible cases in which an association between antecollis and pramipexole might operate in PD.\n==== Body\nINTRODUCTION\nParkinson's disease (PD) is an idiopathic progressive neurological condition associated with degeneration of dopaminergic neurons in the substantia nigra, resulting in dopamine loss in the striatum. Prevalence statistics vary widely but a meta-analysis of US and European studies suggests ∼1% of those aged over 65 suffer from the disease [1]. Common motor deficits (bradykinesia, muscle rigidity and tremor) typically improve with dopaminergic replacement therapy.\n\nPramipexole is a dopamine receptor agonist used to treat PD, particularly in its early stages. A number of studies have indicated continued efficacy of the treatment for up to 4 years while identifying potentially severe side effects such as dyskinesia, asymptomatic orthostatic hypotension and nausea [2, 3]. A small number of recent PD cases have identified a possible link between pramipexole and the development of antecollis (marked neck flexion, disproportionate to trunk flexion) with recovery apparently contingent upon the withdrawal of treatment [4, 5].\n\nCASE REPORT\nA 62-year-old Italian man developed slowness and loss of strength of his right arm and hand. In July 2010, after a first neurological examination, he was prescribed l-DOPA, 250 mg/day, resulting in significant improvement of his parkinsonism. PD was therefore indicated using an ex juvantibus reasoning. Subsequent magnetic resonance imaging carried out in October 2010 excluded other conditions. At this point, the diagnosis of PD was confirmed and the neurologist who followed the patient at that time made the decision to change treatment to 1.05 mg/day of pramipexole and the complete cessation of l-DOPA. He was checked twice over a period of 12 months and his condition was considered stable each time.\n\nThe patient had a history of cervical spondylosis, a very common condition in the aging population caused by the progressive degeneration of the neck bones and neck tissues. He also had a straightforward inguinal hernia for which he undertook a corrective operation on 21 November 2011. The operation started at 9:00 am and ended at ∼9:30 am. He did not take pramipexole on the day of the operation. Given the option of general anesthesia or epidural he chose the former, carried out as follows:\n– Stage 1: Analgesic administration: [ultiva (remifentanil); infusion pumps were used]\n\n– Stage 2: Anesthesia induction: (propofol and curare immediately after)\n\n– Stage 3: Intubation: [halogenated anesthetic (sevorane)];\n\n– Stage 4: Before wake up: prostigmina was used to eliminate curare and sevorane was stopped.\n\n\n\nThere were no postoperative complications and the patient was discharged on the same day. He restarted taking pramipexole (1.05 mg) on the morning after the operation. On the same day, he developed neck rigidity and his head dropped forward. The local general practitioner treated him with painkillers, but these proved ineffective.\n\nFrom the immediate onset of antecollis the patient's life was severely impaired: he needed assistance at work, could not drive his car and experienced difficulties when eating and speaking. On 3 April 2012, the patient decided to consult a professional physiotherapist who objectively confirmed severe antecollis: his neck was bent forward at an angle of 80–90°. He could actively extend his head up only of about 50–40° with obvious compensation of the posterior and inferior (lumbar) muscles of the vertebral trunk. Therefore, this was not a real extension of the head and could not be sustained beyond ∼30 s. The neck rotation on both left and right sides of the head was severely restricted. He undertook 10 physiotherapy sessions with the aim of reducing the strong contraction of his neck muscles. However, no improvement was observed on treatment completion.\n\nIn June 2012, 6 months from the onset of antecollis, following similar cases reported in the literature [4, 5], it was decided to withdraw pramipexole and reintroduce l-DOPA. The improvement was almost immediate: on the first day, the patient felt less pressure on the neck and gained more flexibility. After a few days, he could easily turn his neck and he started to drive his car again.\n\nOn 13 August 2012, about 2 months after the cessation of pramipexole, the patient decided to undertake a second cycle of physiotherapy. His condition objectively appeared significantly improved, despite the extended period of time in which his neck movements were severely impaired. The only change in his treatment regime from June to August 2012 was the cessation of pramipexole.\n\nSince this second cycle of physiotherapy, neck angle remained about 30° at rest. The patient can now perform extension and rotation movement easily, as shown in Fig. 1.\nFigure 1: A 62-year-old patient with Parkinson's disease who developed antecollis following treatment with pramipexole (1.05 mg/day) showing: (A) prominent antecollis in an upright position during treatment with pramipexole and (B) improvement of antecollis after withdrawal of the pramipexole treatment.\n\n\n\nUnlike the cited cases in which antecollis appeared within a few weeks after taking pramipexole, this patient developed antecollis several months after its introduction for the treatment of PD. This relatively extended period might indicate that some factor(s) other than pramipexole may have induced antecollis, but the improvement upon cessation suggests otherwise. Intriguingly, antecollis emerged immediately after the inguinal hernia operation, raising the possibility that onset was triggered by the surgical procedure—however, this interpretation is highly speculative.\n\nDISCUSSION\nWe report the case of a PD patient who received ∼1-year treatment with pramipexole with no evident side effects, and developed antecollis after an inguinal hernia operation. Physiotherapy did not improve the condition, and ultimately a decision was implemented to cease pramipexole and reintroduce l-DOPA. This change of medication improved his antecollis and allowed him to return to his normal life habits. The patient had a history of cervical spondylosis but had never suffered from muscle rigidity before PD was diagnosed or between diagnosis and his hernia operation.\n\nClaims for a relationship between antecollis and pramipexole have been reported in the literature [4, 5]. In this case report, however, the connection is complicated by the extended delay between the introduction of pramipexole and the onset of antecollis. Nevertheless, the antecollis showed dramatic improvement once pramipexole was withdrawn. Moreover, we tentatively raise the possibility that anesthesia (in this case prior to an inguinal hernia operation) might interact in some way with pramipexole to encourage the onset of antecollis. However, given the rate at which the effects of general anesthetics abate and the chemicals are ‘washed-out’, a viable explanation for such a link is difficult to envisage. The neck positioning during intubation could also have played a role. However, we suggest that this is unlikely given the short duration of the surgical procedure (∼30 min).\n\nIn conclusion, further investigation is needed to determine with confidence the relationship between pramipexole and antecollis in PD. This case report suggests that neurologists should be motivated to inform the scientific community about other possible cases of PD in which an association between antecollis and pramipexole might operate.\n==== Refs\nREFERENCES\n1 Hirtz D Thurman DJ Gwinn-Hardy K Mohamed M Chaudhuri AR Zalutsky R How common are the ‘common’ neurologic disorders? Neurology 2007 68 326 37 17261678 \n2 Möller JC Oertel WH Köster J Pezzoli G Provinciali L Long term efficacy and safety of pramipexole in advanced Parkinson's disease: results from a European multicenter trial Mov Disord 2005 20 602 10 15726540 \n3 Weiner WJ Factor SA Jankovic J Hauser RA Tetrud JW Waters CH The long-term safety and efficacy of pramipexole in advanced Parkinson's disease Parkinsonism Relat Disord 2001 7 115 20 11248592 \n4 Kim HJ Jeon BS Kim HS Han S-H Reversible antecollis associated with pramipexole in a patient with Parkinson's disease J Clin Neurosci 2012 19 903 4 22353251 \n5 Suzuki M Hirai T Ito Y Sakamoto T Oka H Kurita A Pramipexole-induced antecollis in Parkinson's disease J Neurol Sci 2008 264 195 7 17826796\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2014(1)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "8-10",
"pmc": null,
"pmid": "25988008",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports",
"references": "17826796;17261678;22353251;11248592;15726540",
"title": "Possible effects of pramipexole on neck muscles in a patient with Parkinson's disease.",
"title_normalized": "possible effects of pramipexole on neck muscles in a patient with parkinson s disease"
} | [
{
"companynumb": "PHHY2015GB124638",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Systemic Lupus Erythematosus (SLE) and Tuberculosis (TB) are intricately related with an increase in the risk of TB in SLE. Primary mechanisms pertaining to the increased susceptibility for TB are the inherent immunodeficient state of SLE and use of immunosuppressant agents in the treatment of SLE. We report a case series of five female patients of SLE with TB who presented between January 2015 and December 2015 in a tertiary care teaching hospital in North Eastern India. All the patients were young to middle aged females having SLE with or without lupus nephritis who were on immunosuppressive therapy with corticosteroids, mycophenolate mofetil or cyclophosphamide. Two of the cases had sputum positive pulmonary tuberculosis while rest had Extra-Pulmonary TB (EPTB). The response to anti-tubercular therapy led to clinical improvement in all the cases except one who had an adverse outcome. Our series further substantiates the increased risk of TB in SLE thus, prompting further research towards better management of these two disease entities in conjunction.",
"affiliations": "Professor and Head, Department of General Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences , Shillong, Meghalaya, India .;Assistant Professor, Department of General Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences , Shillong, Meghalaya, India .;Postgraduate Student, Department of General Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences , Shillong, Meghalaya, India .;Postgraduate Student, Department of General Medicine, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences , Shillong, Meghalaya, India .",
"authors": "Bhattacharya|Prasanta Kumar|PK|;Jamil|Md|M|;Roy|Aakash|A|;Talukdar|Kishore Kumar|KK|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2017/22749.9398",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "11(2)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Auto-immunity; Immunosuppression; Lupus; Tubercular infection",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "OR01-OR03",
"pmc": null,
"pmid": "28384925",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "9324032;15801014;11447699;16686263;12455821;17940720;20739781;19590444;10764341;24456934;11830432;19548122;16463407;16239382;15176665;19080137;23102827",
"title": "SLE and Tuberculosis: A Case Series and Review of Literature.",
"title_normalized": "sle and tuberculosis a case series and review of literature"
} | [
{
"companynumb": "IN-CONCORDIA PHARMACEUTICALS INC.-GSH201704-002590",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "Contrast echocardiography demonstrating microbubbles in the pericardial space has often been cited as evidence of ventricular rupture requiring emergent surgical intervention. We report a case where no myocardial perforation was found during post-myocardial infarction surgery despite prior echocardiographic evidence of contrast extravasation into the pericardial effusion. Clinical decision making requires balancing imaging evidence with clinical circumstances to determine the optimal timing for surgical intervention.",
"affiliations": "Department of Cardiology, Mount Sinai Beth Israel, New York, New York.;Department of Medicine, Mount Sinai Beth Israel, New York City, NY.;Department of Cardiothoracic Surgery, Mount Sinai Beth Israel, New York, New York.;Department of Cardiology, Mount Sinai Beth Israel, New York, New York.;Department of Cardiothoracic Surgery, Mount Sinai Beth Israel, New York, New York.",
"authors": "Katz|Jonathan S|JS|;Heching|Moshe|M|http://orcid.org/0000-0001-8073-3973;Hoffman|Darryl M|DM|;Danilov|Tatyana|T|;Tranbaugh|Robert F|RF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/echo.13033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-2822",
"issue": "33(1)",
"journal": "Echocardiography (Mount Kisco, N.Y.)",
"keywords": "contrast; echocardiography; myocardial infarction; pericardium; rupture; surgery",
"medline_ta": "Echocardiography",
"mesh_terms": "D000368:Aged; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006341:Heart Rupture; D006801:Humans; D008297:Male; D045423:Microbubbles; D014463:Ultrasonography",
"nlm_unique_id": "8511187",
"other_id": null,
"pages": "150-3",
"pmc": null,
"pmid": "26299914",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Echocardiography and Cardiac Rupture: Is Contrast Extravasation an Indication for Surgery?",
"title_normalized": "echocardiography and cardiac rupture is contrast extravasation an indication for surgery"
} | [
{
"companynumb": "US-ROCHE-1709341",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENECTEPLASE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "The incidence of malignancy is greater in kidney transplant recipients compared to the general population, though the higher risk is not equally distributed to all types of cancers. In face of the increased longevity of renal transplant recipients, certain cancers, such as acute leukemias, are becoming more prevalent. Acute myeloid leukemia (AML) typically presents with cytopenias and infections, both common findings after kidney transplantation. Therefore, the diagnosis of AML may be initially overlooked in these patients. We report the case of a 33-year-old man who presented with fever, pancytopenia and acute worsening of his renal allograft function 9 years after a living unrelated kidney transplant. After initial negative infectious work-up, a kidney biopsy revealed C4d-positive antibody-mediated rejection in combination with scattered atypical inflammatory cells. A subsequent bone marrow biopsy confirmed AML. He underwent successful induction chemotherapy with daunorubucin and cytarabine and ultimately achieved a complete remission. However, he developed a Page kidney with worsening renal function and abdominal pain three weeks after biopsy in the setting of chemotherapy-induced thrombocytopenia. Herein, we discuss the prevalence, risk factors, presentation and management of leukemia after kidney transplantation.",
"affiliations": "Beth Israel Deaconess Medical Center, Harvard Medical School, USA.;Brigham & Women' Hospital, Harvard Medical School, USA.;Brigham & Women' Hospital, Harvard Medical School, USA.;Brigham & Women' Hospital, Harvard Medical School, USA.;Brigham & Women' Hospital, Harvard Medical School, USA.",
"authors": "Cardarelli|Francesca|F|;Bijol|Vanesa|V|;Chandraker|Anil|A|;Varga|Cindy|C|;Riella|Leonardo V|LV|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.5935/0101-2800.20160072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0101-2800",
"issue": "38(4)",
"journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia",
"keywords": null,
"medline_ta": "J Bras Nefrol",
"mesh_terms": "D000328:Adult; D006801:Humans; D016030:Kidney Transplantation; D015470:Leukemia, Myeloid, Acute; D008297:Male; D011183:Postoperative Complications",
"nlm_unique_id": "9426946",
"other_id": null,
"pages": "455-461",
"pmc": null,
"pmid": "28001189",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acute myeloid leukemia after kidney transplantation: a case report and literature review.",
"title_normalized": "acute myeloid leukemia after kidney transplantation a case report and literature review"
} | [
{
"companynumb": "US-TEVA-2018-US-864528",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "Endoscopic obturation by cyanoacrylate glue is currently the treatment of reference of gastric varices bleeding in patients with portal hypertension with a good efficacy for bleeding control and secondary prophylaxis. However, several adverse events related to this treatment have been described including immediate rebleeding and glue embolism. Here we present a case of gastric variceal obturation by cyanoacrylate inducing an acute pericarditis due to glue embolism in mediastinal, pericardial and phrenic veins that was managed conservatively. We also discussed pathophysiological explanations and surveillance modality.",
"affiliations": "Service d'hépatologie, Hôpital Jean-Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Établissements Sorbonne Paris Cité, Paris, France.;Service d'hépatologie, Hôpital Jean-Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Établissements Sorbonne Paris Cité, Paris, France.;Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Établissements Sorbonne Paris Cité, Paris, France; Service de radiologie, Hôpital Jean-Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris, Bondy, France.;Service d'hépatologie, Hôpital Jean-Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Établissements Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, Sorbonne Université, 75006 Paris, France; Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, 75006 Paris, France. Electronic address: naultjc@gmail.com.",
"authors": "Soualy|Adil|A|;Walter|Aurélie|A|;Sutter|Olivier|O|;Nault|Jean-Charles|JC|",
"chemical_list": "D003487:Cyanoacrylates",
"country": "France",
"delete": false,
"doi": "10.1016/j.clinre.2019.06.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2210-7401",
"issue": "44(2)",
"journal": "Clinics and research in hepatology and gastroenterology",
"keywords": "Gastric varices; Glue embolism; Pericarditis; Varices obturation",
"medline_ta": "Clin Res Hepatol Gastroenterol",
"mesh_terms": "D000208:Acute Disease; D003487:Cyanoacrylates; D004932:Esophageal and Gastric Varices; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010493:Pericarditis",
"nlm_unique_id": "101553659",
"other_id": null,
"pages": "e25-e28",
"pmc": null,
"pmid": "31401042",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute pericarditis: A rare complication of gastric variceal obturation with cyanoacrylate glue.",
"title_normalized": "acute pericarditis a rare complication of gastric variceal obturation with cyanoacrylate glue"
} | [
{
"companynumb": "FR-GUERBET-FR-20200192",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETHIODIZED OIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLamotrigine is a sodium channel blocking agent that is widely prescribed for treatment of seizure. Although life-threatening effects are rarely observed in overdose, some previous reports have described the occurrence of cardiac toxicity. The management of sodium channel blocking agent-induced cardiotoxicity conventionally requires sodium bicarbonate administration. Recent case reports describe intravenous lipid administration as a successful treatment for refractory cardiovascular collapse induced by sodium channel blocking medications.\n\n\nOBJECTIVE\nThe objective of this study is to report the use of intravenous lipid emulsion as adjunctive therapy in a case of lamotrigine overdose in which electrocardiographic changes were unresponsive to bicarbonate therapy.\n\n\nMETHODS\nWe report a case of intentional lamotrigine overdose in a 50-year-old woman who lost consciousness and developed electrocardiographic aberrations, including widening of QRS with occurrence of left bundle branch block. The patient was initially treated with sodium bicarbonate without effect. Recovery of cardiac conduction was rapidly achieved after infusion of a 20% lipid emulsion. The exact mechanism of action of lipid emulsion is not fully understood. The lipophilic properties of lamotrigine suggest that it was partially removed by the plasmatic lipid emulsion.\n\n\nCONCLUSIONS\nThis case provides additional insight into the potential benefit of using lipid emulsion in refractory sodium channel blocking intoxications.",
"affiliations": "Department of Intensive Care, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.",
"authors": "Castanares-Zapatero|Diego|D|;Wittebole|Xavier|X|;Huberlant|Vincent|V|;Morunglav|Mihaiela|M|;Hantson|Philippe|P|",
"chemical_list": "D002121:Calcium Channel Blockers; D005217:Fat Emulsions, Intravenous; D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2010.11.055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "42(1)",
"journal": "The Journal of emergency medicine",
"keywords": null,
"medline_ta": "J Emerg Med",
"mesh_terms": "D002121:Calcium Channel Blockers; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008875:Middle Aged; D016879:Salvage Therapy; D013406:Suicide, Attempted; D016896:Treatment Outcome; D014227:Triazines",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "48-51",
"pmc": null,
"pmid": "21621362",
"pubdate": "2012-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lipid emulsion as rescue therapy in lamotrigine overdose.",
"title_normalized": "lipid emulsion as rescue therapy in lamotrigine overdose"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-03273",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drug... |
{
"abstract": "OBJECTIVE\nMesalazine is a widely prescribed medication, developed as an alternative to sulfasalazine in the treatment of inflammatory bowel disease. In contrast to sulfasalazine, there are only a few case reports on its causing hepatic injury. We here report on a patient with cholestasis after mesalazine therapy for Crohn's disease of the ileum.\n\n\nRESULTS\nThe patient, a 30-year-old man, developed clinical signs of severe hepatic injury 4 months after treatment with mesalazine (4 g/day) including biopsy-proven hepatocellular cholestasis with minimal focal mononuclear inflammatory infiltration. Contrary to previous reports, no symptoms of generalized hypersensitivity were seen. The patient's illness was resolved by discontinuing the mesalazine treatment and he recovered completely in 40 days.\n\n\nCONCLUSIONS\nThis case reinforces the possibility of a causal relationship between mesalazine treatment and toxic hepatic injury without systemic hypersensitivity.",
"affiliations": "Department of Medicine, University of Bonn, Germany.",
"authors": "Stoschus|B|B|;Meybehm|M|M|;Spengler|U|U|;Scheurlen|C|C|;Sauerbruch|T|T|",
"chemical_list": "D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/s0168-8278(97)80061-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0168-8278",
"issue": "26(2)",
"journal": "Journal of hepatology",
"keywords": null,
"medline_ta": "J Hepatol",
"mesh_terms": "D000328:Adult; D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002779:Cholestasis; D003424:Crohn Disease; D006801:Humans; D008297:Male; D019804:Mesalamine",
"nlm_unique_id": "8503886",
"other_id": null,
"pages": "425-8",
"pmc": null,
"pmid": "9059966",
"pubdate": "1997-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cholestasis associated with mesalazine therapy in a patient with Crohn's disease.",
"title_normalized": "cholestasis associated with mesalazine therapy in a patient with crohn s disease"
} | [
{
"companynumb": "DE-SHIRE-DE201938032",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "1",
"d... |
{
"abstract": "We report a case of leukocytoclastic vasculitis-induced penile necrosis in a 69-year-old male with no previous urologic history. After suffering an ischemic event to the distal shaft of the penis as well as an ischemic event involving the right side of the bladder, he underwent suprapubic tube placement for urinary diversion. Despite attempts at anticoagulation for penile salvage, he lost the distal aspect of the glans penis to auto-necrosis. Ultimately, the underlying disease was determined to be systemic ANCA-associated vasculitis, and the patient was treated with rituximab and prednisone as well as penile wound debridement.",
"affiliations": "Warren Alpert Medical School, Brown University, Providence, RI, 02903, USA.;Department of Urology, Warren Alpert Medical School, Brown University, RI, 02903, USA.;Department of Urology, Warren Alpert Medical School, Brown University, RI, 02903, USA.;Department of Urology, Warren Alpert Medical School, Brown University, RI, 02903, USA.;Department of Urology, Warren Alpert Medical School, Brown University, RI, 02903, USA.",
"authors": "Moseley|Isabelle|I|;Greenberg|Rachel|R|;Wasserman|Meredith|M|;Thavaseelan|Simone|S|;Cancian|Madeline|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2021.101902",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(21)00342-9\n10.1016/j.eucr.2021.101902\n101902\nTrauma and Reconstruction\nLeukocytoclastic vasculitis leading to penile necrosis and ischemia of the bladder and urethra\nMoseley Isabelle Isabelle_moseley@brown.edu\na∗\nGreenberg Rachel b\nWasserman Meredith b\nThavaseelan Simone b\nCancian Madeline b\na Warren Alpert Medical School, Brown University, Providence, RI, 02903, USA\nb Department of Urology, Warren Alpert Medical School, Brown University, RI, 02903, USA\n∗ Corresponding author. Warren Alpert Medical School, Brown University, 339 Eddy Street Providence, RI, 02903, USA. Isabelle_moseley@brown.edu\n19 10 2021\n1 2022\n19 10 2021\n40 10190210 10 2021\n16 10 2021\n© 2021 Published by Elsevier Inc.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe report a case of leukocytoclastic vasculitis-induced penile necrosis in a 69-year-old male with no previous urologic history. After suffering an ischemic event to the distal shaft of the penis as well as an ischemic event involving the right side of the bladder, he underwent suprapubic tube placement for urinary diversion. Despite attempts at anticoagulation for penile salvage, he lost the distal aspect of the glans penis to auto-necrosis. Ultimately, the underlying disease was determined to be systemic ANCA-associated vasculitis, and the patient was treated with rituximab and prednisone as well as penile wound debridement.\n\nKeywords\n\nPenile necrosis\nLeukocytoclastic vasculitis\nReconstructive urology\n==== Body\npmc1 Introduction\n\nLeukocytoclastic vasculitis (LCV) is a common form of small vessel vasculitis with histopathology demonstrating neutrophil-predominant inflammation, fibrinoid necrosis, and leukocytoclasia.1 LCV can be caused by infections, paraneoplastic conditions, or systemic diseases.1 The leading clinical presentation of LCV is palpable purpura, but frank necrosis, including penile necrosis, has been reported.1 Here we report a complex case of LCV-associated penile necrosis associated with segmental bladder ischemia.\n\n2 Case report\n\nA 70-year-old male (Patient “M”) having history of hypertension, hyperlipidemia, segmental colitis associated with diverticula (SCAD), and unprovoked extensive bilateral lower extremity DVT and PE six months prior, with a recent diagnosis of leukoclastic vasculitis (LCV), presented to the emergency department with two days of penile pain, swelling, and discoloration. On anticoagulation for the past six months, this was held two days prior to presentation for upcoming endoscopy. He had been diagnosed with LCV from a skin biopsy after developing spontaneous large bilateral flank hematomas, thought to be warfarin-induced, and thus had been transitioned to apixaban.\n\nPhysical exam was notable for ischemic, cold glans tissue with demarcation at the distal shaft commensurate with his circumcision scar. The shaft was edematous, but the corpora were palpably soft (Fig. 1). A penile blood gas showed pH 6.88 and pO2 < 30. Despite the ischemic blood gas, history and physical examination were not consistent with priapism; thus, no further drainage was performed.Fig. 1 a and b. Penis at time of presentation to ER. c and d. Improvement in ischemia on HD4 after initiation of heparin and steroids.\n\nFig. 1\n\nLabs demonstrated a leukocytosis to 19.8, hemoglobin 9.4, and acute kidney injury (AKI) with creatinine 2.38. Urinalysis demonstrated >180 RBCs. CT of the abdomen and pelvis revealed bilateral corpora cavernosum were expanded and hypodense, with inflammatory change along the corpora into the preperitoneal space. CT cystogram was performed due to history of gross hematuria and stranding around the bladder which showed no evidence of bladder perforation.\n\nHematology and Rheumatology initiated heparin high intensity protocol with further workup over concern for thrombotic event because of held anticoagulation. He was started on high dose steroidal therapy due to concern for a vasculitic process. Vascular imaging was considered but unfortunately, due to his AKI, he could not receive intravenous contrast. A foley catheter was placed for initial urinary drainage.\n\nMild improvement in skin discoloration after initiation of the above therapy was noted (Fig. 2). Due to significant discomfort from the foley catheter, options for alternative urinary diversion were discussed with the patient, who opted for suprapubic tube (SPT) placement. Cystourethroscopy during SPT placement revealed evidence of vascular congestion/necrotic change of the bulbar urethra and devitalization of the right lateral bladder wall, causing concern for bladder infarction.Fig. 2 Autoamputation of the penile glans.\n\nFig. 2\n\nThe diagnosis was ANCA-associated leukocytoclastic vasculitis which was treated with rituximab and prednisone and transition back to apixaban. On hospital day sixteen, he was discharged.\n\nFollowed closely by urology as an outpatient, approximately two months later M's glans was noted to have autoamputated (Fig. 3). His penile wound received local care and clobetasol cream to allow healing via secondary intention. Cystoscopy three months post-injury was notable for significant debris but showed healthy and well-perfused bladder and urethral mucosa. Urodynamics revealed small bladder capacity at 163 ccs and hypoactive detrusor muscle with max pdet of 33 cm H2O. When his SPT was removed, he was voiding on his own 18 months post-injury with improving frequency and urge incontinence. He continued pelvic floor physical therapy and anticholinergic medication.Fig. 3 Admission CT abdomen and pelvis.\n\nFig. 3\n\n3 Discussion\n\nThis case highlights the importance of care coordination between specialties for complex presentations. M's medical history contained features concerning for numerous reported causes of penile necrosis. For example, isolated gangrene of the penis has been reported in patients with ESRD as a localized manifestation of vascular calcification.2 Based on M's proteinuria and acute kidney injury, calciphylaxis in the setting of ESRD warranted consideration; however, the workup was negative. Hematology investigated a potential underlying hypercoagulable or paraneoplastic process. Thrombus was not noted on imaging; tissue biopsies, chest and abdominal imaging, and colonoscopy results revealed no concerns for malignancy.\n\nThe edematous shaft made ischemic priapism an immediate concern, requiring urology consultation. Anticoagulant use is a known risk factor for ischemic priapism, and penile blood gas analysis revealed oxygen deprivation.3 However, the corpora appeared soft on physical examination, so priapism treatment was not pursued.\n\nThe possibility of Fournier's gangrene also required immediate attention; treatment delay is associated with up to 90% lethality.4 In Fournier's gangrene, bacteremia of the urogenital tract, anorectal area, or genital skin initiates a cytokine cascade, leading to endothelial damage and subsequent activation of the coagulation cascade with inhibition of fibrinolysis and disseminated microthrombosis of vessels feeding the fascia. With inflammation, these factors produce ischemic necrosis of the fascia. Local manifestations begin with ulceration of the glans, prepuce, skin of the penis, or scrotum, progressing to tissue necrosis within hours, sometimes leading to sepsis, multi-organ failure, and death. Despite the penile ischemia and necrosis, our patient was alert and oriented, demonstrating no signs of altered mental status, making Fournier's highly unlikely.4\n\nPer Rheumatology, due to M's atypical p-ANCA of 1:320, positive PR3 of 1.7, and biopsy proven LCV, ANCA-associated vasculitis (AAV) was a potential cause of his presentation. Prior case studies described LCV-associated penile necrosis with underlying AAV, as well as several other LCV-associated systemic conditions, including Crohn's Disease (CrD), Henoch-Schönlein purpura (HSP), cryoglobulinemia, polyarteritis nodosa (PAN), antiphospholipid syndrome (APLS), and Bechet's Disease (BD).2,5\n\nConsidering M's biopsy-proven LCV, recurrent clots, positive atypical p-ANCA and PR3, and the involvement of multiple vascular territory infarcts, ANCA-associated LCV was concluded as the most likely cause of M's presentation. The high level of collaboration between our medical and surgical teams optimized the care M received at our institution.\n\n4 Conclusion\n\nAlthough penile necrosis is rare due to the rich circulation network of the perineum and lower abdomen, a wide range of causes have been reported, including ischemic priapism and Fournier's gangrene in addition to numerous paraneoplastic and systemic conditions related to LCV. In patients suffering from penile necrosis, surgical management must be combined with multidisciplinary evaluation to determine the best course of treatment.\n\nConsent\n\nWritten consent was obtained from the patient for use of medical health information and pictures.\n\nDeclaration of competing interest\n\nThe authors of this article have no conflicts of interest to disclose.\n==== Refs\nReferences\n\n1 Fraticelli P. Benfaremo D. Gabrielli A. Diagnosis and management of leukocytoclastic vasculitis Internal Emerg Med 16 4 2021 831 841 33713282\n2 Chiang I.N. Chang S.J. Kuo Y.C. Liu S.P. Yu H.J. Hsieh J.T. Management of ischemic penile gangrene: prompt partial penectomy and other treatment options J Sex Med 5 11 2008 2725 2733 18565112\n3 Ridgley J. Raison N. Sheikh M.I. Dasgupta P. Khan M.S. Ahmed K. Ischaemic priapism: a clinical review Turk J Urol 43 1 2017 1 8 28270944\n4 Chernyadyev S.A. Ufimtseva M.A. Vishnevskaya I.F. Fournier's gangrene: literature review and clinical cases Urol Int 101 1 2018 91 97 29949811\n5 Daniels A.H. Wilson C.L. Harrison R.A. Hepatitis C–associated leukocytoclastic vasculitis with anticardiolipin antibodies causing penile necrosis and deep venous thrombosis in the absence of cryoglobulinemia J Hosp Med 3 2 2008 170 172 18438797\n\n",
