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"abstract": "Myeloma relapse remains challenging. Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) was proven highly effective in relapsed or refractory multiple myeloma (RRMM) in randomized controlled trials. The recommended schedule of dara is weekly for eight doses, followed by 2-weekly for eight doses, and then every 4-weekly thereafter. However, the cost of daratumumab is daunting, precluding widespread and prolonged use in some countries. In this study, we aimed to evaluate the efficacy of using a 3-weekly daratumumab regimen in RRMM.\nThirteen RRMM patients were treated with dara-IMiD-dex till maximal response, followed by single-agent IMiD maintenance until disease progression. Dara (every 6 weekly) would be added upon significant biochemical disease progression.\nAfter a median of four daratumumab infusions (range: 3-10), the best responses included complete response (CR) in seven patients (53.8%), very good partial response (VGPR) in four patients (30.8%), and partial response (PR) in two patients (15.4%). The median time to VGPR was four weeks. At 10 months, the overall survival was 90%, and progression-free survival was 54.7%. Two of three patients tested achieved MRD-ve CR. Another patient, who had PET-CT reassessment, showed PET-ve CR.\nDespite less frequent daratumumab use, we reported rapid responses with a median time to VGPR of only four weeks, and a response rate of 100% including CR rate of 54%. Despite less frequent daratumumab use, grade ¾ neutropenia remained common with a frequency comparable to that observed in Pollux.\nThis 3-weekly dara-IMiD-dex regimen preserves a high efficacy with rapid, deep responses including MRD-ve and PET-ve CR, hence a cost-effective regimen.",
"affiliations": "Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pok Fu Lam, Hong Kong.;Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Pharmacy, Queen Mary Hospital, Pok Fu Lam, Hong Kong.;Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pok Fu Lam, Hong Kong.;Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pok Fu Lam, Hong Kong.",
"authors": "Chim|Chor Sang|CS|0000-0003-2427-915X;Kumar|Shaji|S|0000-0001-5392-9284;Wong|Vincent Kai Chung|VKC|;Ngai|Cheong|C|0000-0002-6438-2170;Kwong|Yok Lam|YL|0000-0001-8156-6978",
"chemical_list": "D000911:Antibodies, Monoclonal; C556306:daratumumab; D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1080/16078454.2021.1965737",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-5332",
"issue": "26(1)",
"journal": "Hematology (Amsterdam, Netherlands)",
"keywords": "3-weekly daratumumab regimen; MRD-ve CR; PET-ve CR; affordability; dara-IMID-dex regimen; efficacy; rapid deep responses; relapsed or refractory multiple myeloma",
"medline_ta": "Hematology",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D015996:Survival Rate; D013792:Thalidomide",
"nlm_unique_id": "9708388",
"other_id": null,
"pages": "652-655",
"pmc": null,
"pmid": "34474661",
"pubdate": "2021-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D059040:Video-Audio Media",
"references": null,
"title": "3-weekly daratumumab-lenalidomide/pomalidomide-dexamethasone is highly effective in relapsed and refractory multiple myeloma.",
"title_normalized": "3 weekly daratumumab lenalidomide pomalidomide dexamethasone is highly effective in relapsed and refractory multiple myeloma"
} | [
{
"companynumb": "HK-TAKEDA-2021TUS056379",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nPatients with high risk recurrences after bacillus Calmette-Guérin failure have limited options. We performed an open label study to evaluate the efficacy and safety of intravesical MCNA in this setting.\n\n\nMETHODS\nPatients were treated intravesically with 8 mg MCNA weekly for 6 weeks followed by 3 weekly instillations at months 3, 6, 12, 18 and 24. Cystoscopy and cytology were performed every 3 months for 2 years with mandatory biopsy at 6 months and as clinically indicated thereafter. The primary efficacy end point was the disease-free survival rate at 1 year.\n\n\nRESULTS\nA total of 129 patients were enrolled in study, including 91 with carcinoma in situ with or without papillary disease and 38 with papillary only tumors. Most patients had high risk disease. A total of 107 cases were bacillus Calmette-Guérin refractory and 2 or more prior bacillus Calmette-Guérin induction courses had been given in 68. Median followup in all patients was 34.7 months. The overall disease-free survival rate was 25.0% at 1 year and 19.0% at 2 years. In patients with papillary only tumors the disease-free survival rate was 35.1% and 32.2% at 1 and 2 years, respectively. The median disease-free duration in the 30 responders was 32.7 months. The progression-free survival rate was 87.3%, 79.8% and 77.7% at 1, 2 and 3 years, respectively, with a progression event in 28 patients. MCNA was well tolerated and few adverse events led to treatment discontinuation.\n\n\nCONCLUSIONS\nIntravesical MCNA achieved significant activity in patients at high risk with nonmuscle invasive bladder cancer in whom bacillus Calmette-Guérin treatment failed, especially those with papillary only tumors and those with bacillus Calmette-Guérin relapse. A durable response was seen, particularly in patients with a response at 1 year. MCNA offers an option for patients who are not candidates for or who refuse cystectomy.",
"affiliations": "Queen's University, Toronto, Ontario, Canada.;Memorial Sloan Kettering Cancer Center, New York, New York.;University of Chicago Medical Center, Chicago, Illinois.;Urology of Virginia, Virginia Beach, Virginia.;Bioniche Therapeutics Corp., Pointe-Claire, Quebec, Canada.;Kingston and McDougall Scientific Ltd., Toronto, Ontario, Canada.;University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: akamat@mdanderson.org.",
"authors": "Morales|Alvaro|A|;Herr|Harry|H|;Steinberg|Gary|G|;Given|Robert|R|;Cohen|Zvi|Z|;Amrhein|John|J|;Kamat|Ashish M|AM|",
"chemical_list": "D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D009696:Nucleic Acids",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-5347",
"issue": "193(4)",
"journal": "The Journal of urology",
"keywords": "BCG vaccine; Mycobacterium phlei; nucleic acids; treatment failure; urinary bladder neoplasms",
"medline_ta": "J Urol",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000283:Administration, Intravesical; D000368:Aged; D001500:BCG Vaccine; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D009168:Mycobacterium phlei; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009696:Nucleic Acids; D012307:Risk Factors; D017211:Treatment Failure; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0376374",
"other_id": null,
"pages": "1135-43",
"pmc": null,
"pmid": "25286009",
"pubdate": "2015-04",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guérin.",
"title_normalized": "efficacy and safety of mcna in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus calmette gu rin"
} | [
{
"companynumb": "IN-SA-2015SA035074",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
... |
{
"abstract": "A 52-year-old male patient developed RA in March 2009 at the age of 43, with symmetric polyarthritis and active synovitis affecting hands, knees, ankles and both feet without symptoms or signs suggestive of extra-articular features. Laboratory investigations showed negative RF and positive anti-CCP antibodies, negative ANA, negative anti-dsDNA antibodies; the X-rays of both hands showed typical erosive changes in RA and fulfilled the new ACR/EULAR (2010) criteria of RA. The patient achieved remission on a combination of DMARDs. He did well until January 2017 when he developed acute onset of progressive chest pain, dyspnea, and acute respiratory failure. High-resolution CT of the lung showed extensive areas of ground glass veiling, and interstitial subpleural infiltrates were found consistent with aggressive interstitial lung disease (ILD). Autoantibodies against extractable nuclear antigens were screened and showed positive results for anti-RO and anti-Jo1 autoantibodies. The positive anti-Jo1was an expression of anti-synthetase syndrome complicating the RA course and explained the rapidly aggressive course of ILD.",
"affiliations": "Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Electronic address: yasseremad68@gmail.com.;Radiology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.;Chest department, Ain Shams faculty of medicine, Cairo, Egypt.;Faculty of Behavioral, Management and Social Sciences, Department Psychology, Health and Technology, University of Twente, Enschede, The Netherlands.",
"authors": "Emad|Yasser|Y|;Ragab|Yasser|Y|;Abd-Elsalam|Magdy|M|;Rasker|Johannes J|JJ|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.reuma.2018.06.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5743",
"issue": "16(5 Pt 2)",
"journal": "Reumatologia clinica",
"keywords": "Antisynthetase syndrome; Artritis reumatoide; Overlapping rheumatoid arthritis and antisynthetase syndrome; Rheumatoid arthritis; Sobreposición de artritis reumatoide y síndrome antisintetasa; Síndrome antisintetasa",
"medline_ta": "Reumatol Clin (Engl Ed)",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D006801:Humans; D008297:Male; D008875:Middle Aged; D009220:Myositis",
"nlm_unique_id": "101717526",
"other_id": null,
"pages": "419-422",
"pmc": null,
"pmid": "30120021",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antisynthetase syndrome complicating the course of established case with rheumatoid arthritis: A rare and under-recognized overlapping disease.",
"title_normalized": "antisynthetase syndrome complicating the course of established case with rheumatoid arthritis a rare and under recognized overlapping disease"
} | [
{
"companynumb": "NVSC2020EG314608",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": null,
... |
{
"abstract": "Despite the promising result with FLT3 inhibitors in AML, the emergence of resistance poses a significant challenge, leading to a shorter response duration and inferior survival. This is frequently driven by on-target or parallel prosurvival mutations. The emergence of BCR-ABL1 as a mechanism of possible clonal evolution in relapsed AML has rarely been reported. Here we report our experience with three patients who had emergent BCR-ABL1 fusion at relapse after FLT3 inhibitors-based therapies. The first patient was refractory to multiple lines of therapies, including FLT3 inhibitors-based therapy. Patients 2 and 3 showed some response to combined FLT3-inhibitor and BCR-ABL targeted therapy (gilteritinib and ponatinib). The availability of effective targeted therapies for BCR-ABL1 makes this an important aberration to proactively identify and possibly target at relapse post-FLT3-inhibitor therapies.",
"affiliations": "The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.;The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States.",
"authors": "Alotaibi|Ahmad S|AS|;Yilmaz|Musa|M|;Loghavi|Sanam|S|;DiNardo|Courtney|C|;Borthakur|Gautam|G|;Kadia|Tapan M|TM|;Thakral|Beenu|B|;Pemmaraju|Naveen|N|;Issa|Ghayas C|GC|;Konopleva|Marina|M|;Short|Nicholas J|NJ|;Patel|Keyur|K|;Tang|Guilin|G|;Ravandi|Farhad|F|;Daver|Naval|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.588876",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.588876\nOncology\nCase Report\nEmergence of BCR–ABL1 Fusion in AML Post–FLT3 Inhibitor-Based Therapy: A Potentially Targetable Mechanism of Resistance – A Case Series\nAlotaibi Ahmad S. 1 Yilmaz Musa 1 Loghavi Sanam 2 DiNardo Courtney 1 Borthakur Gautam 1 Kadia Tapan M. 1 Thakral Beenu 2 Pemmaraju Naveen 1 Issa Ghayas C. 1 Konopleva Marina 1 Short Nicholas J. 1 Patel Keyur 2 Tang Guilin 2 Ravandi Farhad 1 Daver Naval 1* 1The Department of Leukemia, MD Anderson Cancer Center, Houston, TX, United States\n2The Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, United States\nEdited by: Alessandro Isidori, AORMN Hospital, Italy\n\nReviewed by: Amir Fathi, Massachusetts General Hospital and Harvard Medical School, United States; Prasanth Ganesan, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), India\n\n*Correspondence: Naval Daver, ndaver@mdanderson.orgThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n\n20 10 2020 \n2020 \n10 58887629 7 2020 11 9 2020 Copyright © 2020 Alotaibi, Yilmaz, Loghavi, DiNardo, Borthakur, Kadia, Thakral, Pemmaraju, Issa, Konopleva, Short, Patel, Tang, Ravandi and Daver.2020Alotaibi, Yilmaz, Loghavi, DiNardo, Borthakur, Kadia, Thakral, Pemmaraju, Issa, Konopleva, Short, Patel, Tang, Ravandi and DaverThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Despite the promising result with FLT3 inhibitors in AML, the emergence of resistance poses a significant challenge, leading to a shorter response duration and inferior survival. This is frequently driven by on-target or parallel prosurvival mutations. The emergence of BCR–ABL1 as a mechanism of possible clonal evolution in relapsed AML has rarely been reported. Here we report our experience with three patients who had emergent BCR–ABL1 fusion at relapse after FLT3 inhibitors–based therapies. The first patient was refractory to multiple lines of therapies, including FLT3 inhibitors–based therapy. Patients 2 and 3 showed some response to combined FLT3-inhibitor and BCR–ABL targeted therapy (gilteritinib and ponatinib). The availability of effective targeted therapies for BCR–ABL1 makes this an important aberration to proactively identify and possibly target at relapse post–FLT3-inhibitor therapies.\n\nFLT3BCR-ABLFLT3 inhibitorssecondary mutationsAMLUniversity of Texas MD Anderson Cancer Center10.13039/100007313CA016672\n==== Body\nIntroduction\nThe development of multiple small-molecule kinase inhibitors targeting FLT3 has improved the outcome of FLT3-mutated acute myeloid leukemia (AML) (1). Despite high response rates with FLT3 inhibitor–based therapies, the emergence of new mutations frequently drives resistance, and resulting in short durations of response and survival (2–5). These emergent mutations may involve the activating loop or gatekeeper residues of the FLT3 (on target resistance) (2, 3, 5) or genes regulating parallel prosurvival signaling pathways such as PI3K/AKT and RAS/MAPK (off-target resistance) (4, 5). Herein, we report the cases of three patients who relapsed following an FLT3 inhibitor–based therapy, with an emergent BCR–ABL1 fusion, rendering a potentially targetable mechanism of resistance.\n\nClinical Summary\nPatient 1\nA 33-year-old woman was diagnosed with AML with a normal karyotype (no molecular testing done locally at baseline). She received 7 + 3 induction without a response and was reinduced with fludarabine and cytarabine (FLAG) with complete remission (CR), followed by four cycles of high-dose cytarabine (HiDAC) consolidation. She relapsed 5 months after the last consolidation and was referred to our institution following an unsuccessful salvage attempt with FLAG.\n\nOur initial bone marrow biopsy revealed 60% blasts, normal karyotype, FLT3–ITD (allelic ratio 0.33), with no BCR–ABL1 fusion or NPM1, RAS, IDH1&2, or KIT mutations. The patient received azacitidine with sorafenib with marrow remission after four cycles and underwent allogeneic stem cell transplant (ASCT), but relapsed 60 days post-ASCT with 58% bone marrow blasts, normal karyotype, and FLT3–ITD (allelic ratio 0.02). After achieving a short-term remission with idarubicin, cytarabine, and sorafenib combination, subsequent relapse bone marrow demonstrated t(9,22) in 7/20 metaphases with a positive BCR–ABL1 fusion transcript (55%) and FLT3–ITD (allelic ratio 0.12) (Figure 1A). The patient died after not responding to phase I agent BP-1001 (L-Grb-2 antisense oligonucleotide NCT01159028) (6).\n\nFIGURE 1 Graphical representation of mutational acquisition/expansion. (A) Patient 1, (B) patient 2, and (C) patient 3. Clonal size was estimated based on variant allelic frequency (VAF) for mutations detected by NGS, allelic ratio for FLT3, percentage of BCR–ABL to ABL transcripts, and number of aberrant metaphases in karyotype. Clones could have coexisted or be mutually exclusive, mutations with high clonal size at the same given point of time were considered to be coexisted, for other mutations, the two possibilities were represented. At last relapse/progression in (A,B), the two branch graphs represent the possibility of coexistence or mutually exclusivity of FLT3 mutation and BCR/ABL.\n\nPatient 2\nA 47-year-old man was diagnosed with AML with [add (7) (q32)], and DNMT3A, RUNX1, and U2AF1 mutations on a myeloid NGS panel [no FLT3 ITD/tyrosine kinase domain (TKD) mutation] at diagnosis at a local institution. He received consecutive therapies with CPX-351, decitabine, and FLAG-IDA, without a response. Repeat bone marrow analysis revealed an emergent FLT3–ITD mutation (allelic ratio not known). After receiving a single-agent gilteritinib salvage therapy for 2 months, he was referred to our institution with progressive disease. The initial bone marrow revealed 70% blasts, normal karyotype [no t(9,22) detected], positive for BCR–ABL1 rearrangement (2.8% by FISH) and BCR–ABL1 fusion (1.92%), FLT-3 ITD (allelic ratio 0.49), RUNX1, U2AF1, and KRAS (Figure 1B) (7). The patient did not respond to cladribine, idarubicin, cytarabine, and sorafenib combination, with increased BCR–ABL1 fusion transcript (7.05%) posttreatment. After failing the next salvage therapy (decitabine, venetoclax, and ponatinib), the patient received CPX-351 plus venetoclax, ponatinib, and gilteritinib combination with a marrow remission (MLFS) (BCR–ABL1 fusion transcript 0.05%). ASCT was performed with a CR on day 30 post-ASCT (no detectable measurable residual disease by multiparametric flow cytometry, undetectable BCR–ABL1 fusion). The patient died 8 months post-ASCT in CR because of infectious complications.\n\nPatient 3\nA 53-year-old woman with AML, diploid karyotype, and FLT3–ITD mutation achieved CR with 7 + 3 plus midostaurin. She relapsed 2 months later with t(6,11) (p24,q14), FLT3–ITD, ASXL1, and KMT2A (ASXL1, KMT2A were not detectable at baseline). After failing mitoxantrone, etoposide, and cytarabine combination and then salvage with single-agent gilteritinib, the bone marrow revealed 50% blasts with BCR–ABL1 rearrangement (91% by FISH). Upon referral to our institution, repeat bone marrow biopsy showed 38% blasts, complex cytogenetics with t(9,22), BCR–ABL1 fusion transcript (63.9%), FLT3–ITD (allelic ratio 0.48), RUNX1, WT1 (three distinct mutations) (Figure 1C). On day 21 of the salvage therapy (decitabine, gilteritinib, and ponatinib), the patient had MLFS (persistent BCR–ABL1 at a level of 76.19%) and later died because of infectious complications.