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"keywords": "Leukocytoclastic vasculitis; Penile necrosis; Reconstructive urology",
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"title": "Leukocytoclastic vasculitis leading to penile necrosis and ischemia of the bladder and urethra.",
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"abstract": "BACKGROUND\nAdministering intravenous IV tissue plasminogen activator (tPA) is the recommended standard of care in acute ischemic stroke (AIS), although it is not recommended to administer intravenous thrombolysis with tPA following heparin reversal with protamine sulfate in patients with AIS.\n\n\nMETHODS\nWe describe a case series of three patients and the most comprehensive literature review published to date in this specific subset of AIS patients undergoing thrombolysis following heparin reversal with protamine sulfate. The literature review was based on a scoping review methodology performed on four databases; PubMed, CINAHL, Web of Science, and Cochrane Library. All sources were searched from the inauguration of the database until February 2019. A total of six articles involving eight patients were identified.\n\n\nRESULTS\nThe primary safety outcome of no symptomatic intracranial hemorrhage (sICH) was met in all eleven patients, although only seven cases had a good functional outcome at 3 months.\n\n\nCONCLUSIONS\nIn appropriately selected AIS patients, coagulopathy correction appears to be safe from an sICH standpoint and may be beneficial. However, given the potential for bias with observational databases, case reports and case series, extreme caution is warranted in applying these results to routine clinical practice.",
"affiliations": "Department of Neurology, West Virginia University, Morgantown, West Virginia. Electronic address: tamrar@gmail.com.;Health Science Library, West Virginia University, Morgantown, West Virginia.;Department of Pharmacy, West Virginia University, Morgantown, West Virginia.;Department of Neurology, West Virginia University, Morgantown, West Virginia.",
"authors": "Ranasinghe|Tamra|T|;Mays|Traci|T|;Quedado|Jeff|J|;Adcock|Amelia|A|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006494:Heparin Antagonists; D011479:Protamines; D006493:Heparin; D010959:Tissue Plasminogen Activator",
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"keywords": "Acute ischemic stroke; IV tPA; case series; heparin reversal; literature review; protamine sulfate; symptomatic intracranial hemorrhage; thrombolysis",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001777:Blood Coagulation; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D006493:Heparin; D006494:Heparin Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D011479:Protamines; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
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"title": "Thrombolysis Following Heparin Reversal With Protamine Sulfate in Acute Ischemic Stroke: Case Series and Literature Review.",
"title_normalized": "thrombolysis following heparin reversal with protamine sulfate in acute ischemic stroke case series and literature review"
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"abstract": "We describe a case of septic arthritis in a native knee due to Corynebacterium striatum, gram-positive bacilli that are usually commensal organisms of skin and mucosal membranes, but are seldom implicated in native septic arthritis. An 84-year-old man with Corynebacterium striatum septic arthritis of his native left knee and no response to conventional antibiotic therapy. Thus, the patient was allowed to take dalbavancin for compassionate use, with an excellent clinical outcome. This case emphasizes de role of Corynebacterium striatum in native joint infections and highlights the importance of early detection and appropriate treatment in improving the clinical outcome.",
"affiliations": "Servicio de Reumatología, Hospital Universitario La Paz, Madrid, España. Electronic address: molinacolladajuan@gmail.com.;Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario La Paz, Madrid, España.;Servicio de Geriatría, Hospital Universitario La Paz, Madrid, España.;Servicio de Reumatología, Hospital Universitario La Paz, Madrid, España.",
"authors": "Molina Collada|Juan|J|;Rico Nieto|Alicia|A|;Díaz de Bustamante Ussia|Macarena|M|;Balsa Criado|Alejandro|A|",
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"issue": "14(5)",
"journal": "Reumatologia clinica",
"keywords": "Arthritis; Artritis; Corynebacterium striatum; Dalbavancin; Dalbavancina",
"medline_ta": "Reumatol Clin (Engl Ed)",
"mesh_terms": "D000369:Aged, 80 and over; D001170:Arthritis, Infectious; D003354:Corynebacterium Infections; D006801:Humans; D007719:Knee Joint; D008297:Male",
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"title": "Septic arthritis in a native knee due to Corynebacterium striatum.",
"title_normalized": "septic arthritis in a native knee due to corynebacterium striatum"
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"abstract": "BACKGROUND Malignant hypercalcemia is a rare finding in the pediatric population, even more rare in hematological malignancies, such as leukemia. CASE REPORT We present a case of a 6-year-old female patient who was diagnosed with acute lymphoblastic leukemia, with secondary hypercalcemia. She started chemotherapy following the IC-BFM ALL2002 protocol with simultaneous calcitonin, diuretics and aggressive hydration for hypercalcemia, and went into complete remission after the induction therapy. After 4 months of chemotherapy, she was diagnosed with relapse associated again with malignant hypercalcemia, and underwent chemotherapy with the relapse protocol. There was no response after the first 2 cycles, so we decided to start her on clofarabine. Due to the severe hypercalcemia and consecutive osteolysis, she developed several bone fractures and needed gypsum immobilization. We started her again on calcitonin, but she developed severe adverse reactions, so we found it necessary to start bisphosphonates, first zoledronic acid intravenously, and afterwards clodronate orally. Consolidation of bone fractures was achieved, but due to prolonged immobilization she developed bedsores, superinfected with Lichtheimia corymbifera. We started posaconazole orally, but she rapidly went into severe sepsis with multiple organ failure. The leukemia showed no response to chemotherapy, progressed rapidly, and the patient died. CONCLUSIONS Malignant hypercalcemia is associated with a poor prognosis in leukemia, and might need a more aggressive therapy.",
"affiliations": "Department of Pediatrics, University of Medicine and Pharmacy \"Iuliu Hatieganu\", Cluj-Napoca, Romania.;Department of Pediatrics, University of Medicine and Pharmacy \"Iuliu Hatieganu\", Cluj-Napoca, Romania.;Department of Pediatrics, University of Medicine and Pharmacy \"Iuliu Hatieganu\", Cluj-Napoca, Romania.;Department of Pediatric Surgery and Orthopedics, University of Medicine and Pharmacy \"Iuliu Hatieganu\", Cluj-Napoca, Romania.;Department of Pediatrics, University of Medicine and Pharmacy \"Iuliu Hatieganu\", Cluj-Napoca, Romania.",
"authors": "Bota|Mădălina|M|;Popa|Gheorghe|G|;Neaga|Alexandra|A|;Gocan|Horatiu|H|;Blag|Cristina Lucia|CL|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3091824210.12659/AJCR.914303914303ArticlesAcute Lymphoblastic Leukemia with Malignant Hypercalcemia: A Case Report Bota Mădălina ABCDEF1Popa Gheorghe CDF1Neaga Alexandra ABC1Gocan Horaţiu CDF2Blag Cristina Lucia ABCDEF1\n1 Department of Pediatrics, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania\n2 Department of Pediatric Surgery and Orthopedics, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, RomaniaAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Cristina Lucia Blag, e-mail: cristinablag@yahoo.com2019 28 3 2019 20 402 405 27 11 2018 17 1 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 6\n\nFinal Diagnosis: Acute lymphoblastic leukemia\n\nSymptoms: Abdominal pain • bloody diarrhea • malaise • vomiting\n\nMedication: —\n\nClinical Procedure: Chemotherapy\n\nSpecialty: Oncology\n\nObjective:\nUnusual clinical course\n\nBackground:\nMalignant hypercalcemia is a rare finding in the pediatric population, even more rare in hematological malignancies, such as leukemia.\n\nCase Report:\nWe present a case of a 6-year-old female patient who was diagnosed with acute lymphoblastic leukemia, with secondary hypercalcemia. She started chemotherapy following the IC-BFM ALL2002 protocol with simultaneous calcitonin, diuretics and aggressive hydration for hypercalcemia, and went into complete remission after the induction therapy. After 4 months of chemotherapy, she was diagnosed with relapse associated again with malignant hypercalcemia, and underwent chemotherapy with the relapse protocol. There was no response after the first 2 cycles, so we decided to start her on clofarabine. Due to the severe hypercalcemia and consecutive osteolysis, she developed several bone fractures and needed gypsum immobilization. We started her again on calcitonin, but she developed severe adverse reactions, so we found it necessary to start bisphosphonates, first zoledronic acid intravenously, and afterwards clodronate orally. Consolidation of bone fractures was achieved, but due to prolonged immobilization she developed bedsores, superinfected with Lichtheimia corymbifera. We started posaconazole orally, but she rapidly went into severe sepsis with multiple organ failure. The leukemia showed no response to chemotherapy, progressed rapidly, and the patient died.\n\nConclusions:\nMalignant hypercalcemia is associated with a poor prognosis in leukemia, and might need a more aggressive therapy.\n\nMeSH Keywords:\nChildHypercalcemiaPrecursor Cell Lymphoblastic Leukemia-Lymphoma\n==== Body\nBackground\nMalignant hypercalcemia is a rare finding in the pediatric population, the overall incidence being at 0.4–1.3% [1]. Most often it is described in solid tumors, such as Ewing’s sarcoma, neuroblastoma, rhabdomyosarcoma, non-Hodgkin lymphoma, and in rare situations associated to acute leukemia or chronic myeloid leukemia, mostly in the accelerated or blast phases [1–4]. The mechanism is most likely humoral and dependent on the parathormone-related protein (PTHrP) [3,5]. The clinical manifestations vary according to the values of hypercalcemia, and can lead to life-threatening symptoms. Most commonly, patients present with nausea, vomiting, and constipation, but high levels can also present with arrhythmias and renal failure. Early management of hypercalcemia starts with aggressive hydration, forced diuresis with furosemide, and calcitonin respectively [5]. If necessary, therapy with bisphosphonates, such as zoledronic acid, pamidronate, or clodronate, is another option. Dialysis can be instituted if there is no response to medical treatment, or in life-threatening situations [6]. Denosumab, a monoclonal antibody, can be used in refractory disease [3].\n\nWe present the case of a 6-year-old female patient diagnosed and treated in our clinic for acute lymphoblastic leukemia with secondary malignant hypercalcemia.\n\nCase Report\nOur 6-year-old patient was first diagnosed in August 2016 when she came with malaise, abdominal pain, vomiting, and bloody diarrhea. Clinical examination, peripheral hematological tests, bone marrow aspirate, and immunophenotyping confirmed the diagnosis of B-cell precursor acute lymphoblastic leukemia with paraneoplastic hypercalcemia (Table 1). The initial level of calcium was at 14.9 mg/dL, with signs of tumor lysis syndrome, with high uric acid (9.9 mg/dL) and renal failure (BUN 66 mg/dL and creatinine 1.01 mg/dL). We as well determined the values of PTH and 1,25-OH-vitamin D, which were both decreased.\n\nIntensive chemotherapy was started according to the IC-BFM ALL 2002. Concurrently we administered calcitonin intramuscularly (4 UI/kg every 12 hours), abundant hydration (3.000 mL/m2) and furosemide starting with 1 mg/kg/day, and then up to 3 mg/kg/day. Calcium levels started to decrease, and the patient went into complete remission after the induction therapy.\n\nAfter 4 months, during the consolidation therapy, the patient presented again with malaise, vomiting, diarrhea, and high calcium levels. Very early relapse was diagnosed by bone marrow aspirate and immunophenotyping and we started intensive chemotherapy according to the IC-BFM ALL 2002 REZ (Table 1). Calcium levels were high, but this time the patient did not experience tumor lysis syndrome with renal failure (Table 2).\n\nWe first controlled hypercalcemia with calcitonin (4 UI/kg every 12 hours), but at the third dose the patient developed blurred vision, so calcitonin had to be stopped. The patient developed, due to severe osteolytic lesions, a spontaneous bone fracture of the left femur, so we found it necessary to start bisphosphonates. The patient received an intravenous dose of 2 mg zoledronic acid, developing thereafter moderate hypocalcemia with the need of calcium supplementation for approximately 10 days (Table 3). After the stabilization of calcium levels, we switched to clodronate orally. Unfortunately, she experienced another bone fracture of the contralateral leg and needed a pelvipedios gypsum immobilization (Figure 1). After 8 weeks of gypsum immobilization association with clodronate, consolidation of bone fractures was achieved.\n\nThe patient didn’t respond to induction chemotherapy, after the first 2 blocks, we declared progressive disease, so third-line therapy with clofarabine was started.\n\nDue to severe pancytopenia, gypsum, and prolonged immobilization she developed bedsores, which evolved into necrosis. Cultures were collected and infection with Lichtheimia corymbifera was diagnosed. We decided to start treatment with posaconazole orally, but unfortunately, the patient developed severe sepsis, with multiple organ failure.\n\nAt the same time, her leukemia showed no response to chemotherapy with clofarabine and the patient died with progressive disease.\n\nDiscussion\nMalignant hypercalcemia is very rare in children, and has been described mostly in solid tumors and lymphomas. The pathogenesis describes a humoral pattern dependent on the PTHrP. There are 3 different known mechanism, from which the humoral pattern is the most common one, where both the PTH and the 1,25-OH vitamin D levels are low and the PTHrP level is high [3]. The other 2 mechanisms, the direct invasion of the bone and the 1,25OH-D mediated one, are characterized by low PTHrP level and low PTH level. The level of 1,25OH-D is only high in the pattern it mediates [3,5–7]. Being unable to determine the level of PTHrP, we only assumed that our case had the humoral pattern, being characterized by both low PTH and 1,25OH-D levels.\n\nStudies have underlined the association of malignant hypercalcemia with a B-precursor phenotype leukemia with aberrant expression of CD13 and CD33, a leucocyte count of less than 20 000/mm3 at diagnosis, with the hypercalcemia being present as well at the time of diagnosis as at the time of relapse. All these were confirmed in our case, as well [8].\n\nThere are some published case reports that link the malignant hypercalcemia to the translocation (17;19) [8–12]. The t(17;19) (q22;p13) translocation generates the E2A-HLF chime-ric transcription factor and is associated with a high risk of relapse and poor prognosis, with an event-free survival (EFS) at 5 years of 0% [8,10,11]. This was confirmed also in our case, as the patient had a very early relapse and the leukemia was refractory even to third-line therapy with clofarabine, leading to the death of the patient.\n\nTreatment of paraneoplastic hypercalcemia depends on the level of calcemia. With only low hypercalcemia protocols recommending the use of calcitonin, diuretics such as furosemide, concomitantly with aggressive hydration. In cases with high levels of calcemia, or a poor response to the first-line treatment, and nonetheless in life-threatening situations, the use of bisphosphonates is recommended. Bisphosphonates are rarely used in children, because of their early and late potential side-effects. However, pamidronate has been shown to be efficient with few side-effects in adults with malignant hypercalcemia [13]. Studies have shown that hypercalcemia decreases faster if bisphosphonates are used [14,15]. Little is known about the correct dosage, but there are some suggestions regarding its administration. Doses range from 0.025 mg/kg to 0.05 mg/kg, and as well-fixed doses of 4 mg of zoledronic acid [3,7,16], and a dose of 1 to 2 mg/kg, with a maximum of 60 mg of pamidronate [2]. We decided to administer only 2 mg of zoledronic acid. Even with a smaller amount, the patient still developed hypocalcemia and needed calcium supplementation for more than 1 week. We did not experience any cardiac side-effects. Even though we continued to administer clodronate orally after the calcium levels stabilized, the patient still suffered another bone fracture.\n\nAnother particularity of our case was the infectious complication with Lichtheimia corimbyfera, a fungus known to infect immunosuppressed patients. It most commonly affects the central nervous system (CNS), but in some particular situations can also infect traumatized skin [17]. In our case, due to her severe pancytopenia secondary to intensive chemotherapy, and the immobilization with pelvipedios gypsum, the patient developed bedsores underneath the gypsum. We started local and systemic treatment with antibiotic and antifungals ointments, a broad-spectrum antibiotic, and voriconazole, respectively. The evolution of bedsores was poor with the development of necrosis. Literature studies suggest that the best treatment option for this fungus type is amphotericin B, but this product is not available in our country. Therefore, we decided to start oral posaconazole [17,18].\n\nConclusions\nMalignant hypercalcemia may offer, in acute lymphoblastic leukemia in children, a poor prognosis, as was shown in our case report. The limitation of our case report was the lack of possibility to determine the translocation, both due to the absence of a specialized laboratory at the time of diagnosis, and the impossibility to draw enough bone marrow blood at the relapse, because of high fragility of the bone.\n\nFigure 1. Bone radiography: severe osteopenia. Left distal femur fracture. Left proximal femur callus formation (possible old fracture).\n\nTable 1. Characteristics of leukemia at diagnosis and at relapse.\n\nLeukemia\tDiagnosis\tRelapse\t\nLeucocytes\t12 400/mm3\t4000/mm3\t\nBone marrow aspirate\t97% blasts with a morphology of acute lymphoblastic leukemia, L1 (FAB classification)\t32% blasts with a morphology of acute lymphoblastic leukemia, L1, relapse 1\t\nImmunophenotyping\t95% pro-B CALLA positive, with aberrant coexpression of myeloid marker (CD33) and partial maturation asynchronism (partial IgM positive).\t95% pro-B CALLA positive, with aberrant coexpression of myeloid marker (CD33, CD13)\t\nTranslocations\tNegative BCR-ABL, TEL-AML, MLL\tnegative BCR-ABL, TEL-AML, MLL\t\nKaryotype\t10 metaphases had a karyotype of 45,XX,+6,–9,–12, and the rest were with normal karyotype of 46,XX\tNot performed\t\nTable 2. Comparative values of parameters at diagnosis and at relapse.\n\n\tDiagnosis\tRelapse\t\nTotal calcium\t14.9 mg/dL\t15.5 mg/dL\t\nUric acid\t9.9 mg/dL\t\t\nBUN\t66 mg/dL\t29 mg/dL\t\nCreatinine\t1.01 mg/dL\t0.62 mg/dL\t\nPeripheral blasts\t1.600/mm3\tAbsent\t\nBone marrow aspirate\t97% blasts\t32% blasts\t\nPTH\t10.1 pg/mL\tNot performed\t\n1,25-OH vitamin D\t<5 pg/mL\tNot performed\t\nTable 3. Calcium level variations after zoledronic therapy.\n\n\tDay 1 – zoledronic acid administration\tDay 2\tDay 3 – initiation of calcium supplementation\tDay 4\tDay 5\tDay 6\tDay 7\tDay 8\tDay 9\t\nCalcium levels (mg/dL)\t13.7\t12.2\t8.6\t7.9\t7.6\t7.3\t8.1\t8.7\t9.2\n==== Refs\nReferences:\n1. Bahoush G Miri-Aliabad G Severe hypercalcemia: A rare and unusual presentation of childhood acute lymphoblastic leukemia Int J Hematol Oncol Stem Cell Res 2014 8 2 38 40 24800038 \n2. Schmid I Stachel D Schon C Pamidronate and calcitonin as therapy of acute cancer-related hypercalcemia in children Klin Padiatr 2001 213 1 30 34 11225473 \n3. Sternlicht H Glezerman IG Hypercalcemia of malignancy and new treatment options Ther Clin Risk Manag 2015 11 1779 88 26675713 \n4. Toro-Tobon D Agosto S Ahmadi S Chronic myeloid leukemia associated hypercalcemia: A case report and literature review Am J Case Rep 2017 18 203 7 28239141 \n5. Sargent JT Smith OP Haematological emergencies managing hypercalcaemia in adults and children with haematological disorders Br J Haematol 2010 149 4 465 77 20377591 \n6. Hoyoux C Lombet J Nicolescu CR Malignancy-induced hypercalcemia-diagnostic challenges Front Pediatr 2017 5 233 29181374 \n7. Kolyva S Efthymiadou A Gkentzi D Hypercalcemia and osteolytic lesions as presenting symptoms of acute lymphoblastic leukemia in childhood. The use of zoledronic acid and review of the literature J Pediatr Endocrinol Metab 2014 27 3–4 349 54 23934636 \n8. Lokadasan R Prem S Koshy SM Jayasudha AV Hypercalcaemia with disseminated osteolytic lesions: A rare presentation of childhood acute lymphoblastic leukaemia Ecancermedicalscience 2015 9 542 26082799 \n9. Martins AL Moniz M Nunes PS Severe hypercalcemia as a form of acute lymphoblastic leukemia presentation in children Rev Bras Ter Intensiva 2015 27 4 402 5 26761480 \n10. Inukai T Hirose K Inaba T Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19 Leukemia 2007 21 2 288 96 17183364 \n11. Minson KA Prasad P Vear S t(17;19) in children with acute lymphocytic leukemia: A report of 3 cases and a review of the literature Case Rep Hematol 2013 2013 563291 23346431 \n12. Poiree M Dupont A Gondon E Life-threatening hypercalcemia as the initial presentation of childhood acute lymphoblastic leukemia Arch Pediatr 2015 22 6 608 12 25896627 \n13. Mahmoud S Mitwally H El Zeer HS Use of pamidronate to treat hypercalcemia in an oncology dialysis patient: A case report Am J Case Rep 2018 19 1087 89 30209247 \n14. Kerdudo C Aerts I Fattet S Hypercalcemia and childhood cancer: A 7-year experience J Pediatr Hematol Oncol 2005 27 1 23 27 15654274 \n15. Trehan A Cheetham T Bailey S Hypercalcemia in acute lymphoblastic leukemia: An overview J Pediatr Hematol Oncol 2009 31 6 424 27 19648791 \n16. Park HJ Choi EJ Kim JK A successful treatment of hypercalcemia with zoledronic acid in a 15-year-old boy with acute lymphoblastic leukemia Ann Pediatr Endocrinol Metab 2016 21 2 99 104 27462588 \n17. Blazquez D Ruiz-Contreras J Fernandez-Cooke E Lichtheimiacorymbifera subcutaneous infection successfully treated with amphotericin B, early debridement, and vacuum-assisted closure J Pediatr Surg 2010 45 12 e13 15 \n18. Kleinotiene G Posiunas G Raistenskis J Liposomal amphotericin B and surgery as successful therapy for pulmonary Lichtheimia corymbifera zygomycosis in a pediatric patient with acute promyelocytic leukemia on antifungal prophylaxis with posaconazole Med Oncol 2013 30 1 433 23307250\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D002648:Child; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D010257:Paraneoplastic Syndromes; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011859:Radiography",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "402-405",
"pmc": null,
"pmid": "30918242",
"pubdate": "2019-03-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11225473;15654274;17183364;19648791;20377591;21129524;23307250;23346431;23934636;24800038;25896627;26082799;26675713;26761480;27462588;28239141;29181374;30209247",
"title": "Acute Lymphoblastic Leukemia with Malignant Hypercalcemia: A Case Report.",
"title_normalized": "acute lymphoblastic leukemia with malignant hypercalcemia a case report"
} | [
{
"companynumb": "RO-FRESENIUS KABI-FK201910225",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nAseptic meningitis is a rare and aggressive complication of rheumatoid arthritis (RA), usually histologically characterised by rheumatoid nodules and lymphocytic aggregates in leptomeninges. The aim of this study was to describe the clinical onset and evolution of aseptic meningitis occurring during anti-TNF-alpha (TNF-α) therapy.\n\n\nMETHODS\nwe retrospectively analysed the clinical records of patients with RA or ankylosing apondylitis (AS) treated by TNF-α drugs in the last 10 years.\n\n\nRESULTS\nFour out of 718 patients, treated with TNF-α, developed meningitis after a mean of 5 years (SD: 3.7) of TNF-α exposure (0.55%). Three subjects were affected by long-standing RA (median: 11 years, IQR:8.5-25), one patient by active AS of 8 years' duration. RA patients were treated with etanercept (2 cases) and infliximab (1 case), in association with methotrexate and prednisone. The AS patient was treated with adalimumab. Neurological onset was focal epilepsy (3 cases) and dysarthria (1 case). RM showed leptomeningeal enhancement of basal nuclei (1 case) or fronto-parietal zone (3 cases), associated in one patient with cerebritis. Bacterial, viral or parasitic infections were excluded. One patient underwent cerebral biopsy showing T and B lymphocytes' aggregates. All patients discontinued TNF-α drugs and were treated with high dose of steroids, added to methotrexate in two cases. Neurological symptoms resolved without residuals, and meningeal enhancement showed resolution with high latency.\n\n\nCONCLUSIONS\nMeningeal inflammation is a rare manifestation occurring in long-standing RA and AS in clinical remission. TNF-α therapy did not prevent this extra-articular complication.",
"affiliations": "Rheumatology and Clinical Immunology Unit, Spedali Civili di Brescia, Brescia, Italy. ilariacava@virgilio.it.",
"authors": "Cavazzana|Ilaria|I|;Taraborelli|Mara|M|;Fredi|Micaela|M|;Tincani|Angela|A|;Franceschini|Franco|F|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "32(5)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008582:Meningitis, Aseptic; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D013167:Spondylitis, Ankylosing; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "732-4",
"pmc": null,
"pmid": "25198168",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aseptic meningitis occurring during anti-TNF-alpha therapy in rheumatoid arthritis and ankylosing spondylitis.",
"title_normalized": "aseptic meningitis occurring during anti tnf alpha therapy in rheumatoid arthritis and ankylosing spondylitis"
} | [
{
"companynumb": "IT-JNJFOC-20141006117",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "LMB-100 is a recombinant immunotoxin (iTox) consisting of a mesothelin-binding Fab for targeting and a modified Pseudomonas exotoxin A payload. Preclinical studies showed that combining taxanes with iTox results in synergistic antitumor activity. The objectives of this phase I/II study were to determine the MTD of LMB-100 when administered with nanoalbumin bound (nab)-paclitaxel to patients with previously treated advanced pancreatic adenocarcinoma and to assess the objective response rate.\n\n\n\nPatients (n = 20) received fixed-dose nab-paclitaxel (125 mg/m2 on days 1 and 8) with LMB-100 (65 or 100 μg/kg on days 1, 3, and 5) in 21-day cycles for 1-3 cycles.\n\n\n\nFourteen patients were treated on the dose escalation and an additional six in the phase II expansion. MTD of 65 μg/kg was established for the combination. Dose-limiting toxicity resulting from capillary leak syndrome (CLS) was seen in two of five patients treated at 100 μg/kg and one of six evaluable phase I patients receiving the MTD. Severity of CLS was associated with increases in apoptotic circulating endothelial cells. LMB-100 exposure was unaffected by anti-LMB-100 antibody formation in five of 13 patients during cycle 2. Seven of 17 evaluable patients experienced >50% decrease in CA 19-9, including three with previous exposure to nab-paclitaxel. One patient developed an objective partial response. Patients with biomarker responses had higher tumor mesothelin expression.\n\n\n\nAlthough clinical activity was observed, the combination was not well tolerated and alternative drug combinations with LMB-100 will be pursued.",
"affiliations": "Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. alewinecc@mail.nih.gov.;Office of Research Nursing, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Clinical Pharmacology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Medical Oncology Service, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Clinical Pharmacology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Biostatistics and Data Management Section, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Clinical Pharmacology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.;Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.",
"authors": "Alewine|Christine|C|;Ahmad|Mehwish|M|;Peer|Cody J|CJ|;Hu|Zishuo I|ZI|;Lee|Min-Jung|MJ|;Yuno|Akira|A|;Kindrick|Jessica D|JD|;Thomas|Anish|A|;Steinberg|Seth M|SM|;Trepel|Jane B|JB|;Figg|William D|WD|;Hassan|Raffit|R|;Pastan|Ira|I|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; C000597116:LMB-100; D000090204:Mesothelin; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-19-2586",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "26(4)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D004334:Drug Administration Schedule; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D018796:Immunoconjugates; D008297:Male; D020714:Maximum Tolerated Dose; D000090204:Mesothelin; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D017239:Paclitaxel; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "828-836",
"pmc": null,
"pmid": "31792036",
"pubdate": "2020-02-15",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "9815960;30051098;27863199;21561347;15930349;26082895;25366685;25239937;28242752;27601652;29152082;28754816;18191625;27507537;29313949;31157963;27999204;25824606;30575490;24928849;24131140",
"title": "Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma.",
"title_normalized": "phase i ii study of the mesothelin targeted immunotoxin lmb 100 with nab paclitaxel for patients with advanced pancreatic adenocarcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2020M1034140",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report the incidence and risk factors for contrast material ( CM contrast material )-induced nephropathy ( CIN CM-induced nephropathy ) in patients with no history of chronic kidney disease and estimated glomerular filtration rate that exceeded 30 mL/min/1.73 m(2) after a relatively high dose of CM contrast material (≥250 mL) during neuroendovascular procedures.\n\n\nMETHODS\nAn institutional review board-approved retrospective chart review was performed for all patients who received a dose of CM contrast material 250 mL or greater while they underwent a neuroendovascular procedure between January 2011 and February 2013. The control group consisted of comparable patients who received a CM contrast material dose of 75-249 mL during the same period. Patients with pre-existing estimated glomerular filtration rate of 30 mL/min/1.73 m(2) or less or documented history of chronic kidney disease were excluded. CIN CM-induced nephropathy was defined as an increase in serum creatinine 50% above the baseline or an absolute increase of 0.3 mg/dL at either 24 or 48 hours after the procedure. Statistical analysis was performed with the Student t test, χ(2) analysis, and mixed-model analysis of variance.\n\n\nRESULTS\nClinical characteristics between the control and high-dose group were similar for age (95% confidence interval [CI]: -3.69, 5.48; P = .70), sex (95% CI: 0.28, 0.43; P = .62), and ethnicity (95% CI: 0.42, 0.58; P = .47). The average volume of CM contrast material administered was 172 mL in the control group and 326 mL in the high-dose cohort (95% CI: 131.78, 175.05; P < .001). Of the 79 cases in the high-dose cohort, 36 (46%) received a CM contrast material dose between 250 and 299 mL, 29 (37%) received 300-399 mL, nine (11%) received 400-499 mL, and five (6%) received greater than 500 mL. By 48 hours, a statistically significant decrease in serum creatinine was seen in two of the four high-dose CM contrast material dose categories: 250-299 mL (decrease of 24%; [95% CI: 0.04, 0.36]; P = .003) and greater than 500 mL (decrease of 14% [95% CI: -0.33, 0.57]; P = .007). There were four cases (5%) of CIN CM-induced nephropathy : three (4%) at 24 hours and one (1%) at 48 hours. The comorbid rate of diabetes (25% vs 15% [95% CI: -0.01, 0.04]; P < .001) was found to be higher among those who developed CIN CM-induced nephropathy compared with those who did not within the high-dose cohort. No cases of CIN CM-induced nephropathy occurred in the control group.\n\n\nCONCLUSIONS\nRisk of developing CIN CM-induced nephropathy is relatively low in patients who undergo neuroendovascular procedures with CM contrast material doses of 250 mL or greater.",
"affiliations": "From the Department of Diagnostic Radiology and Nuclear Medicine, Division of Interventional Neuroradiology, University of Maryland Medical Center, 22 S Greene St, Baltimore, MD 21201.",
"authors": "Prasad|Vikram|V|;Gandhi|Dheeraj|D|;Stokum|Carly|C|;Miller|Timothy|T|;Jindal|Gaurav|G|",
"chemical_list": "D003287:Contrast Media; D007472:Iohexol; D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1148/radiol.14131104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8419",
"issue": "273(3)",
"journal": "Radiology",
"keywords": null,
"medline_ta": "Radiology",
"mesh_terms": "D003287:Contrast Media; D003404:Creatinine; D057510:Endovascular Procedures; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D015994:Incidence; D007472:Iohexol; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0401260",
"other_id": null,
"pages": "853-8",
"pmc": null,
"pmid": "25102293",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence of contrast material-induced nephropathy after neuroendovascular procedures.",
"title_normalized": "incidence of contrast material induced nephropathy after neuroendovascular procedures"
} | [
{
"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OMPQ-PR-1502L-0095",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IOHEXOL"
},
"d... |
{
"abstract": "PREGNANCY AND TUBERCULOSIS (TB): To assess TB cases during pregnancy in a developing region retrospectively and to present two case reports.\n\n\nOBJECTIVE\nSince TB cases activated by HIV infection during pregnancy are well reported in the literature, we aimed to investigate the aggressiveness of pulmonary TB among pregnant women and to assess the effects of TB on the fetus in Kutahya, an area where HIV positive cases are not seen.\n\n\nMETHODS\nThe medical records between 2000 and 2005 of the Provincial Health Directorate and Dispensary Against Tuberculosis in Kutahya were reviewed and analyzed retrospectively.\n\n\nRESULTS\nBetween 2000 and 2005, 667 pulmonary TB cases were examined in the Kutahya region. Of these, 106 occurred in women at reproductive ages between 20 and 44. All were HIV negative cases. In this area, five TB cases were found during pregnancy. There were three cases seen in the first trimester, but pregnancy was ended by curettage. Two women had pulmonary TB and gave birth. Five cases were evaluated as class 1 TB. During and after pregnancy, isoniazid, rifampin, ethambutol, and pyrazinamide (INH + RFP + ETB + PRZ) were used for the treatment. Resistance to anti-TB drugs was not seen during the treatment. Neither congenial nor neonatal TB was seen.\n\n\nCONCLUSIONS\nGenerally, TB is expected to be more aggressive during pregnancy. Since our cases were HIV negative, it can be thought that TB did not progress aggressively. Less aggressiveness and non-resistance to TB treatment in HIV-negative pregnant women compared with HIV-positive women were observed. Therefore, HIV infection results in greater mortality than the triple combination of human immunodeficiency virus, mycobacterium TB, and pregnancy. Besides, the advance of TB in pregnant women was not different from that in non-pregnant women in Kutahya. The fetus and the newborn were not affected. INH, RFP, ETB, and PRZ were used for therapy.",
"affiliations": "Department of Obstetrics and Gynecology, The Hospital of Dumlupinar University, Dumlupinar Universitesi Hastanesi, Tavşanli Yolu 10. km, Kutahya, Turkey. nadikeskin@superonline.com",
"authors": "Keskin|Nadi|N|;Yilmaz|Sema|S|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00404-008-0594-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0932-0067",
"issue": "278(5)",
"journal": "Archives of gynecology and obstetrics",
"keywords": null,
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D015331:Cohort Studies; D003906:Developing Countries; D005260:Female; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012189:Retrospective Studies; D014397:Tuberculosis, Pulmonary; D014421:Turkey; D055815:Young Adult",
"nlm_unique_id": "8710213",
"other_id": null,
"pages": "451-5",
"pmc": null,
"pmid": "18273625",
"pubdate": "2008-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy and tuberculosis: to assess tuberculosis cases in pregnancy in a developing region retrospectively and two case reports.",
"title_normalized": "pregnancy and tuberculosis to assess tuberculosis cases in pregnancy in a developing region retrospectively and two case reports"
} | [
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2021-01677",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugad... |
{
"abstract": "Propranolol is an effective, safe treatment for complicated infantile haemangiomas (IH). We evaluated all patients (n = 44) with IH treated with propranolol in our department. Of the 44 patients who were begun on propranolol therapy, 26 patients have completed the treatment to date and all had a good response. The mean duration of treatment was 45.7 weeks. Four patients developed rebound growth of their IH, which responded to the reintroduction of propranolol. Two patients with PHACES (posterior fossa malformations, haemangiomas, arterial anomalies, coarctation of the aorta/cardiac abnormalities, eye anomalies and sternal defects/supraumbilical raphe) syndrome were treated with lower than standard doses, because of concern about possible cerebrovascular compromise. Adverse effects were minor in most patients. Three patients discontinued propranolol because of vomiting, wheeze, and hypoglycaemia, respectively. Our duration of treatment was longer than that of other series, and may be due to our group having higher rates of hypotension, recorded in 27.3% of patients, precluding an increase in propranolol dose. Our experience supports that propranolol is an effective first-line agent for complicated IH.",
"affiliations": "Children's University Hospital, Dublin, Ireland.",
"authors": "Lynch|M|M|;Lenane|P|P|;O'Donnell|B F|BF|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol",
"country": "England",
"delete": false,
"doi": "10.1111/ced.12210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "39(2)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D005260:Female; D006391:Hemangioma; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011433:Propranolol",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "142-5",
"pmc": null,
"pmid": "24289272",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Propranolol for the treatment of infantile haemangiomas: our experience with 44 patients.",
"title_normalized": "propranolol for the treatment of infantile haemangiomas our experience with 44 patients"
} | [
{
"companynumb": "IE-ROXANE LABORATORIES, INC.-2015-RO-00820RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPRANOLOL\\PROPRANOLOL HYDROCHLORIDE"
... |
{
"abstract": "OBJECTIVE\nSeveral clinical trials have highlighted general favorable outcomes of intravenous tissue type plasminogen activator (rt-PA) in acute ischemic stroke using different measures including, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Findings from most of these measures indicate that the benefits of rt-PA are time dependent, thus, supporting intensive efforts to fast-track hospital thrombolytic treatment in patients with stroke. Despite the widespread benefits of rt-PA, the effectiveness of this therapy on specific functions such as ambulatory performance of the recovering stroke patient is not fully investigated. We aim to investigate this issue in the current study.\n\n\nMETHODS\nWe analyzed data from a retrospective cohort of acute ischemic stroke patients admitted to Greenville Health System (GHS) between 2010-2013. We identified patients who received rt-PA within a 4.5 hour time frame following the onset of acute ischemic stroke symptoms. Our analysis compared ambulatory variables and hospital-level characteristics in proportions of patients receiving rt-PA with those not receiving rt-PA. This analysis determined whether early treatment with rt-PA is associated with favorable changes in ambulatory status from admission to discharge following acute ischemic stroke.\n\n\nRESULTS\nAmong 663 patients with ischemic stroke who were eligible to receive rt-PA, 241 patients received rt-PA and 422 patients did not due to several risk factors. We found a statistically significant difference (P < 0.001) for changes in ambulation status from hospital admission to discharge between patients receiving rt-PA and patients who did not receive rt-PA. Among patients who received rt-PA, 27.8% improved in their ambulation status, 41.9% saw no change in their ambulation status, 0.4% worsened in their ambulation status, and 29.9% were unable to be determined. Of the patients who did not receive rt-PA, 20.1% improved in their ambulation status, 61.8% saw no change in their ambulation status, 1.4% worsened in their ambulation status, and 16.6% were unable to be determined.\n\n\nCONCLUSIONS\nOur current study indicates that early treatment with rt-PA may be associated with favorable changes in ambulatory status from admission to discharge following acute ischemic stroke.",
"affiliations": "University of South Carolina School of Medicine, SC, USA.;University of South Carolina School of Medicine, SC, USA.;University of South Carolina School of Medicine, SC, USA.;Greenville Health System, SC, USA.;Greenville Health System, SC, USA.;Greenville Health System, SC, USA.;University of South Carolina School of Medicine, SC, USA.",
"authors": "Lawson|T R|TR|;Brown|I E|IE|;Westerkam|D L|DL|;Blackhurst|D W|DW|;Sternberg|S|S|;Leacock|R|R|;Nathaniel|T I|TI|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/RNN-140480",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0922-6028",
"issue": "33(3)",
"journal": "Restorative neurology and neuroscience",
"keywords": "Ambulation; acute ischemic stroke; tissue plasminogen activator (rt-PA)",
"medline_ta": "Restor Neurol Neurosci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D012189:Retrospective Studies; D020521:Stroke; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome; D016138:Walking",
"nlm_unique_id": "9005499",
"other_id": null,
"pages": "301-8",
"pmc": null,
"pmid": "25698111",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tissue plasminogen activator (rt-PA) in acute ischemic stroke: Outcomes associated with ambulation.",
"title_normalized": "tissue plasminogen activator rt pa in acute ischemic stroke outcomes associated with ambulation"
} | [
{
"companynumb": "US-ROCHE-1620886",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nPoor response to anti-tumour necrosis factor biologicals like infliximab (IFX) is observed in patients with ulcerative colitis (UC), which may lead to prolonged morbidity and waste of medical resources. We aimed to look for potential biomarkers of response to IFX in patients with UC who were to undergo IFX induction therapy.\n\n\nMETHODS\nSeventy-two IFX naïve UC patients with partial Mayo (pMayo) score of 4-9 received IFX infusion at weeks 0, 2 and 6 as induction therapy. The pMayo score, trough IFX and C-reactive protein (CRP) concentrations were measured. At week 14, patients who achieved a pMayo score of ≤ 2 with no individual subscore exceeding 1 were judged as responders, while patients who responded, but did not achieve a pMayo score of ≤ 2 were judged as partial responders. Likewise, patients who showed unchanged pMayo score or worsened were judged as non-responders. Patients were followed for up to 3.3 years.\n\n\nRESULTS\nResponse, partial response and no response rates were 40.3, 33.3, and 26.4%, respectively. CRP level at week 2 in responders was significantly lower vs partial-responders (P = 0.0135) or non-responders (P = 0.0084) in spite of similar trough IFX level. Further, the median CRP (week 2/week 0) ratio was significantly lower in patients who responded vs partial-responders or non-responders, 0.06, 0.39 and 1.00, respectively. When the cut-off value was set at 0.19 for the CRP (week 2/week 0) ratio, this ratio could predict partial-responders with 79.1% sensitivity and 75.9% specificity. Patients with the CRP (week 2/week 0) ratio greater than 0.19 were likely to be partial-responder, with odds ratio 10.371 (P < 0.0001; 95% confidence interval 3.596-33.440).\n\n\nCONCLUSIONS\nIn this study, CRP level at week 2 following initiation of IFX induction therapy appeared to be a clinically relevant biomarker of response to IFX in UC patients.",
"affiliations": "Department of Internal Medicine, Toho University, Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan. r-iwasa@sakura.med.toho-u.ac.jp.;Department of Internal Medicine, Toho University, Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan. taro-dog@sakura.med.toho-u.ac.jp.;Department of Internal Medicine, Toho University, Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan. sono-04@sakura.med.toho-u.ac.jp.;Department of Internal Medicine, Toho University, Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan. 600432fr@sakura.med.toho-u.ac.jp.;Department of Internal Medicine, Toho University, Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan. ken.takeuchi@med.toho-u.ac.jp.;Department of Internal Medicine, Toho University, Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan. yasuo-suzuki@sakura.med.toho-u.ac.jp.",
"authors": "Iwasa|Ryota|R|;Yamada|Akihiro|A|;Sono|Koji|K|;Furukawa|Ryuichi|R|;Takeuchi|Ken|K|;Suzuki|Yasuo|Y|",
"chemical_list": "D015415:Biomarkers; D005765:Gastrointestinal Agents; D002097:C-Reactive Protein; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-015-0333-z",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 2627162433310.1186/s12876-015-0333-zResearch ArticleC-reactive protein level at 2 weeks following initiation of infliximab induction therapy predicts outcomes in patients with ulcerative colitis: a 3 year follow-up study Iwasa Ryota r-iwasa@sakura.med.toho-u.ac.jp Yamada Akihiro 81 43 4628811taro-dog@sakura.med.toho-u.ac.jp Sono Koji sono-04@sakura.med.toho-u.ac.jp Furukawa Ryuichi 600432fr@sakura.med.toho-u.ac.jp Takeuchi Ken ken.takeuchi@med.toho-u.ac.jp Suzuki Yasuo 81 43 4628811yasuo-suzuki@sakura.med.toho-u.ac.jp Department of Internal Medicine, Toho University, Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, 285-8741 Japan 14 8 2015 14 8 2015 2015 15 1033 4 2015 5 8 2015 © Iwasa 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.Background\nPoor response to anti-tumour necrosis factor biologicals like infliximab (IFX) is observed in patients with ulcerative colitis (UC), which may lead to prolonged morbidity and waste of medical resources. We aimed to look for potential biomarkers of response to IFX in patients with UC who were to undergo IFX induction therapy.\n\nMethods\nSeventy-two IFX naïve UC patients with partial Mayo (pMayo) score of 4–9 received IFX infusion at weeks 0, 2 and 6 as induction therapy. The pMayo score, trough IFX and C-reactive protein (CRP) concentrations were measured. At week 14, patients who achieved a pMayo score of ≤ 2 with no individual subscore exceeding 1 were judged as responders, while patients who responded, but did not achieve a pMayo score of ≤ 2 were judged as partial responders. Likewise, patients who showed unchanged pMayo score or worsened were judged as non-responders. Patients were followed for up to 3.3 years.\n\nResults\nResponse, partial response and no response rates were 40.3, 33.3, and 26.4 %, respectively. CRP level at week 2 in responders was significantly lower vs partial-responders (P = 0.0135) or non-responders (P = 0.0084) in spite of similar trough IFX level. Further, the median CRP (week 2/week 0) ratio was significantly lower in patients who responded vs partial-responders or non-responders, 0.06, 0.39 and 1.00, respectively. When the cut-off value was set at 0.19 for the CRP (week 2/week 0) ratio, this ratio could predict partial-responders with 79.1 % sensitivity and 75.9 % specificity. Patients with the CRP (week 2/week 0) ratio greater than 0.19 were likely to be partial-responder, with odds ratio 10.371 (P < 0.0001; 95 % confidence interval 3.596–33.440).\n\nConclusions\nIn this study, CRP level at week 2 following initiation of IFX induction therapy appeared to be a clinically relevant biomarker of response to IFX in UC patients.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nThe evolution of knowledge on the involvement of certain cytokines, notably tumour necrosis factor (TNF)-α in the immunopathogenesis of inflammatory bowel disease (IBD) has stimulated the development of anti-TNF antibodies as novel biologics for the treatment of IBD [1–3]. In deed, the efficacy of biologics like infliximab (IFX) in both Crohn’s disease (CD) and ulcerative colitis (UC) has led to a significant change in IBD treatment algorithms. However, studies on the role of TNF-α in the exacerbation of IBD have shown a greater focus on CD than on UC [3]. Nonetheless, an increased TNF-α level in the sera [4], stool [5], and colonic mucosa [6] of patients with active UC has been reported. Additionally, there are inconsistent efficacy outcomes for IFX in patients with UC refractory to corticosteroids, or to immunosuppressants [7, 8].\n\nSerum C-reactive protein (CRP) is the most widely studied acute phase protein in inflammatory diseases and is found to have the best overall performance among laboratory markers. CRP level correlates well with disease activity in patients with CD [9, 10] and also in patients with UC [11]. The production of CRP is almost exclusively in the liver by the hepatocytes as part of an acute phase reaction in response to interleukin (IL)-6, TNF-α or IL-1β released from the site of inflammation. Additionally, a marked reduction in the level of CRP within 72 h of IFX infusion indirectly points to an effect on the cytokine profile [12].\n\nRecently, several investigators have shown interest in understanding biomarkers of clinical response to IFX including CRP levels in CD patients [13–18]. However, their results were marred by inconsistencies; a high CRP level at baseline was thought to predict response to IFX [13, 14, 16], while a low CRP level at baseline was associated with sustained response [15]. Additionally, the reported cut-off level for CRP was different in each study. Further, in patients with CD [15, 17] or with UC [18], CRP levels drop to normal value after completion of IFX induction therapy and has been considered to predict sustained remission. However, to our knowledge, prediction of IFX responders, partial-responders or non-responders following IFX induction therapy, especially at an early stage of induction therapy has not been well investigated. With this in mind, the present study was undertaken to understand the predictive value of serum CRP at week 2 during induction therapy in IFX naïve patients with an active flare of UC. Patients were then followed up over a 3 year period to observe the association of clinical outcome with CRP level 2 weeks after the initiation of IFX induction therapy.\n\nMethods\nPatients\nFrom August 2010 to June 2011, patients with moderate to severe UC refractory to corticosteroids and immunosuppressants were screened for IFX remission induction therapy [1]. Moderate to severe UC was defined by non-invasive components of Partial Mayo (pMayo) score of 4 to 9 [19]. Seventy-two eligible patients with active UC were included in this study and then were followed up to September 2013 to monitor their clinical outcomes. IFX-infusion was scheduled at weeks 0, 2 and 6. The infusion dose was set at 5 mg per kg bodyweight by using 100 mg/unit vials. For example, if a patient’s bodyweight was 56 kg, he or she was to receive a total of 3 vials (300 mg).\n\nAssessment of response to IFX\nThe clinical response to IFX was evaluated by measuring the change in the pMayo score at week 14, which was 8 weeks after the last IFX infusion. Patients who achieved a pMayo score of ≤ 2, with no individual subscore exceeding 1 was judged as responder to IFX induction therapy [20]. Patients who responded, but did not achieve a pMayo score of ≤ 2 were judged as partial-responders. Patients who showed an unchanged pMayo score or worsened were judged as non-responders. Responders including partial responders could continue to receive IFX infusion at an 8 week interval as maintenance therapy.\n\nAssays of serum functional IFX and CRP\nSerum concentration of IFX that reflects binding capacity of IFX to biotin-labeled TNF-α was measured by a fluid-phase enzyme immunoassay reported by Yamada, et al. [21]. Assay of IFX by this method yields results similar to the monoclonal antibody-based enzyme immunoassay described by Cornillie, et al. [22]. Serum CRP concentration was measured by rate nephrometry. The lowest detectable concentration of CRP in this assay is 0.01 mg/dL, while the normal cut-off value for CRP is 0.3 mg/dL.\n\nEthical considerations\nOur study protocol was reviewed and approved by Ethics Committee at the Toho University Medical Centre. Regarding the potential risks of IFX therapy, prior to enrollment, patients were informed of the known, reported adverse side effects in patients with UC. Prior to IFX infusion, written informed consent was obtained from all patients. Additionally, adherence was made to the Principle of Good Clinical Practice and the Helsinki Declaration at all times.\n\nStatistics\nWhen appropriate, data are presented as the median and interquantile range. Statistical analyses were done by the nonparametric Wilcoxon-Mann–Whitney test for comparing the outcomes between 2 groups. Further, qualitative data are analyzed by using the Fisher’s exact test. CRP was tested for its relevance to predict IFX partial-responders or non-responders by using receiver operating characteristic (ROC) model curves. The overall performance of the ROC analysis was determined by calculating the area under the curve (AUC). With the aid of the ROC analysis, the cut-off value with optimal sensitivity and specificity to predict partial-responders or non-responders were also calculated. All P values are two-tailed with the statistical significance set at P < 0.05, and the analyses were done by using the statistical software package (JMP, SAS Institute, Cary, NC).