\n\nDiscussion\nTargeting FLT3 mutations has improved outcomes in AML. Acquisition/expansion of mutations drives secondary resistance to FLT3-inhibitor therapy. Activation of parallel signaling pathways, such as PI3K/AKT and RAS/MAPK, is an increasingly recognized mechanism of FLT3-inhibitor resistance (2, 4). Targeted NGS at baseline and relapse in 41 relapsed FLT3-mutated patients before and after single-agent gilteritinib demonstrated emergent RAS/MAPK pathway mutations (NRAS, KRAS, PTPN11, and NF1) in 15 (36.6%) and newly detectable BCR/ABL1 fusions in 2 (5%) patients (5).\n\nThe Philadelphia chromosome, t(9,22) (q34,q11.2), results in a BCR–ABL1 fusion gene, encoding a constitutively active oncogenic tyrosine kinase. The incidence of the Ph chromosome in de novo AML ranges from 0.5 to 3% (8). Acquisition of BCR–ABL1 as a secondary abnormality and a mechanism of possible clonal evolution in relapsed AML has rarely been reported postchemotherapy treatment (9) and now post–FLT3 inhibitor–based therapy (5, 10).\n\nAlthough rare (3–5%), identification of BCR–ABL1 fusion at relapse has clinical significance as it is a targetable mutation. In this report, patients 2 and 3 were refractory to FLT3 inhibitor–based therapies, but eventually responded to combined FLT3-inhibitor and BCR–ABL targeted therapy (gilteritinib and ponatinib). Patient 1 remained refractory to multiple conventional salvage chemotherapy plus FLT3-inhibitor regimens, possibly in some part due to BCR–ABL–mediated resistance to FLT3 inhibitor–based therapies. Ponatinib is a potent kinase inhibitor with pan-BCR–ABL1 inhibitor activity and strong FLT3-inhibitor activity. Smith et al. (11) demonstrated in vitro activity of ponatinib against FLT3–ITD and F691 gatekeeper mutation. Gilteritinib is a selective FLT3 inhibitor with potent activity against FLT3–ITD, as well as TKD mutations, although 5 (12.2%) of 42 patients acquired F691 gatekeeper mutations at relapse post–gilteritinib therapy (5). Combinatorial or sequential use of gilteritinib and ponatinib to overcome each individual drug resistance could be of interest for prospective evaluation, especially in FLT3-mutated patients with detectable subclonal acquisition of BCR–ABL1 fusion. Combining these two potent FLT 3 inhibitors should ideally be performed under clinical investigation/trial setting, with close monitoring and caution for myelosuppression, ideally in large leukemia centers with significant expertise. An increased understanding of the mechanisms of FLT3-inhibitor resistance may help identify and target known druggable pathways of resistance to overcome primary and secondary resistance in clinical practice.\n\nData Availability Statement\nAll datasets generated in this study are included in the article/supplementary material.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by the Institutional Review Board (IRB), MD Anderson Cancer Center (MDACC) IRB protocol DR09-0223 and PA12-0395. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nND, AA, and MY collected the data, conceived, designed, and wrote the manuscript. SL, KP, BT, and GT analyzed and reported the molecular and cytogenetics data. CD, GB, TK, NP, GI, MK, NS, and FR treated the patients, read, revised, and approved the final manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. This work was supported in part by the MD Anderson Cancer Centre Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, and the Charif Souki Cancer Research Fund.\n\nSpecial thanks to Jordan Pietz, MA, CMI for his assistance in creating the visual artwork. All copyrights to the visual artwork are retained by MD Anderson Cancer Center.\n==== Refs\nReferences\n1. Daver N Schlenk RF Russell NH Levis MJ. \nTargeting FLT3 mutations in AML: review of current knowledge and evidence.\n\nLeukemia. (2019 ) 33 :299 –312\n. 10.1038/s41375-018-0357-9 \n30651634 \n2. Daver N Cortes J Ravandi F Patel KP Burger JA Konopleva M \nSecondary mutations as mediators of resistance to targeted therapy in leukemia.\n\nBlood. (2015 ) 125 :3236 –45\n. 10.1182/blood-2014-10-605808 \n25795921 \n3. Cools J Mentens N Furet P Fabbro D Clark JJ Griffin JD \nPrediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia.\n\nCancer Res. (2004 ) 64 :6385 –9\n. 10.1158/0008-5472.CAN-04-2148 \n15374944 \n4. Piloto O Wright M Brown P Kim KT Levis M Small D. \nProlonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways.\n\nBlood. (2007 ) 109 :1643 –52\n. 10.1182/blood-2006-05-023804 \n17047150 \n5. McMahon CM Ferng T Canaani J Wang ES Morrissette JJD Eastburn DJ \nClonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia.\n\nCancer Discov. (2019 ) 9 :1050 –63\n. 10.1158/2159-8290.CD-18-1453 \n31088841 \n6. Ohanian M Kantarjian HM Ravandi F Borthakur G Garcia-Manero G Andreeff M \nSafety, pharmacokinetics, and efficacy of BP-100-1.01 (Liposomal Grb-2 antisense oligonucleotide) in patients with refractory or relapsed acute myeloid leukemia (AML), philadelphia chromosome positive chronic myelogenous leukemia (CML), acute lymphoblasti.\n\nBlood. (2015 ) 126 :3801 \n10.1182/blood.v126.23.3801.3801 \n7. Luthra R Patel KP Reddy NG Haghshenas V Routbort MJ Harmon MA \nNext-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring.\n\nHaematologica. (2014 ) 99 :465 –73\n. 10.3324/haematol.2013.093765 \n24142997 \n8. Konoplev S Yin CC Kornblau SM Kantarjian HM Konopleva M Andreeff M \nMolecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia.\n\nLeuk Lymphoma. (2013 ) 54 :138 –44\n. 10.3109/10428194.2012.701739 \n22691121 \n9. Kurt H Zheng L Kantarjian HM Tang G Ravandi F Garcia-Manero G \nSecondary philadelphia chromosome acquired during therapy of acute leukemia and myelodysplastic syndrome.\n\nMod Pathol. (2018 ) 31 :1141 –54\n. 10.1038/s41379-018-0014-x \n29449681 \n10. Kasi PM Litzow MR Patnaik MM Hashmi SK Gangat N. \nClonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets.\n\nLeuk Res Rep. (2016 ) 5 :7 –10\n. 10.1016/j.lrr.2016.01.002 \n26904404 \n11. Smith CC Lasater EA Zhu X Lin KC Stewart WK Damon LE \nActivity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD.\n\nBlood. (2013 ) 121 :3165 –71\n. 10.1182/blood-2012-07-442871 \n23430109\n\n",
"fulltext_license": "CC BY",
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"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "AML; BCR-ABL; FLT3; FLT3 inhibitors; secondary mutations",
"medline_ta": "Front Oncol",
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"pmid": "33194747",
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"title": "Emergence of BCR-ABL1 Fusion in AML Post-FLT3 Inhibitor-Based Therapy: A Potentially Targetable Mechanism of Resistance - A Case Series.",
"title_normalized": "emergence of bcr abl1 fusion in aml post flt3 inhibitor based therapy a potentially targetable mechanism of resistance a case series"
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"abstract": "Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) that shows overlap with classical Hodgkin lymphoma (CHL) and a favorable prognosis compared to mediastinal gray-zone lymphoma (MGZL). We performed immunohistochemistry on initial diagnostic specimens of 49 cases of uniformly treated PMBL to determine the frequency and clinical significance of expression of antigens commonly seen in CHL and MGZL, along with markers previously shown to be prognostic in DLBCL, not otherwise specified. The median age was 37 years with a female:male ratio of 2.3. After a median follow-up of 78 months, 24% of patients had relapsed or refractory disease and 22% had died; the 5-year PFS was 70%. Variable CD15 expression was seen in 31% of cases, but was not associated with adverse outcome. Hans cell-of-origin, proliferation index, and MYC/BCL2 coexpression were not associated with outcome, while low PDL1 (P = 0.011) and high MUM1 (P = 0.065) staining were each associated with shorter PFS. A biologic risk score (one point each for low PDL1 and high MUM1) stratified patients into three prognostic risk groups for PFS (P = 0.001) and OS (P = 0.032). On separate multivariate models, low PDL1 was independent of R-IPI risk group for PFS (HR 6.0, P = 0.023), as was a biologic risk score of 2 (HR 5.6, P = 0.011). Incorporation of the biologic risk score sub-stratified patients within R-IPI groups for both PFS (P < 0.001) and OS (P < 0.001). In summary, we characterize the immunophenotypic spectrum of PMBL and identify PDL1 and MUM1 as prognostic biomarkers for high-risk disease. Am. J. Hematol. 91:E436-E441, 2016. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.;Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, North Shore Medical Center, Salem, Massachusetts.;Department of Pathology, University of Michigan, Ann Arbor, Michigan.;Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.;Center for Lymphoma, Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.;Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. arsohani@partners.org.",
"authors": "Bledsoe|Jacob R|JR|;Redd|Robert A|RA|;Hasserjian|Robert P|RP|;Soumerai|Jacob D|JD|;Nishino|Ha T|HT|;Boyer|Daniel F|DF|;Ferry|Judith A|JA|;Zukerberg|Lawrence R|LR|;Harris|Nancy Lee|NL|;Abramson|Jeremy S|JS|;Sohani|Aliyah R|AR|",
"chemical_list": "D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D050835:Interferon Regulatory Factors; C094531:interferon regulatory factor-4",
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"keywords": null,
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D018572:Disease-Free Survival; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D016130:Immunophenotyping; D050835:Interferon Regulatory Factors; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D011379:Prognosis; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
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"pages": "E436-41",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The immunophenotypic spectrum of primary mediastinal large B-cell lymphoma reveals prognostic biomarkers associated with outcome.",
"title_normalized": "the immunophenotypic spectrum of primary mediastinal large b cell lymphoma reveals prognostic biomarkers associated with outcome"
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"abstract": "In patients with septic shock refractory to pharmacological agents, mechanical devices have been used successfully, although the reports are scarce. We report a case of septic shock where intra-aortic balloon pump (IABP) initiation leads to drastic improvement and survival from severe septic cardiomyopathy when conventional therapy was not effective. A 19-year-old male patient underwent surgery for adenocarcinoma descending colon. On day 8 he was reoperated for anastomotic leak and developed severe cardiomyopathy associated with septic shock, postoperatively. When he was in a vicious cycle of refractory hypotension, metabolic acidosis and severe cardiomyopathy, IABP was instituted along with other management for septic shock. Over next 3 days patient's hemodynamics improved and IABP was weaned off. While recovering from shock he developed posterior reversible encephalopathy syndrome which was promptly managed. This case report emphasizes on early institution of IABP in case of severe left ventricular dysfunction in septic shock. How to cite this article: Saxena A, Bhargava V, et al. Posterior Reversible Encephalopathy Syndrome in a Patient of Sepsis-induced Cardiomyopathy, Successfully Managed with Intra-aortic Balloon Pump. Indian J Crit Care Med 2019;23(4):188-190.",
"affiliations": "Department of Anesthesiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.;Department of Anesthesiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.;Department of Gastrointestinal Surgery, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.;Department of Cardiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.;Department of Cardiac Anesthesiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.",
"authors": "Saxena|Anudeep|A|;Bhargava|Vivek|V|;Shreya|Aditya|A|;Patodia|Anshul|A|;Goyal|Pradeep|P|",
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"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XJaypee Brothers Medical Publishers 10.5005/jp-journals-10071-23152Case ReportPosterior Reversible Encephalopathy Syndrome in a Patient of Sepsis-induced Cardiomyopathy, Successfully Managed with Intra-aortic Balloon Pump Saxena Anudeep 1Bhargava Vivek 2Shreya Aditya 3Patodia Anshul 4Goyal Pradeep 51,2 Department of Anesthesiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.3 Department of Gastrointestinal Surgery, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.4 Department of Cardiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.5 Department of Cardiac Anesthesiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India.Anudeep Saxena, Department of Anesthesiology, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India, e-mail: dranudeepsaxena@yahoo.in4 2019 23 4 188 190 Copyright © 2019; Jaypee Brothers Medical Publishers (P) Ltd.2019This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ABSTRACT\nIn patients with septic shock refractory to pharmacological agents, mechanical devices have been used successfully, although the reports are scarce. We report a case of septic shock where intra-aortic balloon pump (IABP) initiation leads to drastic improvement and survival from severe septic cardiomyopathy when conventional therapy was not effective. A 19-year-old male patient underwent surgery for adenocarcinoma descending colon. On day 8 he was reoperated for anastomotic leak and developed severe cardiomyopathy associated with septic shock, postoperatively. When he was in a vicious cycle of refractory hypotension, metabolic acidosis and severe cardiomyopathy, IABP was instituted along with other management for septic shock. Over next 3 days patient's hemodynamics improved and IABP was weaned off. While recovering from shock he developed posterior reversible encephalopathy syndrome which was promptly managed. This case report emphasizes on early institution of IABP in case of severe left ventricular dysfunction in septic shock.\n\nHow to cite this article: Saxena A, Bhargava V, et al. Posterior Reversible Encephalopathy Syndrome in a Patient of Sepsis-induced Cardiomyopathy, Successfully Managed with Intra-aortic Balloon Pump. Indian J Crit Care Med 2019;23(4):188–190.\n\nKeywords\nIntra-aortic balloon pumpPosterior reversible encephalopathy syndromeSeptic cardiomyopathy\n==== Body\nINTRODUCTION\nSepsis-induced cardiomyopathy is a complication of severe sepsis and septic shock described as a reversible myocardial depression that occurs in patients with septic shock. Sepsis-induced cardiomyopathy has three characteristics: left ventricular dilatation, depressed ejection fraction, and recovery in 7–10 days.1 Incidence of sepsis-induced left ventricular hypokinesia has been reported to be as high as 60%.2 Use of IABP has been reported to be lifesaving in certain sepsis-induced cardiomyopathy.3,4 We report a case with IABP introduction leading to drastic improvement, and survival from severe septic cardiomyopathy when conventional therapy was not effective, also how the course in the hospital was complicated by posterior reversible encephalopathy syndrome (PRES).\n\nCASE REPORT\nA 19-year-old Indian male was admitted with complains of abdominal pain, nausea, vomiting, and weight loss. He was diagnosed with moderately differentiated adenocarcinoma (T2N0M0) and underwent left hemicolectomy, colocolic, and jejunojejunal anastomosis. Seven days postoperatively patient developed anastomotic leak for which he was reoperated. Postoperatively (day 2 of ICU), patient required high dose vasopressor, his condition worsened and had to be put on mechanical ventilation for pulmonary edema (Fig. 1). 2D-echocardiography revealed severely depressed left ventricular function.\n\nEcho findings are as follows: Global hypokinesia more in anteroseptal wall, anterior wall, and intraventricular septum. Left ventricular ejection fraction (LVEF) is 15–20% (visually estimated). Mild mitral regurgitation, mild tricuspid regurgitation, no pulmonary artery hypertension, intra-ventricular and intra-atrial septum are intact. No pericardial effusion, clot or vegetation seen.\n\nECG showed sinus tachycardia (heart rate—150 bpm), poor R wave progression and nonspecific ST-T changes. Troponin I 1.69 ng/mL, CPK-MB 5.2 ng/mL, BNP 2000 pg/mL.\n\nPossibility of acute coronary syndrome was kept as a differential, but possibility of septic myocarditis was strongly considered. Patient was started on daily aspirin 75 mg, clopidogrel 75 mg, injection fondaparinux 2.5 mg, and injection torsemide 20 mg thrice daily.\n\nOver the next 24 hours (day 3) patient's hypotension and metabolic acidosis worsened despite high dosage of epinephrine, norepinephrine and dobutamine as well as stress dose of hydrocortisone. His tachycardia was bothersome. He had chilled peripheries and seemed to be maximally vasoconstricted. His urine output started falling. Antibiotics were escalated according to pus culture sensitivity reports. Considering cardiogenic shock to be primarily responsible for the patient's condition, it was planned to put IABP. Without wasting time 34 Fr IABP catheter was inserted through right femoral artery. IABP support was initiated with the use of 1:1 electrocardiographic triggering. In few hours CVP was reduced from 18 mm Hg to 10 mm Hg and heart rate settled from 160 bpm to 120 bpm.\n\nFig. 1 X-ray chest of patient on day 2 of intensive care unit (ICU) admission when he developed pulmonary edema.\n\nOver next 48 hours patient's hemodynamic improved. Lungs were clearer (Fig. 2). Heart rate started settling from 120 bpm to around 100 bpm. Ionotropic supports were gradually tapered maintaining a mean arterial pressure of 65 mm Hg. Patient started pouring good urine output. On day 6 (day 3 of starting IABP), platelet counts started falling. Patient was maintaining his blood pressure at minimum dose of epinephrine and norepinephrine. IABP was removed. Till next day, when the effect of atracurium was completely weaned off, patient did not become alert. He was opening eyes spontaneously but was not following command; gaze was upward, bilateral extensor planter reflex. MRI brain was done which showed symmetrical mild ill-defined hyperintensity in bilateral occipital lobes, basal ganglia-thalamic region and splenium of corpus callosum (Fig. 3). This was suggestive of possibility of PRES.