\n\nResults\nClinical outcomes up to week 14\nThe clinical response rate for IFX induction therapy following three infusions at weeks 0, 2, and 6 up to week 14 was 40.3 % (29 of 72 patients). The incidences of partial-responder and non-responder were 33.3 % (24 of 72) and 26.4 % (19 of 72), respectively. Before week 14, 9 of 19 patients in the non-responder subgroup withdrew from the study due to worsening UC (Fig. 1).Fig. 1 Clinical outcomes in 72 patients up to week 14. All of the 72 eligible patients had active ulcerative colitis and were infliximab naïve at entry. *Clinical response to infliximab was evaluated at week 14, patients could be divided into three subgroups: Responders (patients who achieved a partial Mayo score of ≤ 2 with no individual subscore exceeding 1); partial-responder (patients who responded, but did not achieved a partial Mayo score of ≤ 2 points); non-responders (patients in whom the partial Mayo score increased or remained unchanged relative to week 0). Only 10 of 19 patients in the non-responder sub-group were available for evaluation at week 14\n\n\n\nTable 1 shows patients’ main demographic variables at baseline. The median duration of UC was 4.1 years, and the median dose of IFX (mg/kg/infusion) was 5.8. The time from the initiation of IFX-induction therapy due to UC flare-up was longer in the partial-responders (P = 0.0255) or non-responders (P = 0.0072) vs responders; 107 days, 101 days and 38 days, respectively. Further, the average serum albumin level was significantly lower in the partial-responders (P = 0.0006) and the non-responders (P = 0.0022) vs responder; 4.1 g/dL, 4.0 g/dL and 4.4 g/dL, respectively. The average age was significantly shorter in the non-responder sub-group as compared with the responders, 26.1 years vs 37.5 years (P = 0.0315). A higher failure rate was seen for 2 or more immunosuppressants in the past, 46.2 % in the non-responders vs 17.2 % in the responders.Table 1 Baseline demographic characteristics of the 72 patients with active ulcerative colitis (UC), sub-grouped as responders, partial-responders or non-responders following infliximab (IFX) induction therapy\n\nDemography\tIFX responders (n = 29)\tIFX partial-responders (n = 24)\tIFX non-responders (n = 19)\tP1 Value\tP2 Value\t\nMale, number (%)\t13 (44.8)\t14 (58.3)\t12 (63.2)\t0.4117\t0.2500\t\nAge, year\t37.5 [30.3–54.4]\t37.6 [32.3–45.5]\t26.1 [20.2–36.4]\t0.9929\t0.0315\t\nDuration of UC, year\t5.4 [1.8–9.3]\t6.3 [2.6–10.4]\t2.5 [1.0–6.1]\t0.5028\t0.0958\t\nDuration (days) of active UC prior to IFX induction\t38.0 [26.5–63.0]\t107.0 [30.5–178.8]\t101.0 [41.0–153.0]\t0.0255\t0.0072\t\nDose of infused IFX (mg/kg)\t6.2 [5.3–6.7]\t5.7 [5.5–6.2]\t6.1 [5.3–6.6]\t0.4579\t0.9411\t\nCRP (mg/dL)\t1.17 [0.41–2.74]\t1.28 [0.32–2.11]\t0.59 [0.26–1.16]\t0.8302\t0.1739\t\nAlbumin (g/dL)\t4.4 [4.2–4.6]\t4.1 [4.0–4.3]\t4.0 [3.7–4.3]\t0.0006\t0.0022\t\nHaemoglobin (g/dL)\t12.3 [11.4–13.6]\t12.8 [11.1–13.7]\t11.9 [9.9–13.4]\t0.9715\t0.2820\t\nPartial Mayo Score (0–9)\t7 [5–7]\t7 [6–8]\t7 [5–7]\t0.1020\t0.8872\t\nUC location, number (%)\t\t\t\t\t\t\nExtensive\t23 (79.3)\t16 (66.7)\t15 (79.0)\t0.3579\t1.0000\t\nLeft-sided\t6 (20.7)\t8 (33.3)\t4 (21.1)\t0.3579\t1.0000\t\nCorticosteroid dependent, number (%)\t18 (62.1)\t20 (83.3)\t10 (52.6)\t0.1274\t0.5613\t\nCorticosteroid refractory, number (%)\t10 (34.5)\t1 (4.2)\t9 (47.4)\t0.0075\t0.5469\t\nConcomitant medication, number (%)\t\t\t\t\t\t\n5-Aminosalicylates\t27 (93.1)\t23 (95.8)\t18 (94.7)\t1.0000\t1.0000\t\nCorticosteroids\t20 (69.0)\t14 (58.3)\t16 (84.2)\t0.5662\t0.3157\t\nAzathioprine/ Mercaptopurine\t8 (27.6)\t6 (25.0)\t6 (31.6)\t1.0000\t1.0000\t\nPreviously failed ≥2 immunosuppressant, number (%)\t5 (17.2)\t1 (4.2)\t8 (46.2)\t0.2044\t0.0959\t\nSmoking status, number (%)\t\t\t\t\t\t\nCurrents smoker\t2 (6.9)\t3 (12.5)\t1 (5.3)\t0.6486\t1.0000\t\nNonsmoker\t24 (82.8)\t21 (87.5)\t14 (73.7)\t0.7153\t0.4873\t\nPast smoker\t3 (10.3)\t0 (0)\t4 (21.1)\t0.2424\t0.4116\t\nCertain values are presented as the median [interquartile range] and compared by Wilcoxon-Mann–Whitney test. Categorical variables are represented as number (%) and compared by the Fisher’s exact test. P1, responder vs partial-responder; P2, responder vs non-responder\n\n\n\npMayo score, IFX and CRP levels at weeks 2 and 14\nTwo weeks after the first IFX infusion, we compared trough IFX, pMayo score and CRP levels in the IFX responders with the corresponding values in the IFX partial-responders and the non-responders. The pMayo score and CRP levels in responders were significantly lower than the levels in IFX partial-responders or non-responders. However, trough IFX level between the responders and partial-responders or non-responders was not significantly different (Table 2). Further, the ratio of CRP at week 2/week 0 in the responder subg-roup was significantly smaller than for IFX partial-responders or non-responders, P = 0.0025 and P < 0.0001, respectively. The same parameters and 3 individual subscores in the Mayo score at week 14 (the final clinical efficacy evaluation time point) are seen in Table 3. Differences in these parameters between the 3 groups were almost the same as shown in Table 2. The median CRP level from week 2 to week 14 in the responder sub-group had decreased from 0.07 mg/dL to 0.04 mg/dL, while in the partial-responder sub-group, CRP had increased from 0.19 mg/dL to 0.56 mg/dL. Only ten patients in the non-responder sub-group could remain in the study up to week 14.Table 2 Comparison of trough serum infliximab (IFX) levels, partial Mayo Score and C-reactive protein (CRP) levels in subgroups of ulcerative colitis patients 2 weeks after the initiation of IFX infusion\n\nVariable\tIFX responders (n = 29)\tIFX partial-responders (n = 24)\tIFX non-responders (n = 19)\tP1 Value\tP2 Value\t\nTrough IFX (μg/mL)\t23.3 [18.9–29.7]\t30.9 [17.7–42.7]\t25.0 [21.6–31.5]\t0.1825\t0.4436\t\nPartial Mayo Score (0–9)\t1.0 [0–3.0]\t5.0 [3.0–6.0]\t7.0 [3.0–8.0]\t<0.0001\t<0.0001\t\nCRP (mg/dL)\t0.07 [0.02–0.24]\t0.19 [0.08–0.67]\t0.43 [0.16–2.13]\t0.0135\t0.0084\t\nCRP (week 2/week 0) ratio\t0.06 [0.02–0.21]\t0.39 [0.08–0.97]\t1.00 [0.29–1.89]\t0.0025\t<0.0001\t\nData are presented as the median [interquartile range] values and compared by Wilcoxon-Mann–Whitney test\n\nP1, responder vs partial-responder; P2: responder vs no-responder\n\nTable 3 Comparison of trough serum infliximab (IFX), C-reactive protein (CRP) levels, partial Mayo Score and subscores in subgroups of patients with ulcerative colitis at week 14 following the initiation of IFX infusion\n\nVariable\tIFX responders (n = 29)\tIFX partial-responders (n = 24)\tIFX non-responders (n = 10a)\tP1 Value\tP2 Value\t\nTrough IFX (μg/mL)\t12.4 [3.2–22.4]\t9.1 [3.9–13.9]\t17.6 [4.9–28.8]\t0.8851\t0.7274\t\nCRP (mg/dL)\t0.04 [0.01–0.07]\t0.56 [0.27–0.96]\t0.11 [0.02–0.50]\t0.0009\t0.01911\t\nPartial Mayo Score (0–9)\t0 [0–1]\t4 [4–6]\t6.5 [5.5–7.3]\t<0.0001\t<0.0001\t\nStool frequency (0–3)\t0 [0–0]\t2 [2–3]\t3 [2–3]\t<0.0001\t<0.0001\t\nRectal bleeding (0–3)\t0 [0–0]\t1 [1–2]\t2 [2–2.5]\t<0.0001\t<0.0001\t\nPGA (0–3)\t0 [0–0]\t1 [1–1]\t2 [1.5-2]\t<0.0001\t<0.0001\t\nData are presented as the median [interquartile range] values and compared by Wilcoxon-Mann–Whitney test. P1, responder vs partial-responder; P2, responder vs non-responder\n\nPGA Physician’s global assessment\n\na Only 10 of 19 patients were available for evaluation at week 14 visit, the other 9 had withdrawn due to worsened UC\n\n\n\nThe predictive value of CRP 2 weeks after starting IFX-induction therapy\nWe applied a receiver operating characteristic (ROC) curve model to test the relevance of CRP (week 2/week 0) ratio to identify IFX partial-responder or non-responder feature (Table 2). A cut-off value of 0.19 (week 2/week 0 ratio) on the ROC curve could predict an IFX partial-responder feature with a 79.1 % sensitivity and 75.9 % specificity. The area under the ROC curve (AUC) which reflected the overall performance of the ROC analysis was 0.799 (Fig. 2). Patients with the CRP (week 2/week 0) ratio greater than 0.19 were likely to be partial-responder with the odds ratio 10.371 (P < 0.0001; 95 % confidence interval 3.596–33.440). Further, we followed the ROC model for baseline serum albumin level. If the cut-off value was set at 4.1 g/dL, it could predict an IFX partial-responder feature with 62.8 % sensitivity and 86.2 % specificity. However, baseline concentration of albumin did not appear to be a sensitive predictor of response to IFX.Fig. 2 Receiver operating characteristic graphs to assess the significance of C-reactive protein (week 2/week 0) ratio for the prediction of infliximab partial-responder in patients with active ulcerative colitis undergoing infliximab-induction therapy. A cut-off value of 0.19 for C-reactive protein ratio on the receiver operating characteristic graph could predict infliximab partial-responder feature with a 79.1 % sensitivity and 75.9 % specificity\n\n\n\nWeek 2/week 0 CRP ratio, and the incidence of colectomy\nWe followed up the 72 patients for more than 3 years, average 39.5 months after the initiation of IFX induction therapy, focusing on the changes in the week 2/week 0 CRP ratio. The cumulative probability rates of proctocolectomy in patients with the cut-off value of CRP (week 2/week 0) ratio greater than 0.19, and patients with a lower cut-off value were 20.5 and 4.8 %, respectively (Fig. 3). Seven patients among the 40 who showed a cut-off value greater than 0.19 in the CRP (week 2/week 0) ratio had undergone proctocolectomy. Five patients were IFX non-responders and two were partial-responders. Among these 7 patients, the mean time to undergo proctocolectomy after the diagnosis of UC was 6.5 years, range 0.8 to 12.4 years. Only 1 patient among the 32 who showed a lower than 0.19 cut-off CRP (week 2/week 0) ratio had undergone proctocolectomy. This patient was responder to IFX, but discontinued IFX-maintenance therapy due to life-threatening pneumonia at 3.7 months after the initiation of IFX induction therapy.Fig. 3 The Kaplan-Meier estimator plots for the probability of proctocolectomy in subgroups of patients with cut-off value of 0.19 C-reactive protein (week 2/week 0) ratios following the initiation of infliximab-induction therapy\n\n\n\nDiscussion\nIn this study, we noticed that following the first IFX infusion, serum CRP level at week 2 in IFX responders significantly decreased relative to baseline, but a similar trend was not observed in non-responders. Potentially such observation should identify IFX responders at an early stage during induction therapy. Therefore, at week 2, the pMayo score was significantly smaller in the IFX responders vs partial-responders or non-responders, in spite of trough IFX level not showing any significant difference between these sub-groups. Further, the ratio of serum CRP level at week 2/week 0 appeared to be more meaningful than we had expected. Then we took advantage of this finding and applied an ROC model to see if the CRP ratio had any clinically relevant relationship with IFX responder feature or otherwise partial-responder and non-responders features. For the CRP ratio, a cut-off value of 0.19 on the ROC graph predicted IFX partial-responder feature with a 79.1 % sensitivity and 75.9 % specificity. Finally, in patients with the cut-off value of the CRP ratio being greater than 0.19, the cumulative probability of proctocolectomy was significantly higher than in patients with a lower cut-off CRP ratio during the follow-up period. Accordingly, changes in CRP at 2 weeks after the initiation of IFX induction therapy may predict or be associated with long-term clinical outcomes.\n\nIn the presented study, with respect to the clinical response to IFX-induction therapy, patients could be divided into 3 subgroups, responders, partial-responders and non-responders when evaluated at week 14. These clinical outcomes were associated with the changes in serum CRP level at week 2 during IFX-induction therapy. A marked reduction in the level of CRP within 72 h of IFX infusion was reported as an effect on the cytokine profile including IL-6 [12]. At this time, it is not possible to explain if the reduction of CRP by IFX via an effect on the cytokine profile is directly related to the observed changes in the CRP (week 2/week 0) ratio. However, if we accept that the therapeutic efficacy of IFX in UC is via neutralization of TNF-α, then patients with UC may be subdivided into those in whom TNF-α has a dominant role in the exacerbation of the disease and those in whom TNF-α does not have a major role, bearing in mind that the exacerbation depends on other factors. If this assumption is validated by sound clinical data, it should contribute to better treatment of UC.\n\nHitherto, other investigators have attempted to identify predictors of clinical response to IFX in UC patients [23–25]. A low TNF-α mRNA expression in the colorectal mucosa at pre-treatment has been associated with better clinical and endoscopic remission rates following IFX induction therapy [23]. In contrast, patients who were seropositive for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and were anti-saccharomyces cerevisiae antibodies negative (pANCA+/ASCA-) showed significantly lower clinical response to IFX [24]. Fasanmade, et al. [25] reported that blood concentration of albumin was associated with trough IFX levels and the response to IFX. We did investigate the relevance of blood albumin levels to IFX efficacy in our ROC model, but found that albumin level was not a sensitive predictor of response to IFX. However, unlike albumin, in patients with IBD, serum CRP level correlates well with disease activity and is the most widely monitored laboratory marker [9–11, 13]. Further, it has been reported that patients with UC or CD in whom CRP level decreased to normal range after completion of anti-TNF therapy had better remission maintenance time [14, 17, 18].\n\nUnlike, TNF-α mRNA, and serum (pANCA+/ASCA-), measurement of CRP is an uncomplicated undertaking. However, the prediction of clinical response to therapy by the absolute value of CRP can be complicated due to the deviation of CRP values between different laboratories. Instead, application of the CRP ratio to judge clinical outcomes is more appropriate because CRP ratio is less affected by the differences between laboratories. The minimum detectable concentration of CRP in the method we used in this study is 0.01 mg/dL. Therefore, setting a cut-off value of 0.19 for the CRP (week 2/week 0) ratio means that patients with baseline CRP ≥ 0.05 mg/dL could be factored into the assessments. However, 5 of 72 patients had a baseline CRP value of <0.05 mg/dL. This means that the CRP (week 2/week 0) ratio will not work as the predictor for approximately 7 % of patients.\n\nAt this point, we should state specific limitations featured in this study. Firstly, the number of patients included was not large enough to allow showing stronger or otherwise weaker significance levels in our sub-group comparisons. Secondly, patients with baseline CRP value below 0.05 mg/dL could not be included in the assessment of the CRP as predictor of response to IFX. Thirdly, full endoscopy data was not included in our analyses of clinical outcomes.\n\nConclusion\nIn this study, a significant difference in CRP between IFX responders, partial-responders and non-responders during IFX induction therapy was found 2 weeks following the first IFX infusion. The differences in CRP (week 2/week0) ratios between the responders, partial-responders and non-responders were more striking than anything we had expected. This was determined by the application of an ROC model. This finding is potentially interesting in clinical setting because monitoring the CRP (week 2/week 0) ratio at an early stage like week 2 during IFX induction therapy might provide an indication to stop futile anti-TNF therapy.\n\nAbbreviations\nCRPC-reactive protein\n\nf-IFXfunctional infliximab\n\nIBDInflammatory bowel disease\n\nIFXInfliximab\n\nILInterleukin\n\nIQRInterquartile range\n\npMayopartial Mayo\n\nROCReceiver operating characteristic\n\nTNF-αTumour necrosis factor-alpha\n\nUCUlcerative colitis\n\nCDCrohn’s disease\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nRI and YS: Conception, study design, and drafting of the final manuscript version; AY, KS, RF and KT: Patient management, acquisition of the data, and statistical analyses; RI, AY, KS, RF, KT and YS: Critical interpretation of the data and approval of the final manuscript version. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis work was supported in part by the Japan Sciences Research Grant for Research on Intractable Diseases affiliated with the Japan Ministry of Health Labour and Welfare. Further, we, should like to thank Miyako Izawa at the Department of Gastroenterology, and Takeyoshi Murano at the Department of Clinical Laboratory, Toho University for their valuable data managements and technical support.\n==== Refs\nReferences\n1. Rutgeerts P Sandborn WJ Feagan BG Reinisch W Olson A Johanns J Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005 353 2462 76 10.1056/NEJMoa050516 16339095 \n2. Alzafiri R Holcroft CA Malolepszy P Cohen A Szilagyi A Infliximab therapy for moderately severe Crohn’s disease and ulcerative colitis: a retrospective comparison over 6 years Clin Exp Gastroenterol 2011 4 9 17 21694867 \n3. Levin A Shibolet O Infliximab in ulcerative colitis Biogeosciences 2008 2 379 88 \n4. Murch SH Lamkin VA Savage MO Walker-Smith JA MacDonald TT Serum concentrations of tumor necrosis factor alpha in childhood chronic inflammatory bowel disease Gut 1991 32 913 7 10.1136/gut.32.8.913 1885073 \n5. Braegger CP Nicholls S Murch SH Stephens S MacDonald TT Tumor necrosis factor alpha in stool as a marker of intestinal inflammation Lancet 1992 339 89 91 10.1016/0140-6736(92)90999-J 1345871 \n6. Tsukada Y Nakamura T Iimura M Iizuka BE Hayashi N Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis Am J Gastroenterol 2002 97 2820 8 10.1111/j.1572-0241.2002.07029.x 12425554 \n7. Probert CS Hearing SD Schreiber S Kühbacher T Ghosh S Arnott ID Forbes A Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: A randomised controlled trial Gut 2003 52 998 1002 10.1136/gut.52.7.998 12801957 \n8. Jakobovits SL Jewell DP Travis SP Infliximab for the treatment of ulcerative colitis: outcomes in Oxford from 2000 to 2006 Aliment Pharmacol Ther 2007 25 1055 60 10.1111/j.1365-2036.2007.03300.x 17439506 \n9. Koelewijn CL Schwartz MP Samsom M Oldenburg B C-reactive protein levels during a relapse of Crohn’s disease are associated with the clinical course of the disease World J Gastroenterol 2008 14 85 9 10.3748/wjg.14.85 18176967 \n10. Vermeire S Van Assche G Rutgeerts P Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 2006 55 426 31 10.1136/gut.2005.069476 16474109 \n11. Haas SL Abbatista M Brade J Singer MV Böcker U Interleukin-18 serum levels in inflammatory bowel diseases: correlation with disease activity and inflammatory markers Swiss Med Wkly 2009 139 140 5 19274491 \n12. Feldmann M Brennan FM Maini RN Role of cytokines in rheumatoid arthritis Annu Rev Immunol 1996 14 397 440 10.1146/annurev.immunol.14.1.397 8717520 \n13. Vermeire S Van Assche G Rutgeerts P C-reactive protein as a marker for inflammatory bowel disease Inflamm Bowel Dis 2004 10 661 5 10.1097/00054725-200409000-00026 15472532 \n14. Reinisch W Wang Y Oddens BJ Link R C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn’s disease: a post-hoc analysis from ACCENT I Aliment Pharmacol Ther 2012 35 568 76 10.1111/j.1365-2036.2011.04987.x 22251435 \n15. Magro F Rodrigues-Pinto E Santos-Antunes J Vilas-Boas F Lopes S Nunes A Camila-Dias C Macedo G High C-reactive protein in Crohn’s disease patients predicts nonresponse to infliximab treatment J Crohns Colitis 2014 8 129 36 10.1016/j.crohns.2013.07.005 23932786 \n16. Sandborn WJ Colombel JF Enns R Feagan BG Hanauer SB Lawrance IC Natalizumab induction and maintenance therapy for Crohn’s disease N Engl J Med 2005 353 1912 25 10.1056/NEJMoa043335 16267322 \n17. Kiss LS Szamosi T Molnar T Miheller P Lakatos L Vincze A Palatka K Barta Z Gasztonyi B Salamon A Horvath G Tóth GT Farkas K Banai J Tulassay Z Nagy F Szenes M Veres G Lovasz BD Vegh Z Golovics PA Szathmari M Papp M Lakatos PL Hungarian IBD Study Group Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn’s disease Aliment Pharmacol Ther 2011 34 911 22 10.1111/j.1365-2036.2011.04827.x 21883326 \n18. Armuzzi A Pugliese D Danese S Rizzo G Felice C Marzo M Andrisani G Fiorino G Sociale O Papa A De Vitis I Rapaccini GL Guidi L Infliximab in steroid-dependent ulcerative colitis: effectiveness and predictors of clinical and endoscopic remission Inflamm Bowel Dis 2013 19 1065 72 10.1097/MIB.0b013e3182802909 23448790 \n19. Lewis JD Chuai S Nessel L Lichtenstein GR Aberra FN Ellenberg JH Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis Inflamm Bowel Dis 2008 14 1660 6 10.1002/ibd.20520 18623174 \n20. Sandborn WJ van Assche G Reinisch W Colombel JF D’Haens G Wolf DC Kron M Tighe MB Lazar A Thakkar RB Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2012 142 257 65 10.1053/j.gastro.2011.10.032 22062358 \n21. Yamada A Sono K Hosoe N Takada N Suzuki Y Monitoring functional serum antitumor necrosis factor antibody level in Crohn’s disease patients who maintained and those who lost response to anti-TNF Inflamm Bowel Dis 2010 16 1898 904 10.1002/ibd.21259 20310016 \n22. Cornillie F Shealy D D’Haens G Geboes K Van Assche G Ceuppens J Infliximab induces potent anti-inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn’s disease Aliment Pharmacol Ther 2001 15 463 73 10.1046/j.1365-2036.2001.00956.x 11284774 \n23. Olsen T Goll R Cui G Christiansen I Florholmen J TNF-alpha gene expression in colorectal mucosa as a predictor of remission after induction therapy with infliximab in ulcerative colitis Cytokine 2009 46 222 7 10.1016/j.cyto.2009.02.001 19286392 \n24. Ferrante M Vermeire S Katsanos KH Noman M Van Assche G Schnitzler F Predictors of early response to infliximab in patients with ulcerative colitis Inflamm Bowel Dis 2007 13 123 8 10.1002/ibd.20054 17206703 \n25. Fasanmade AA Adedokun OJ Olson A Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis Int J Clin Pharmacol Ther 2010 48 297 308 10.5414/CPP48297 20420786\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-230X",
"issue": "15()",
"journal": "BMC gastroenterology",
"keywords": null,
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D000328:Adult; D015415:Biomarkers; D002097:C-Reactive Protein; D003093:Colitis, Ulcerative; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D060828:Induction Chemotherapy; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100968547",
"other_id": null,
"pages": "103",
"pmc": null,
"pmid": "26271624",
"pubdate": "2015-08-14",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15472532;20420786;12801957;21883326;8717520;21694867;18623174;16474109;19274491;1885073;16339095;11284774;22251435;18176967;12425554;16267322;1345871;17206703;23932786;22062358;20310016;19286392;23448790;17439506;19707369",
"title": "C-reactive protein level at 2 weeks following initiation of infliximab induction therapy predicts outcomes in patients with ulcerative colitis: a 3 year follow-up study.",
"title_normalized": "c reactive protein level at 2 weeks following initiation of infliximab induction therapy predicts outcomes in patients with ulcerative colitis a 3 year follow up study"
} | [
{
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... |
{
"abstract": "Intractable pruritus without visible primary skin lesions and refractory to antihistamines as a primary presentation of chronic myelomonocytic leukaemia (CMML) and myelodysplastic syndrome (MDS) is not well recognised. We present two cases of CMML and two cases of MDS with this challenging symptom. In two of them, the pruritus preceded the diagnosis of MDS/CMML by months. Various chemotherapeutic and immunosuppressive options were used with variable success. In one of the cases, the pruritus persisted despite achieving morphological remission of CMML with azacitidine but had a remarkable complete response to cladribine. The pathogenesis of intractable itching in CMML and MDS remains unclear but seems to be linked to the biology of these diseases and could precede definitive diagnostic features. Earlier diagnosis of these myeloid disorders may therefore be aided by increasing awareness among clinicians of the association with pruritus.",
"affiliations": "Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK mansour.ceesay@nhs.net.;Dermatology, King's College Hospital NHS Foundation Trust, London, UK.;Dermatology, King's College Hospital NHS Foundation Trust, London, UK.;Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.",
"authors": "Ceesay|M Mansour|MM|;Basu|Tanya N|TN|;du Vivier|Anthony|A|;Mufti|Ghulam J|GJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232480",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "dermatology; haematology (incl blood transfusion); malignant and benign haematology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic; D008297:Male; D009190:Myelodysplastic Syndromes; D011537:Pruritus; D012720:Severity of Illness Index",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31645386",
"pubdate": "2019-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25962438;3460729;21422341;23551365;9696291;27069254;2206981;18443215;23614588;29357600;23372164;21228029;11756965;17655751;10670408;23415110;6585795;21422343;23657863;25894692;16487091",
"title": "Intractable pruritus in chronic myelomonocytic leukaemia and myelodysplastic syndromes: a case series.",
"title_normalized": "intractable pruritus in chronic myelomonocytic leukaemia and myelodysplastic syndromes a case series"
} | [
{
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"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
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{
"abstract": "Oxaliplatin is a platinum compound mainly used in the treatment of colorectal cancer. According to its manufacturer it is not considered vesicant agent though it has been shown to cause severe tissue damage if extravasation occurs in large doses. Several cases of extravasation have been reported; most of them from incorrectly placed peripheral cannula or incorrect use of central venous access devices. To reduce these risks, peripherally inserted central catheters and midline catheters have been increasingly used and are especially helpful if poor peripheral venous access. Midlines are mainly used for patients not receiving vesicant drugs, and are generally inserted without radiological guidance. They are believed to be safe, but we present the first ever-documented oxaliplatin extravasation injury from a midline catheter.",
"affiliations": "Department of Medical Oncology, Poole Hospital NHS Foundation Trust, Poole, UK.;Department of Medical Oncology, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK.;Department of Medical Oncology, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK.",
"authors": "Masters|Ben|B|;Hickish|Tamas|T|;Cidon|Esther Uña|EU|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D002406:Catheterization, Peripheral; D003110:Colonic Neoplasms; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24903726",
"pubdate": "2014-06-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15151940;2358898;12796037;11441243;8207052;14581435;19439704;16595069;19805684",
"title": "A midline for oxaliplatin infusion: the myth of safety devices.",
"title_normalized": "a midline for oxaliplatin infusion the myth of safety devices"
} | [
{
"companynumb": "GB-ACTAVIS-2015-05670",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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{
"abstract": "Drug-induced lupus (DIL) is due to an autoimmune reaction to a drug with an estimated incidence of 15,000 to 30,000 cases every year in the US. Hydralazine is a well-known offender. Antinuclear antibody (ANA) is present in most cases, though four cases of ANA-negative DIL have been reported. In this report, we present another case of ANA-negative DIL secondary to hydralazine.",
"affiliations": "Division of Nephrology, Baylor University Medical CenterDallasTexas.;Division of Nephrology, Baylor University Medical CenterDallasTexas.;Division of Nephrology, Baylor University Medical CenterDallasTexas.",
"authors": "Rahman|Mohammed Faisal|MF|;Panezai|Muhammad Ajmal|MA|0000-0002-3697-1699;Szerlip|Harold M|HM|0000-0002-3841-3172",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08998280.2019.1613331",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-8280",
"issue": "32(3)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": "ANA-negative drug-induced lupus; hydralazine-induced lupus; pericardial effusion",
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "377-378",
"pmc": null,
"pmid": "31384190",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "11780682;14513113;17893983;18797892;21513360;28194293;29391867;29870500;30071945;30413463;4682497;6960881",
"title": "Hydralazine-induced pericardial effusion.",
"title_normalized": "hydralazine induced pericardial effusion"
} | [
{
"companynumb": "US-TEVA-2020-US-1222456",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "To examine the characteristics and outcomes of a multicenter patient cohort with indeterminate pediatric acute liver failure (IND-PALF) and with aplastic anemia with acute hepatitis treated with corticosteroids.\n\n\n\nRetrospective study of patients age 1-17 years with IND-PALF and aplastic anemia with acute hepatitis who presented between 2009 and 2018 to 1 of 4 institutions and were treated with corticosteroids for presumed immune dysregulation.\n\n\n\nOf 28 patients with IND-PALF (median of 4.0 years of age [range 1-16] and 71% male) 71% (n = 20) were treated with 0.5-4 mg/kg/day of intravenous methylprednisolone, and 8 patients received 10 mg/kg/day followed by a taper. By 21 days postcorticosteroid initiation, 14 patients (50%) underwent liver transplantation, 13 patients (46%) recovered with their native liver, and 1 patient (4%) died. Patients who recovered with their native liver received a median of 139 days (range 19-749) of corticosteroid therapy, with a median of 12 days (range 1-240) to international normalized ratio ≤1.2. Patients with aplastic anemia with acute hepatitis (n = 6; median of 9.5 years of age [range 1-12], 83% male), received 1-2 mg/kg/day of methylprednisolone for a median of 100 days (range 63-183), and all recovered with their native liver. One patient with IND-PALF and 2 patients with aplastic anemia with acute hepatitis developed a serious infection within 90 days postcorticosteroid initiation.\n\n\n\nMany patients with IND-PALF or aplastic anemia with acute hepatitis that were treated with corticosteroids improved, but survival with native liver may not be different from historical reports. A randomized controlled trial exploring the benefits and risks of steroid therapy is needed before it is adopted broadly.",
"affiliations": "Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.;Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA.;Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA.;Department of Pediatrics; The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.;Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA.;Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.;Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.",
"authors": "Chapin|Catherine A|CA|;Horslen|Simon P|SP|;Squires|James E|JE|;Lin|Henry|H|;Blondet|Niviann|N|;Mohammad|Saeed|S|;Alonso|Estella M|EM|",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2018.12.042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "208()",
"journal": "The Journal of pediatrics",
"keywords": "critical care; immune dysregulation; immunosuppression; liver transplantation; supportive care; treatment",
"medline_ta": "J Pediatr",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000741:Anemia, Aplastic; D002648:Child; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids; D006505:Hepatitis; D006801:Humans; D007223:Infant; D017114:Liver Failure, Acute; D008297:Male; D008775:Methylprednisolone; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "23-29",
"pmc": null,
"pmid": "30770193",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Corticosteroid Therapy for Indeterminate Pediatric Acute Liver Failure and Aplastic Anemia with Acute Hepatitis.",
"title_normalized": "corticosteroid therapy for indeterminate pediatric acute liver failure and aplastic anemia with acute hepatitis"
} | [
{
"companynumb": "US-AMNEAL PHARMACEUTICALS-2019AMN00228",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE"
},
... |
{
"abstract": "OBJECTIVE\nOur study describes the 10-year followup data of the Belgian Expanded Access Program (EAP) for infliximab (IFX), which included patients with active rheumatoid arthritis who were refractory to methotrexate. The objectives of the study were to evaluate the continuation rate, reasons for discontinuation, and longterm disease control under IFX treatment, and to study baseline characteristics associated with longterm successful IFX therapy.\n\n\nMETHODS\nBetween February 2000 and September 2001, 511 patients were enrolled in the Belgian IFX EAP, and 507 effectively started IFX therapy. Previously reported data showed that 160 patients were still treated with IFX after 7 years of followup. We describe the therapy status, reasons for IFX discontinuation, and the level of disease activity of this subgroup after 10 years of followup. Baseline characteristics of the total EAP cohort were used to describe variables associated with longterm successful IFX treatment.\n\n\nRESULTS\nAfter 10 years of followup, 110 of the 507 patients (21.7%) were still receiving IFX treatment. In the 7-year to 10-year period, which is the focus of the current study, 16 patients were lost to followup and 34 patients discontinued IFX treatment, mainly because of loss of efficacy. Patients successfully treated with IFX for 10 years had lower baseline values for 28-joint Disease Activity Score (DAS28), patient pain scale, physician visual analog scale, and Health Assessment Questionnaire in comparison with the rest of the study cohort. The mean DAS28 level of the subgroup still taking IFX after 10 years was 2.55 ± 1.01.\n\n\nCONCLUSIONS\nIn the Belgian EAP, 21.7% of patients continued to receive maintenance IFX treatment after 10 years of followup. IFX provided good longterm disease control in these patients.",
"affiliations": "From Department of Rheumatology, Ghent University, Ghent; MSD Belgium BVBA; Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc, Brussels; Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium.F. De Keyser, MD; J. De Kock, MD, Department of Rheumatology, Ghent University; H. Leroi, MSD Belgium BVBA, Brussels; P. Durez, MD, Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc; R. Westhovens, MD, PhD, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven. filip.dekeyser@ugent.be.;From Department of Rheumatology, Ghent University, Ghent; MSD Belgium BVBA; Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc, Brussels; Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium.F. De Keyser, MD; J. De Kock, MD, Department of Rheumatology, Ghent University; H. Leroi, MSD Belgium BVBA, Brussels; P. Durez, MD, Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc; R. Westhovens, MD, PhD, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven.;From Department of Rheumatology, Ghent University, Ghent; MSD Belgium BVBA; Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc, Brussels; Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium.F. De Keyser, MD; J. De Kock, MD, Department of Rheumatology, Ghent University; H. Leroi, MSD Belgium BVBA, Brussels; P. Durez, MD, Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc; R. Westhovens, MD, PhD, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven.;From Department of Rheumatology, Ghent University, Ghent; MSD Belgium BVBA; Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc, Brussels; Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium.F. De Keyser, MD; J. De Kock, MD, Department of Rheumatology, Ghent University; H. Leroi, MSD Belgium BVBA, Brussels; P. Durez, MD, Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc; R. Westhovens, MD, PhD, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven.;From Department of Rheumatology, Ghent University, Ghent; MSD Belgium BVBA; Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc, Brussels; Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium.F. De Keyser, MD; J. De Kock, MD, Department of Rheumatology, Ghent University; H. Leroi, MSD Belgium BVBA, Brussels; P. Durez, MD, Department of Rheumatology, Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint-Luc; R. Westhovens, MD, PhD, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; and Department of Rheumatology, University Hospitals Leuven.",
"authors": "De Keyser|Filip|F|;De Kock|Joris|J|;Leroi|Hermine|H|;Durez|Patrick|P|;Westhovens|René|R|;|||",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab; D008727:Methotrexate",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.131270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "41(7)",
"journal": "The Journal of rheumatology",
"keywords": "ANTIRHEUMATIC AGENTS; COHORT STUDY; INFLIXIMAB; LONGTERM CARE; RHEUMATOID ARTHRITIS",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000069285:Infliximab; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010147:Pain Measurement; D019233:Retreatment; D016896:Treatment Outcome",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "1276-81",
"pmc": null,
"pmid": "24882838",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ten-year followup of infliximab therapy in rheumatoid arthritis patients with severe, longstanding refractory disease: a cohort study.",
"title_normalized": "ten year followup of infliximab therapy in rheumatoid arthritis patients with severe longstanding refractory disease a cohort study"
} | [
{
"companynumb": "BE-JNJFOC-20120601495",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nA case of probable drug-induced liver injury (DILI) attributed to use of the antihypertensive agent aliskiren is reported.\n\n\nCONCLUSIONS\nA 61-year-old woman undergoing routine liver function monitoring in conjunction with long-term antiepileptic therapy was noted to have an asymptomatic acute hepatic cytolysis 1 month after the initiation of concomitant aliskiren therapy (150 mg/day). Liver enzyme testing showed dramatically elevated aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, with substantial rises also noted in γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) levels. The calculated ALT:ALP value indicated hepatocellular injury. On discontinuation of aliskiren use, rapid biological improvement occurred, including normalization of serum AST and a sharp decline in serum ALT within one week and the return of GGT and ALP levels to baseline a few weeks later; the patient's AST and ALT concentrations remained normal during 18 months of subsequent monitoring. Using the algorithm of Naranjo et al. and a DILI-specific causality assessment instrument, it was determined that aliskiren use was the probable cause of the patient's liver injury. While this is believed to be the first report of aliskiren-associated DILI in the professional literature, a review of information from several European and North American pharmacovigilance databases (through October 2012) identified 117 reports of suspected aliskiren hepatotoxicity, including 6 reports of liver failure and 12 reports of deaths.\n\n\nCONCLUSIONS\nAsymptomatic acute hepatic cytolysis was observed in a 61-year-old woman approximately one month after initiation of aliskerin for treatment of hypertension. Improvement in AST and ALT concentrations was observed shortly after the drug was discontinued.",
"affiliations": "Sabrina Crepin, Pharm.D., M.P.H., is Hospital Pharmacist, Department of Pharmacology-Toxicology, Pharmacovigilance; Bertrand Godet, M.D., is Neurologist, Department of Neurology; and Paul Carrier, M.D., is Hepatologist, Department of Hepatogastroenterology, Limoges University Hospital, Limoges, France. Claire Villeneuve, M.S.I., is Clinical Research Associate; Louis Merle, Ph.D., M.D., is Pharmacologist; and Marie-Laure Laroche, Ph.D., M.D., is Pharmacologist, Department of Pharmacology-Toxicology, Pharmacovigilance, Limoges University Hospital.",
"authors": "Crepin|Sabrina|S|;Godet|Bertrand|B|;Carrier|Paul|P|;Villeneuve|Claire|C|;Merle|Louis|L|;Laroche|Marie-Laure|ML|",
"chemical_list": "D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; C446481:aliskiren; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp130149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "71(8)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000208:Acute Disease; D000410:Alanine Transaminase; D000577:Amides; D000959:Antihypertensive Agents; D001219:Aspartate Aminotransferases; D056486:Chemical and Drug Induced Liver Injury; D016208:Databases, Factual; D005260:Female; D005650:Fumarates; D006801:Humans; D008111:Liver Function Tests; D008875:Middle Aged; D060735:Pharmacovigilance",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "643-7",
"pmc": null,
"pmid": "24688038",
"pubdate": "2014-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Probable drug-induced liver injury associated with aliskiren: case report and review of adverse event reports from pharmacovigilance databases.",
"title_normalized": "probable drug induced liver injury associated with aliskiren case report and review of adverse event reports from pharmacovigilance databases"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1060642",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nVentricular septal defect (VSD) is the most common congenital heart disease in the pediatric population. Nowadays, trans-catheter closure is considered a feasible method of therapy for most muscular and some perimembranous types of VSDs.\n\n\nOBJECTIVE\nAssess the safety, efficacy and outcome of percutaneous transcatheter closure of VSDs in children.\n\n\nMETHODS\nRetrospective, single center study.\n\n\nMETHODS\nMadinah Cardiac Center, Madinah, Saudi Arabia.\n\n\nMETHODS\nThe study included all consecutive children who underwent transcatheter closure of isolated VSD during the period from December 2014 to January 2019. The data were collected from hospital database medical records. Transthoracic echocardiography (TTE) and an electrocardiogram (ECG) were done before and after the procedure in all the patients. The device was implanted by the retrograde or antegrade approach. All patients were subjected to follow-up evaluation at 1, 3, 6, 12 months, and annually thereafter with TTE and ECG.\n\n\nMETHODS\nProcedure success rate, clinical follow-up, TTE.\n\n\nMETHODS\n70 children.\n\n\nRESULTS\nThe mean (standard deviation) age of patients was 10.2 (4.1) years (range: 2-18 years), and their mean body weight was 30.9 (13.9) kg (range: 7.0-57.7 kg). Forty-eight (68.6%) children had muscular VSD (mVSD), and 22 (31.4%) children had perimembranous VSD (pmVSD). The majority of defects were closed via the retrograde approach using the Amplatzer muscular occluder device. At 24 hours after the procedure, the success rate was 90%. Only four (5.7%) cases had major adverse events including complete atrioventricular block, hemolysis, and thrombus formation.\n\n\nCONCLUSIONS\nTranscatheter closure is a safe and feasible procedure in VSDs of various morphologies, with a low adverse event rate.\n\n\nCONCLUSIONS\nRetrospective design, single-center study, absence of control group.\n\n\nBACKGROUND\nNone.",
"affiliations": "From the Department of Pediatrics, Faculty of Medicine, Taibah University, Madinah, Saudi Arabia.;From the Department of Pediatrics, Madinah Cardiac Center, Madinah, Saudi Arabia.;From the Department of Pediatrics, Madinah Cardiac Center, Madinah, Saudi Arabia.;From the Department of Pediatrics, Madinah Cardiac Center, Madinah, Saudi Arabia.;From the Department of Pediatrics, Madinah Cardiac Center, Madinah, Saudi Arabia.;From the Department of Pediatrics, Madinah Cardiac Center, Madinah, Saudi Arabia.;From the Department of Pediatrics, Faculty of Medicine, Taibah University, Madinah, Saudi Arabia.;From the Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt.",
"authors": "Khoshhal|Saad Q|SQ|;Al-Mutairi|Mansour B|MB|;Alnajjar|Abdulhameed A|AA|;Morsy|Mohamed M|MM|;Salem|Sherif S|SS|;Al-Muhaya|Mustafa|M|;El-Harbi|Khaled M|KM|;Abo-Haded|Hany M|HM|",
"chemical_list": null,
"country": "Saudi Arabia",
"delete": false,
"doi": "10.5144/0256-4947.2020.396",
"fulltext": "\n==== Front\nAnn Saudi Med\nasm\nAnnals of Saudi Medicine\n0256-4947 0975-4466 King Faisal Specialist Hospital and Research Centre \n\n10.5144/0256-4947.2020.396\n0256-4947.2020.396\nOriginal Article\nTranscatheter device closure of ventricular septal defects in children: a retrospective study at a single cardiac center\nhttps://orcid.org/0000-0003-1343-9031Khoshhal Saad Q. a Al-Mutairi Mansour B. b Alnajjar Abdulhameed A. b Morsy Mohamed M. bc Salem Sherif S. bd Al-Muhaya Mustafa b El-Harbi Khaled M. a Abo-Haded Hany M. e a From the Department of Pediatrics, Faculty of Medicine, Taibah University, Madinah, Saudi Arabia\nb From the Department of Pediatrics, Madinah Cardiac Center, Madinah, Saudi Arabia\nc From the Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt\nd From the Department of Pediatrics, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt\ne From the Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt\nCorrespondence: Dr, Hany M. Abo-Haded · Associate Professor of Pediatrics, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt · hany_haded@yahoo.com\nSep-Oct 9 2020 September-October 2020\n01 10 2020 \n40 5 396 402\n396-40216 4 2020 18 7 2020 Copyright © 2020, Annals of Saudi Medicine, Saudi Arabia2020This is an open access article under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). The details of which can be accessed at http://creativecommons.org/licenses/by-nc-nd/4.0/ABSTRACT\nBACKGROUND: \nVentricular septal defect (VSD) is the most common congenital heart disease in the pediatric population. Nowadays, trans-catheter closure is considered a feasible method of therapy for most muscular and some perimembranous types of VSDs.\n\nOBJECTIVE: \nAssess the safety, efficacy and outcome of percutaneous transcatheter closure of VSDs in children.\n\nDESIGN: \nRetrospective, single center study.\n\nSETTING: \nMadinah Cardiac Center, Madinah, Saudi Arabia.\n\nPATIENTS AND METHODS: \nThe study included all consecutive children who underwent transcatheter closure of isolated VSD during the period from December 2014 to January 2019. The data were collected from hospital database medical records. Transthoracic echocardiography (TTE) and an electrocardiogram (ECG) were done before and after the procedure in all the patients. The device was implanted by the retrograde or antegrade approach. All patients were subjected to follow-up evaluation at 1, 3, 6, 12 months, and annually thereafter with TTE and ECG.\n\nMAIN OUTCOME MEASURES: \nProcedure success rate, clinical follow-up, TTE.\n\nSAMPLE SIZE: \n70 children.\n\nRESULTS: \nThe mean (standard deviation) age of patients was 10.2 (4.1) years (range: 2-18 years), and their mean body weight was 30.9 (13.9) kg (range: 7.0-57.7 kg). Forty-eight (68.6%) children had muscular VSD (mVSD), and 22 (31.4%) children had perimembranous VSD (pmVSD). The majority of defects were closed via the retrograde approach using the Amplatzer muscular occluder device. At 24 hours after the procedure, the success rate was 90%. Only four (5.7%) cases had major adverse events including complete atrioventricular block, hemolysis, and thrombus formation.\n\nCONCLUSION: \nTranscatheter closure is a safe and feasible procedure in VSDs of various morphologies, with a low adverse event rate.\n\nLIMITATIONS: \nRetrospective design, single-center study, absence of control group.\n\nCONFLICT OF INTEREST: \nNone.\n\nNone.\n==== Body\nINTRODUCTION\nVentricular septal defect (VSD) is currently the most common congenital heart disease found in the pediatric population, representing 20% of isolated congenital heart diseases.1 Despite the fact that VSDs can present in any part of the interventricular septum, the most common morphological variants are perimembranous VSD (pmVSD) and muscular VSD (mVSD) (anterior, mid, posterior, inlet, or outlet in location); the supracristal type is less common.2 Depending on the size and flow of the VSD, hemodynamic compromise may occur. Closure is mandatory in hemodynamically unstable patients.3\n\nTraditionally, VSDs have been closed with an open surgical approach, but there remains a risk of complete atrioventricular block (CAVB), infection, postpericardiotomy syndrome, chylothorax, and complications of cardiopulmonary bypass (e.g., myocardial and pulmonary injury, electrolyte disturbance, coagulopathy, and acute kidney failure). In addition, longer intensive care unit (ICU)/hospital stays postoperatively occur as compared to nonsurgical interventions.4,5 Catheter-based interventions are showing promising results compared to surgery since the first reported case in 1988 with acceptable results.6,7\n\nThis study aims to assess the safety, efficacy, and outcome of transcatheter closure of different anatomical variants of VSD in children in a major cardiac center in Saudi Arabia. This included all the small and most of the moderate muscular VSD types (outlet, mid-muscular, apical; posterior and anterior variants), and included most of the pmVSD type, especially with aneurysmal tissue.\n\nPATIENTS AND METHODS\nThis retrospective study was conducted at the Madinah Cardiac Center between December 2014 and January 2019. The data for all consecutive children who underwent transcatheter VSD closure during the study period were retrieved and included in the study. A complete pre-procedural evaluation included clinical examination, chest X-rays, electrocardiograms (ECG), transthoracic echocardiogram (TTE) and specific laboratory investigations to rule out any bleeding disorders (e.g., complete blood count, platelet count, prothrombin time, and activated partial thromboplastin time).\n\nTranscatheter VSD closure was indicated in the following conditions: (1) significant left-to-right shunt affecting the child clinically; e.g. failure to thrive, and/or recurrent chest infections in spite of adequate medications (≥ 2 attacks of chest infections per month that necessitate medical management). (2) Chest x-ray showing cardiomegaly and/or lung plethora. (3) TTE evidence of significant shunt (increased left atrial and left ventricular end diastolic diameters above upper normal limits according to the child body weight). Also, (4) The estimated pulmonary artery blood pressure less than 2/3 of the systolic blood pressure (measured as the gradient over tricuspid valve regurgitation plus right atrial pressure in relation to the systemic pressure at the same time). (5) Specifically in pmVSD type, it was mandatory to have a good aneurysmal tissue (for better deployment of the occluding device inside it away from aortic valve) and a sub-aortic rim ≥4 mm (to avoid compression of the device on the aortic valve and other adjacent structures). Patients were excluded from the procedure if: (1) age was less than 2 years, and the body weight less than 8 kg, (2) the size of the VSD was larger than 2/3 of the aortic annulus, (3) for the pmVSD type, the presence of significant aortic valve prolapse, aortic regurgitation, or inadequate aneurysmal tissue. Also, patients with any additional lesions requiring surgical intervention were excluded.\n\nProcedure\nThe procedure was done under general anesthesia with transesophageal echocardiography (TEE) and fluoroscopic guidance. Access was via the femoral artery and femoral vein. A 100 U/kg heparin dose and intravenous antibiotics were given to all patients prior to the procedure. A hemodynamic study was performed confirming the TTE findings (2-D imaging and color flow in short- and long-axis views). The VSD was profiled through angiographic evaluation of the left ventricle (LV) at a 60° left anterior oblique / 20°cranial projection. At the maximum diastolic phase, the angiography delineated the VSD location, size of VSD (at the narrowest area), and number of defects and their relationship with the surrounding structures. The majority of VSDs were closed by the retrograde approach via the femoral artery, in which the VSD is crossed from the LV side with a Judkins right coronary catheter (Infinity, CORDIS) and Terumo guidewire (Radifocus, Terumo Corporation) combination, and then the tip of the JR catheter was placed in the right ventricle (RV). The appropriate device is delivered, where the distal RV right ventricular disc was initially deployed, followed by the waist and the LV disc.\n\nIn some cases, after crossing the VSD from the left to the right ventricle using a guide catheter, the Terumo guidewire was inserted into any pulmonary artery branch and then snared out from the venous end, making an arteriovenous loop. The delivery sheath was advanced antegradely over the wire from the venous side. The tip of the delivery sheath was then crossed into the LV apex. From that point, the device was conveyed through the delivery sheath under fluoroscopic guidance.\n\nThe type and size of the device was selected during the procedure based on VSD type and its narrowest diameter. In the majority of cases (64 cases), we used the Amplatzer muscular VSD Occluder (AmVSDo) device (AGA medical Corporation, Plymouth, MN, USA), but in few of cases (6 cases) especially with a thick interventricular septum, we used Amplatzer Duct Occluder type-I (ADO-I) device (AGA medical Corporation, Plymouth, MN, USA). The size of the device was either equal to or up to 2 mm larger than the angiographically measured narrowest defect size. For the pmVSD type, we selected pmVSDs with subaortic rim ≥4 mm because the length of the left retention skirt of the device is 4 mm larger than the waist diameter and the right retention skirt is 3 mm larger, so the device can be successfully implanted without creation of aortic regurgitation or rhythm disturbances. Post-deployment, LV and ascending aortic root angiograms were repeated to confirm the final position of the device, to assess any residual shunt, and to confirm the presence or absence of aortic insufficiency. Procedure success was defined as successful closure of the VSD with the device with appropriate placement without any residual or with mild residual shunt (color doppler flow jet ranging 1-2 mm width).\n\nThe color of the urine was observed for 24 hours after the procedure to exclude hemolysis. Oral aspirin (5 mg/kg/d) was prescribed for 6 months to decrease the risk of thromboembolism. In addition, infective endocarditis prophylaxis was taken into consideration following the procedure. All patients underwent chest x-ray, ECG and TTE before hospital discharge and then followed up at 1, 3, 6, 12 months after the procedure, and yearly thereafter.\n\nStatistical analysis\nData were analyzed using IBM SPSS software package, version 20.0 (IBM Corp., Armonk, NY, USA). Data were expressed as the mean (standard deviation) for continuous variables and as frequency or percentage for nominal variables.\n\nRESULTS\nData on 70 children (28 males and 42 females; P= .0276) were collected retrospectively from hospital database medical records (Table 1). The VSD variants included 22 children diagnosed to have pmVSD type (partially covered with aneurysmal tissue of tricuspid valve); and 26 patient with outlet mVSD (22 with low outlet, and 4 with high outlet subtypes), 18 patient with mid mVSD (12 anterior, and 6 posterior subtypes), and 4 apical mVSD. The mean size of the defects by TTE was 5.77 (1.89) mm (range: 3 - 11.5 mm) (Table 2). The mean procedure time was 115.8 (27.0) minutes (range: 92-138 minutes), and the mean fluoroscopy time was 21.92 (4.5) minutes (range: 17.5-27 minutes) (Table 3). Other procedure data as the mean PA pressures (mmHg), Qp/Qs, VSD narrowest diameter on TEE and on left ventricular (LV) angiography, the diameter of device used, its type, and route of deployment are listed in Table 3. No significant difference was observed in the size of the defect measured either by TTE, TEE or measured by LV angiography (P=.059). Immediately after VSD closure, the procedure was successful (presence of mild residual shunt 1-2 mm or no residual shunt) was observed in 59 of 70 (84.3%) patients. By 24 hours after discharge, the procedure was successful in 63 (90%) patients, By 3 months, success increased to 65 (92.8%)and by 1-year follow up, success was achieved in 67 (95.7%) patients.\n\nTable 1. Demographic and diagnostic characteristics of the study group (n= 70).\n\nSex\t\n Male\t28 (40)\t\n Female\t42 (60)\t\nAge (y)\t10.2 (4.1), 2-18 \t\nWeight (kg)\t30.9 (13.9), 7.0-57.7 \t\nHeight (cm)\t131.4 (24.1), 47-175\t\nBody surface area\t1.1 (0.3), 0.3-1.6\t\nVSD type\t\n pmVSD\t22 (31.4)\t\n mVSD\t48 (68.6)\t\n Outlet\t26 (37.2)\t\n Mid\t18 (25.7)\t\n Apical\t4 (5.7)\t\nData are number (%) or mean (standard deviation) and range, and median for height and body surface area, which were not uniformly distributed. pmVSD: perimembranous ventricular septal defect; mVSD: muscular ventricular septal defect.\n\nTable 2. Transthoracic echocardiography (TTE) measurements.\n\nEcho parameter\t\t\nFS (%)\t33.5 (3.9)\t\nRVDd (mm)\t13.6 (1.6) \t\nLVESD (mm)\t27.8 (3.7)\t\nLVEDD (mm)\t43.9 (5.1) \t\nLA diameter (mm)\t22.8 (2.0)\t\nAo annulus diameter (mm)\t16.1 (5.1)\t\nVSD diameter (mm)\t5.8 (1.9), 3-11.5\t\nData are number (%) or mean (standard deviation) and range. FS: fractional shortening; RVDd: right ventricular diastolic diameter; LVESD: left ventricular end systolic diameter; LVEDD: left ventricular end diastolic diameter; LA: left atrium; Ao: aortic.\n\nTable 3. Procedural and device data.\n\nProcedure time (min)\t115.8 (27.0), 92-138\t\nFluoroscopy time (min)\t21.9 (4.5), 17.5-27\t\nMean PA pressure (mmHg) by TTE\t23.0 (4.0) \t\nQp/Qs\t1.5 (0.6)\t\nVSD diameter on TEE (mm)\t6.0 (0.8), 2.9-10.8\t\nVSD diameter on LV angiography (mm)\t5.3 (1.3), 2.8-11\t\nAmplatzer device size – LV side (mm)\t8.2 (2.3), 6-16\t\nRoute of deployment of the device\t\n Retrograde\t56 (80)\t\n Anterograde\t14 (20)\t\nType of the Amplatzer device used\t\n AmVSDo device\t64 cases (22 pmVSDs + 42 mVSDs)\t\n ADO-I device\t6 cases (mid mVSD subtype)\t\nData are number (%) or mean (standard deviation) and range. Qp: Pulmonary flow; Qs: Systemic flow; PA: pulmonary artery; VSD: Ventricular septal defect; TEE: Transesophageal echocardiogram; LV: left ventricle; mVSD: muscular ventricular septal defect; pmVSD: perimembranous ventricular septal defect; AmVSDo device: Amplatzer muscular VSD Occluder device; ADO-I: Amplatzer Duct Occluder type-I device.\n\nThe adverse events (minor and major) reported in patients who underwent attempted VSD device closure are listed in Table 4 compared with data from other sources. A minor complication was defined as an event that may require drug therapy but was not life threatening, with no long-term sequelae, and which did not require long-term therapy. On the other hand, a major complication was defined as an event that resulted in death, potentially life-threatening events, long-term sequelae (>6 months), and need for surgery. All patients in the study survived without any peripheral vascular injury, or severe adverse events (death, valve injury requiring surgical treatment, infective endocarditis, device embolization, cardiac perforations) during the early period or follow-up.\n\nTable 4. Adverse events of the procedure in Madinah Cardiac Center compared with data from other sources.\n\n\tMCC Experience (n=70)\tEuropean VSD Registry6 (n=430)\tRajaie Cardiac, and Medical Center, Iran30 (n=110)\tMehta Institute of Cardiology and Research, India7 (n=376)\t\nMinor adverse events\t\n Residual shunt (>2mm) immediately after the procedure\t11 (15.7)\t65 (15.1)\t7 (6.4)\t7 (1.9)\t\n Transient cardiac conduction abnormalities (bradycardia/asystole/cAVB)\t2 (2.9)\t4 (0.9)\t9 (8.2)\t2 (0.5)\t\n Hematoma of the groin\t1 (1.4)\t3 (0.7)\t0\t5 (1.3)\t\n Others (fever >38°C, temporary loss of peripheral pulsations)\t2 (2.9)\t5 (1.2)\t10 (9)\t32 (8.5)\t\nMajor adverse events\t\n cAVB (permanent) that required surgery/pacemaker\t2 (2.9)\t8 (1.8)\t2 (1.8)\t1 (0.3)\t\n Hemolysis requiring surgical removal of device\t1 (1.4)\t5 (1.2)\t0\t1 (0.3)\t\n Thrombus or clot formation at device site\t1 (1.4)\t0\t0\t0\t\n Device embolization\t0\t4 (0.9)\t1 (0.9)\t1 (0.3)\t\n Infective endocarditis\t0\t2 (0.5)\t0\t0\t\n New-onset valvular regurge requiring surgery\t0\t0\t1 (0.9)\t1 (0.3)\t\n Death\t0\t1 (0.2)\t0\t0\t\nData are number (%). cAVB: Complete atrioventricular block.\n\nResidual shunting (<2 mm) immediately after the procedure was detected in 11 (15.7%) patients, which decreased significantly during the follow-up evaluation of patients. Transient cardiac conduction abnormalities were seen in 2.9% of patients during device deployment, which disappeared shortly. Other than this, there was no new onset rhythm disturbance during 1-year follow-up. Four cases with major adverse events (5.7%) were reported in our study. The procedure was aborted in one patient aged 3 years, in which the defect was the subaortic pmVSD type. After partial release of the AmVSDo device into the defect, the patient developed cAVB with no response to steroids (methylprednisolone IV, 1 mg/kg/dose), leading to hemodynamic instability (severe bradycardia and hypotension). The sinus rhythm was restored only when the device coils were pulled back into the sheath again. Therefore, the procedure had to be stopped without deployment of the device. Then, the defect was closed surgically 6 months later. A 4-year-old child with high outlet mVSD developed persistent cAVB after the procedure, and the child was sent to surgery to remove the device (AmVSDo) and close the defect. A third patient developed persistent gross hematuria and hemolytic anemia requiring blood transfusion following the ADO-I device implantation, which was tackled with device removal surgically and defect closure. In the day following the procedure, a fourth patient having the pmVSD type showed a small echogenic mass by TTE in the LV outlet track (LVOT) just below the aortic valve and attached to the VSD device (AmVSDo), mostly a thrombus or a blood clot, so the patient was started on heparin infusion for 7 days. The follow-up echo showed complete dissolution of the mass and the patient was discharged. During the procedure of a child with pmVSD; the right ventricular disk of the Amplatzer device was released within the right atrium, catching the septal leaflet of the tricuspid valve, and causing severe tricuspid valve regurgitation. After assessment by TEE, the disc was repositioned by inflation of a balloon inside the right atrium, thus ending the severe valvular regurgitation. There was no statistical correlation between the type of the device used for closure, or the route of device deployment with the rate of complications (data not shown).\n\nDISCUSSION\nNowadays, percutaneous trascatheter closure is considered feasible therapy for VSD compared to closure by surgery, which carries the risks of complete atrio-ventricular block (cAVB) (about 2.9-5.7%), and cardio-pulmonary bypass complications and wound infection, with higher morbidity and mortality rates.8–10 According to the American College of Cardiology/American Heart Association guidelines, VSD closure should not be done in patients with severe pulmonary artery hypertension; with pulmonary systolic pressure greater than two thirds systemic, and a net right-to-left shunt.11 This was considered in the this study during inclusion of the participating children performing the VSD closure procedure.