\n\nFig. 2 X-ray chest of patient on day 6. Intra-aortic balloon pump can be seen just distal to arch of aorta. Clearing of pulmonary edema as compared to the previous X-ray can be noted.\n\nFig. 3 There is presence of fairly bilaterally symmetrical, ill defined, mild T2, and FLAIR hyperintensity in bilateral basal ganglia and thalamus. In the splenium of corpus callosum and in the cortical–subcortical aspect of bilateral occipital lobes and left posterior parietal lobe there is mild DWI hyperintensity with corresponding mild hypointensity on ADC images (predominantly in the splenium of corpus callosum and in subcortical aspect of left posterior parietal lobe), suggesting diffusion restriction.\n\nOn day 9 of ICU admission patient's tracheostomy was done. Patient continued to be on vasopressor and inotropes, although requirement was low. Antibiotics were further modified according to blood and other fluid culture reports. Over next 5 days epinephrine and norepinephrine were completely withdrawn. Patient neurologically improved and started following commands. After pressure support trial for a day, on day 16 of ICU admission his ventilator support was withdrawn. On day 18, patient's repeat 2D echo was performed which showed an improved LVEF of 40–45% with mild septal hypokinesia. He was shifted out of ICU.\n\nHis trachea was decannulated and on day 21 he was discharged from the hospital with functioning colostomy in situ.\n\nDISCUSSION AND CONCLUSION\nIn sepsis, both the peripheral oxygen requirement and cardiac output are generally increased. However, in patients with septic cardiomyopathy, the cardiac output becomes inadequate to supply the increased systemic and myocardial oxygen requirement. Metabolic acidosis further impairs myocardial contractility; patient enters in a vicious circle and eventually succumbs. The two primary benefits of IABP are augmented coronary perfusion and reduced LV afterload thereby increased cardiac output.\n\nOur idea of initiating IABP was to buy time for the antibiotics to start acting. So that the oxygen requirement of the patient comes down to normal, that could be sustained by a compromised heart.\n\nThe time of initiating IABP is particularly important as shown previously by Ogunbayo G et al.5 They have concluded that early use of IABP (within 24 hours of presentation) appears to offer a mortality benefit. In our patient we initiated IABP within 12 hours of identification of cardiomyopathy and LV dysfunction.\n\nPosterior reversible encephalopathy syndrome is commonly, but not always associated with acute hypertension.6 In a retrospective study, Bartynski et al. reported an association of PRES with infection, sepsis and shock in 26.3% (25 out of 106) patients.7 In our patient there was no episode of hypertension. In sepsis, an alteration in vascular tone develops secondary to competing vasoconstrictive (platelet degranulation with thromboxane release, endothelin-1, angiotensin, vasopressin, and central sympathetic stimulation) and vasodilatory (nitric oxide, prostacyclin) effects.8,9\n\nWe suggest that in a patient of septic shock with cardiomyopathy, if pharmacologic agents are insufficient in maintaining systemic perfusion, then IABP should be considered promptly, particularly in patients with severe LV dysfunction (LVF <30%). Further elaborated trials are required before these mechanical devices would probably establish their place in future sepsis guidelines.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nREFERENCES\n1. Sato R, Nasu M. A review of sepsis-induced cardiomyopathy. J Intensive Care 2015; 3: 48. 26566443 \n2. Vieillard-Baron A, Caille V, et al. Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 2008; 36: 1701- 1706. 18496368 \n3. Nakamura K, Doi K, et al. Endotoxin adsorption by polymyxin B column or intra-aortic balloon pumping use for severe septic cardiomyopathy. Am J Emerg Med 2013; 31: 893. e1–3. \n4. Hiromi T, Toida C, et al. Two cases with intra-aortic balloon pumping use for severe septic cardiomyopathy. Acute Med Surg 2017; 4: 446- 450. 29123906 \n5. Ogunbayo G, Olorunfemi O, et al. Outcomes of intra-aortic balloon pump use in myocarditis complicated by cardiogenic shock. J Am Coll Cardiol 2017; 69: 860. \n6. McKinney AM, Short J, et al. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. Am J Roentgenol 2007; 189: 904- 912. 17885064 \n7. Bartynski WS, Boardman JF, et al. Posterior reversible encephalopathy syndrome in infection, sepsis, and shock. Am J Neuroradiol 2006; 27: 2179- 2190. 17110690 \n8. Munford RS. Sepsis, severe sepsis, and septic shock. Mandell GL, Bennett JE, Dolin R (Eds). Principles and Practice of Infectious Disease. Philadelphia: Elsevier; 2005. pp. 906- 926. \n9. Symeonides S, Balk RA. Nitric oxide in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13: 449- 463, x. 10340177\n\n",
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"issn_linking": "0972-5229",
"issue": "23(4)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Intra-aortic balloon pump; Posterior reversible encephalopathy syndrome; Septic cardiomyopathy",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "188-190",
"pmc": null,
"pmid": "31130792",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "10340177;17110690;17885064;18496368;23399331;26566443;29123906",
"title": "Posterior Reversible Encephalopathy Syndrome in a Patient of Sepsis-induced Cardiomyopathy, Successfully Managed with Intra-aortic Balloon Pump.",
"title_normalized": "posterior reversible encephalopathy syndrome in a patient of sepsis induced cardiomyopathy successfully managed with intra aortic balloon pump"
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"abstract": "Drugs that prolong the electrocardiographic QT interval increase the risk of ventricular arrhythmias, particularly torsades de pointes. Ondansetron, a 5-hydroxytryptamine type 3 receptor antagonist antiemetic, is one such drug. We present the cases of 2 patients who were given intravenous ondansetron and subsequently developed torsades de pointes. Both had normal QT intervals at baseline but were discovered to have risk factors that predisposed them to drug-induced QT prolongation and ventricular arrhythmias. We briefly review the mechanisms for torsades de pointes caused by QT-prolonging medications, describe characteristics that increase patients' susceptibility to drug-induced QT prolongation, and call attention to the risk of ventricular arrhythmias in patients who are given ondansetron.",
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"authors": "Lee|Danny Y|DY|;Trinh|Tri|T|;Roy|Sion K|SK|",
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"issue": "44(5)",
"journal": "Texas Heart Institute journal",
"keywords": "Arrhythmias, cardiac/chemically induced; dose-response relationship, drug; drug-related side effects and adverse reactions; electrocardiography/drug effects; emergency treatment; ondansetron/administration & dosage/adverse effects/therapeutic use; product surveillance, postmarketing; risk factors; serotonin 5-HT3 receptor antagonists/therapeutic use; torsades de pointes/chemically induced/physiopathology",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D004562:Electrocardiography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017294:Ondansetron; D012702:Serotonin Antagonists; D016171:Torsades de Pointes",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "366-369",
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"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8797136;24314899;22046106;22470245;4956181;23696066;23716765;14999113;22045830;1357506;15888497;26084332;15915019",
"title": "Torsades de Pointes after Ondansetron Infusion in 2 Patients.",
"title_normalized": "torsades de pointes after ondansetron infusion in 2 patients"
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"abstract": "•Metastatic SCC arising from the ovary is rare, and the optimal treatment is unknown.•Pembrolizumab successfully treated a patient with metastatic SCC.•Patients on pembrolizumab should be monitored for immune-related adverse events.",
"affiliations": "Department of Medicine, University of Chicago, Chicago, IL, United States.;Department of Pathology, University of Chicago, Chicago, IL, United States.;Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL, United States.;Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, United States.;Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, United States.",
"authors": "Wu|Meng|M|;Bennett|Jennifer A|JA|;Reid|Pankti|P|;Fleming|Gini F|GF|;Kurnit|Katherine C|KC|",
"chemical_list": null,
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"doi": "10.1016/j.gore.2021.100837",
"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789\nElsevier\n\nS2352-5789(21)00141-7\n10.1016/j.gore.2021.100837\n100837\nCase Reports and Case Series\nSuccessful treatment of squamous cell carcinoma arising from a presumed ovarian mature cystic teratoma with pembrolizumab\nWu Meng a\nBennett Jennifer A. b\nReid Pankti c\nFleming Gini F. d\nKurnit Katherine C. kkurnit@bsd.uchicago.edu\ne⁎\na Department of Medicine, University of Chicago, Chicago, IL, United States\nb Department of Pathology, University of Chicago, Chicago, IL, United States\nc Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL, United States\nd Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, United States\ne Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, United States\n⁎ Corresponding author at: Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Chicago, 5841 S. Maryland Ave, Chicago, IL 60637, United States. kkurnit@bsd.uchicago.edu\n22 7 2021\n8 2021\n22 7 2021\n37 10083723 5 2021\n16 7 2021\n© 2021 The Authors. 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/).\nHighlights\n\n• Metastatic SCC arising from the ovary is rare, and the optimal treatment is unknown.\n\n• Pembrolizumab successfully treated a patient with metastatic SCC.\n\n• Patients on pembrolizumab should be monitored for immune-related adverse events.\n\nKeywords\n\nOvarian squamous cell carcinoma\nMature cystic teratoma\nImmune checkpoint inhibitor\nPembrolizumab\n==== Body\n1 Introduction\n\nSquamous cell carcinoma (SCC) of the ovary is a rare clinical entity that most commonly arises from a mature cystic teratoma (MCT). While MCT is generally a benign ovarian germ cell tumor, malignant transformation occurs in <2% of cases, with the majority (>80%) of these events being SCC (Li et al., 2019, Hackethal et al., 2008). The prognosis is poor for patients diagnosed at International Federation of Gynecology and Obstetrician (FIGO) stage II or higher. While adjuvant chemotherapy has evidence of a survival benefit in advanced disease, the optimal first-line regimen is unclear, and management is often adapted from treatment for epithelial ovarian cancer or SCC of other sites (Li et al., 2019, Hackethal et al., 2008).\n\nIn recent years, the advent of immune checkpoint inhibitors (ICIs) has vastly expanded the oncological armamentarium. Among these agents, pembrolizumab (Keytruda®, Merck and Co., Inc.) is a humanized monoclonal antibody that blocks the binding of programmed death-1 (PD-1) receptor to programmed death ligand-1 and 2 (PD-L1 and PD-L2) and has shown efficacy against a wide variety of solid tumors. For treatment of gynecological malignancies, it has been approved by the United States Food and Drug Administration for use in recurrent or metastatic cervical cancer and as part of combination therapy for advanced endometrial cancer (Merck Sharp & Dohme, 2020).\n\nTo our knowledge, there have been no reports in the literature of SCC arising from an ovarian MCT treated with an ICI. We report here the first case of a patient with metastatic SCC presumed to arise from an ovarian MCT who was successfully treated with pembrolizumab after progressing through platinum-based combination chemotherapy.\n\n2 Case report\n\nA 36-year-old multiparous woman with a past medical history significant for uterine fibroids presented to her local gynecologist with symptoms of left flank pain, urinary urgency, and pelvic pain. She had an Eastern Cooperative Oncology Group (ECOG) score of 0. Six weeks prior to surgery, she underwent computerized tomography (CT) and magnetic resonance imaging (MRI) studies that revealed a 6 cm pelvic mass thought to be arising from the uterus and moderate left-sided hydronephrosis due to mass effect. A CA 125 level was normal at 27 U/mL. Due to initial concern for uterine fibroids, she received one dose of leuprolide, but did not tolerate the side-effects. She self-referred to gynecologic oncology and was recommended for surgical evaluation. The patient underwent a diagnostic laparoscopy converted to a laparotomy. Intraoperatively, she was found to have a pelvic mass densely adherent to the left pelvic sidewall, completely obstructing the left ureter and adherent to the sigmoid colon (Fig. 1). Palpable liver lesions were also present. The left ovary was unable to be identified. She had an en bloc resection of the uterus, cervix, left pelvic mass, and a portion of the sigmoid colon, and underwent a liver biopsy. Frozen pathology was consistent with a poorly differentiated epithelioid neoplasm, and the contralateral ovary was also removed. At the completion of the case she had residual disease remaining in the bilateral pelvic sidewalls and liver. A ureteral stent was unable to be inserted intraoperatively due to complete obstruction, and a percutaneous nephrostomy tube was placed postoperatively. Her preoperative creatinine was 1.1 mg/dL.Fig. 1 White-yellow firm mass in the left adnexal region invading into the myometrium. Note an additional nodule in the left parametrium (*). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)\n\nFinal pathology showed a metastatic poorly differentiated SCC (Fig. 2a) involving the left parametrium, cervical stroma, myometrium, pelvic sidewall, colon, liver, and two lymph nodes that was positive for p40 (diffuse), GATA-3 (patchy), and CK20 (weak, non-specific), but negative for p16 and CK7. Multiple sections were examined of the mass in the left adnexal region, but the tissue was completely infarcted and no viable tumor, residual ovary, nor fallopian tube were identified. While morphology and immunoprofile were compatible with SCC, the origin of the tumor was unclear. The disease distribution (i.e., tumor growing into the uterus), lack of overlying squamous dysplasia, and a negative p16 argued against a cervical origin. Similarly, the absence of a vaginal, vulvar, or anogenital mass, and a negative p16 made an HPV-associated lower genital tract SCC unlikely. Due to the encasement of the ureter, a urothelial cell carcinoma with extensive squamous differentiation was considered but was improbable as CK7 was negative. Thus, in the absence of a known primary elsewhere, an ovarian origin was favored. Ovarian SCC are uncommon; they most commonly arise from a MCT, and less likely from a malignant Brenner tumor with extensive squamous differentiation. As the latter are generally CK7 positive, development from a MCT was favored as the primary lesion. Tumor PD-L1 expression was 50–60% (Fig. 2b). Next generation sequencing showed that the tumor was microsatellite stable with TP53, NF2, and NOTCH1 mutations, CDKN2A/2B loss, and RAD21 amplification.Fig. 2 (A) Poorly differentiated squamous cell carcinoma with perineural invasion (*) (Hematoxylin and eosin stain, 400X). (B) A subset of tumor cells showed partial or complete membranous staining of moderate intensity for PD-L1 (PD-L1 immunostain, 400X).\n\nThe case was discussed at multidisciplinary tumor board, and she was recommended for adjuvant carboplatin and paclitaxel with addition of bevacizumab at cycle two. A baseline postoperative CT scan of the chest, abdomen, and pelvis prior to initiation of chemotherapy showed interval development of metastases to the lungs, liver, retroperitoneum, mesentery, and omentum. Serum levels of CA 125, CEA, CA 19–9, and AFP obtained prior to chemotherapy initiation were all within normal limits.\n\nFive weeks after surgery, the patient was initiated on carboplatin at intravenously (IV) AUC 6 dose and paclitaxel IV 175 mg/m2. During her second cycle, bevacizumab 15 mg/kg was added. The patient tolerated three cycles of this regimen, however, restaging CT showed progression of disease. Unfortunately, the patient’s ECOG performance status declined to a score of 2 due to rapid disease progression. As such, she was not eligible for any available clinical trials.\n\nGiven the tumor’s PD-L1 positivity, the decision was made to pursue therapy with pembrolizumab IV 200 mg every three weeks. She began to symptomatically improve after cycle one and a restaging CT scan after cycle three showed a decreased size of all lesions with the exception of a new pleural lesion. Imaging after six months on therapy showed a decreased size of most reference lesions including the pleural lesion (Fig. 3).Fig. 3 Axial CT scans of the chest, abdomen, and pelvis. (A) Imaging prior to adjuvant chemo. Reference hepatic lesion measures 4.4 × 3.2 cm. (B) Imaging after cycle 3 of carboplatin, paclitaxel, and bevacizumab. Hepatic lesion measures 3.8 × 5.1 cm. (C) Imaging after cycle 6 of pembrolizumab. Hepatic lesion measures 3.5 × 3.0 cm.\n\nAt cycle six, the patient was transitioned to pembrolizumab 400 mg dosed every six weeks. However, she experienced grade 3 arthritis with significant, prolonged morning stiffness of her hands along with grade 2 sicca syndrome. She consequently resumed her previous dosing schedule. After cycle eight of treatment, she experienced grade 4 hypercalcemia with a maximum serum calcium up to 14.1 mg/dL and required hospital admission. Other laboratory work-up showed normal serum albumin (3.8 g/dL), low parathyroid hormone (PTH) (<6 pg/mL), normal 25-hydroxy vitamin D (28 ng/mL), and normal PTH-related protein (1.1 pmol/L). The etiology was thought to be an immune-related adverse event (irAE) secondary to pembrolizumab therapy. Pembrolizumab was held for one cycle and the patient received intravenous fluids, but her calcium level rose again despite initial improvement. With hypercalcemia, arthritis, and sicca, the clinical picture had features of sarcoidosis although her anti-angiotensin antibodies were unremarkable. She then received a systemic corticosteroid taper in addition to zolendronic acid with significant improvement in her serum calcium level and arthritis and was subsequently able to resume pembrolizumab.