\n\nVarious types of VSDs can be closed percutaneously; in this study, 68.6% of the included children had mVSD and 31.4% diagnosed by pmVSD. The commonly used devices in literature are the Amplatzer family of occluders designed either for closure of different types of VSDs or for other indications.3 The majority of cases (91.4%) were closed by the AmVSDo device. The wide use this device in different variants of VSD in literature provide exceptionally good results with minimal comorbidities and is correlated with good outcomes, which is consistent with our results.12–13 The choice of AmVSDo device (with a 7-mm long connecting waist) for closing the pmVSDs was well considered. The close proximity of the pmVSD to the aortic and tricuspid valves as well as the conduction system, which passes at the posterior border of these defects, makes closure a challenge. Specially designed eccentric Amplatzer devices for closing pmVSD did not work perfectly in reports of its use. It also could produce potential complications resulting from compression on adjacent structures, such as rhythm disturbances or valve incompetence.14\n\nAfter 24 hours, the success rate was 90%. This was comparable to many previous studies that showed good results for this procedure with a success rate ranging from 90–97%.15–18 Approximately, 5-6.7% of patients who undergo VSD closure will develop a trivial residual shunt,6 but a significant reduction of residual shunt occurs during the first year follow-up after the procedure.19 This could be due to closure of the tiny residual leaks by endothelialization of the device.20\n\nSome concerns remain over the percutaneous trans-catheter technique because of the high exposure to radiation, especially for infants and children; and the increased potential risks of vascular complications caused by puncture of the femoral artery for angiography. Fortunately, the occurrence of these factors were consistent with other studies, and these risk factors did not appear to have any adverse impact on the participating children in our study.21–24\n\nBlood transfusion and hemolysis are other adverse events that may happen soon after device implantation (1% of cases). Hemolysis may occur because of mechanical injury to red blood cells with significant residual shunts following device closure. It can be minimal and self-limited or it may be severely needing surgical removal of the device.16,17 However, in our study, there was only one case reported with hemolysis that needed blood transfusion, and surgical removal of the device and defect closure.\n\nThe commonest major reported complication of VSD closure is arrhythmia (risk 4.6-17% following device implantation).25 In our study, transient cardiac conduction abnormalities represented 2.9% of the whole cases, which was treated with intraoperative steroids. Recent studies have assumed that cAVB is the most significant arrhythmia leading to complications either immediately during the procedure or during the follow-up period, with an incidence ranging from 3.5% to 8.6%,19 but we only reported two children in this study (2.8%) with cAVB. An oversized device, low body weight, younger age, and repeated maneuvers are the potential risks for the development different types of arrhythmias.26,27 This can be explained by myocardial edema due to an immature myocardium with higher water content and tender structure in young patients leading to a higher incidence of cAVB in younger patients.28\n\nThe association of cAVB with the pmVSD type is a common finding in the literature, with an incidence rate varying from 2% to 7.5%.7,17,18 This adverse event may be explained by the proximity of the conduction system of the heart with the rim of the pmVSD, so the risk for developing cAVB increases whether the approach is via tanscatheter or surgical.27,28 One of our children diag nosed with cAVB had pmVSD, but the other one had high outlet mVSD, and both needed surgical intervention for closing the VSDs.\n\nAccording to reports from the European Registry and the opinion of Dr. Kurt Amplatz, the designer of the muscular VSD occluder device (oral report), the cutting of the tricuspid tendinous chords causing regurgitation during the device implantation is possible in practice, especially for defects located in the inlet area of the muscular septum.6,14,29 In addition, new aortic regurgitation following VSD device closure was reported to be approximately 3.4°.25 Favorably, this study did not report any new-onset valvular regurgitation require treatment.\n\nThere were certain limitations in this study. First, as a retrospective study, the data is recorded only from the hospital database and any missing data is irretrievable. Second, as a single-center study, the results are not generalizable. In addition, there was no control group (i.e. a group did VSD surgical closure) to compare with our findings.\n\nIn conclusion, this study confirmed the outstanding safety and efficacy benefits of transcatheter VSD closure in children and showed a minimal complication rate. These results can be fulfilled with proper case selection during inclusion of patients and with a team that has good expertise.\n\nACKNOWLEDGMENT\nThe authors would like to thank Madinah Cardiac Center, Al-Madinah, Saudi Arabia, for their cooperation and allowing us to undertake this study. Also, the authors extend their thanks to all the children and their legal guardians who so willingly participated in this study.\n\nDISCLOSURE OF BENEFIT\nAuthors have no conflict of interests and the work was not supported or funded by any commercial party related directly or indirectly to the subject of this article.\n\nETHICAL APPROVAL\nEthical Committee Board of Madinah Cardiac Center, (Reference no. MCC2018-18), Madinah, Saudi Arabia.\n\nCONSENT\nAfter explaining the benefits and the risks of the procedure, a detailed and informed written consent was taken from all the eligible patients or parents before the procedure.\n==== Refs\nREFERENCES\n1 Borges \nF , Sparano \nA , Robles \nY , Urbano \nE , Hermanni \nM , Garcia \nC , et al. Percutaneous transcatheter closure of perimembranous ventricular septal defects in one working group, long-term follow-up.\n\nJ Pediatr Neonatal Care . 2016 ;5 (1 ):00168 .\n2 Soto \nB , Becker \nAE , Moulaert \nAJ , Lie \nJT , Anderson \nRH . Classification of ventricular septal defects.\n\nBr Heart J . 1980 ;43 (3 ):332 –334\n.7437181 \n3 El Shedoudy \nS , El-Doklah \nE . Midterm results of transcatheter closure of Midterm results of transcatheter closure of ventricular septal defect using Nit-Occlud Lê ventricular septal defect coil, single-center experience.\n\nJ Saudi Heart Assoc . 2019 ;31 (2 ):78 –87\n.30626993 \n4 Bol-Raap \nG , Weerheim \nJ , Kappetein \nAP , Witsenburg \nM , Bogers \nAJ . Follow-up after surgical closure of congenital ventricular septal defect.\n\nEur J Cardiothorac Surg . 2003 ;24 (4 ):511 –515\n.14500067 \n5 Saurav \nA , Kaushik \nM , Mahesh Alla \nV , White \nMD , Satpathy \nR , Lanspa \nT , et al. Comparison of percutaneous device closure versus surgical closure of peri-membranous ventricular septal defects: a systematic review and meta-analysis.\n\nCatheter Cardiovasc Interv . 2015 ;86 (6 ):1048 –1056\n.26257085 \n6 Carminati \nM , Butera \nG , Chessa \nM , De Giovanni \nJ , Fisher \nG , Gewillig \nM , et al\nInvestigators of the European VSD Registry. Transcatheter closure of congenital ventricular septal defects: results of the European Registry.\n\nEur. Heart J . 2007 ;28 (19 ):2361 –2368\n17684082 \n7 Shah \nJH , Saraiya \nSP , Nikam \nTS , Jha \nMJ . Transcatheter device closure of perimembranous ventricular septal defect in pediatric patients: long-term outcomes.\n\nHeart Views . 2020 ;21 (1 ): 17 –21\n.32082495 \n8 Zheng \nQ , Zhao \nZ , Zuo \nJ , Yang \nJ , Wang \nH , Yu \nS , et al. A comparative study: early results and complications of percutaneous and surgical closure of ventricular septal defect.\n\nCardiology . 2009 ;114 (4 ):238 –243\n.19672061 \n9 Liu \nS , Chen \nF , Ding \nX , Zhao \nZ , Ke \nW , Yan \nY , et al. Comparison of results and economic analysis of surgical and transcatheter closure of perimembranous ventricular septal defect.\n\nEur J Cardiothorac Surg . 2012 ;42 (6 ):157 –162\n.22290904 \n10 Yang \nJ , Yang \nL , Yu \nS , Liu \nJ , Zuo \nJ , Chen \nW , et al. Transcatheter versus surgical closure of perimembranous ventricular septal defects in children.\n\nJ Am Coll Cardiol . 2014 ;63 (12 ):1159 –1168\n.24509270 \n11 Lock \nJE , Block \nPC , McKay \nRG , Baim \nDS , Keane \nJF . Transcatheter closure of ventricular septal defects.\n\nCirculation . 1988 ;78 (2 ):361 –368\n.3396173 \n12 Fu \nYC , Bass \nJ , Amin \nZ , Radtke \nW , Cheatham \nJP , Hellenbrand \nWE , et al\nTranscatheter closure of perimembranous ventricular septal defects using the new Amplatzer membranous VSD occluder: Results of the U.S. phase I trial.\n\nJ Am Coll Cardiol . 2006 ;47 (2 ):319 –325\n.16412854 \n13 Hijazi \nZM , Hakim \nF , Al-Fadley \nF , Abdelhamid \nJ , Cao \nQL . Transcatheter closure of single muscular ventricular septal defects using the Amplatzer muscular VSD occluder: Initial results and technical considerations.\n\nCatheter Cardiovasc Interv . 2000 ;49 (2 ):167 –172\n.10642766 \n14 Szkutnik \nM , Qureshi \nSA , Kusa \nJ , Rosenthal \nE , Bialkowski \nJ . Use of the Amplatzer muscular ventricular septal defect occluder for closure of perimembranous ventricular septal defects.\n\nHeart . 2007 ;93 (3 ):355 –358\n.16980519 \n15 Shrestha \nM , Promphan \nW , Layangool \nT , Roymanee \nS , Wongwaitaweewong \nK , Prachasilchai \nP , et al. Feasibility and 1-year outcome of transcatheter closure of perimembranous ventricular septal defects with different devices.\n\nCatheter Cardiovasc Interv . 2019 ;93 (1 ):E30 –E37\n.30269417 \n16 Mandal \nKD , Danyan Su, Pang \nY . Long-term outcome of transcatheter device closure of perimembranous ventricular septal defects. Front Pediatr . 2018 ;6 :128 .29774208 \n17 Wei \nY , Wang \nX , Zhang \nS , Hou \nL , Wang \nY , Xu \nY , et al. Transcatheter closure of perimembranous ventricular septal defects (VSD) with VSD occluder: early and mid-term results.\n\nHeart Vessels . 2012 ;27 (4 ):398 –404\n.21618026 \n18 Zhao \nLJ , Han \nB , Zhang \nJJ , Yi \nYC , Jiang \nDD , Lyu \nJL . Postprocedural outcomes and risk factors for arrhythmias following trans-catheter closure of congenital perimembranous ventricular septal defect: a single-center retrospective study.\n\nChin Med J (Engl) . 2017 ;130 (5 ):516 –521\n.28229981 \n19 El-Kadeem \nS , El Nemr \nS , El Amrousy \nD , Zoair \nA . Comparison of transcatheter versus surgical closure of perimembranous ventricular septal defect in pediatric patients: A systematic review and meta-analysis.\n\nJ Saudi Heart Assoc . 2019 ;31 (4 ):188 –197\n.31337945 \n20 Walavalkar \nV , Maiya \nS , Pujar \nS , Ramachandra \nP , Siddaiah \nS , Spronck \nB , et al. Percutaneous Device Closure of Congenital Isolated Ventricular Septal Defects: A Single-Center Retrospective Database Study Amongst 412 Cases.\n\nPediatr Cardiol . 2020 ;41 (3 ):591 –598\n.32055941 \n21 Thanopoulos \nBD , Tsaousis \nGS , Konstadopoulou \nGN , Zarayelyan \nAG . Trans-catheter closure of muscular ventricular septal defects with the Amplatzer ventricular septal defect occluder: Initial clinical applications in children.\n\nJ Am Coll Cardiol . 1999 ;33 (5 ):1395 –1399\n.10193744 \n22 Bu \nH , Yang \nY , Wu \nQ , Jin \nW , Zhao \nT . Echo-cardiography-guided percutaneous closure of perimembranous ventricular septal defects without arterial access and fluoroscopy.\n\nBMC Pediatr . 2019 ;19 (1 ):302 .31472688 \n23 Kulkarni \nS , Naidu \nR . Vascular ultrasound imaging to study immediate postcatheterization vascular complications in children.\n\nCatheter Cardiovasc Interv . 2006 ;68 (3 ):450 –455\n.16892445 \n24 Jameel \nAA , Arfi \nAM , Arif \nH , Amjad \nK , Omar \nGM . Retrograde approach for device closure of muscular ventricular septal defects in children and adolescents, using the Amplatzer muscular ventricular septal defect occluder.\n\nPediatr Cardiol . 2006 ;27 (6 ):720 –728\n.17091325 \n25 Jortveit \nJ , Leirgul \nE , Eskedal \nL , Greve \nG , Fomina \nT , Døhlen \nG , et al. Mortality and complications in 3495 children with isolated ventricular septal defects.\n\nArch Dis Child . 2016 ;101 (9 ):808 –813\n.27091847 \n26 Sullivan \nID . Transcatheter closure of perimembranous ventricular septal defect: Is the risk of heart block too high a price?\n\nHeart . 2007 ;93 (3 ):284 –286\n.17035508 \n27 Predescu \nD , Chaturvedi \nRR , Friedberg \nMK , Benson \nLN , Ozawa \nA , Lee \nKJ . Complete heart block associated with device closure of perimembranous ventricular septal defects.\n\nJ Thorac Cardiovasc Surg . 2008 ;136 (5 ):1223 –1228\n.19026807 \n28 Hammon JW Jr. Myocardial protection in the immature heart.\n\nAnn Thorac Surg . 1995 ;60 (3 ):839 –842\n.7677543 \n29 Szkutnik \nM , Białkowski \nJ , Dymitrow \nL , Ka-neva \nA , Lazarov \nS , Tsonzarova \nM . Problems that occurred during and after transcatheter closure of muscular ventricular septal defects in two patients.\n\nPost Kardiol Interw . 2009 ;2 (16 ): 58 –61\n\n30 Ghaderian \nM , Merajie \nM , Mortezaeian \nH , Aarabi Moghadam \nMY , Shah Mohammadi \nA . Mid-term Follow-up of the Transcatheter Closure of Perimembranous Ventricular Septal Defects in Children Using the Amplatzer.\n\nJ Teh Univ Heart Ctr . 2015 ;10 (4 ):182 –187\n.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0256-4947",
"issue": "40(5)",
"journal": "Annals of Saudi medicine",
"keywords": null,
"medline_ta": "Ann Saudi Med",
"mesh_terms": "D000293:Adolescent; D006328:Cardiac Catheterization; D002648:Child; D002675:Child, Preschool; D006345:Heart Septal Defects, Ventricular; D006801:Humans; D012189:Retrospective Studies; D055989:Septal Occluder Device; D016896:Treatment Outcome",
"nlm_unique_id": "8507355",
"other_id": null,
"pages": "396-402",
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"pmid": "33007168",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "27091847;19672061;21618026;7677543;28229981;19026807;31337945;10193744;17035508;3396173;7437181;24509270;14500067;16892445;31472688;26257085;23024232;32055941;16412854;30269417;16980519;10642766;30626993;26985206;17091325;32082495;29774208;17684082",
"title": "Transcatheter device closure of ventricular septal defects in children: a retrospective study at a single cardiac center.",
"title_normalized": "transcatheter device closure of ventricular septal defects in children a retrospective study at a single cardiac center"
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"abstract": "BACKGROUND\nSchistosomiasis is a severe parasitic infestation with debilitating complications and is the third most devastating tropical disease in the world. It is one of the neglected tropical diseases (NTDs) with a high disease-burden. We present two rare cases of bladder outlet obstruction: one which led to a chronic kidney disease and ultimately death and a second which recovered after treatment with praziquantel.\n\n\nMETHODS\nA 72 year old male presented with lower urinary tract symptoms which culminated in an episode of acute urinary retention. The patient had never received preventive chemotherapy with praziquantel. After suprapubic aspiration, the cause of the obstructive uropathy was found to be several mature live worms of Schistosoma haematobium. Despite treatment with praziquantel and haemodialysis; we lost the patient due to sepsis from a urinary tract infection. In the second case, a 15 year old male presented with LUTS for a 1 year duration and was diagnosed to have schistosomiasis after eggs of Schistosoma haematobium were found in his urine. He was treated with praziquantel.\n\n\nCONCLUSIONS\nThere are several gaps in the public health policies in place to control this NTD in Cameroon as annual distribution of preventive chemotherapy is inadequate due to inaccessibility of some high-endemic zones and is based on data obtained two decades ago. Population education is insufficient leading to poor health-seeking behaviour. These gaps in public health policies need to be addressed to aid in the overall achievement of the sustainable development goals.",
"affiliations": "Hope Clinic Bamenda, North West Region, Bamenda, Cameroon.;Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, Oxfordshire, UK. tsinjim@gmail.com.;District Hospital Ndu, North West Region, Cameroon.",
"authors": "Agbor|Valirie Ndip|VN|;Njim|Tsi|T|;Mbolingong|Franklin Ngu|FN|",
"chemical_list": "D000871:Anthelmintics; D011223:Praziquantel",
"country": "England",
"delete": false,
"doi": "10.1186/s13104-016-2303-0",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 230310.1186/s13104-016-2303-0Case ReportBladder outlet obstruction; a rare complication of the neglected schistosome, Schistosoma haematobium: two case reports and public health challenges Agbor Valirie Ndip nvagbor@gmail.com 1Njim Tsi 00 237 674221905tsinjim@gmail.com 23Mbolingong Franklin Ngu ngufrank@yahoo.com 41 Hope Clinic Bamenda, North West Region, Bamenda, Cameroon 2 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, Oxfordshire UK 3 Health and Human Development (2HD) Research Group, Douala, Cameroon 4 District Hospital Ndu, North West Region, Cameroon 22 11 2016 22 11 2016 2016 9 49314 4 2016 16 11 2016 © The Author(s) 2016\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\nSchistosomiasis is a severe parasitic infestation with debilitating complications and is the third most devastating tropical disease in the world. It is one of the neglected tropical diseases (NTDs) with a high disease-burden. We present two rare cases of bladder outlet obstruction: one which led to a chronic kidney disease and ultimately death and a second which recovered after treatment with praziquantel.\n\nCase presentations\nA 72 year old male presented with lower urinary tract symptoms which culminated in an episode of acute urinary retention. The patient had never received preventive chemotherapy with praziquantel. After suprapubic aspiration, the cause of the obstructive uropathy was found to be several mature live worms of Schistosoma haematobium. Despite treatment with praziquantel and haemodialysis; we lost the patient due to sepsis from a urinary tract infection. In the second case, a 15 year old male presented with LUTS for a 1 year duration and was diagnosed to have schistosomiasis after eggs of Schistosoma haematobium were found in his urine. He was treated with praziquantel.\n\nConclusion\nThere are several gaps in the public health policies in place to control this NTD in Cameroon as annual distribution of preventive chemotherapy is inadequate due to inaccessibility of some high-endemic zones and is based on data obtained two decades ago. Population education is insufficient leading to poor health-seeking behaviour. These gaps in public health policies need to be addressed to aid in the overall achievement of the sustainable development goals.\n\nKeywords\nSchistosomiasisNeglected tropical diseasesBladder outlet obstructionCameroonissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSchistosomiasis (Bilharziasis) is a parasitic infestation associated with a high degree of morbidity and mortality in third world countries, especially in Africa [1]. Schistosomiasis is endemic in some regions in Africa; of the 261 million people who required preventive treatment for the disease in 2013, 90% resided in this continent. In Cameroon, five million people are estimated to be at risk of infection with the disease, with two million current infections [2]. So far, three species have been identified as causative agents of schistosomiasis in Cameroon: Schistosoma mansoni, Schistosoma haematobium and Schistosoma guineensis (the Lower Guinea species) [3]. Two-third of the cases of schistosomiasis are caused by S. haematobium: the species causing urogenital schistosomiasis [4]. In this case series, we present two rare cases of bladder outlet obstruction caused by S. haematobium; one which led to a chronic kidney disease and ultimately death and a second which recovered after treatment with Praziquantel.\n\nCase presentations\nCase 1\nA 72 year old African male from Wum, in the far North west region of Cameroon, presented with a 3 year history of lower urinary tract symptoms (LUTS) both obstructive and irritative in nature; and an International Prostate Symptom Score (IPSS) of 22 with a moderate degree of bother, which culminated in an episode of acute urinary retention for which he sought a consult at our health services. The patient like most in his neighbourhood used water from a nearby stream for his baths and claims he had never received any preventive chemotherapy against schistosomiasis.\n\nOn examination, the patient was anxious with a tender, renitent hypogastic swelling which increased the zeal to urinate on palpation. A diagnosis of bladder outlet obstruction due to a benign prostate hypertrophy was advocated. Blood samples were collected and a transurethral catheter was placed which relieved the symptoms; with collection of 800 ml of clear urine.\n\nResults of investigations showed: a normal full blood count; prostate specific antigen value of 4.21 ng/dl; normal size and structure of the prostate on ultrasound; serum urea = 321 mg/dl, serum creatinine = 3.2 mg/dl, serum K+ = 6 mEq/l and a microscopic haematuria on urinalysis. A follow up renal ultrasound showed a decrease in the size of the kidneys.\n\nOn day 2, the patient started having macroscopic hematuria with blockage of urinary catheter. A suprapubic puncture was done with extraction of several live worms which were confirmed to be S. haematobium in the laboratory (Fig. 1). The patient was then placed on praziquantel 40 mg/kg and hemodialysis.Fig. 1 Urine aspirate from supra-pubic puncture; showing adult worms of Schistosoma haematobium (white arrow) and a macroscopic haematuria (black arrow)\n\n\n\n\nDay 6 of hospitalization was marked by the onset of pyuria and fever and the patient was placed on broad spectrum antibiotics and a urine culture requested. We finally lost the patient on day 9 of admission due to sepsis from a urinary tract infection.\n\nCase 2\nA 15 year old African male from Fundong in the North west region of Cameroon, presented with a 1 year history of macroscopic haematuria and dysuria associated with obstructive and irritative LUTS (weak stream, intermittency and frequency), an IPSS of 15 and a moderate degree of bother. He had consulted severally in the health centres in this region by nurses and received multiple treatment with broad spectrum antibiotics. He frequently swam in a river near his home like most children of his age and he had never received any preventive chemotherapy. On examination, the patient had a good general state with normal vital signs. He had mild suprapubic tenderness. Results of investigations revealed a normal FBC; Urinalysis: presence of red blood cells, white blood cells and eggs of S. haematobium and serum creatinine: 0.8 mg/dl. He was treated with praziquatel 40 mg/kg which relieved the symptoms. He presented 1 month later for a follow-up visit with no further complaints.\n\nDiscussion\nSchistosomiasis, sometimes known as bilharziasis or snail fever is a water borne disease transmitted through skin contact with infested fresh water bodies. According to the World Health Organisation (WHO), schistosomiasis is one of the four neglected tropical diseases (NTDs) controlled through “preventive chemotherapy” intervention (the others include soil transmitted helminthiasis, onchocerciasis and lymphatic filiariasis) [5].\n\n\nSchistosoma haematobium is the second most common isolated species in Cameroon, responsible for up to 95.92% prevalence in some health districts like the Malantouen health district, in the West region [3].\n\nThe life cycle of S. haematobium begins with the excretion of the egg into fresh water bodies, after which they hatch into the miracidia and penetrate bulinus species (the intermediate host). The parasite emerges from the snails in the larva stage, penetrating the human skin (the definitive host) in contact with the infested water. The larvae then migrate to the lungs and liver. The worms then mature, copulate, and adult female worms deposit their eggs in the pelvic vessels which progressively penetrate urinary and genital system. Eggs deposited during the active phase induce a granulomatous reaction with a resultant fibrosis [6].\n\nEarly manifestations of infection include; cough, fever, hepatomegaly, splenomegaly, lymphadenopathies and difficulty in breathing following an initial pruritic papular skin rash (“swimmer’s itch”).\n\nIndividuals can develop chronic debilitating complications years after infestation, which include: haematuria, stunting and wasting, bladder cancer, ureteric obstruction, hydronephrosis, urinary tract infections, renal failure and ultimately death [7, 8]. Also, S. haematobium is associated with high mortality especially in school-aged children (7–14 years) [9, 10]. Furthermore, 75% of chronically infected females suffer from female genital schistosomiasis which presents with contact bleeding, abnormal discharges, dyspareunia and diminished fertility which is a potential source of stigmatisation and shame [11]. Lastly, the eggs of S. haematobium eggs have been reported as Group I carcinogens, causing squamous cell carcinoma; and has also been incriminated as a cofactor for the transmission of the HIV in Africa [12–14].\n\nFrom the above complications, it is clear that schistosomiasis has a high disease-burden. Despite its public health importance, S. haematobium has been labeled ‘‘the neglected schistosome’’ [15, 16]. This is true in Africa, and Cameroon in particular, where research on the disease is inadequate. A PubMed search over the last 10 years revealed 13 papers on schistosomiasis from Cameroon, with only two of these papers focused on S. haematobium. Furthermore, the failure to control and eradicate schistosomiasis which is one of the NTDs, could be associated with the failure to achieve the Millennium Development Goal (MDG) 6 in most developing countries endemic to the disease in Africa like Cameroon.\n\nCameroon adopted a plan in 2004 to combat schistosomiasis and soil transmitted helminthiasis (STH) which was implemented in all ten regions by the year 2007. Annual national deworming campaigns were executed with administration of albendazole or mebendazole to school-aged children, whereas the distribution of praziquantel was only to highly endemic for schistosomiasis [17]. In order to control NTDs, the Cameroonian government implemented an integrative approach which involves co-implementing other control intervention measures and co-administering several drugs like ivermectin, praziquantel, mebendazole and albendazole. Since 2009, Cameroon receives assistance from the United States Agency for International Development (USAID) through its NTD Control Program, currently ENVISION program, managed by Response to Intervention (RTI) International. ENVISION facilitates incorporation of national programs and reinforces mass drug administration (MDA) [18].\n\nHowever, the control data of schistosomiasis in Cameroon is not encouraging. A study carried out in 2013 by Tchuenté et al. showed an increase in transmission foci of schistosomiasis compared to previous data in 1985–1987 [19].\n\nThe above program therefore has some gaps in health policies as accentuated by the case reports above. These gaps need to be addressed in order to attain the newly set Sustainable Development Goals (SDGs) amongst which the control and eradication of Schistosomiasis and other NTDs (SDG 3) remains a priority [20].\n\nDue to poor accessibility of most remote areas most individuals inhabiting these zones do not receive treatment. Also, out-of-school children are not reached and preschoolers and adults are not being treated. The annual distribution of praziquantel is therefore defective in controlling and/or eradicating schistosomiasis. Both patients in this case series lived in North West region of Cameroon; in areas with poor accessibility. They and several other members of their community did not receive preventive chemotherapy though they lived in schistosomiasis-endemic zones. Moreso, distribution of prazinquantel is only in highly endemic zones obtained from data 28 years ago. However, there are rapid reinfection rates in high transmission settings due to intense water contact. Control programs are supposed to be coupled with intense monitoring to assess the impact of these interventions. This is however not the case in Cameroon. Hence, newly endemic zones cannot be identified and individuals with the disease go undiagnosed for long periods without access to preventive chemotherapy. Furthermore, there’s the complete absence of environmental control program (snail control and sanitation improvement) which when added to annual drugs distribution may go a long in disease control and eventually disease eradication [21]. Also, the Cameroonian population is deficient in knowledge concerning schistosomiasis including; the mode of transmission, prevention like avoiding wading, swimming, or others contacts with fresh water, and treatment with praziquantel. The patient in case 1 above experienced disabling symptoms for over 3 years and only arrived the hospital at a later stage with an irreversible complication. Population education on the symptoms of the disease and its prevention would lead to better health-seeking behaviors and progress in eventual control of the disease. Finally, the patient in case 2 experienced the disabling conditions of the disease for over 1 year despite several consults at health facilities. This calls for the need for training of healthcare providers on the recognition and management of NTDs like onchocerciasis [22] and schistosomiasis in Cameroon.\n\nConclusion\nSchistosomiasis is still a major public health problem in Cameroon, associated with significant morbidity and mortality. Individuals, especially school-aged children, adolescents and young adults in endemic zones are at an increased risk to the debilitating conditions of this disease. As shown above, the current health policies have to be revisited and more research has to be done regularly to map out new endemic zones in Cameroon in order to help with the control of the disease and the eventual achievement of the SDGs.\n\nAbbreviations\nNTDneglected tropical diseases\n\nSDGsustainable development goals\n\nLUTSlower urinary tract symptoms\n\nIPSSinternational prostate symptom score\n\nWHOWorld Health Organisation\n\nMDGmillennium development goals\n\nSTHsoil transmitted helminthiasis\n\nUSAIDUnited States Agency for International Development\n\nRTIresponse to intervention\n\nMDAmassive drug administration\n\nAuthors’ contributions\nVNA: Acquisition of data and writing of initial manuscript. TN: Management of patient (case 1), acquisition of data, supervision of writing of initial manuscript and critical revisions of the manuscript. FMN: Management of patient (case 2) and revisions of manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank the families of both patients for allowing them to publish this findings and the images herein. TN and FNM would like to thank Dr. Julius Atashili for teaching him the basis of scientific writing. He left a golden trail. May his legacy live on. TN also thank Prof. Simeon-Pierre Choukem for his constant guidance.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and material\nAll data generated\nduring this case report are included in this published article [and its\nsupplementary information files].\n\nConsent to publish\nThe authors obtained written consent from the first of kin and guardian of the first and second patient respectively to publish the information and images in this case report.\n==== Refs\nReferences\n1. World Health Organisation. Schistosomiasis. [http://www.who.int/mediacenter/factsheets/fs115/en/ (2010). Accessed 14 Dec 2015.\n2. MINSANTE: Programme National de Lutte contre la Schistosomiase et les Helminthiases Intestinales: Plan strategique 2005–2010. Ministere de la Sante Publique, Cameroun; 2005.\n3. Tchuenté LA Ngassam RI Sumo L Ngassam P Noumedem CD Nzu DD Mapping of schistosomiasis and soil-transmitted helminthiasis in the regions of centre, east and west Cameroon PLoS Negl Trop Dis. 2012 6 3 e1553 10.1371/journal.pntd.0001553 22413029 \n4. WHO: World Health Organization. http://www.who.int/mediacenter/factsheets/fs115/en/ (2015). Accessed 21 Dec 2015.\n5. WHO: 10 facts about schistosomiasis. http://www.who.int/features/factfiles/schistosomiasis/facts/en/index4.html (2015). Accessed 21 Dec 2015.\n6. Neal PM Schistosomiasis—an unusual cause of ureteral obstruction a case history and perspective Clin Med Res. 2004 2 4 216 227 10.3121/cmr.2.4.216 15931361 \n7. Brindley P Hotez P Break out: urogenital schistosomiasis and Schistosoma haematobium infection in the post-genomic era PLoS Negl Trop Dis. 2013 7 3 e1961 10.1371/journal.pntd.0001961 23556007 \n8. Botelho MC Machado A Carvalho A Vilaca M Conceicao O Rosa F Schistosoma haematobium in Guinea-Bissau: unacknowledged morbidity due to a particularly neglected parasite in a particularly neglected country Parasitol Res 2016 115 4 1567 1572 10.1007/s00436-015-4891-3 26755362 \n9. Moussa S Magnussen P Keita A Traoré M Landouré A Doucouré A Impact of Schistosoma haematobium infection on urinary tract pathology, nutritional status and anaemia in school-aged children in two different endemic areas of the Niger River Basin, Mali Acta Trop 2011 120S S142 S150 \n10. Befidi-Mengue R Ratard R D’Alessandro D Rice J Befidi-Mengue R Kouemeni L Impact of Schistosoma haematobium infection and of praziquantel treatment on anaemia of primary school children in Bertoua Cameroon J Trop Med Hyg. 1992 95 404 409 1460700 \n11. Kjetland E Leutscher P Dudhlovu P A review of female genital schistosomiasis Trends Parasitol 2012 28 58 65 10.1016/j.pt.2011.10.008 22245065 \n12. Shiff C Veltri R Naples J Quartey J Otchere J Anyan W Ultrasound verification of bladder damage is associated with known bio-markers of bladder cancer in adults chronically infected with Schistosoma haematobium in Ghana Trans R Soc Trop Med Hyg 2006 100 847 854 10.1016/j.trstmh.2005.10.010 16443246 \n13. Botelho MC Machado JC Brindley PJ Correia da Costa JM Targeting molecular signaling pathways of Schistosoma haemotobium infection in bladder cancer Virulence. 2011 2 4 267 279 10.4161/viru.2.4.16734 21788729 \n14. Hotez P Fenwick A Kjetland E Africa’s 32 cents solution for HIV/AIDS Plos Negl Trop Dis. 2009 3 e430 10.1371/journal.pntd.0000430 19479041 \n15. Rollingson D Wake up call for urinary schistosomiasis: reconciling research effort with public health importance Parasitology 2009 136 1593 1610 10.1017/S0031182009990552 19627633 \n16. Ronaldi G Okatcha T Popratiloff A Ayuk M Suttiprapa S Genetic manipulation of Schistosoma haematobium, the neglected schistosome PLoS Negl Trop Dis. 2011 5 e1348 10.1371/journal.pntd.0001348 22022628 \n17. Tchuenté L N’Goran E Schistosomiasis and soil-transmitted helminthiasis control in Cameroon and Cote d’Ivoire: implementing control on a limited budget Parasitology 2009 136 1739 1745 10.1017/S0031182009005988 19490723 \n18. Linehan M Hanson C Weaver A Baker M Kabore A Zoerhoff K Integrated implementation of programs targeting neglected tropical diseases through preventive chemotherapy: proving the feasibility at national scale Am J Trop Med Hyg 2011 84 1 5 14 10.4269/ajtmh.2011.10-0411 21212194 \n19. Tchuenté L Noumedem C Ngassam P Kenfack C Gipwe N Dankoni E Mapping of schistosomiasis and soil-transmitted helminthiasis in the regions of Littoral, North-West, South and South-West Cameroon and recommendations for treatment BMC Infect Dis 2013 13 602 10.1186/1471-2334-13-602 24365046 \n20. Williams E An equitable challenge: when sustainable development goals set the post-2015 agenda Aust N Z J Public Heal. 2013 37 6 591 592 10.1111/1753-6405.12131 \n21. Williams S Water-based intervention for schistosomiasis control Pathog Glob Health. 2014 108 5 246 254 10.1179/2047773214Y.0000000149 25175875 \n22. Njim T Ngum JN Aminde LN Cutaneous onchocerciasis in Dumbu, a pastoral area in the North–West region of Cameroon: diagnostic challenge and socio-economic implications Pan Afr Med J. 2015 22 248 10.11604/pamj.2015.22.298.7707 26958111\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "9(1)",