\n\nAt the time of this publication, the patient continues on pembrolizumab at 15 months with stable disease. She is more than 18 months out from her initial diagnosis and has returned to an ECOG performance status of 0.\n\n3 Discussion\n\nOvarian SCC arising from MCT is a rare clinical entity that exhibits a poor prognosis when diagnosed at advanced stages. In the largest systematic review of ovarian SCC to date, Li et al. (2019) examined data from 435 cases and showed that while patients diagnosed at stage I had a 5-year overall survival of 85.8%, those diagnosed at stages II, III, and IV had significantly reduced survival rates of 39.1%, 26.2%, and 0% respectively. Our patient was found to have stage IVb disease, and the extent of her tumor burden prevented full resection at time of surgery. In cases of advanced disease, chemotherapy has been shown in retrospective studies to confer survival benefit, although given the rarity of ovarian SCC, prospective randomized data on optimal adjuvant treatment do not exist (Li et al., 2019). In a Gynecologic Cancer InterGroup consensus review, Glasspool et al. (2014) noted that platinum-based combination therapy was frequently used. Our patient’s initial regimen of carboplatin, paclitaxel, and bevacizumab was selected based on first-line therapy for advanced ovarian cancer, in addition to activity seen in cervical SCC. Unfortunately, she showed rapid disease progression without a clear second-line option recognized within the literature.\n\nGiven positive tumor PD-L1 expression, it was hypothesized that the patient’s disease may be responsive to ICI therapy. There are no data regarding prevalence of PD-L1 expression in ovarian SCC, but studies of SCC of other primary sites have shown PD-L1 positivity ranging from 33 to 59% in squamous non-small cell lung cancer to 83.7% in cervical cancer (Chung et al., 2019, Yu et al., 2016). A recent comprehensive molecular analysis of carcinomas arising from MCT from Tamura et al. (2020) found that, compared to SCC of other sites, SCC arising from MCT resulted in tumor cells that stably overexpress the gene XCL1, which produces a cytokine that contributes to activation of CD8+ cytotoxic T cells. XCL1 overexpression was significantly associated with both CD8+ T cell tumor infiltration and PD-L1 tumor expression. Although we do not have information regarding XCL1 expression in our patient, this may be one mechanism that explains her durable response to pembrolizumab therapy.\n\nAlthough pembrolizumab has a relatively favorable safety profile compared to cytotoxic chemotherapy agents, our patient experienced grade 2 sicca syndrome, grade 3 arthritis, and grade 4 hypercalcemia potentially attributable to pembrolizumab. While hypercalcemia of all grades occurred in 14% of cervical cancer patients who received pembrolizumab in the KEYNOTE-158 trial, only 2.6% were grades 3–4 (Merck Sharp & Dohme, 2020). Our patient also presented with a clinical picture suggestive of a more systemic autoimmune process during the episode of hypercalcemia, prompting treatment with a steroid taper for possible sarcoid-like reaction secondary to ICI therapy. IrAEs secondary to ICIs are well-described, and there have been reports of sarcoidosis exacerbated or induced by pembrolizumab therapy (Gkiozos et al., 2018). Our patient ultimately responded well to a course of systemic corticosteroids and zoledronic acid. She was able to continue on pembrolizumab without recurrence of her hypercalcemia to date.\n\n4 Conclusion\n\nThe prognosis for ovarian SCC remains grim in cases diagnosed at stage II and greater, and the optimal second line treatment regimen is unclear. Given the success of ICIs in multiple solid tumors, patients who progress through or fail to respond to an initial line of chemotherapy should be considered for immunotherapy, preferably on a clinical trial if one is available. Further investigation into the genomic characteristics of ovarian SCC may help guide selection of those patients who may most benefit most from ICI therapy.\n\n5 Consent\n\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nCRediT authorship contribution statement\n\nMeng Wu: Writing - original draft. Jennifer A. Bennett: Writing - review & editing. Pankti Reid: Writing - review & editing. Gini F. Fleming: Conceptualization, Writing - review & editing. Katherine C. Kurnit: Conceptualization, Supervision, Writing - review & editing.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\nChung H.C. Ros W. Delord J.P. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study J. Clin. Oncol. 37 17 2019 1470 1478 10.1200/JCO.18.01265 30943124\nGkiozos I. Kopitopoulou A. Kalkanis A. Vamvakaris I.N. Judson M.A. Syrigos K.N. Sarcoidosis-like reactions induced by checkpoint inhibitors J. Thorac. Oncol. 13 8 2018 1076 1082 10.1016/j.jtho.2018.04.031 29763666\nGlasspool R.M. González Martín A. Millan D. Gynecologic Cancer InterGroup (GCIG) consensus review for squamous cell carcinoma of the ovary Int. J. Gynecol. Cancer. 24 9 Suppl 3 2014 S26 S29 10.1097/IGC.0000000000000209 25126954\nHackethal A. Brueggmann D. Bohlmann M.K. Franke F.E. Tinneberg H.R. Münstedt K. Squamous-cell carcinoma in mature cystic teratoma of the ovary: systematic review and analysis of published data [published correction appears in Lancet Oncol. 2009 May;10(5):446] Lancet Oncol. 12 9 2008 1173 1180 10.1016/S1470-2045(08)70306-1\nKeytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ, Merck Sharp & Dohme, 2020.\nLi C. Zhang Q. Zhang S. Squamous cell carcinoma transformation in mature cystic teratoma of the ovary: a systematic review BMC Cancer. 19 1 2019 217 10.1186/s12885-019-5393-y Published 2019 Mar 11 30866852\nTamura R. Yoshihara K. Nakaoka H. XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary Oncogene 39 17 2020 3541 3554 10.1038/s41388-020-1237-0 32115573\nYu H. Boyle T.A. Zhou C. Rimm D.L. Hirsch F.R. PD-L1 Expression in Lung Cancer [published correction appears in J Thorac Oncol. 2017 Jan;12 (1):157-159] J. Thorac. Oncol. 11 7 2016 964 975 10.1016/j.jtho.2016.04.014 27117833\n\n",
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"title": "Successful treatment of squamous cell carcinoma arising from a presumed ovarian mature cystic teratoma with pembrolizumab.",
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"abstract": "We report a case of glycogen storage disease type 1b that was successfully treated with bone marrow transplantation after life-threatening complications related to neutropenia and thrombocytopenia. Concomitant reduction in inflammatory bowel disease-related symptoms and improved metabolic stability were also observed.",
"affiliations": "Department of Inherited Metabolic Disease, Birmingham Children's Hospital NHS Trust, Birmingham, United Kingdom.",
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"abstract": "OBJECTIVE\nTo present a case of gemfibrozil-induced myositis which precipitated an acute compartment syndrome.\n\n\nMETHODS\nA 49-year-old woman with chronic renal failure was given gemfibrozil for hyperlipidaemia. She developed myositis in the sixth week of therapy. Her symptoms initially persisted despite withdrawal of gemfibrozil and she developed an acute compartment syndrome.\n\n\nRESULTS\nEmergency fasciotomy was performed. She gradually improved and complete recovery occurred eight weeks after cessation of gemfibrozil therapy.\n\n\nCONCLUSIONS\nGemfibrozil may induce a local myositis which, in our patient, precipitated an acute compartment syndrome. One should be alert to symptoms of possible drug-induced myositis in patients receiving gemfibrozil. Extreme caution should be exercised in its use in patients with impaired renal function.",
"affiliations": "Institute of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong.",
"authors": "Chow|L T|LT|;Chow|W H|WH|",
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"title": "Acute compartment syndrome: an unusual presentation of gemfibrozil induced myositis.",
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"abstract": "Intravenous haloperidol has been associated with torsades de pointes (TdP). These two sudden deaths were probable adverse drug reactions (ADRs) following intramuscular (IM) antipsychotics. The autopsies described lack of heart pathology and were highly compatible with the possibility of TdP in the absence of risk factors other than the accumulation of antipsychotics with a high serum peak after the last injection, leading to death within hours. The first case was a 27-year-old African-American male with schizophrenia but no medical issues. His death was probably caused by repeated IM haloperidol injections of 10 mg (totaling 35 mg in 2 days). The second case involves a 42-year-old African-American female with metabolic syndrome. Her probable cause of death was the last ziprasidone IM injection of 20 mg in addition to (1) three extra haloperidol doses (2 hours before the ziprasidone injection, 5 mg oral haloperidol; approximately 21 hours earlier, 5 mg oral haloperidol; and 2 days prior, one 10 mg IM haloperidol injection), (2) 10 mg/day of scheduled oral haloperidol for 6 days before death, and (3) a long-acting paliperidone injection of 156 mg 18 days before death. The study of haloperidol glucuronidation and its impairment in some African-Americans is urgently recommended.",
"affiliations": "Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY 40509, USA.;Department of Behavioral Health, Developmental and Intellectual Disabilities, Frankfort, KY 40621, USA.;Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY 40509, USA; Department of Behavioral Health, Developmental and Intellectual Disabilities, Frankfort, KY 40621, USA.;Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY 40509, USA; Eastern State Hospital, University of Kentucky Mental Health Research Center, Lexington, KY 40511, USA; Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, 18971 Granada, Spain; Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apóstol Hospital, University of the Basque Country, 01004 Vitoria, Spain.",
"authors": "Wahidi|Nasratullah|N|0000-0002-7167-2993;Johnson|Katie M|KM|0000-0002-3664-9392;Brenzel|Allen|A|;de Leon|Jose|J|0000-0002-7756-2314",
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"fulltext": "\n==== Front\nCase Rep PsychiatryCase Rep PsychiatryCRIPSCase Reports in Psychiatry2090-682X2090-6838Hindawi Publishing Corporation 10.1155/2016/9406813Case ReportTwo Sudden and Unexpected Deaths of Patients with Schizophrenia Associated with Intramuscular Injections of Antipsychotics and Practice Guidelines to Limit the Use of High Doses of Intramuscular Antipsychotics http://orcid.org/0000-0002-7167-2993Wahidi Nasratullah \n1\nhttp://orcid.org/0000-0002-3664-9392Johnson Katie M. \n2\nBrenzel Allen \n1\n\n2\nhttp://orcid.org/0000-0002-7756-2314de Leon Jose \n1\n\n3\n\n4\n\n5\n\n*\n1Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY 40509, USA2Department of Behavioral Health, Developmental and Intellectual Disabilities, Frankfort, KY 40621, USA3Eastern State Hospital, University of Kentucky Mental Health Research Center, Lexington, KY 40511, USA4Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, 18971 Granada, Spain5Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apóstol Hospital, University of the Basque Country, 01004 Vitoria, Spain*Jose de Leon: jdeleon@uky.eduAcademic Editor: Erik Jönsson\n\n2016 15 8 2016 2016 94068139 5 2016 3 7 2016 Copyright © 2016 Nasratullah Wahidi 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.Intravenous haloperidol has been associated with torsades de pointes (TdP). These two sudden deaths were probable adverse drug reactions (ADRs) following intramuscular (IM) antipsychotics. The autopsies described lack of heart pathology and were highly compatible with the possibility of TdP in the absence of risk factors other than the accumulation of antipsychotics with a high serum peak after the last injection, leading to death within hours. The first case was a 27-year-old African-American male with schizophrenia but no medical issues. His death was probably caused by repeated IM haloperidol injections of 10 mg (totaling 35 mg in 2 days). The second case involves a 42-year-old African-American female with metabolic syndrome. Her probable cause of death was the last ziprasidone IM injection of 20 mg in addition to (1) three extra haloperidol doses (2 hours before the ziprasidone injection, 5 mg oral haloperidol; approximately 21 hours earlier, 5 mg oral haloperidol; and 2 days prior, one 10 mg IM haloperidol injection), (2) 10 mg/day of scheduled oral haloperidol for 6 days before death, and (3) a long-acting paliperidone injection of 156 mg 18 days before death. The study of haloperidol glucuronidation and its impairment in some African-Americans is urgently recommended.\n==== Body\n1. Introduction\nThioridazine was introduced in the US market in 1959 [1]. In 1964 [2], Kelly et al. reported that thioridazine was associated with quinidine-like electrocardiogram (EKG) abnormalities in 28 patients and with two cases of ventricular tachycardia leading to death in patients taking 1500 mg/day and 3600 mg/day, respectively. The awareness of these deaths before publication led the pharmaceutical company to talk to Ban and St. Jean [3]. Ban proposed completing a prospective EKG study using four doses of thioridazine and four doses of chlorpromazine and trifluoperazine as controls. EKG abnormalities resembling those caused by quinidine and hypokalemia were present in all 6 patients taking thioridazine (versus 3/6 for chlorpromazine and 1/6 for trifluoperazine) [3]. Before Ban and St. Jean published their study, Desautels et al. identified a patient who survived ventricular tachycardia while receiving 1500 mg/day of thioridazine for 6 weeks [4]. Some other studies were published regarding the matter [1], including one by Simpson as senior author [5] describing thioridazine-induced EKG changes as very likely in the elderly and, therefore, recommending against thioridazine as a drug for the elderly. According to Shorter, Ban tried to convince the pharmaceutical company of the clinical relevance of thioridazine-induced arrhythmias but was not successful [1]. As a matter of fact, the company did not change the prescribing information to warn physicians of the risk of thioridazine causing torsades de pointes (TdP) until 2000 [1]. Finally, in 2006, more than 40 years after the first deaths associated with thioridazine, the drug was withdrawn from the US market [6].\n\nAfter slowly increasing awareness, the relationship between drugs, including antipsychotics, and TdP, a potentially lethal adverse drug reaction (ADR), became irrefutable in the 1990s and the US Food and Drug Administration (FDA) had no choice but to intervene. The turning point came in 1996 [7]. Terfenadine was a second-generation antihistamine that had been approved in the USA in 1985 [6] after no systematic studies on drug-drug interactions (DDIs) and on drug metabolism. The randomized controlled trials (RCTs) in healthy subjects with limited comedication had demonstrated that it was a very safe drug. Once approved, terfenadine was widely used in the general population including in patients who were taking erythromycin, ketoconazole, and itraconazole. These 3 drugs are powerful cytochrome P450 (CYP) 3A4 (CYP3A4) inhibitors and terfenadine was metabolized by CYP3A4. In 1996, the FDA became aware [7] that there were at least 125 deaths in the US caused by terfenadine. Patients taking any of these major CYP3A4 inhibitors had major accumulations of terfenadine with very high serum concentrations leading to TdP. The FDA required warning labels in the prescribing information for terfenadine and the CYP3A4 inhibitors; terfenadine was finally withdrawn from the market in 1998 [6]. The terfenadine deaths explained by DDIs led to the FDA's awareness of the need to study CYP metabolism and DDIs for new drug submissions. The requirements were progressively increased in the late 1990s, after several other drugs metabolized by CYP3A4 and with potential to cause TdP were withdrawn from the market [6].\n\nSertindole, a second-generation antipsychotic, was introduced in Europe in 1996 [8]. It rapidly became associated with sudden cardiac deaths and an in vitro study demonstrated that sertindole has high affinity as an antagonist of the cardiac potassium channel [9]. In humans, the delayed rectifier potassium current is mediated by the ion channel KCNH2 encoded by the human ether-a-go-go–related gene (HERG) [9]. After the publication of this article describing that sertindole was an antagonist of the channel encoded by HERG [9], it became evident that first-generation antipsychotics, such as thioridazine, must have the same antagonist properties at the same cardiac channel; this also explained why hypokalemia is a risk factor for antipsychotic-induced TdP [10].\n\nSince TdP is a very rare event, in the late 1990s the FDA proposed using prolongation of the QT interval as a TdP risk marker. This was a complex decision since there is general agreement that the QT interval needs to be corrected by heart frequency, which is called corrected QT (QTc), but there are several formulas for doing it and no agreement among experts concerning which one is best. Another issue is how good QTc prolongation proves to be as a sign of the blockade of the cardiac potassium channel, which is determined by drug affinity and the serum concentrations in a specific patient. Thioridazine appears to have the highest affinity among antipsychotics and the use of very high doses >1,000 mg/day, such as the doses used in the 1960s, led to very high serum concentrations and extremely high potential for TdP in many, if not all, patients.