"journal": "BMC research notes",
"keywords": "Bladder outlet obstruction; Cameroon; Neglected tropical diseases; Schistosomiasis",
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000293:Adolescent; D000368:Aged; D000818:Animals; D000871:Anthelmintics; D002163:Cameroon; D057210:Delayed Diagnosis; D007722:Health Knowledge, Attitudes, Practice; D006801:Humans; D008297:Male; D011223:Praziquantel; D011634:Public Health; D012548:Schistosoma haematobium; D012553:Schistosomiasis haematobia; D001743:Urinary Bladder; D001748:Urinary Bladder Neck Obstruction; D014552:Urinary Tract Infections",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "493",
"pmc": null,
"pmid": "27876076",
"pubdate": "2016-11-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24365046;22245065;19627633;15931361;22413029;1460700;24892163;16443246;26755362;21212194;21195046;19479041;19490723;25175875;21788729;23556007;26966494;22022628",
"title": "Bladder outlet obstruction; a rare complication of the neglected schistosome, Schistosoma haematobium: two case reports and public health challenges.",
"title_normalized": "bladder outlet obstruction a rare complication of the neglected schistosome schistosoma haematobium two case reports and public health challenges"
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"abstract": "Primary pulmonary tumors are extremely rare in the pediatric population; however, sporadic cases of invasive pulmonary adenocarcinoma as a second malignant neoplasm (SMN) have been described in survivors of pediatric cancers. Pediatric patients with rhabdomyosarcoma (RMS) have a particularly increased risk of developing a SMN when compared to the general population, though pulmonary adenocarcinoma has not been previously described in a RMS patient. A 12-year-old female previously treated for stage IV pelvic RMS was found to have a left pulmonary nodule on surveillance computed tomography. The nodule was detected 4.25 years after the completion of treatment, which included resection, chemotherapy, and radiation to the abdomen and pelvis. Wedge resection of the pulmonary lesion was performed with negative margins. Histopathological examination revealed minimally invasive adenocarcinoma. Pulmonary adenocarcinoma may rarely present as a SMN in pediatric cancer survivors. The pathogenesis of this association is not yet entirely clear, but may include chemotherapy-induced mutagenesis and/or genetic predisposition. As pulmonary adenocarcinoma may present as a lung lesion radiographically indistinguishable from metastatic RMS, it should be considered in the differential diagnosis of any pediatric RMS survivor presenting with a new pulmonary nodule, especially in cases with late recurrence.",
"affiliations": "University of Minnesota Medical School, Masonic Children's Hospital, Minneapolis, Minnesota.;University of Minnesota Medical School, Masonic Children's Hospital, Minneapolis, Minnesota.;Department of Laboratory Medicine and Pathology, University of Minnesota, Masonic Children's Hospital, Minneapolis, Minnesota.;Department of Oncology, Essentia Health, Minnesota.;Department of Surgery, University of Minnesota, Masonic Children's Hospital, Minneapolis, Minnesota.",
"authors": "Bradee|Allison R|AR|;Lehman|Alice|A|;Reed|Robyn C|RC|;Watson|Andrea|A|;Acton|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25642",
"fulltext": null,
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"issn_linking": "1545-5009",
"issue": "63(2)",
"journal": "Pediatric blood & cancer",
"keywords": "bronchioloalveolar carcinoma; lung cancer; pediatric; pulmonary adenocarcinoma; rhabdomyosarcoma; second malignant neoplasm",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000293:Adolescent; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D016609:Neoplasms, Second Primary; D012208:Rhabdomyosarcoma; D012983:Soft Tissue Neoplasms",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "344-7",
"pmc": null,
"pmid": "26174135",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minimally Invasive Adenocarcinoma of the Lung as Second Malignant Neoplasm Following Pediatric Rhabdomyosarcoma.",
"title_normalized": "minimally invasive adenocarcinoma of the lung as second malignant neoplasm following pediatric rhabdomyosarcoma"
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"companynumb": "US-PFIZER INC-2017065937",
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"abstract": "OBJECTIVE\nTo report a case of central retinal artery occlusion (CRAO) in a young human immunodeficiency virus (HIV)-infected patient recently started on highly active antiretroviral therapy.\n\n\nMETHODS\nCase report observation of a 33-year-old HIV-infected patient who developed a CRAO after starting highly active antiretroviral therapy.\n\n\nRESULTS\nElevated triglycerides caused by starting highly active antiretroviral therapy preceded the development of CRAO in an HIV-infected patient.\n\n\nCONCLUSIONS\nAtherosclerotic vascular disease is an important complication of HIV therapy, which can ultimately lead to cardiovascular disease. An unusual case of a young patient developing a CRAO after the initiation of highly active antiretroviral therapy is reported. In the patient, the authors expound that elevated lipids from efavirenz/emtricitabine/tenofovir resulted in carotid atherosclerosis, ultimately leading to CRAO. Eye care providers, as well as the internal medicine colleagues, should be aware of the possibility of this devastating condition in HIV-infected patients on antiretroviral therapy.",
"affiliations": "Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.",
"authors": "Lenci|Lucas T|LT|;Chin|Eric K|EK|;Almeida|David R P|DR|",
"chemical_list": "D014280:Triglycerides",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000318",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "11(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D002340:Carotid Artery Diseases; D015658:HIV Infections; D006801:Humans; D008297:Male; D015356:Retinal Artery Occlusion; D014280:Triglycerides",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "160-162",
"pmc": null,
"pmid": "27111556",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "CENTRAL RETINAL ARTERY OCCLUSION IN A YOUNG HIV-INFECTED PATIENT ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY.",
"title_normalized": "central retinal artery occlusion in a young hiv infected patient on highly active antiretroviral therapy"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US04759",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EFAVIRENZ\\EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
... |
{
"abstract": "BACKGROUND\nAdrenocortical carcinoma (ACC) is a rare and aggressive disease that is often diagnosed at an advanced stage. There is no standard treatment for metastatic ACC; EDP-M (etoposide, doxorubicin, and cisplatin plus mitotane) is one treatment option. A randomized controlled trial (FIRM-ACT) evaluating the efficacy of EDP-M showed progression-free survival (PFS) was 5.0 months, overall survival (OS) was 14.8 months, the response rate was 19%, and adrenal insufficiency occurred in 3.4% of patients. However, the efficacy and safety of this regimen in Asia are not fully reported.\n\n\nMETHODS\nWe retrospectively analyzed 43 patients diagnosed with metastatic ACC at the National Cancer Center Hospital between 1997 and 2020. We evaluated PFS, OS, and response in 17 patients who received EDP-M as first-line therapy.\n\n\nRESULTS\nThe median age at treatment initiation was 45 years (range 18-74). Eight patients (47%) had autonomous hormone production, including six patients with hypercortisolism. The best response of partial response and stable disease was seen in two (12%) and ten (59%) patients, respectively. The median PFS was 6.2 months [95% confidence interval (CI): 4.3-10.0]. The median OS was 15.4 months (95% CI 11.6-not reached). Three patients received only one cycle due to adverse effects associated with hypercortisolism. Grade 3/4 adverse events associated with adrenal insufficiency occurred in three (17%) cases, resulting in EDP-M discontinuation.\n\n\nCONCLUSIONS\nThe EDP-M regimen had similar PFS to that observed in FIRM-ACT. Adrenal insufficiency was more frequent in the current study, but this could be managed with supportive endocrinological care such as cortisol replacement.",
"affiliations": "Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.;Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. mtanioka@ncc.go.jp.;Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.;Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.;Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.;Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.;Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.;Department of Diagnostic Pathology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.;Department of Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.",
"authors": "Uchihara|Masaki|M|;Tanioka|Maki|M|http://orcid.org/0000-0002-6558-2246;Kojima|Yuki|Y|;Nishikawa|Tadaaki|T|;Sudo|Kazuki|K|;Shimoi|Tatsunori|T|;Noguchi|Emi|E|;Maeshima|Akiko Miyagi|AM|;Yonemori|Kan|K|",
"chemical_list": "D005047:Etoposide; D008939:Mitotane; D004317:Doxorubicin; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-021-02021-8",
"fulltext": null,
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"issn_linking": "1341-9625",
"issue": "26(12)",
"journal": "International journal of clinical oncology",
"keywords": "Adrenal insufficiency; Adrenocortical carcinoma; EDP; Hypercortisolism; Mitotane",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000306:Adrenal Cortex Neoplasms; D018268:Adrenocortical Carcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D004317:Doxorubicin; D005047:Etoposide; D006801:Humans; D008875:Middle Aged; D008939:Mitotane; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "2275-2281",
"pmc": null,
"pmid": "34468885",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "16680602;23561851;22551107;29903850;25724314;32802458;21958460;19097774;28780517;18824557;28203371;24268504;26676603;11745214;21470991;33578890;25795408;24423320;22189997;30348224;30400026;19240185;20592067;28432084;29187510",
"title": "Clinical management and outcomes associated with etoposide, doxorubicin, and cisplatin plus mitotane treatment in metastatic adrenocortical carcinoma: a single institute experience.",
"title_normalized": "clinical management and outcomes associated with etoposide doxorubicin and cisplatin plus mitotane treatment in metastatic adrenocortical carcinoma a single institute experience"
} | [
{
"companynumb": "JP-TEVA-2022-JP-2009314",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Sulfasalazine is an anti-inflammatory agent commonly used in the treatment of autoimmune conditions such as inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine is converted by gut bacteria into sulfapyridine and the clinically active metabolite 5-aminosalicylic acid (5-ASA), and its efficacy is proportional to the 5-ASA concentration within the intestinal lumen. Renal complications are commonly reported for the chemically similar 5-ASA derivative mesalamine, but are not well-known side effects of sulfasalazine therapy. We report a 72-year-old patient with Crohn's disease managed with sulfasalazine for more than 10 years who presented with severe acute kidney injury (serum creatinine, 9.7mg/dL). Renal ultrasound revealed calculi and he subsequently spontaneously voided innumerable stones, which were composed of sulfasalazine metabolites. His renal calculi cleared and serum creatinine concentration improved to 3.1mg/dL after discontinuing sulfasalazine therapy and intravenous fluid hydration. His kidney function eventually returned to baseline. This case demonstrates that renal complications, in particular nephrolithiasis, may be an under-reported but potentially serious phenomenon in patients with inflammatory bowel disease treated with sulfasalazine and that their hydration status may play an important role in this process.",
"affiliations": "Department of Internal Medicine, Emory University, Atlanta, GA; Division of Nephrology, Department of Internal Medicine, University of Arizona, Tucson, AZ. Electronic address: mdurando@email.arizona.edu.;Division of Nephrology, Department of Internal Medicine, University of Arizona, Tucson, AZ.;Department of Internal Medicine, Emory University, Atlanta, GA.",
"authors": "Durando|Michael|M|;Tiu|Hannah|H|;Kim|James Soo|JS|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000978:Antiparkinson Agents; D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D007189:Indans; D010880:Piperidines; C009265:carbidopa, levodopa drug combination; D012460:Sulfasalazine; D007980:Levodopa; D000077265:Donepezil; D002230:Carbidopa",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2017.05.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "70(6)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Crohn’s disease; Sulfasalazine; acute kidney injury (AKI); adverse effect; case report; crystalluria; inflammatory bowel disease (IBD); kidney stones; nephrolithiasis; renal calculi",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000978:Antiparkinson Agents; D002230:Carbidopa; D002800:Cholinesterase Inhibitors; D003424:Crohn Disease; D000077265:Donepezil; D004338:Drug Combinations; D005440:Fluid Therapy; D006801:Humans; D007189:Indans; D007669:Kidney Calculi; D007980:Levodopa; D008297:Male; D010300:Parkinson Disease; D010880:Piperidines; D012720:Severity of Illness Index; D012460:Sulfasalazine; D014463:Ultrasonography",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "869-873",
"pmc": null,
"pmid": "28669550",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sulfasalazine-Induced Crystalluria Causing Severe Acute Kidney Injury.",
"title_normalized": "sulfasalazine induced crystalluria causing severe acute kidney injury"
} | [
{
"companynumb": "US-PFIZER INC-2017294361",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": "1",
... |
{
"abstract": "This case report highlights the merits of using fine needle aspiration biopsy to obtain gene expression profiling of individual choroidal melanomas when more than one tumor arises in the same eye. It is also the first such case to document laser ablation therapy as the primary treatment.\n\n\n\nThis report describes a case of two primary choroidal melanomas with different genetic profiles in the same eye.\n\n\n\nAn 80-year-old man presented to the office with a neoplasm of uncertain behavior in the left eye. The patient's visual acuity and IOP in the left eye, respectively, at the time of his first visit to the office were 20/25 and 8 mmHg. A dilated fundus examination revealed that there were two choroidal lesions in the left eye. The macular lesion was classified as type 1A, and the ciliochoroidal lesion was classified as type 1B. The patient underwent a vitrectomy of the left eye, followed by endolaser ablation of the tumors. The patient was also injected with bevacizumab. To date, the patient is free of known metastasis. Most recently, his visual acuity and IOP in the left eye were 20/30 and 14 mmHg, respectively.\n\n\n\nAlthough rare, multiple melanomas in the same eye may have differing genetic profiles, which may alter prognosis and management, depending on the class of tumor detected.",
"affiliations": "Murray Ocular Oncology and Retina, Miami, Florida.;Murray Ocular Oncology and Retina, Miami, Florida.;Murray Ocular Oncology and Retina, Miami, Florida.",
"authors": "Saigal|Khushi|K|;El Hamichi|Sophia|S|;Gold|Aaron S|AS|;Murray|Timothy G|TG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/OPX.0000000000001769",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-5488",
"issue": "98(9)",
"journal": "Optometry and vision science : official publication of the American Academy of Optometry",
"keywords": null,
"medline_ta": "Optom Vis Sci",
"mesh_terms": "D000369:Aged, 80 and over; D002829:Choroid; D002830:Choroid Neoplasms; D006801:Humans; D008297:Male; D008545:Melanoma; D014792:Visual Acuity; D014821:Vitrectomy",
"nlm_unique_id": "8904931",
"other_id": null,
"pages": "1011-1015",
"pmc": null,
"pmid": "34433203",
"pubdate": "2021-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: Two Genetically Distinct Choroidal Melanomas in the Same Eye Treated with Endolaser Therapy.",
"title_normalized": "case report two genetically distinct choroidal melanomas in the same eye treated with endolaser therapy"
} | [
{
"companynumb": "US-ROCHE-2924490",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "4",
"drug... |
{
"abstract": "We describe a 66-year-old woman who received folinic acid, leucovorin, fluorouracil and oxaliplatin for advanced rectal carcinoma. These drugs were initiated on day 1, and a pelvic abscess was identified on day 7. Piperacillin-tazobactam was initially administered, but was changed to ceftriaxone and metronidazole on day 14 on the basis of antimicrobial susceptibility testing. On the following day, the patient reported blindness, and MRI of the brain showed signal abnormalities in the splenium of the corpus callosum on DWI, suggestive of metronidazole encephalopathy. Although the total body exposure was 2 g, metronidazole was discontinued. The patient developed coma a few days later, and MRI of the brain on day 26 showed high signal intensity extensively involving the white matter in the cerebrum as well as the brainstem and cerebellum. She died 37 days after the initial administration of the chemotherapy. Pathological studies demonstrated decreased staining intensity in the myelin sheath and multiple vacuolar alterations, consistent with toxicity induced by metronidazole and fluorouracil. Care should be taken when administering a combination of these drugs, even if the total body exposure to each drug is limited.",
"affiliations": "Department of Neurology, Kameda General Hospital.;Department of Neurology, Kameda General Hospital.;Department of Neurology, Kameda General Hospital.;Department of Neurology, Kameda General Hospital.;Department of Neurology, Tokyo Metropolitan Geriatric Hospital.;Department of Neurology, Kameda General Hospital.",
"authors": "Fukumoto|Tatsuya|T|;Katada|Fumiaki|F|;Sato|Susumu|S|;Shibayama|Hidehiro|H|;Murayama|Shigeo|S|;Fukutake|Toshio|T|",
"chemical_list": "D009944:Organoplatinum Compounds; D008795:Metronidazole; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-001105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "58(2)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": "5-FU; leukoencephalopathy; metronidazole; pathology",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001921:Brain; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D056784:Leukoencephalopathies; D008279:Magnetic Resonance Imaging; D008795:Metronidazole; D059906:Neuroimaging; D009944:Organoplatinum Compounds",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "118-123",
"pmc": null,
"pmid": "29386497",
"pubdate": "2018-02-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of acute leukoencephalopathy induced by a combination of 5-fluorouracil and metronidazole.",
"title_normalized": "a case of acute leukoencephalopathy induced by a combination of 5 fluorouracil and metronidazole"
} | [
{
"companynumb": "JP-VIVIMED-2018SP004392",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nStreptococcus pseudoporcinus (S. pseudoporcinus) was first identified in 2006. It cross-reacts with Lancefield group B antigen agglutination reagents and has been misidentified as S. agalactiae. Sites of S. pseudoporcinus isolation include the female genitourinary tract, urine, wounds, and dairy products. The prevalence of vaginal colonization is reportedly between 1 and 5.4%. Two uneventful cases of soft tissue infection caused by S. pseudoporcinus were reported in the past. However, since late 2019, six cases of invasive S. pseudoporcinus infections have emerged in the literature, one of which was fatal.\n\n\nMETHODS\nWe describe a fatal case of a Caucasian male with spontaneous bacterial peritonitis associated with bacteremia due to a multidrug-resistant S. pseudoporcinus strain in a patient with decompensated liver cirrhosis. Despite the patient's good general condition and stable blood test results when he had visited the outpatient clinic for large-volume paracentesis a few days before admission, this time he presented to the emergency department with a rapidly worsening clinical condition and with laboratory features consistent with multiple-organ dysfunction syndrome, and succumbed within a short period.\n\n\nCONCLUSIONS\nContrary to what was thought until recently, multidrug-resistant S. pseudoporcinus may cause invasive, disseminated, fatal disease in humans. According to current limited data, vancomycin, linezolid, daptomycin, levofloxacin, clindamycin, and tetracycline seem to be the most effective antimicrobial agents against multidrug-resistant strains, and should be the empirical choice in cases of disseminated S. pseudoporcinus infection until laboratory antimicrobial susceptibility results are available. Improvements and new approaches for bacterial identification in routine clinical microbiology laboratories may reveal the real spectrum of S. pseudoporcinus infections in humans, which is currently believed to be underestimated. SS. pseudoporcinus could emerge as a serious medical problem in the near future, similar to other β-hemolytic streptococci.",
"affiliations": "Department of Internal Medicine, \"Hippokration\" General Hospital, 114 Vass. Sophia's Ave., 115 27, Athens, Greece. geoliatsos@yahoo.gr.;Department of Microbiology, \"Hippokration\" General Hospital, Athens, Greece.;2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, \"Hippokration\" General Hospital, Athens, Greece.",
"authors": "Liatsos|George D|GD|http://orcid.org/0000-0002-8203-2748;Tsiriga|Athanasia|A|;Dourakis|Spyridon P|SP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02832-3",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2832\n10.1186/s13256-021-02832-3\nCase Report\nFatal Streptococcus pseudoporcinus disseminated infection in decompensated liver cirrhosis: a case report\nhttp://orcid.org/0000-0002-8203-2748\nLiatsos George D. geoliatsos@yahoo.gr\n\n1\nTsiriga Athanasia nantsir@gmail.com\n\n2\nDourakis Spyridon P. spdour@med.uoa.gr\n\n3\n1 grid.414122.0 0000 0004 0621 2899 Department of Internal Medicine, “Hippokration” General Hospital, 114 Vass. Sophia’s Ave., 115 27 Athens, Greece\n2 grid.414122.0 0000 0004 0621 2899 Department of Microbiology, “Hippokration” General Hospital, Athens, Greece\n3 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, “Hippokration” General Hospital, Athens, Greece\n16 5 2021\n16 5 2021\n2021\n15 24022 5 2019\n29 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nStreptococcus pseudoporcinus (S. pseudoporcinus) was first identified in 2006. It cross-reacts with Lancefield group B antigen agglutination reagents and has been misidentified as S. agalactiae. Sites of S. pseudoporcinus isolation include the female genitourinary tract, urine, wounds, and dairy products. The prevalence of vaginal colonization is reportedly between 1 and 5.4%. Two uneventful cases of soft tissue infection caused by S. pseudoporcinus were reported in the past. However, since late 2019, six cases of invasive S. pseudoporcinus infections have emerged in the literature, one of which was fatal.\n\nCase presentation\n\nWe describe a fatal case of a Caucasian male with spontaneous bacterial peritonitis associated with bacteremia due to a multidrug-resistant S. pseudoporcinus strain in a patient with decompensated liver cirrhosis. Despite the patient’s good general condition and stable blood test results when he had visited the outpatient clinic for large-volume paracentesis a few days before admission, this time he presented to the emergency department with a rapidly worsening clinical condition and with laboratory features consistent with multiple-organ dysfunction syndrome, and succumbed within a short period.\n\nConclusions\n\nContrary to what was thought until recently, multidrug-resistant S. pseudoporcinus may cause invasive, disseminated, fatal disease in humans. According to current limited data, vancomycin, linezolid, daptomycin, levofloxacin, clindamycin, and tetracycline seem to be the most effective antimicrobial agents against multidrug-resistant strains, and should be the empirical choice in cases of disseminated S. pseudoporcinus infection until laboratory antimicrobial susceptibility results are available. Improvements and new approaches for bacterial identification in routine clinical microbiology laboratories may reveal the real spectrum of S. pseudoporcinus infections in humans, which is currently believed to be underestimated. SS. pseudoporcinus could emerge as a serious medical problem in the near future, similar to other β-hemolytic streptococci.\n\nKeywords\n\nStreptococcus pseudoporcinus\nGroup B streptococci\nSpontaneous bacterial peritonitis\nFatal infection\nMultidrug-resistant strain\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nStreptococcus pseudoporcinus (S. pseudoporcinus) was first described in 2006 after several human isolates recovered from the female genitourinary tract, phenotypically identified as S. porcinus, were finally investigated by 16S ribosomal ribonucleic acid (16S rRNA) gene sequencing and were found to be over 2.1% dissimilar to any other Streptococcus species [1]. It has biochemical characteristics similar to those of S. agalactiae (group B Streptococcus, GBS). It often cross-reacts with Lancefield group B antigen agglutination reagents of standard GBS testing kits, thus raising concerns that S. pseudoporcinus has been misidentified as GBS in routine cultures.\n\nApart from female colonization and infections in pregnant women, S. pseudoporcinus has been rarely recovered from urine cultures, wounds, endophthalmitis samples, and dairy products [2, 3]. Two uneventful cases of soft tissue infections in which S. pseudoporcinus was identified as the virulent factor were also published [4, 5]. Researchers have speculated that S. pseudoporcinus might not be associated with invasive disease to the same extent as S. agalactiae infection [3]. We present the case of an invasive, disseminated, fatal infection due to a multidrug-resistant S. pseudoporcinus strain. We also review six additional cases of S. pseudoporcinus bacteremia that recently emerged in the literature.