\n\nIn the late 1990s, the company developing ziprasidone was trying to introduce it into the US market, but ziprasidone has affinity for the human cardiac potassium channels and caused prolongations of the QTc interval. To allay the FDA's concerns, ziprasidone's marketer decided to complete a milestone prospective randomized study [11] comparing 6 oral antipsychotics (haloperidol, quetiapine, olanzapine, risperidone, thioridazine, and ziprasidone) by themselves and in the presence of CYP inhibitors (fluvoxamine for CYP1A2, ketoconazole for CYP3A4, and paroxetine for CYP2D6). With the specific doses used in that study, thioridazine was associated with greater QTc prolongations with a mean increase of 30.1 milliseconds (ms), ziprasidone was second with 15.9 ms, and haloperidol was third with 7.1 ms. Following this study, ziprasidone was permitted in the US market in 2001 with some warnings about QTc prolongation in the prescribing information. Then, some of the first-generation antipsychotics started to be withdrawn from some markets due to TdP risk. This led to major discussions in the US and international journals [12–14] and major disagreement on the advertising by the company marketing antipsychotics about the clinical relevance of antipsychotic-induced QTc prolongations and the virtues or weaknesses of various second-generation antipsychotics regarding their effects on the QTc interval. The problems [14] are that (1) sudden death on oral antipsychotics has a very low incidence: around 1 in every 10,000 patients. This requires 10,000 patients taking medications for an extended period to identify a few cases, making it very difficult to study; and (2) these large pharmacoepidemiological naturalistic studies include sudden death cases with multiple confounding factors and no guarantee that they are explained by TdP versus other causes of sudden death or by TdP explained by the combination of multiple factors besides an antipsychotic. Review articles started recommending a QTc limit (e.g., >500 ms) as a risk marker for TdP [12]. This became controversial since other authors recommended other values, such as >450 ms [13]. Moreover, the literature clearly indicated that women have a greater mean QTc; therefore, a sex-corrected QTc limit for predicting risk for TdP may be needed (e.g., >450 ms in men and >470 ms in women) [13].\n\nThese controversies concerning QTc prolongation are not easy to resolve since there is limited reliable data on TdP cases caused by antipsychotics. Summarizing our current knowledge [14], we can describe most cases of drug-induced TdP as occurring in the context of substantial prolongation of the QTc interval, typically to values >500 ms, but QTc alone is a relatively poor predictor of arrhythmic risk in any individual patient. Some drugs that substantially prolong the QTc interval produce very low rates of TdP while others have much smaller QTc effects but are considerably more prone to cause TdP [15]. The psychiatric literature describing clinical cases of TdP is very complex [14], since the cases are frequently associated with polypharmacy and DDIs, with a pharmacodynamic component involving multiple drugs with HERG channel inhibitory properties and sometimes a pharmacokinetic component, an inhibitor increasing the plasma concentrations of one or several of the drugs. Other risk factors for TdP such as female gender, bradycardia, hypokalemia, and hypomagnesemia may be important, too [16].\n\nSince 2001, oral ziprasidone has occasionally been associated with TdP, but most of the cases include patients with other TdP risk factors [17]. A large 1-year mortality study randomly assigning its 18,000 patients to ziprasidone or olanzapine concluded that these drugs have similar nonsuicide mortality, but the study acknowledged that it did not have enough power to detect rare events such as TdP [18]. In a comprehensive review of the literature, sponsored by ziprasidone's marketer and focused on the company's RCT and the postmarketing surveillance data, Camm et al. [19] concluded that ziprasidone is safe if used as indicated. On the other hand, a more recent pharmacoepidemiology review by independent investigators suggested that there were 3 antipsychotics definitively associated with TdP: amisulpride, haloperidol, and ziprasidone [20]. As population clinical data [19] and laboratory pharmacological studies [21] indicate that drug-induced QTc prolongations are without doubt driven by higher serum concentrations, the parenteral administration of any of these antipsychotics, which is associated with much higher peak concentrations than oral administration, should substantially increase the risk of antipsychotic-induced TdP in patients receiving intramuscular (IM) formulations. IM ziprasidone was approved in the US for agitation in schizophrenia patients in 2002. After a healthy young Chinese male patient with schizophrenia demonstrated a QTc interval prolongation of 83 ms after receiving a single IM injection with 20 mg of ziprasidone, Li et al. [22] completed a systematic review on the effects of IM ziprasidone on the QTc interval prolongation. They identified 19 trials in English or Chinese with a total of 1428 patients, many using haloperidol IM as a control. Their review identified two cases of patients who experienced symptoms probably related to QTc prolongation after IM ziprasidone. If one assumes that published IM ziprasidone cases are representative, one can estimate you need only 1,000 patients on IM ziprasidone to identify symptoms of TdP versus 10,000s required to identify sudden deaths associated with oral antipsychotics. In the systematic review, mean QTc change from baseline to end of each trial ranged from −3.7 to 12.8 ms after IM ziprasidone (compared with −3.5 to 14.7 ms on haloperidol IM). Four RCTs were used to calculate a meta-analysis of QTc interval prolongation; it showed no significant differences between IM ziprasidone and IM haloperidol groups. In summary, IM ziprasidone appeared to have some risk for TdP that did not look different from IM haloperidol.\n\nThe history of haloperidol-induced TdP is also as protracted as that of thioridazine-induced TdP. Haloperidol is a first-generation antipsychotic marketed in the 1960s but with the peculiarity of having formulations for IM and intravenous (IV) administration that are more risky for TdP since they provide much higher peak serum concentrations than oral formulations. IV haloperidol is mainly used for sedation by internists rather than by psychiatrists and internists use it in continuous administration controlled by nurses; there is potential for huge doses since haloperidol is not a potent drug for sedating patients. Psychiatrists tend to use haloperidol IM and combine it with other more sedating drugs (e.g., lorazepam and/or diphenhydramine). During the 1990s and 2000s, there was a progressive increase in cases demonstrating the association between extremely high accumulated doses of haloperidol IV and TdP [23–26], to the point that the FDA required a warning in the US haloperidol prescribing information in 2007 [27]. Based on the case reports of potentially fatal cardiac events, the FDA warned that haloperidol is not approved for IV administration, but if IV administration is used, EKG monitoring should be performed. Meyer-Masseti et al. [27] considered the FDA's recommendations in 2007 confusing. The FDA warned that QTc prolongation and risk of TdP were increased with IV administration of haloperidol or administration of haloperidol at greater-than-recommended doses in any formulation. However, Meyer-Masseti et al. [27] stressed that neither the “typical” dosing range nor the minimum dose associated with these cardiac ADRs was specified in the haloperidol prescribing information. In their review of the literature [27], Meyer-Masseti et al. identified a total of 70 cases of IV haloperidol associated with QTc prolongation and/or TdP. When postevent QTc data were reported, QTc was prolonged >450 ms in 96% of the cases. Most (97%) of the patients had additional risk factors for TdP, mainly the coprescription of other proarrhythmic agents. Patients experiencing haloperidol-associated TdP received a wide range of cumulative doses from 5 mg to 645 mg. In their review, Meyer-Masseti et al. do not address the crucial issue: what do we know about TdP only caused by IV haloperidol in the absence of other major risk factors? It is obvious that IV haloperidol should not be used in patients with TdP risk factors, but we do not know what doses of IV haloperidol may be risky in patients with no known TdP risk factors.\n\nThe association between oral and IM haloperidol with TdP has received much less attention in the literature than the association with IV haloperidol. Jackson et al. [28] published a TdP case associated with 4 mg oral haloperidol (2 doses of 2 mg separated by 8 hours) in a 66-year-old woman. Harvey et al. [29] studied 12 volunteers with schizophrenia who were given a single IM injection of 7.5 mg haloperidol or 4 mg lorazepam in a blinded, randomized, placebo-controlled crossover design. Mean changes in the QTc interval in those receiving the haloperidol IM dose ranged from 3.6 to 5.1 ms, depending on the formula used to correct for heart frequency. Harvey et al. [29] concluded that, on average, this dose of IM haloperidol led to minimal prolongation of the QT interval and this effect was of theoretical concern in individuals with risk factors for TdP but seemed unlikely to be a problem in the vast majority of patients. In our literature searches in PubMed, we have not been able to identify clinical studies of QTc prolongation using IM haloperidol formulations with repeated administration, such as those used by psychiatrists to control agitation in the clinical environment or case reports of TdP associated with IM haloperidol. There are IM ziprasidone RCTs using haloperidol IM as a control, but most of the published articles focused on the mean increases in QT prolongation rather than the extreme cases and frequently considered haloperidol-induced QTc changes as not clinically relevant (reviewed in Table 1 of [22]). \n\nIn this paper, we present two cases of sudden death after IM injections of antipsychotics (haloperidol in the first case and a haloperidol-ziprasidone combination in the second case) with autopsies indicating lack of heart pathology and high compatibility with the possibility of TdP. After using two different ADR scales in each patient [30, 31], the authors consider these two sudden deaths to be probable ADRs.\n\n2. The Patient Sample That Led to Two Cases\nThe state of Kentucky is located in the center of the United States and has a population of approximately 4 million people. Most Kentuckians are Caucasians; less than 10% are African-Americans and small numbers of people are from other racial/ethnic backgrounds. The majority of adult patients with severe mental illnesses (SMIs) get admitted to 4 state psychiatric hospitals and 1 forensic facility. According to our centralized database with admissions data, in the last 15 years the annual number of different patients admitted to these four psychiatric state hospitals has ranged between 5,556 and 7,106. Our experience with large published studies [32, 33] in these admitted populations indicates that there are three main groups of diagnoses justifying admission, each approximating one-third of the cases: (1) severe mood disorders, (2) schizophrenia and related psychoses, and (3) complications of substance use disorders [32, 33].\n\nSince 2002, a state mortality review process has provided outside review of the deaths at any state facility, in addition to the internal regulatory process at each facility. The facilities include not only these state psychiatric hospitals but also 3 nursing homes and 4 long-term care facilities for adults with intellectual disabilities. Since 2008, some community deaths have been reviewed as well. Focusing only on deaths occurring during admission at state psychiatric hospitals over 14 years (from 2002 to January 2016), we identified 95 deaths. These 95 patients were 63% male and 87% Caucasian (11% African-American), which roughly corresponds to the admission demographics in our state psychiatric hospitals, based on our published studies including thousands of patients [32, 33]. The mean age of the 95 deceased patients was 58.0 years (standard deviation 16.7 years), apparently higher than the average age of admitted patients every year, which tends to be in the late 30s [32, 33]. Obviously, older patients are more prone to die. Of these 95 deaths, two (approximately 2%) appeared highly compatible with TdP associated with antipsychotic treatment. Both patients were prescribed high doses of IM antipsychotic injections and had autopsies showing no heart abnormalities.\n\nAccording to the committee's evaluation, besides these 2 deaths compatible with TdP, there were 32 other unexpected sudden deaths that may need to be considered in differential diagnosis. Only 7 of these 32 deaths had autopsies but the committee concluded that (1) 17 appear compatible with myocardial infarcts, (2) 9 appear compatible with pulmonary thromboembolism, (3) two appear compatible with sudden death in the context of epilepsy, (4) one appears compatible with a rupture of aortic aneurysm, and (5) three were of unknown origin (including one in which the request for autopsy was denied by the coroner). An antipsychotic-induced arrhythmia was not suspected in any of these 32 deaths since they were not temporally associated with recent IM injections or extremely high doses of oral antipsychotics, but there is no way of ruling out TdP with 100% certainty. An autopsy providing another cause of death (e.g., myocardial infarct) cannot rule out the possibility that the patient had an antipsychotic-induced TdP on top of a myocardial infarct. Nonetheless, the two cases described in detail in this paper were judged to be highly compatible with sudden death after the high doses of IM antipsychotics in the absence of other known risk factors for TdP.\n\n3. Case Presentations\n3.1. Case 1\n3.1.1. Prior History\nThis patient was a 27-year-old African-American male. His weight was 88 Kg (194 pounds). He had been diagnosed with chronic schizophrenia since age 22. He also had a history of polysubstance abuse and was a smoker. He had 9 prior state hospital admissions. During two of these admissions, he received one injection of 5 mg haloperidol IM to control psychosis and agitation, each without any obvious problem. During the 8th admission, he intermittently refused oral antipsychotic treatment medication that was court-ordered, which led to 2 injections of 10 mg haloperidol (and diphenhydramine 50 mg) without any problem, but the second injection was administered 3 days later, when the peak concentrations from the first injection were long gone. During the 9th admission, when he was 25 years old, an EKG showed “sinus bradycardia” (frequency of 58 beats per minute). The QT interval was read as 376 ms and the QTc as 373 ms. At that time he was taking, as oral medications, risperidone 4 mg/day, benztropine 2 mg/day, and divalproex sodium 1500 mg/day and 3 days before the EKG, the patient had also received an injection of long-acting risperidone of 37.5 mg but no other antipsychotic injections in the prior week. Three days before the EKG, electrolytes including potassium were normal. In summary, this EKG during reasonable doses of oral and long-acting risperidone demonstrated a completely normal QTc two years before the patient's death.\n\n3.1.2. Last Admission\nThe patient's 10th admission to state facilities lasted less than 3 days due to his death in the early morning of the third day. It was an involuntary admission with forced medication approved by the court. The patient was transferred from jail where he had had no access to tobacco smoking for weeks. Upon arrival, he was uncooperative and psychotic. His oral medications, risperidone 6 mg/day (3 mg twice a day) and benztropine 2 mg/day (1 mg twice a day), were reordered since it appeared that he had not been taking them in jail. A court-approved forced intramuscular (IM) order of haloperidol 10 mg and diphenhydramine 50 mg was to be administered if he refused any dose of oral risperidone. The admitting psychiatrist was questioned about this high haloperidol IM dose after the patient's death and provided the explanation that 3 years prior, at the same facility (his 8th admission to a state facility), the patient had received the same IM dosage of haloperidol 10 mg IM and diphenhydramine 50 mg without problems when refusing court-ordered oral medications. The psychiatrist was not aware that only 2 such injections were given during that prior admission and they were separated by 3 days. At admission the patient was uncooperative, refused a physical exam, and only cooperated with the measure of blood pressure (130/90 mm of Hg) and pulse (106 beats per minute). During the rest of the admission, he refused offers of completing the physical exam, vital signs and laboratory tests, but the available information indicated no obvious medical problems and he was essentially a medically healthy young man with no history of any serious medical problems during his 9 prior admissions to our facilities.\n\nDuring the first 2 days of this admission, the patient refused all oral medications and received forced IM medication twice a day with total accumulated dosages of IM haloperidol 35 mg and diphenhydramine 200 mg. The patient received 4 IM haloperidol injections but one of the nurses made a mistake, giving only 5 mg. Therefore, the patient received 3 injections of 10 mg and 1 of 5 mg, making a total of 35 mg/day in 2 days. On the second day, particularly, he received a set of injections with dosages of IM haloperidol 10 mg and diphenhydramine 50 mg in the early a.m. and another set at night. Eighteen minutes after the night injection, a staff member checking the room reported that the patient displayed leg movements and 15 minutes later (33 minutes after the haloperidol injection) he was found unresponsive. Cardiopulmonary resuscitation (CPR) was started but the automated external defibrillator (AED) advised no shock. The emergency medical service (EMS) arrived, pronouncing the patient dead 1 hour and 13 minutes after the last haloperidol IM injection of 10 mg.\n\n3.1.3. Autopsy\nThe autopsy showed no obvious anomalies in the heart or other organs that would explain the patient's sudden death. In macroscopic and microscopic examination, the coronary arteries and myocardium were essentially normal.\n\n3.1.4. ADR Scales\nUsing the Liverpool ADR Causality Assessment Tool [30], haloperidol-induced sudden death after 4 haloperidol IM injections with an accumulated dose of 35 mg in 2 days was deemed probable. The patient had not taken any other antipsychotic for weeks. Similarly, based on the Naranjo scale [31], a score of positive 6 (+6) was determined (scoring +1 on items 1, 5, 8, and 10 and +2 on item 2), consistent with a probable ADR. All authors agreed with the scores on both ADR scales. As the patient had no signs of myocardial ischemia or pulmonary thromboembolism, it appears to the authors that haloperidol had to cause the sudden unexpected death by TdP after the accumulation of high serum haloperidol concentrations, particularly with the fourth and last IM injection. The possible contribution of diphenhydramine to this case and to the second case is discussed in detail in the Discussion (see Section 4.5).\n\nAs far as we can tell, the literature typically describes TdP as short-duration phenomena (usually seconds) with two outcomes: (1) death due to cardiac arrest or (2) disappearance but with substantial risk of recurrence [34, 35]. Therefore, it may not be not surprising that the AED did not recommend an electrical shock which may suggest that TdP was not present at the time CPR was initiated in this patient. We do not know how long the patient had been unconscious or in cardiac arrest; we only know that his unconsciousness was identified 33 minutes after the last haloperidol IM injection.\n\n3.2. Case 2\n3.2.1. Prior History\nThis patient was a 42-year-old African-American female who had given birth to one son. She had been diagnosed with chronic schizophrenia since age 18 and had 8 prior admissions to Kentucky state psychiatric facilities. The court had previously declared her legally incompetent and a sister was appointed to make decisions for her. However, in Kentucky, guardians cannot involuntarily admit patients to psychiatric hospitals; a court needs to approve these admissions.\n\n3.2.2. Last Admission\nThe patient's 9th admission to a state psychiatric facility was precipitated by the worsening of her psychotic behavior. She was taken to the emergency room in a university hospital with short-term beds under an involuntary order allowing a 72-hour examination before deciding whether or not to ask a court for an involuntary psychiatric admission. After the filing of court documents for an involuntary admission, she was transferred to a psychiatric state hospital. The admission lasted a total of 7 days until her death. She stayed 4 days in the emergency room and 3 days at the psychiatric hospital.\n\nThe psychiatric diagnosis was chronic paranoid schizophrenia. Her medical diagnoses included obesity, diabetes mellitus type 2, hypertension, hyperlipidemia, asthma, gastroesophageal reflux disease (GERD), seasonal allergy, and valproate-induced alopecia. Her weight was 131.5 kg (290 pounds) and her body mass index 45.5. At the emergency room, the sister reported that the patient was taking divalproex sodium 1000 mg/day (500 mg twice a day) and paliperidone palmitate injections. The sister explained that divalproex sodium had recently been changed to topiramate due to alopecia, but this change had not yet been implemented; moreover, the patient had been noncompliant with the medication at home. The community mental health center providing outpatient treatment reported that the patient had received paliperidone palmitate 156 mg every month for 2 years with the last injection 16 days before the admission. Her medical medications were, for diabetes, insulin glargine 10 units/day and metformin 2000 mg/day (1000 mg twice a day); for hypertension, lisinopril 5 mg/day; and for allergies, loratadine 10 mg/day.\n\nIn the emergency room, she was paranoid, tried to hit the admitting psychiatrist, and showed bizarre behaviors, disrobing and defecating on the bathroom floor. A 5 mg haloperidol IM injection was given and oral psychiatric medication was started, including oral haloperidol, 10 mg/day (5 mg twice a day), and divalproex sodium, 1000 mg/day (500 mg twice a day). The admitting psychiatrist also wrote an “as-needed” oral order for agitation and/or aggression combining 5 mg haloperidol, 2 mg lorazepam, and 25 mg diphenhydramine. These three combined oral drugs (or a single oral drug) could be administered at the discretion of the nurses but with a frequency of not more than every 6 hours. For her medical problems, a diet for diabetic patients was started and aspirin 81 mg/day was added to her prior medical medications (insulin glargine, 10 units/day; metformin, 2000 mg/day; lisinopril, 5 mg/day; and loratadine, 10 mg/day). An EKG on admission (first day at the emergency room after a haloperidol 5 mg IM injection) revealed QT of 336 ms, QTc of 457 ms, and sinus tachycardia (frequency of 111 beats per minute). The routine blood laboratory analyses on the day of admission showed normal electrolytes but presented several abnormalities including glucose of 472 mg/dL (normal range 65–110), white blood cell count of 11,700 leukocytes/mm3 (normal range 4,100–10,800), neutrophil count of 7,900 neutrophil/mm3 (normal range 1,700–6,000), platelet count of 503,000 platelets/mm3 (normal range 140,000–370,000), and glycosylated hemoglobin at 10.4% (normal range 4.8–5.9). Her valproic acid level was undetectable (<3 μg/mL). Her urine showed high glucose, moderate ketones, a few epithelial cells and traces of bacteria. In summary, the laboratory abnormalities suggested that she had not been compliant with her valproate or her antidiabetic medication. Three days later, some of the abnormal levels were reduced: glucose was 330 mg/dL, white blood cell count of 11,740 leukocytes/mm3, neutrophil count of 4,500 neutrophil/mm3 (a normal value), and platelet count of 497,000 platelets/mm3. A lipid profile showed normal values for triglycerides, 133 mg/dL (range 35–150), for cholesterol, 175 mg/dL (range 105–200), and for high density lipoproteins, 37 mg/dL but an elevated low density lipoprotein of 112 mg/dL (range 0–99).\n\nAt the psychiatric hospital, the patient was very agitated, psychotic, paranoid, and uncooperative. She would try to walk into other patients' rooms, including male rooms, and touch staff and other patients. These behaviors could not be controlled by having one staff member closely watching her, since she did not listen to redirection. In the state psychiatric hospital over the 3-day period, the antipsychotic dosage progressively accumulated in addition to the divalproex sodium, 1000 mg/day. On day 3 before her death, she received 10 mg of scheduled oral haloperidol and an extra IM injection of 10 mg of haloperidol (with 2 mg IM lorazepam). On day 2 before her death, she received 10 mg of scheduled oral haloperidol. In the early morning (5 AM), she received an extra oral combination of 5 mg of haloperidol, 2 mg of lorazepam, and 25 mg of diphenhydramine. At night, she was agitated and trying to get into the rooms of other patients and at 11 PM she again received extra oral doses of 5 mg of haloperidol, 2 mg of lorazepam, and 25 mg of diphenhydramine. Forty-five minutes later, as she still could not sleep, she was given 50 mg of oral hydroxyzine pamoate. Shortly thereafter, on the third day of admission, in the early AM, the psychiatrist on call was contacted because the patient continued exhibiting the same behaviors and could not receive another haloperidol dose until 6 hours had passed; the psychiatrist ordered the combination of 2 IM injections, 20 mg IM of ziprasidone and 25 mg diphenhydramine at 1:19 AM (2 hours and 19 minutes after the last extra dose of oral haloperidol). Finally, at 2:20 AM she was described as resting quietly in her room. At 7:15 AM, when staff asked if the patient wanted breakfast, she opened her eyes and responded with a gesture that she did not want it and went back to sleep. At 9:00 AM her breathing sounded abnormal to a staff member, who called for a nurse; the nurse found the patient unresponsive with no radial pulse and a faint carotid pulse. This was 7 hours and 41 minutes after the 20 mg ziprasidone IM injection and approximately 10 hours after the last extra dose of oral haloperidol. CPR was started but the AED advised no shock. The EMS arrived and found her in asystole, so at 9:40 AM the patient was declared dead.\n\n3.2.3. Autopsy\nThe autopsy revealed no obvious anomalies in the heart or other organs that would explain the patient's sudden death. It is important to stress that in spite of her metabolic syndrome, there were no signs of atherosclerosis in the coronary arteries nor any sign of myocardial ischemia in macroscopic or microscopic examinations. There was no evidence of pulmonary thromboembolism. There were some minor abnormalities including mild atherosclerosis at the thoracoabdominal aorta, liver changes compatible with a fatty liver, and a small thyroid mass that microscopic examination demonstrated to be a follicular neoplasm. Postmortem blood toxicology for diphenhydramine was 172 ng/mL (reference range: 30–300 ng/mL) and for hydroxyzine was 35.4 ng/mL (reference range: 22–80 ng/mL).\n\n3.2.4. ADR Scales\nUsing the Liverpool ADR Causality Assessment Tool [30], antipsychotic-induced sudden death was deemed probable. The last ziprasidone IM injection of 20 mg was considered crucial, because it was given in addition to (1) three extra haloperidol doses (approximately 2 hrs before the ziprasidone injection, 5 mg oral haloperidol; approximately 21 hours earlier, 5 mg oral haloperidol; and 2 days before, one 10 mg IM haloperidol), (2) 10 mg/day of scheduled oral haloperidol for 6 days prior to death, and (3) a long-acting paliperidone injection of 156 mg 18 days prior to death. Similarly, on the Naranjo scale [31], a score of +6 was determined (scoring +1 on items 1, 5, 8, and 10 and +2 on item 2), consistent with a probable ADR. All the authors agreed with the scores on both ADR scales. As the patient had no signs of myocardial ischemia or pulmonary thromboembolism, it appears that the combination of antipsychotics, including the addition of IM ziprasidone on top of IM haloperidol, oral haloperidol, and long-acting paliperidone caused the sudden, unexpected death by TdP. The ziprasidone peak from the IM injection probably combined with the slower peak of the extra oral haloperidol administered 2 hours earlier causing the TdP early the following morning. Oral absorption is much slower than IM absorption and the oral haloperidol absorption may have been further delayed by the combination of an antimuscarinic drug, diphenhydramine.\n\nThe possible contribution of diphenhydramine to this case and to the first case is discussed in detail in the Discussion (see Section 4.5).\n\n4. Discussion\n4.1. Limitations of the Patient Sample\nTo identify these 2 sudden deaths, possibly explained by TdP associated with antipsychotics, we started with 95 deaths reviewed retrospectively using the judgment of a committee composed of psychiatrists, nurses, and pharmacists who have expertise in the subject. During the committee's 13 years of reviewing deaths, judgments regarding the medical cause of death were made after discussion by 2 or 3 psychiatrists who were present at the meetings. The senior author was involved in all reviews of all patients and attended all meetings. We know that the weakest part of our reviews is the limited number of autopsies, 17% (16/95). For years, we have encouraged their use, but we have not been too successful in increasing their numbers, particularly due to cost. We were fortunate to have autopsies of these 2 cases that were highly compatible with TdP. Even with all the limitations of our retrospective reviews, we have accumulated substantial experience with >500 deaths in our state facilities and >350 deaths of psychiatric patients in the community.\n\n4.2. Limitations of the Case Reports\nIt is difficult to make causal connections in case reports. Both deaths were sudden and unexpected, with no signs of cardiac ischemia in the autopsies. They were, however, associated with the accumulation of high serum antipsychotic concentrations after IM injections, compatible with probable ADRs, according to the scales. There are other rare causes of sudden death (e.g., genetic long QT syndrome, Brugada syndrome, or catecholaminergic polymorphic ventricular tachycardia) that cannot be completely ruled out [36], but the proximity of the high doses of IM antipsychotics and the lack of known family histories of sudden deaths in both patients suggested that these two sudden deaths were most likely explained by antipsychotic-induced TdP. Electrolyte abnormalities may contribute to TdP. The first patient refused laboratory testing but was a healthy young male and the second patient did not have any electrolyte abnormality, although magnesium is not routinely measured in our hospitals. In summary, a reasonable interpretation is that these two sudden deaths were unfortunate cases of TdP secondary to the accumulation of high serum peaks of antipsychotics after the last IM injection.\n\nSinus bradycardia is a risk factor for TdP [16]. The first patient had an EKG with sinus bradycardia 2 years before his death. The EKG described a frequency of 58 beats per minute which appears to be mild bradycardia to us. We do not know if he had sinus bradycardia at any time during the admission leading to his death since the patient refused EKG and vital signs except at the time of admission when he was tachycardic. It is possible that a sinus bradycardia may have contributed to the development of TdP in the first case but we have no way to prove or disprove it.\n\n4.3. African-American Race\nKnowing that less than 10% of our patients are African-American, we were surprised that both of these deceased patients were African-American. If we assume a frequency of 10% among our patients at psychiatric hospitals in Kentucky, the chance probability that one deceased patient is African-American is 0.10. The chance probability that both are African-Americans is very low: 0.01 (obtained by multiplying 0.10 by 0.10). This is lower than the typical set value of p < 0.05 and suggests that the association of African-American race with 100% (2/2) of the antipsychotic-induced sudden deaths may not be explained by chance. We also formally tested the hypothesis of the association between African-American race and TdP by using as a control the prevalence of African-Americans in sudden deaths not compatible with TdP. A 2-sided Fisher exact test provided a significant difference (p = 0.016) when comparing 100% (2/2) of African-Americans in sudden deaths compatible with TdP versus 7.5% (2/26) of African-Americans in sudden deaths that were not considered to be explained by TdP and in which the race was known.\n\nIn spite of the very small sample size of 2 deaths, both tests of significance were compatible with the possibility that African-American patients may have more risk of death from antipsychotic-induced TdP in our sample. Let us for the moment assume that, as a matter of fact, African-Americans may have a higher risk of dying in our psychiatric hospitals by antipsychotic-induced TdP. Is there any pharmacological mechanism that may explain this association? Yes, there is one; it is the possibility that African-Americans are prone to a higher prevalence of being poor metabolizers (PMs) of haloperidol. Haloperidol metabolism has never been systematically studied to the extent that new drugs are currently studied before they are introduced in the US market. This is important because some old antiepileptics were found to have completely unexpected pharmacokinetic properties when intensively studied prior to introduction in the US market in the 2000s [37]. Psychiatric textbooks and review articles [38] usually indicate that CYP2D6 PMs have decreased ability to eliminate haloperidol. A study of 31 subjects taking haloperidol as a baseline for a clozapine RCT provided an unexpected result [39]. The persistence of serum haloperidol concentrations after haloperidol discontinuation was used to calculate haloperidol elimination half-life in each patient as an approximated marker of haloperidol metabolism. After eliminating patients who had taken haloperidol decanoate, there were a total of 26 patients, of which 16 patients had a half-life <3 days, suggestive of relatively normal haloperidol metabolism, and 10 patients had a half-life ≥3 days, compatible with being haloperidol PMs. Not surprisingly, the only 2 CYP2D6 PMs were in the group with a half-life ≥3 days, suggesting that, in effect, not having CYP2D6 impairs one's ability to eliminate haloperidol. Unexpectedly, the only significant difference (with a p = 0.014) between the 16 haloperidol normal metabolizers and the 10 haloperidol PMs was that all 4 African-Americans were haloperidol PMs and had half-lives ≥3 days (as a matter of fact, all 4 patients had half-lives >7 days) [39]. As haloperidol is at least partly metabolized by glucuronidation and some of the glucuronidation enzymes have lower activity in African-Americans [40], it is possible to hypothesize that some African-Americans may have lower ability to eliminate haloperidol due to decreased activity in haloperidol glucuronidation. Recently, an in vitro study of haloperidol metabolism using human hepatocytes has suggested that the uridine diphosphate glucuronosyltransferase (UGT) 2B7 (UGT2B7) may be important in the metabolism of haloperidol [41]. Although there is substantial variation of UGT2B7 alleles worldwide [42], the clinical relevance of these genetic variations for people with African ancestry is not known [43]. In summary, there is very limited information on haloperidol metabolism, but it is possible that some African-Americans may have impaired ability to eliminate haloperidol. If our two patients had impaired ability to eliminate haloperidol, that impairment may have contributed to higher serum haloperidol concentrations, leading to greater risk for TdP. As the haloperidol serum concentration level increases, the blockade of cardiac potassium channels would likewise increase.