\n\nCase presentation\n\nA 56-year-old Caucasian man presented to the emergency department because of progressive abdominal distension with discomfort and decreased urine volume for the past 2 days. His medical history was significant for decompensated alcoholic liver cirrhosis, type 2 diabetes mellitus, and coronary heart disease. He was married with two children, lived in an urban area, and was employed as an accountant. He was a nonsmoker and reported abstinence from alcohol for the past 6 months. His medication included insulin glargine and diuretics (furosemide plus spironolactone). One year before admission, after suffering his first episode of variceal bleeding, propranolol in combination with endoscopic variceal ligation was prescribed at a starting dose of 10 mg twice daily. The patient could not tolerate higher propranolol dosing during titration because of bradycardia. Ten months before admission, he was started on prophylaxis with ciprofloxacin 500 mg daily after a spontaneous bacterial peritonitis (SBP) episode, but 3 months later he discontinued antibiotic prophylaxis on his own. Over the past 3–4 months he had more frequent hospitalizations than in the past for large-volume ascites paracentesis.\n\nOn clinical examination, he was jaundiced, with blood pressure of 90/50 mmHg (baseline systolic blood pressure 120–130 mm/Hg) and heart rate of 72 beats per minute, and he was afebrile (36.7 °C). On skin examination, jaundice and spider angiomata were found on the trunk, face, and upper limbs; gynecomastia was also seen. Neurological examination revealed lethargy, altered mental status, and mild confusion. Neuromuscular impairment was noted including bradykinesia, asterixis (flapping motions of outstretched hands), slurred speech, ataxia, and hyperactive deep tendon reflexes. Focal neurologic deficits were absent. On chest examination, fine crackles were present at the lung bases. The abdominal wall appearance revealed a caput medusae due to portal hypertension, while dilated abdominal veins were also seen because of inferior and superior vena cava syndrome. Physical examination also showed a remarkable abdominal distension, a fluid wave, and flank dullness to percussion, with diffuse tenderness and normal bowel sounds. The liver was palpable two fingers below the right costal margin, with firm and nodular consistency; an enlarged left lobe was also palpable. Peripheral edema was more pronounced at the lower extremities. A chest X-ray performed on admission showed mild bilateral infiltrates of the lower lung areas (Fig. 1). Laboratory parameter values showed increased white blood cell (WBC) count and C-reactive protein (CRP), substantial acute kidney injury, and severe deterioration of liver biochemistry compared to a recent previous evaluation (Table 1).Table 1 Patient’s laboratory findings at his previous discharge (performed at our hospital) 10 days before his present admission (first column), and during his current 3-day hospitalization\n\nLaboratory value (normal)\t10 Days\nbefore admission\tDay 1\nAdmission\tDay 2\tDay 3\t\nBlood/serum parameters\t\t\t\t\t\nWBC (< 12,400/μL)\t6710\t14,070\t11,960\t12,800\t\nNeut/lymph %\t79.8/9.1\t93.8/1.9\t91/3.3\t90.3/2.8\t\nHct (%)/Hb (g/dL)\t27.3/9.1\t30.2/9.9\t28/9.5\t27.2/9.1\t\nPLT (>150,000/μL)\t168,000\t215,000\t239,000\t227,000\t\nUrea (< 55)/Creat (< 1.2) mg/dL\t58/0.8\t134/4.6\t163/5.4\t174/5.9\t\nSodium > 136/potassium < 5.1 mmol/L\t129/4.4\t121/5.5\t117/6.5\t124/5.6\t\nAST (< 34)/ALT (< 55) U/L\t241/161\t657/351\t2071/1002\t4812/1774\t\nLDH (< 220 U/L)\t290\t758\t2321\t7683\t\nALP (< 150)/γ-GT (< 64)U/L\t148/171\t160/172\t154/147\t233/132\t\nTBIL (< 1.2)/DBIL (mg/dL)\t10.48/6.92\t13.5/9.38\t16.9/11.3\t19.8/13.2\t\nTP (> 6.4)/Alb (> 3.5) g/dL\t6.9/3.3\t7.3/3.3\t6.8/3.1\tND\t\nPT (< 14 sec)/INR\t14.6/1.3\t20/1.8\t21.1/2.0\t40.6/4.1\t\nCRP (< 5 mg/L)\t37.3\t118.7\t134.4\t132.2\t\nBlood gas analysis\t\t\t\t\t\npH/HCO3mmol/L\t7.43/22.1\t7.35/16.7\t7.33/15.0\t7.02/8.1\t\nFiO2/SatO2%\t0.21/97\t0.21/96\t0.21/98\t0.50/98.5\t\nPO2/PCO2mmHg\t89/30\t83/25\t76/22\t94/31\t\nLactate acid (< 1.8 mmol/L)\t1.0\t4.0\t4.1\t9.4\t\nAscitic fluid\t\t\t\t\t\nWBC count/μL\t80\t5920\tND\t3680\t\nNeut/lymph%\tND\t60/30\t\t80/10\t\nGlu/LDH\t130/<90\t85/96\t\tND\t\nTP/Alb g/dL\t1.2/0.6\t1.9/1.0\t\tND\t\nWBC white blood cells, Neut/lymph neutrophil-to-lymphocyte ratio, Hct hematocrit, Hb hemoglobin, PLT platelets, Creat creatinine, AST aspartate transaminase, ALT alanine aminotransferase, LDH lactate dehydrogenase, ALP alkaline phosphatase, γ-GT γ-glutamyltransferase, TBIL total bilirubin, DBIL direct bilirubin, TP total proteins, PT prothrombin time, CRP C-reactive protein, FiO2 fraction of inspired oxygen, SatO2 oxygen saturation, PO2 partial pressure of oxygen PCO2 partial pressure of carbon dioxide, Glu glutamate, LDH lactate dehydrogenase, Alb albumin, ND not done\n\nFig. 1 Patient’s chest X-ray on admission\n\nThe patient was evaluated as having sepsis; he was started on intravenous administration of meropenem (1 g three times daily) and daptomycin (350 mg daily) and hydrocortisone 100 mg four times daily and was admitted to the hospital. On day 2, renal function deteriorated further and he was started on terlipressin 3 mg infused over 24 hours in combination with intravenous albumin (1 g/kg on day 1, and then 20 to 40 g/day thereafter) for a possible type 1 hepatorenal syndrome. Later on the same day, he was subjected to a course of hemodialysis due to hyperkalemia (6.5 mmol/L), anuria, and increased central venous pressure (24 cm/H2O). On day 3, the patient developed severe metabolic acidosis, his liver failure worsened, and he subsequently fell into a coma. Within the context of multiple-organ dysfunction syndrome (MODS), the patient was intubated, but he later died within just a short period after admission to the hospital. No postmortem examination was performed, as the cascade of causes of the patient’s death was documented. The immediate cause of death was MODS as a consequence of sepsis subsequent to bacteremia due to SBP caused by S. pseudoporcinus, which was cultured from the patient’s blood and ascitic fluid (see below). The underlying cause triggering the events resulting in death was decompensated liver cirrhosis.\n\nOn admission, a pair of blood and ascitic fluid cultures (pair of both aerobic and anaerobic bottles) was obtained and incubated in a BACTEC 9240 automated system (Becton Dickinson and Company, Franklin Lakes, NJ, USA) for a total of 5 days. The cultures (both blood and anaerobic ascitic fluid) were positive after 3 days of incubation. Ascitic fluid gram stain revealed small gram-positive cocci arranged in chains which grew on both 5% sheep blood and chocolate agar plates after incubation for 24 hours under 5% carbon dioxide conditions. The isolate was catalase-negative. The GP ID card of the VITEK 2 system (bioMerieux, Marcy L’ Etoile, France) identified the isolate as S. pseudoporcinus, with excellent identification. Susceptibility testing was performed using the disk diffusion method. Minimum inhibitory concentration (MIC) was determined using the VITEK 2 AST-ST01 card and MIC Test Strips (Liofilchem, Roseto Degli Abruzzi, Italy) (Table 2). Both methods (disk diffusion method and MIC Test Strips) were performed on Mueller-Hinton agar plates supplemented with 5% horse blood and incubated under 5% carbon dioxide conditions for 24 hours.Table 2 Drug susceptibility results of Streptococcus pseudoporcinus strain recovered from patient’s blood and ascitic fluid cultures\n\nAntimicrobial agent\tSusceptibility (MIC μg/mL)\t\nAmpicillin\tR (8)\t\nAmoxicillin clavulanate\tR\t\nPenicillin G\tR (≥ 8)\t\nCefuroxime\tR\t\nCefotaxime\tR\t\nCeftriaxone\tR (4)\t\nMeropenem\tR\t\nVancomycin\tS (0.5)\t\nDaptomycin\tS (0.19)\t\nLinezolid\tS (≤ 2)\t\nErythromycin\tR\t\nClindamycin\tS (≤ 0.25)\t\nLevofloxacin\tS (0.5)\t\nTetracycline\tS (≤ 0.25)\t\nRifampicin\tS\t\nChloramphenicol\tS\t\nMIC minimum inhibitory concentration, R resistant, S susceptible\n\nDiscussion\n\nWe report a patient with liver cirrhosis who presented with spontaneous bacterial peritonitis and sepsis, hepatic encephalopathy, type 1 hepatorenal syndrome resulting in metabolic acidosis, acute liver failure, and complications from MODS. Ascitic fluid and blood cultures grew S. pseudoporcinus, an emerging, multidrug-resistant pathogen (resistance to penicillin, to third-generation cephalosporins, and even to carbapenems) which has been previously linked to adverse obstetric outcomes and has been widely misidentified as GBS. This is the second case in the literature (PubMed) reporting on a severe, invasive disseminated S. pseudoporcinus infection with an untoward outcome, and the first case involving a patient with liver cirrhosis. S. pseudoporcinus should be identified as early as possible in such cases, and administration of empirical antibiotics should provide wide coverage against common microorganisms as well as against this important, potentially life-threatening streptococcus.\n\nS. pseudoporcinus has biochemical characteristics similar to S. agalactiae, and its isolates may cross-react with several GBS antigen agglutination kits, causing it to be misidentified as GBS in routine screening cultures. S. pseudoporcinus is a facultative, non-motile, gram-positive coccus arranged in short chains, which produces smooth, round-to-oval, beta-hemolytic colonies on blood agar [3, 6]. In contrast to S. agalactiae, which displays a narrow zone of beta-hemolysis, S. pseudoporcinus exhibits a wide zone. Like S. agalactiae, S. pseudoporcinus produces large colonies after 24 hours of incubation. Its catalase and benzidine tests are negative [1]; it is Christie-Atkins-Munch-Peterson (CAMP) factor-positive and bacitracin-resistant [6]. S. agalactiae is esculin hydrolysis-negative and hippurate hydrolysis-positive, and does not ferment sorbitol or mannitol, while the opposite is true for S. pseudoporcinus [1, 6].\n\nS. pseudoporcinus pathogenesis has been linked to adverse obstetric outcomes such as chorioamnionitis and preterm delivery [6]. It is suggested that an ascending S. pseudoporcinus infection may trigger an inflammation cascade leading to cervical insufficiency or premature rupture of membranes. Other sites of S. pseudoporcinus isolation are wounds, urine, placenta, and dairy products. In the Centers for Disease Control and Prevention (CDC) Streptococcus strain collection, scientists evaluated 97 animal, human, and dairy S. porcinus or S. pseudoporcinus isolates. Seventy-two human and six dairy isolates were identified as S. pseudoporcinus [2]. Three-quarters of the specimens were recovered from the genitourinary tract. The rest related to wound infections in male patients. While blood was listed as the source of five isolates, S. pseudoporcinus invasive disease was not identified in another CDC Streptococcus Laboratory population-based study of invasive disease due to beta-hemolytic streptococci, thus making the existence of those five S. pseudoporcinus blood isolates questionable [2]. Nevertheless, according to recently emerging cases of invasive S. pseudoporcinus infections in the literature [11–15], the sites of S. pseudoporcinus colonization that lead to subsequent bacteremia were presumed to be the gastrointestinal tract and the oropharynx. Regarding S. porcinus, it was first isolated from swine in 1937 and was formally described in 1985. The main reservoir is swine, but it has also been isolated from other animals including cattle, sheep, guinea pigs, rabbits, and dogs.\n\nIn a study conducted to evaluate screening cultures recovered from vaginal and rectal swabs in pregnant women originating from the Caribbean and sub-Saharan Africa, 15 isolates were identified as S. pseudoporcinus (14 from rectovaginal and 1 from urine cultures) [6]. The population prevalence of S. pseudoporcinus colonization was determined to be 5.4% in vaginal and rectal swab samples obtained from sexually active, non-pregnant women of reproductive age, all of which cross-reacted with commercially available GBS serogrouping kits [7]. In another study, 717 consecutive S. agalactiae screening cultures were received from pregnant women. Of those, 260 (36.3%) that were beta-hemolytic and group B antigen-positive were subsequently subjected to matrix-assisted laser desorption/ionization–time of flight mass spectrometry (MALDI-TOF MS). S. agalactiae was confirmed in 248 (34.6%) samples, while six were identified as S. halichoeri, and another six as S. pseudoporcinus. Researchers mentioned that without MALDI-TOF MS, those 12 specimens would have been falsely identified as S. agalactiae [8]. In a large retrospective cohort study of 3704 pregnant women with cultures screened for GBS, the authors concluded that S. pseudoporcinus colonization occurred in 1.6% of all pregnancies, whereas a total of 2.5% of all GBS-positive results by agglutination assay were false-positive, instead reflecting S. pseudoporcinus colonization [9]. In another prospective observational study among 3276 screening cultures that were collected, 32 isolates (1%) of S. pseudoporcinus (25 isolates from pregnant women and 7 from non-pregnant women) and 604 isolates (18.4%) of S. agalactiae were identified by MALDI-TOF MS [3]. The identified risk factors for acquisition of S. pseudoporcinus colonization resulting collectively from all those studies are shown in Table 3.Table 3 Risk factors for Streptococcus pseudoporcinus acquisition and subsequent vaginal-rectal colonization [1–10]\n\nRisk factors\t\nAfrican American, Black race, Jamaican, sub-Saharan\t\nReproductive age\t\nRecent Trichomonas vaginalis infection\t\nPrimary or recurrent genital herpes\t\nBacterial vaginosis by Nugent criteria\t\nTwo or more sexual partners since the last health clinic visit\t\nDiabetes\t\nObesity (BMI > 35)\t\nTobacco use\t\nHistory or current sexually transmitted or urinary tract infection\t\nBMI body mass index\n\nOur patient suffered from a disseminated S. pseudoporcinus infection comprising spontaneous bacterial peritonitis (SBP) with bacteremia that was complicated by acute liver failure, type 1 hepatorenal syndrome, stage III hepatic encephalopathy, hypotension, and lactic acidosis. All of these manifestations were attributed to end-organ hypoperfusion (MODS) due to sepsis. S. pseudoporcinus in our case could have been acquired by the consumption of contaminated dairy products, since the pathogen has been previously recovered from them [10], with subsequent colonization of the gastrointestinal tract. Colonization of the gut lumen could traverse the intestinal wall and colonize mesenteric lymph nodes (bacterial translocation). Bacterial peritonitis occurs if the lymphatic vessel carrying the contaminated lymph ruptures due to portal hypertension or if the pathogen moves from the mesenteric lymphatic system to the systemic circulation (bacteremia). The bacterial isolate was multidrug-resistant. We administered meropenem, to which it was resistant, and daptomycin, with an MIC of 0.19. The latter was preferred to vancomycin because of the patient’s worsening kidney failure. A second diagnostic paracentesis performed after 48 hours of treatment showed a 40% decrease in ascitic fluid white blood cell (WBC) count and negative cultures. However, the patient at presentation was already severely ill with MODS, and such patients are at very high risk of mortality even with the best supportive treatment.\n\nConclusions\n\nS. pseudoporcinus is an emerging pathogen that colonizes the female genitourinary tract, with a population prevalence ranging between 1 and 5.4%, and is associated with adverse obstetric outcomes. A few isolates have been recovered from urine cultures and wounds [2, 3] and one from an endophthalmitis sample [10]. In two uneventful cases, S. pseudoporcinus was identified as the virulent factor of soft tissue infections [4, 5]. In a large study published in 2015, the authors speculated that S. pseudoporcinus might not be associated with invasive disease to the same extent as S. agalactiae [3]. Nonetheless, since late 2019, six new cases of severe invasive S. pseudoporcinus infection have emerged in the literature: six cases of invasive S. pseudoporcinus infections with bacteremia (four cases of endocarditis, one associated with syphilis-human immunodeficiency virus, another with a multiloculated pleural empyema [11–14]), and an additional obstetric case of maternal sepsis and fetal demise [15]. Herein, we present a documented fatal case of SBP associated with bacteremia due to a multidrug-resistant S. pseudoporcinus strain that rapidly resulted in MODS. Risk factors associated with invasive infection are shown in Table 4, as they emerge collectively from the seven recently reported cases [11–15], including our case. S. pseudoporcinus could be an emerging multidrug-resistant pathogen, as it is now more easily recognizable with the new advanced biochemical techniques.Table 4 Risk factors for Streptococcus pseudoporcinus acquisition and probable sites of colonization with subsequent bacteremia and severe invasive disease (6 cases [11–15] including the present case)\n\nRisk factors\t\t\nAge\t40–81 (mean 55) years\t\nDiabetes mellitus\t2/7\t\nHypertension\t2/7\t\nImmunosuppression\t3/7\t\nChronic heart failure\t3/7\t\nObesity\t1/7\t\nProbable sites of Streptococcus pseudoporcinus colonization\t\nGastrointestinal tract/oropharynx\t(6/7)\t\nGenitourinary tract\t(1/7)\t\n\nThe pathogenetic role of S. pseudoporcinus and its prevalence in humans warrants further investigation, and may be currently underestimated due to its misidentification as S. agalactiae. Recent studies underline the potential of S. pseudoporcinus to cause severe, invasive infections via gastrointestinal/oropharynx colonization and subsequent bacteremia, leading to life-threatening diseases [11–14]. New techniques for bacterial identification in routine clinical microbiology may affect its known prevalence, revealing its true significance as a human pathogen. S. pseudoporcinus resistance to penicillin, to third-generation cephalosporins, and even to carbapenems was reported in a previous case [5], and is consistent with the antibiotic susceptibility of our isolate. To date, multidrug-resistant S. pseudoporcinus has been found to be susceptible to vancomycin, daptomycin, linezolid, levofloxacin, clindamycin, and tetracycline. S. pseudoporcinus should be identified as early as possible in such cases, and administration of empirical antibiotics should provide wide coverage against common microorganisms as well as against this important, potentially life-threatening streptococcus.\n\nAbbreviations\n\nBP Blood pressure\n\nbpm Beats per minute\n\nCDC Centers for Disease Control and Prevention\n\nCRP C-Reactive protein\n\nGBS Group B Streptococcus\n\nLDH Lactate dehydrogenase\n\nMIC Minimum inhibitory concentration\n\nMODS Multiple-organ dysfunction syndrome\n\nWBC White blood cells\n\nAcknowledgements\n\nNone.\n\nAuthors' contributions\n\nGDL conceived the idea for the manuscript and drafted the manuscript. AT was the microbiologist responsible for the isolation and identification of Streptococcus pseudoporcinus in blood and ascitic fluid cultures. SPD is the Director of the Department of Internal Medicine as well as the hepatologist who was responsible for the patient’s outpatient monitoring. SPD and GDL were responsible for the patient’s hospitalization. All authors read and approved the final manuscript.\n\nFunding\n\nNone of the authors received funding from any source for this research.\n\nAvailability of data and materials\n\nNot applicable.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient‘s son, given that the patient had died, for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that there is no conflict of interest to disclose.\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. Bekal S Gaudreau C Laurence RA Simoneau E Raynal L Streptococcus pseudoporcinus sp. nov., a novel species isolated from the genitourinary tract of women J Clin Microbiol. 2006 44 2584 2586 10.1128/JCM.02707-05 16825387\n2. Shewmaker PL Steigerwalt AG Whitney AM Morey RE Graziano JC Facklam RR Evaluation of methods for identification and determination of the taxonomic status of strains belonging to the Streptococcus porcinus-Streptococcus pseudoporcinus complex isolated from animal, human, and dairy sources J Clin Microbiol. 2012 50 3591 3597 10.1128/JCM.01481-12 22933599\n3. Suwantarat N Grundy M Rubin M Harris R Miller JA Romagnoli M Recognition of Streptococcus pseudoporcinus colonization in women as a consequence of using matrix-assisted laser desorption ionization-time of flight mass spectrometry for Group B Streptococcus identification J Clin Microbiol. 2015 53 3926 3930 10.1128/JCM.02363-15 26468502\n4. Mahlen SD Clarridge JE 3rd Thumb infection caused by Streptococcus pseudoporcinus J Clin Microbiol. 2009 47 3041 3042 10.1128/JCM.00802-09 19571017\n5. Sawamura S Niimori D Ihn H A case of leg cellulitis caused by multidrug-resistant Streptococcus pseudoporcinus Intractable Rare Dis Res. 2018 7 280 282 10.5582/irdr.2018.01110 30560022\n6. Gaudreau C Simoneau E Labrecque O Laurence RA Laferrière C Miller M Epidemiological, biochemical and antimicrobial susceptibility characteristics of Streptococcus pseudoporcinus isolated in Quebec, Canada, from 1997 to 2006 J Med Microbiol. 2007 56 1620 1624 10.1099/jmm.0.47295-0 18033830\n7. Stoner KA Rabe LK Austin MN Meyn LA Hillier SL Incidence and epidemiology of Streptococcus pseudoporcinus in the genital tract J Clin Microbiol. 2011 49 883 886 10.1128/JCM.01965-10 21191057\n8. Salimnia H Robinson-Dunn B Gundel A Campbell A Mitchell R Taylor M Suggested modifications to improve the sensitivity and specificity of the 2010 CDC-recommended routine Streptococcus agalactiae screening culture for pregnant women J Clin Microbiol. 2019 57 e00446 e519 10.1128/JCM.00446-19 31167841\n9. Grundy M Suwantarat N Rubin M Harris R Hanlon A Tekle T Differentiating Streptococcus Pseudoporcinus from GBS: could this have implications in pregnancy? Am J Obstet Gynecol. 2019 220 490.e1 490.e7 10.1016/j.ajog.2019.01.219 30690012\n10. Marquart ME Benton AH Galloway RC Stempak LM Antibiotic susceptibility, cytotoxicity, and protease activity of viridans group streptococci causing endophthalmitis PLoS ONE 2018 13 e0209849 10.1371/journal.pone.0209849 30576393\n11. Khan S Wong TT Prasad N Lee B Urban C Segal-Maurer S Streptococcus pseudoporcinus: case reports and review of the literature Case Rep Infect Dis. 2020 2020 4135246 32373373\n12. Akagi M Iwanaga N Torisu Y Fujita H Kawahara C Horai Y IgA vasculitis triggered by infective endocarditis of pulmonary artery with congenitally corrected transposition of the great arteries Int Heart J. 2020 61 404 408 10.1536/ihj.19-446 32173704\n13. Hai PD Dung NM Son PN Phuong LL Thuyet BT Hoa LV First report of infective endocarditis caused by Streptococcus pseudoporcinus in Vietnam New Microbes New Infect. 2020 34 100643 10.1016/j.nmni.2019.100643 32071724\n14. Gupta K Mohanty M Rath S Bacteremia because of Streptococcus pseudoporcinus in a Syphilis-HIV co-infected patient: a case report J Family Med Prim Care. 2020 9 2119 2120 10.4103/jfmpc.jfmpc_663_19 32670977\n15. Pierce SL Shibib DR Robison D Edwards RK A case of maternal sepsis and fetal demise associated with Streptococcus pseudoporcinus Case Rep Obstet Gynecol. 2019 10.1155/2019/4309191 31885964\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Fatal infection; Group B streptococci; Multidrug-resistant strain; Spontaneous bacterial peritonitis; Streptococcus pseudoporcinus",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002981:Clindamycin; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis; D008297:Male; D013290:Streptococcal Infections; D013291:Streptococcus",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "240",
"pmc": null,
"pmid": "33992114",
"pubdate": "2021-05-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26468502;31167841;30576393;30560022;32373373;18033830;19571017;32173704;32670977;16825387;22933599;30690012;21191057;31885964;32071724",
"title": "Fatal Streptococcus pseudoporcinus disseminated infection in decompensated liver cirrhosis: a case report.",
"title_normalized": "fatal streptococcus pseudoporcinus disseminated infection in decompensated liver cirrhosis a case report"
} | [
{
"companynumb": "GR-PFIZER INC-2021623799",
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"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": "4",
... |
{
"abstract": "Autoimmune-mediated bowel disease has been reported after pediatric heart transplantation. Recognition and treatment of these patients has been difficult. We describe a patient who responded to steroids and basiliximab therapy after an inflammatory process secondary to abnormal T-cell activation. Our patient is a 28-month-old female who received a heart transplant at five wk of age. At 24 months post-transplant, she developed fever and bloody stools. Initial investigations were significant for an elevated ESR (>120) and CRP (15.2). Symptoms persisted despite bowel rest and mycophenolate discontinuation. Endoscopic evaluation revealed discontinuous ulcerative disease involving esophagus, terminal ileum, right and left colon, necessitating extensive bowel resection. She had additional airway inflammation leading to a TEF at the site of esophageal ulceration, requiring tracheostomy. Immune evaluation revealed autoimmune dysregulation that responded to parenteral methylprednisolone. Chronic basiliximab therapy allowed for successful weaning of steroids with sustained remission. She has been transitioned to sirolimus and tacrolimus maintenance immunosuppression with plans to discontinue basiliximab once off steroids. In conclusion, bowel disease in the setting of pediatric heart transplantation can be severe and refractory to traditional treatment methods. Tailoring immune therapy to activated T cells can result in remission. Basiliximab therapy was used in our patient to maintain steroid-induced remission, but long-term complications of this disease process are unknown.",
"affiliations": "The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Otolaryngology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Pediatric Cardiology, CS Mott Children's Hospital, Ann Arbor, MI, USA.;The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.",
"authors": "Puri|K|K|;Kocoshis|S|S|;Risma|K|K|;Perez|L|L|;Hart|C|C|;Chin|C|C|;Ryan|T D|TD|;Jefferies|J L|JL|;Schumacher|K R|KR|;Castleberry|C|C|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12584",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "19(7)",
"journal": "Pediatric transplantation",
"keywords": "basiliximab; inflammatory bowel disease; pediatric heart transplant",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000911:Antibodies, Monoclonal; D001327:Autoimmune Diseases; D000077552:Basiliximab; D002675:Child, Preschool; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D011183:Postoperative Complications; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E165-9",
"pmc": null,
"pmid": "26374667",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18275074;16212644;7557954;23312343;24372990;15531736;18811694;23103332;22001864;16227984;23501398;12100901;22773060;17889201;15059198;16424228;9040206;23774108;21628415;18719139;23442098;18671816;24707135",
"title": "Basiliximab treatment for autoimmune bowel disease in a pediatric heart transplant patient.",
"title_normalized": "basiliximab treatment for autoimmune bowel disease in a pediatric heart transplant patient"
} | [
{
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{
"abstract": "Kaposi sarcoma (KS) herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m(2) combined with liposomal doxorubicin 20 mg/m(2) (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months' potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222.",
"affiliations": "HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;;HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;;HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;;HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;;AIDS and Cancer Virus Program, Viral Oncology Section, Leidos-Frederick, National Cancer Institute, Frederick, MD; and.;AIDS and Cancer Virus Program, Viral Oncology Section, Leidos-Frederick, National Cancer Institute, Frederick, MD; and.;HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;;Laboratory of Pathology and.;HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;;Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD.;HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;;HIV & AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;",
"authors": "Uldrick|Thomas S|TS|;Polizzotto|Mark N|MN|;Aleman|Karen|K|;Wyvill|Kathleen M|KM|;Marshall|Vickie|V|;Whitby|Denise|D|;Wang|Victoria|V|;Pittaluga|Stefania|S|;O'Mahony|Deirdre|D|;Steinberg|Seth M|SM|;Little|Richard F|RF|;Yarchoan|Robert|R|",
"chemical_list": "D044966:Anti-Retroviral Agents; D000903:Antibiotics, Antineoplastic; D058846:Antibodies, Monoclonal, Murine-Derived; C508600:IL6 protein, human; D015850:Interleukin-6; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000069283:Rituximab; D004317:Doxorubicin; D002097:C-Reactive Protein",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2014-07-586800",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "124(24)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D000903:Antibiotics, Antineoplastic; D058846:Antibodies, Monoclonal, Murine-Derived; D002097:C-Reactive Protein; D005871:Castleman Disease; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D006566:Herpesviridae Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D015850:Interleukin-6; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011446:Prospective Studies; D000069283:Rituximab; D015996:Survival Rate; D019562:Viral Load",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3544-52",
"pmc": null,
"pmid": "25331113",
"pubdate": "2014-12-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "20048176;10979949;6224088;18449205;24174627;20583924;12842986;1376041;12856221;10987728;10196314;15143468;20688959;18087054;8695812;8932544;24622327;18955561;10666218;2829354;8990095;16892074;7632932;14615380;22729151;11164492;14648716;17664482;11684931;2671281;24958337;8924253;9508198;22223822;14670091;18385778;22718364;11264181;18319288;1563109;17066452;21555697;19222502;7700311;2159561;20443737;2719427;20130244;11857400;20981030;11895764;19723153;12701121;25042199;23659971;18983461;12590797;11719390;21487108;12226829;22893577;21511959;18670234;15914552;7997879;16044438;24442228",
"title": "Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease.",
"title_normalized": "rituximab plus liposomal doxorubicin in hiv infected patients with kshv associated multicentric castleman disease"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01643",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR"
},
"drugadditional": null,
... |
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