\n\n4.4. Accumulation of One or Several Antipsychotic Formulations\nWe think that, in these two patients, the last antipsychotic IM injection served as “the straw that broke the camel's back” by providing an even higher peak in serum antipsychotic concentration which contributed to further blockade of cardiac potassium channels encoded by HERG reaching a very high level, leading to TdP. In the first patient, this was achieved after 4 haloperidol IM injections with an accumulated dosage of 25 mg in 2 days before the fourth and last injection of 10 mg, making a total of 35 mg. In the second patient, it was achieved after the last ziprasidone IM injection of 20 mg in addition to (1) three extra haloperidol doses (approximately 2 hours before the ziprasidone injection, 5 mg oral haloperidol; approximately 21 hours earlier, 5 mg oral haloperidol; and 2 days before, one 10 mg IM haloperidol), (2) 10 mg/day of scheduled oral haloperidol for 6 days prior to death, and (3) a long-acting paliperidone injection of 156 mg 18 days prior to death. The second patient received 5 mg oral haloperidol at 11 PM; therefore, the nurse could not administer another as-needed haloperidol dose until 5 AM the next morning and called the psychiatrist on call. In retrospect, we think that the on-call psychiatrist who responded to the nurse and prescribed 20 mg IM of ziprasidone at 1:19 AM on top of the prior extra dose of oral haloperidol made a huge mistake. Both ziprasidone and haloperidol appear to be potent blockers of cardiac potassium channels in clinical doses [11]. Therefore, in this second case, the effects of ziprasidone blocking the cardiac potassium channels encoded by HERG were added to the blocking effects of the prior haloperidol dose. In retrospect, it would have been better to control the agitation of this patient only with lorazepam, which has no relevant effects on the QTc interval [29].\n\n4.5. Comedications in Addition to Antipsychotics\nThe only comedication received by the first patient was IM diphenhydramine. The second patient received, besides IM diphenhydramine, several medications (valproate, insulin, metformin, lisinopril, lorazepam, and hydroxyzine), which have not been associated with TdP or relevant QTc prolongation.\n\nDiphenhydramine has been associated with (1) TdP, occasionally during voluntary overdoses [44–46]; (2) a strong signal for TdP in the databases from drug regulatory agencies [47]; (3) QTc prolongations during voluntary overdoses [48–52], and (4) QTc prolongations in EKGs completed at the emergency room when prescribed by itself or with other drugs that prolong the QTc interval [53]. However, some of these diphenhydramine overdose studies with EKG data, including 126 cases of overdoses with no TdP case [48] and 1 case monitored for several days [50], suggested that diphenhydramine causes tachycardia and this has a major effect on protecting from TdP in situations of QTc prolongation.\n\nThe accumulated diphenhydramine dosage was 200 mg IM during the last 3 days of Case 1 and 75 mg during the last 2 days of Case 2 (25 mg IM 2 days prior to death and 50 mg oral on the day before death). We doubt that these doses of diphenhydramine had any relevance in the sudden deaths of these two patients because (1) TdP induced by diphenhydramine overdoses appears to require huge quantities measured in grams [44, 45], (2) diphenhydramine-induced tachycardia may protect from TdP in situations of QTc prolongation [48, 50], and (3) some animal models of clinical relevance in humans for drugs that prolong QTc cannot detect any effect for diphenhydramine doses trying to replicate clinical dosing [54].\n\n4.6. Reflections on the History of Antipsychotic-Induced TdP\nThe next section discusses a practice guideline limiting high doses of haloperidol and/or ziprasidone IM injections in the hope of preventing the repetition of similar TdP cases in our Kentucky facilities. Ideally, practice guidelines should be based on principles following the hierarchical thinking proposed by evidence-based medicine, which gives higher value to RCTs. In the real world, those researchers insisting on the evidence-based medicine (EBM) approach are not aware that evidence related to ADRs is seriously distorted by the effects of pharmaceutical companies to cover the ADRs resulting from their drugs and their lack of attention to ADRs during studies undertaken for market approval [55]. Moreover, RCTs focus on mean effects, but when a very rare ADR, such as TdP, is studied, mean values are irrelevant and outliers are important [56]. Therefore, some authors can dismiss the risk of haloperidol-induced TdP because it is mainly based on case reports and not RCT data [57]. How unwise is it to ask clinicians to wait for RCT data on haloperidol-induced TdP? It is very unwise; a randomized study of >18,000 patients followed for 1 year had no statistical power to detect ziprasidone-induced TdP [18]. Haloperidol is off-patent; therefore, nobody is going to finance a large RCT of 10,000s of patients for several years to detect statistical differences between haloperidol and other drugs in causing TdP. Imagine that the thioridazine marketer had paid attention to Ban [1] in the late 1960s, performed more studies, and withdrawn thioridazine from the market instead of waiting until 2006. The outcome of that decision, based on “limited” case reports would probably have led to saving hundreds or thousands of lives worldwide during the last 30 years. Psychiatrists would have prescribed other antipsychotics with less risk for TdP rather instead of prescribing thioridazine, which may be the oral antipsychotic that most frequently causes sudden death [58]. Similarly, it would be a mistake to ignore the risk of TdP associated with high doses of haloperidol IM, suggested by our 2 case reports.\n\n4.7. Practice Guidelines\nBoth deaths were considered possibly preventable if the prescribing psychiatrist had better understood the risk of a standing as-needed order for agitation using IM antipsychotics with potential to cause TdP. This type of order is written for all our patients but is rarely used by nurses. If they are used in a patient, IM antipsychotic injections are rarely repeated within a few hours. In the first case, the psychiatrist allowed a high dosage of 10 mg haloperidol IM every 12 hours, which is rarely prescribed in our hospitals (most psychiatrists prescribe 5 mg every 6 hours at most). The psychiatrist thought it was safe because the same order had been written for the same patient at the same hospital 3 years before, but 3 years before it was scarcely used. In the second case, the as-needed order of 5 mg every 6 hours was written as administered by the oral route, but when it was not enough to control the agitation of the patient, the nurses called the on-call psychiatrist who circumvented the limit of a haloperidol dose every 6 hours by adding 20 mg IM ziprasidone in close proximity to the last oral dose of haloperidol.\n\nThe medical literature has addressed the risk of TdP during IV haloperidol treatment, but the psychiatric literature including practice guidelines [59] has paid little attention to the risk of TdP after IM haloperidol and/or IM ziprasidone. Therefore, a practice guideline was developed for IM antipsychotics to limit dosing for haloperidol and/or ziprasidone IM in order to prevent future TdP cases and sudden deaths in our public psychiatric hospitals in Kentucky.\n\nThe practice guideline that is shown in the Appendix was based on (1) a comprehensive review of the literature on the use of IM antipsychotics to treat agitation, including review articles [60–74] and prior practice guidelines [59, 75–79]; (2) learning from the mistakes in these two cases; and (3) a review of the pharmacokinetic and pharmacodynamic mechanisms behind the DDIs contributing to antipsychotic-induced TdP [14, 80, 81].\n\n5. Conclusion\nThe medical literature has addressed the risk of TdP during IV haloperidol treatment but the psychiatric literature has paid little attention to TdP risk after IM haloperidol and/or IM ziprasidone [59]. In this paper, we presented two cases of sudden death after IM injections of antipsychotics, which were considered to be probable ADRs. The autopsies described lack of heart pathology and were highly compatible with the possibility of TdP in the absence of risk factors other than the accumulation of antipsychotics with an even higher serum peak after a last injection led to death within a few hours. It is possible that these cases were explained by a combination of high serum concentrations of antipsychotics with particular individual vulnerability. Some studies suggest that rare genetic variations at potassium channels may contribute to predisposition to drug-induced TdP [82].\n\nThe first case describes a 27-year-old African-American male with schizophrenia but no medical issues. His death occurred in the early morning of the third day and was probably caused by repeated IM haloperidol injections of 10 mg (totaling 35 mg in 2 days). The second case involves a 42-year-old African-American female with a metabolic syndrome. Her death was probably caused by a last ziprasidone IM injection of 20 mg in addition to (1) three extra haloperidol doses (approximately 2 hours before the ziprasidone injection, 5 mg oral haloperidol; approximately 21 hours earlier, 5 mg oral haloperidol; and 2 days prior, one 10 mg IM haloperidol), (2) 10 mg/day of scheduled oral haloperidol for 6 days prior to death, and (3) a long-acting paliperidone injection of 156 mg 18 days prior to death. The association of TdP deaths with African-American race in spite of the small sample size appears to suggest a significant overrepresentation when compared with our patients at Kentucky public psychiatric hospitals. As a matter of fact, patients with poor capacity to metabolize haloperidol might be overrepresented among African-Americans. The study of haloperidol metabolism through glucuronidation in African-Americans is urgently recommended since the percentage of impaired individuals may be overrepresented in African-American individuals. If it is demonstrated that African-Americans have lower ability to metabolize haloperidol, this would indicate the need to consider race and possibly genetics, in the dosing of IM antipsychotics for agitation and for the need to include these differences in the practice guidelines for agitation.\n\nAcknowledgments\nThis paper was completed without any external funding. Lorraine Maw, M.A., at the UK Mental Health Research Center, helped with editing.\n\nAppendix\nProposed practice guidelines for dosing parenteral antipsychotics in order to avoid TdP during the control of agitation at psychiatric hospitals are as follows.\n\n\nIV Haloperidol. The use of IV haloperidol is not recommended and it cannot be used unless continuous EKG monitoring is available.\n\n\nIM Chlorpromazine. The use of IM chlorpromazine is not recommended because of the lack of studies and very limited number of RCTs [60] and the potential for oral chlorpromazine to cause TdP and orthostatic hypotension [61]. IM chlorpromazine cannot be used unless there is (1) an absence of any of the risk factors for TdP (see below) and (2) a baseline EKG that shows QTc < 450 ms on the same medication that the patient is currently taking.\n\n\nCombining IM Haloperidol and IM Ziprasidone. Orders for IM haloperidol and IM ziprasidone cannot be combined in the same patient. If a patient has received IM haloperidol, no IM ziprasidone can be administered for 24 hours and if a patient has received IM ziprasidone, no IM haloperidol can be administered for 24 hours.\n\n\nIM Haloperidol\n (1) IM Haloperidol cannot be used in any patient with risk factors for TdP (see below).\n\n (2) Standard agitation as-needed orders for IM haloperidol doses ≥10 mg cannot be written unless there is a baseline EKG that shows QTc < 450 ms on the same medication that the patient is currently taking. See below for an exception for patients on potent inducers.\n\n (3) Standard agitation as-needed orders for IM haloperidol doses of 5 mg should not recommend administration with a frequency <12 hours unless there is a baseline EKG that shows QTc < 450 ms on the same medication that the patient is currently taking. The combination of IM haloperidol with IM benzodiazepines and/or IM antihistaminic/anticholinergics has not been systematically studied but is frequently used by our clinicians. To decrease the total number of haloperidol doses and reduce the potential for sedation, clinicians are encouraged to combine haloperidol IM injections of 5 mg with simultaneous administration of a benzodiazepine IM injection (such as IM lorazepam) and/or IM anticholinergic/antihistamine injection (such as IM diphenhydramine). As these latter medications do not appear to be associated with risk for QTc prolongation, they can be administered at frequencies of less than 12 hours.\n\n (4) If there is no baseline EKG while on current medications, it is OK to write standard orders for agitation for haloperidol 5 mg every 12 hours while using other IM drugs with less potential for QTc prolongation more frequently (e.g., for 1 mg of lorazepam every 6 hours and/or for 25 mg of diphenhydramine every 6 hours).\n\n (5) Fluoxetine is at least a mild inhibitor of haloperidol metabolism [81]. In patients taking fluoxetine or who have taken it in the last month (norfluoxetine stays in the body for weeks after discontinuation), clinicians need to be aware that the doses of haloperidol IM that they write may produce higher effects. The limited available published information [81] suggests that adding fluoxetine is equivalent to increasing serum haloperidol concentrations by 33% after 12 weeks on fluoxetine. This is equivalent to multiplying the effects of the haloperidol IM dose by a factor of 1.33 and to compensate, this will require multiplying IM haloperidol doses by 0.75 (calculated by dividing 1/1.33 = 0.75). There are no haloperidol studies of the effects of fluoxetine over several months and at steady state for inhibition of haloperidol metabolism; therefore, it is possible that patients taking fluoxetine may require even lower IM haloperidol doses. It may be safer to avoid IM haloperidol in patients taking fluoxetine since fluoxetine also prolongs QTc.\n\n\n\n\n\nIM Ziprasidone\nIM ziprasidone cannot be used in any patient with risk factors for TdP (see below).\n\nThe prescribing information recommends maximum total daily doses of ≤40 mg/day and intervals for doses of ≥2 hours for 10 mg and ≥4 hours for 20 mg injections.\n\nStandard agitation as-needed orders for IM ziprasidone of 20 mg should not recommend administration with a frequency of <12 hours unless there is a baseline EKG that shows QTc < 450 ms on the same medication that the patient is currently taking.\n\n\n\n\n\nIM Olanzapine\nIM olanzapine appears to have less risk for QTc prolongation than IM haloperidol and/or IM ziprasidone. If there is a need for IM antipsychotics in a patient with risk factors for TdP, olanzapine IM is a better choice than haloperidol or ziprasidone IM [65].\n\nThe olanzapine prescribing information recommends maximum total daily doses of ≤30 mg/day and an interval for 10 mg doses of ≥2 hours after the initial injection and ≥4 hours after the second IM injection.\n\nAlthough oral olanzapine is not usually linked to orthostatic hypotension, IM olanzapine has been associated with syncope. The prescribing information recommends doses ≤5 mg in geriatric patients (≥65 years) and doses of 2.5 mg in patients with risk for orthostatic hypotension.\n\nIM olanzapine is a fairly sedating drug and there is no need to combine it with benzodiazepines. As a matter of fact, it should not be combined with IM benzodiazepines since this combination has occasionally been associated with hypotension [71] and even rarely with death [67]. The decision to add an IM olanzapine injection within 24 hours of a benzodiazepine IM injection would require chart documentation for the reason and a written order to closely monitor the patient for orthostatic hypotension and/or respiratory depression to avoid any risk, since we have very limited data about the safety of this combination, which is discouraged by olanzapine's marketer [63]. Obviously, if the patient is lying in bed, there is no need to monitor for orthostatic changes unless the patient needs to get up.\n\nIf the patient is taking fluvoxamine, IM olanzapine should be used in lower doses due to the inhibition of olanzapine metabolism. The clinician should consider using half the dosage he/she typically uses [14]. \n\n\n\n\n\nIM Aripiprazole\nIM aripiprazole appears to have less risk for QTc prolongation than IM haloperidol and/or IM ziprasidone.\n\nThe aripiprazole prescribing information recommends (a) maximum total daily doses of ≤30 mg/day, (b) a dose of 9.75 mg (range 5.25–15 mg), and (c) and an interval between injections ≥2 hours.\n\nIf the patient is taking powerful CY3PA4 inhibitors or CYP2D6 inhibitors (including paroxetine and fluoxetine), halving the doses is recommended. Duloxetine and bupropion are moderate CYP2D6 inhibitors; therefore, using half the dosage used for typical patients appears to be a good idea [14].\n\nThere is limited information comparing IM aripiprazole with other IM second-generation antipsychotics, but the available information suggests that IM aripiprazole may be less effective for controlling agitation than IM olanzapine or IM ziprasidone [61, 62]. \n\n\n\n\n\nPatients with Risk for TdP. Having any of the following is considered a risk factor for TdP: (1) history of sudden death in the family, (2) personal history of syncope, (3) active or residual serious heart disease, (4) geriatric age (≥65 years), (5) bradycardia (<60 beats per minute), (6) hypokalemia, (7) hypomagnesemia, or (7) the use of nonpsychiatric drugs with risk for QTc prolongation including antiarrhythmics (amiodarone dofetilide, quinidine, procainamide, and sotalol), some antibiotics (e.g., gatifloxacin and moxifloxacin), or others (e.g., arsenic trioxide, mefloquine, methadone, pentamidine, and tacrolimus).\n\nSome of these factors can be easily reversed; therefore, correcting electrolyte abnormalities or discontinuing drugs associated with QTc prolongation should be considered before adding orders for IM antipsychotics. IM benzodiazepines do not appear to prolong QTc interval; therefore, it appears safe to use them in patients with risk for TdP [67]. \n\n\nPatients on Scheduled Antipsychotics or Antidepressants with Risk for TdP. Some oral antipsychotics (including amisulpride, haloperidol, iloperidone, phenothiazines, pimozide, or ziprasidone), haloperidol decanoate, fluphenazine decanoate, and antidepressants (including SSRIs and TCAs) have been definitively associated with clinically relevant potential to prolong QTc; therefore, it is better to avoid adding IM haloperidol and IM ziprasidone for agitation in a patient taking any of these drugs. IM benzodiazepines or IM olanzapine should be considered for as-needed orders for agitation in these patients. If the clinician considers the riskier path of adding IM haloperidol or IM ziprasidone to these psychiatric medications, he/she needs to consider using lower doses and provide written justification.\n\n\nPatients on Inducers. If the patient is on a potent inducer (e.g., rifampin or some antiepileptic drugs: carbamazepine, phenytoin, or phenobarbital), he/she may metabolize some antipsychotics such as aripiprazole, haloperidol, or olanzapine very fast [80] and may need higher doses of these IM antipsychotics beyond what is typically recommended. If the clinician needs to write higher doses of any of these IM antipsychotics, he/she should consult the pharmacy first before writing an order for unusually high doses of any IM antipsychotics. Potent inducers appear to have small effects on ziprasidone metabolism [80]; therefore, although this has not been studied well, patients taking potent inducers may respond to normal doses of IM ziprasidone. Normal doses of ziprasidone IM may be a rational choice for patients taking potent inducers.\n\n\nPatients with Alcohol Intake/Intoxication. IM antipsychotics should be judiciously used to manage agitation in patients with recent alcohol intake or alcohol intoxication. IM olanzapine [71, 72] and IM ziprasidone with or without benzodiazepines [70] have been associated with decreases in oxygen saturation.\n\n\nIndividualized Treatment. This set of guidelines for IM antipsychotics was developed to discourage the use of high doses of IM haloperidol, IM ziprasidone, or the combination of IM haloperidol with IM ziprasidone for standard agitation orders for all patients. It does not appear safe to continue to use nurses' judgment to decide the safe frequency of this type of order when this appears to have led to two sudden deaths in our psychiatric hospitals. In emergency situations, a clinician can overrule the dosing limits in this guideline by using a one-time order prescribing high doses as long as he/she understands the risk and has appropriate safeguards in place (see the IM olanzapine and IM benzodiazepine combinations) and documents them in the chart. Once the emergency situation is resolved, the clinician should be ready to have his/her actions reviewed by the hospital pharmacy that may encourage or discourage similar actions in the future based on the peculiarities of the individual case.\n\nAbbreviations\nEKG:Electrocardiogram\n\nIM:Intramuscular\n\nIV:Intravenous\n\nms:Milliseconds\n\nSSRI:Selective serotonin reuptake inhibitor\n\nTCA:Tricyclic antidepressant\n\nTdP:Torsades de pointes.\n\nDisclosure\nNo commercial organizations had any role in the completion or publication of this paper.\n\nCompeting Interests\nDrs. Wahid, Johnson, Brenzel, and de Leon declare no competing interests during the last 36 months.\n==== Refs\n1 Shorter E. The QT interval and the Mellaril story: a cautionary tale INHN web page, http://inhn.org/controversies/edward-shorter-the-q-t-interval-and-the-mellaril-story-a-cautionary-tale.html \n2 Kelly H. G. Fay J. E. Laverty S. G. 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Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) The American Journal of Psychiatry 2011 168 2 193 201 10.1176/appi.ajp.2010.08040484 2-s2.0-79952718641 21041245 \n19 Camm A. J. Karayal O. N. Meltzer H. Ziprasidone and the corrected QT interval: a comprehensive summary of clinical data CNS Drugs 2012 26 4 351 365 10.2165/11599010-000000000-00000 2-s2.0-84859037120 22452529 \n20 Poluzzi E. Raschi E. Koci A. Antipsychotics and torsadogenic risk: signals emerging from the US FDA adverse event reporting system database Drug Safety 2013 36 6 467 479 10.1007/s40264-013-0032-z 2-s2.0-84878698751 23553446 \n21 Kongsamut S. Kang J. Chen X.-L. Roehr J. Rampe D. 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Torsades de pointes associated with intravenous haloperidol in critically ill patients The American Journal of Cardiology 1998 81 2 238 240 10.1016/s0002-9149(97)00888-6 2-s2.0-0032518968 9591913 \n25 Hatta K. Takahashi T. Nakamura H. The association between intravenous haloperidol and prolonged QT interval Journal of Clinical Psychopharmacology 2001 21 3 257 261 10.1097/00004714-200106000-00002 2-s2.0-0035012236 11386487 \n26 Hassaballa H. A. Balk R. A. Torsade de pointes associated with the administration of intravenous haloperidol American Journal of Therapeutics 2003 10 1 58 60 10.1097/00045391-200301000-00013 2-s2.0-0037256150 12522522 \n27 Meyer-Massetti C. Cheng C. M. Sharpe B. A. Meier C. R. Guglielmo B. J. The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions respond? Journal of Hospital Medicine 2010 5 4 E8 E16 10.1002/jhm.691 2-s2.0-77950934586 20394022 \n28 Jackson T. Ditmanson L. Phibbs B. Torsade de pointes and low-dose oral haloperidol Archives of Internal Medicine 1997 157 17 2013 2015 10.1001/archinte.1997.00440380123013 2-s2.0-0030883377 9308514 \n29 Harvey A. T. Flockhart D. Gorski J. C. Intramuscular haloperidol or lorazepam and QT intervals in schizophrenia Journal of Clinical Pharmacology 2004 44 10 1173 1184 10.1177/0091270004267807 2-s2.0-4444352800 15342619 \n30 Gallagher R. M. Kirkham J. J. Mason J. R. Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool PLoS ONE 2011 6 12 e28096 10.1371/journal.pone.0028096 2-s2.0-83355170778 \n31 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology and Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 2-s2.0-0019799332 7249508 \n32 de Leon J. Mallory P. Maw L. Susce M. T. Perez-Rodriguez M. M. Baca-Garcia E. Lack of replication of the association of low serum cholesterol and attempted suicide in another country raises more questions Annals of Clinical Psychiatry 2011 23 3 163 170 2-s2.0-84855589229 21808747 \n33 de Leon J. Susce M. T. Johnson M. DNA microarray technology in the clinical environment: the Amplichip CYP450 test for CYP2D6 and CYP2C19 genotyping CNS Spectrums 2009 14 1 19 34 2-s2.0-62449286261 19169185 \n34 Tzivoni D. Banai S. Schuger C. Treatment of torsade de pointes with magnesium sulfate Circulation 1988 77 2 392 397 10.1161/01.CIR.77.2.392 2-s2.0-0023870752 3338130 \n35 Cleland J. G. F. Krikler D. M. Torsade de pointes: chaos, sixteen years on? British Heart Journal 1992 67 1 1 3 10.1136/hrt.67.1.1 2-s2.0-0026541173 1739518 \n36 Vyas V. Lambiase P. D. The investigation of sudden arrhythmic death syndrome (SADS)-the current approach to family screening and the future role of genomics and stem cell technology Frontiers in Physiology 2013 4, article 199 10.3389/fphys.2013.00199 2-s2.0-84884554847 \n37 de Leon J. False-negative studies may systematically contaminate the literature on the effects of inducers in neuropsychopharmacology—part I: focus on epilepsy Journal of Clinical Psychopharmacology 2014 34 2 177 183 10.1097/jcp.0000000000000093 2-s2.0-84896398660 24525637 \n38 Spina E. de Leon J. Clinical applications of CYP genotyping in psychiatry Journal of Neural Transmission 2015 122 1 5 28 10.1007/s00702-014-1300-5 2-s2.0-84929032233 25200585 \n39 de Leon J. Diaz F. J. Wedlund P. Josiassen R. C. Cooper T. B. Simpson G. M. Haloperidol half-life after chronic dosing Journal of Clinical Psychopharmacology 2004 24 6 656 660 10.1097/01.jcp.0000145340.53417.ca 2-s2.0-8744274006 15538130 \n40 de Leon J. Glucuronidation enzymes, genes and psychiatry International Journal of Neuropsychopharmacology 2003 6 1 57 72 10.1017/s1461145703003249 2-s2.0-0037345011 12899737 \n41 Kato Y. Nakajima M. Oda S. Fukami T. Yokoi T. Human UDP-glucuronosyltransferase isoforms involved in haloperidol glucuronidation and quantitative estimation of their contribution Drug Metabolism and Disposition 2012 40 2 240 248 10.1124/dmd.111.042150 2-s2.0-84863401482 22028316 \n42 Čolić A. Alessandrini M. Pepper M. S. Pharmacogenetics of CYP2B6, CYP2A6 and UGT2B7 in HIV treatment in African populations: focus on efavirenz and nevirapine Drug Metabolism Reviews 2015 47 2 111 123 10.3109/03602532.2014.982864 2-s2.0-84932117610 25391641 \n43 Li J. Menard V. Benish R. L. Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7 : implications for HIV/AIDS treatment Pharmacogenomics 2012 13 5 555 570 10.2217/pgs.11.160 2-s2.0-84859236749 22462748 \n44 Joshi A. K. Sljapic T. Borghei H. Kowey P. R. Case of polymorphic ventricular tachycardia in diphenhydramine poisoning Journal of Cardiovascular Electrophysiology 2004 15 5 591 593 10.1046/j.1540-8167.2004.03173.x 2-s2.0-2442575876 15149431 \n45 Husain Z. Hussain K. Nair R. Steinman R. Diphenhydramine induced QT prolongation and torsade de pointes: an uncommon effect of a common drug Cardiology Journal 2010 17 5 509 511 2-s2.0-77957957228 20865683 \n46 Al-Abri S. A. Woodburn C. Olson K. R. Kearney T. E. Ventricular dysrhythmias associated with poisoning and drug overdose: a 10-year review of statewide poison control center data from California American Journal of Cardiovascular Drugs 2015 15 1 43 50 10.1007/s40256-014-0104-1 2-s2.0-84925508776 25567789 \n47 Poluzzi E. Raschi E. Godman B. Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe PLoS ONE 2015 10 3 e0119551 10.1371/journal.pone.0119551 2-s2.0-84925438683 \n48 Zareba W. Moss A. J. Rosero S. Z. Hajj-Ali R. Konecki J. Andrews M. Electrocardiographic findings in patients with diphenhydramine overdose The American Journal of Cardiology 1997 80 9 1168 1173 10.1016/s0002-9149(97)00634-6 2-s2.0-0030671010 9359544 \n49 Thakur A. C. Aslam A. K. Aslam A. F. Vasavada B. C. Sacchi T. J. Khan I. A. QT interval prolongation in diphenhydramine toxicity International Journal of Cardiology 2005 98 2 341 343 10.1016/j.ijcard.2003.10.051 2-s2.0-15944401346 15686790 \n50 Sype J. W. Khan I. A. Prolonged QT interval with markedly abnormal ventricular repolarization in diphenhydramine overdose International Journal of Cardiology 2005 99 2 333 335 10.1016/j.ijcard.2003.11.035 2-s2.0-14644415585 15749198 \n51 Ramachandran K. Sirop P. Rare complications of diphenhydramine toxicity Connecticut Medicine 2008 72 2 79 82 2-s2.0-39749127069 18306834 \n52 Chen T.-Y. Yeh Y.-W. Kuo S.-C. Chen C.-Y. Lin T.-P. Chang C.-C. Diphenhydramine dependence through deep intramuscular injection resulting in myonecrosis and prolonged QT interval Journal of Clinical Pharmacy and Therapeutics 2014 39 3 325 327 10.1111/jcpt.12142 2-s2.0-84899456021 24597640 \n53 Tay K.-Y. Ewald M. B. Bourgeois F. T. Use of QT-prolonging medications in US emergency departments, 1995–2009 Pharmacoepidemiology and Drug Safety 2014 23 1 9 17 10.1002/pds.3455 2-s2.0-84891635544 23696066 \n54 Toyoshima S. Kanno A. Kitayama T. QT PRODACT: in vivo QT assay in the conscious dog for assessing the potential for QT interval prolongation by human pharmaceuticals Journal of Pharmacological Sciences 2005 99 5 459 471 10.1254/jphs.qt-a2 2-s2.0-33645062178 16493187 \n55 Ioannidis J. P. A. Adverse events in randomized trials: neglected, restricted, distorted, and silenced Archives of Internal Medicine 2009 169 19 1737 1739 10.1001/archinternmed.2009.313 2-s2.0-70350517166 19858427 \n56 de Leon J. Evidence-based medicine versus personalized medicine: are they enemies? Journal of Clinical Psychopharmacology 2012 32 2 153 164 10.1097/jcp.0b013e3182491383 2-s2.0-84857852960 22367661 \n57 Howland R. H. QTc prolongation and haloperidol: just how risky is this drug? Psychosomatics 2014 55 6 741 742 10.1016/j.psym.2014.07.004 2-s2.0-84926361261 25497511 \n58 Salvo F. Pariente A. Shakir S. Sudden cardiac and sudden unexpected death related to antipsychotics: a meta-analysis of observational studies Clinical Pharmacology and Therapeutics 2016 99 3 306 314 10.1002/cpt.250 2-s2.0-84958969139 26272741 \n59 Pacciardi B. Mauri M. Cargioli C. Issues in the management of acute agitation: how much current guidelines consider safety? Frontiers in Psychiatry 2013 4, article 26 10.3389/fpsyt.2013.00026 2-s2.0-84877709780 \n60 Ahmed U. Jones H. Adams C. E. Chlorpromazine for psychosis induced aggression or agitation Cochrane Database Systematic Reviews 2010 4 CD007445 2-s2.0-77952523421 \n61 Battaglia J. Pharmacological management of acute agitation Drugs 2005 65 9 1207 1222 10.2165/00003495-200565090-00003 2-s2.0-22744449459 15916448 \n62 Bosanac P. Hollander Y. Castle D. The comparative efficacy of intramuscular antipsychotics for the management of acute agitation Australasian Psychiatry 2013 21 6 554 562 10.1177/1039856213499620 2-s2.0-84889076755 23996795 \n63 Caine E. D. Clinical perspectives on atypical antipsychotics for treatment of agitation Journal of Clinical Psychiatry 2006 67 10 22 31 2-s2.0-33748926403 16965192 \n64 Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety Journal of Clinical Psychiatry 2007 68 12 1876 1885 10.4088/jcp.v68n1207 2-s2.0-38049002952 18162018 \n65 Kishi T. Matsunaga S. Iwata N. Intramuscular olanzapine for agitated patients: a systematic review and meta-analysis of randomized controlled trials Journal of Psychiatric Research 2015 68 198 209 10.1016/j.jpsychires.2015.07.005 2-s2.0-84937905553 26228420 \n66 Powney M. J. Adams C. E. Jones H. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation) Cochrane Database of Systematic Reviews 2012 11 CD009377 2-s2.0-84872195737 \n67 Ries R. Sayadipour A. Management of psychosis and agitation in medical-surgical patients who have or are at risk for prolonged QT interval Journal of Psychiatric Practice 2014 20 5 338 344 10.1097/01.pra.0000454778.29433.7c 2-s2.0-84913590551 25226194 \n68 San L. Arranz B. Escobar R. Pharmacological management of acutely agitated schizophrenic patients Current Pharmaceutical Design 2005 11 19 2471 2477 10.2174/1381612054367472 2-s2.0-21044449292 16026300 \n69 Tulloch K. J. Zed P. J. Intramuscular olanzapine in the management of acute agitation Annals of Pharmacotherapy 2004 38 12 2128 2135 10.1345/aph.1e258 2-s2.0-12844265985 15522977 \n70 Wilson M. P. Macdonald K. Vilke G. M. Ronquillo L. Feifel D. Intramuscular ziprasidone: influence of alcohol and benzodiazepines on vital signs in the emergency setting Journal of Emergency Medicine 2013 45 6 901 908 10.1016/j.jemermed.2013.07.020 2-s2.0-84888645673 24071032 \n71 Wilson M. P. Chen N. Vilke G. M. Castillo E. M. MacDonald K. S. Minassian A. Olanzapine in ED patients: differential effects on oxygenation in patients with alcohol intoxication American Journal of Emergency Medicine 2012 30 7 1196 1201 10.1016/j.ajem.2012.03.013 2-s2.0-84865446793 22633728 \n72 Wilson M. P. MacDonald K. Vilke G. M. Feifel D. Potential complications of combining intramuscular olanzapine with benzodiazepines in emergency department patients Journal of Emergency Medicine 2012 43 5 889 896 10.1016/j.jemermed.2010.04.012 2-s2.0-84869087917 20542400 \n73 Zacher J. L. Roche-Desilets J. Hypotension secondary to the combination of intramuscular olanzapine and intramuscular lorazepam Journal of Clinical Psychiatry 2005 66 12 1614 1615 10.4088/jcp.v66n1219c 2-s2.0-30344436396 16401168 \n74 Zimbroff D. L. Pharmacological control of acute agitation: focus on intramuscular preparations CNS Drugs 2008 22 3 199 212 10.2165/00023210-200822030-00002 2-s2.0-39349093168 18278976 \n75 Allen M. H. Currier G. W. Carpenter D. Ross R. W. Docherty J. P. Expert Consensus Panel for Behavioral Emergencies 2005 The expert consensus guideline series. Treatment of behavioral emergencies 2005 Journal of Psychiatric Practice 2005 11 supplement 1 5 112 16319571 \n76 Marder S. R. A review of agitation in mental illness: treatment guidelines and current therapies Journal of Clinical Psychiatry 2006 67 10 13 21 10.4088/jcp.1006e13 2-s2.0-33748945158 16965191 \n77 Canadian Agency for Drugs and Technologies in Health Use of Antipsychotics and/or Benzodiazepines as Rapid Tranquilization in In-Patients of Mental Facilities and Emergency Departments: A Review of the Clinical Effectiveness and Guidelines 2015 Ottawa, Canada Canadian Agency for Drugs and Technologies in Health \n78 The British Psychological Society and The Royal College of Psychiatrists Violence and Aggression: Short-Term Management in Mental Health, Health and Community Settings 2015 NICE Guideline NG10 http://nice.org.uk/guidance/ng10 \n79 Tylor D. Paton C. Kapur S. The Maudsley Prescribing Guidelines in Psychiatry 2012 11th Chichester, UK Wiley-Blackwell \n80 de Leon J. Santoro V. D'Arrigo C. Spina E. Interactions between antiepileptics and second-generation antipsychotics Expert Opinion on Drug Metabolism and Toxicology 2012 8 3 311 334 10.1517/17425255.2012.660918 2-s2.0-84857265929 22332980 \n81 Avenoso A. Spina E. Campo G. Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications Pharmacological Research 1997 35 4 335 339 2-s2.0-0030873010 9264051 \n82 Weeke P. Mosley J. D. Hanna D. Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome Journal of the American College of Cardiology 2014 63 14 1430 1437 10.1016/j.jacc.2014.01.031 2-s2.0-84897985012 24561134\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6838",
"issue": "2016()",
"journal": "Case reports in psychiatry",
"keywords": null,
"medline_ta": "Case Rep Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101583308",
"other_id": null,
"pages": "9406813",
"pmc": null,
"pmid": "27597919",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "23675355;11691681;9694935;16026300;1739518;3338130;22367661;23152276;21808747;24062688;8690824;24071032;12522522;15342619;20393959;25391641;9359544;23696066;20921449;21041245;24525637;16493187;22633728;15522977;18162018;20394022;22452529;25200585;15686790;14709949;22114630;26272741;9308514;16401168;23553446;19892525;12899737;14166461;18278976;18306834;16965192;16965191;22028316;16319571;12176106;11386487;9264051;7249508;25226194;24494611;24561134;14045347;24597640;19858427;20865683;21079043;25785934;26228420;15538130;18690965;20856845;15749198;8463445;19169185;14176059;22462748;25497511;25530900;347110;22194808;22332980;20542400;9864072;25567789;9591913;15149431;15916448;23996795",
"title": "Two Sudden and Unexpected Deaths of Patients with Schizophrenia Associated with Intramuscular Injections of Antipsychotics and Practice Guidelines to Limit the Use of High Doses of Intramuscular Antipsychotics.",
"title_normalized": "two sudden and unexpected deaths of patients with schizophrenia associated with intramuscular injections of antipsychotics and practice guidelines to limit the use of high doses of intramuscular antipsychotics"
} | [
{
"companynumb": "US-JNJFOC-20160910461",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to analyze and compare the clinicopathologic characteristics, treatment, and survival in patients with uterine leiomyosarcoma (ULMS) during the last 10 years in 3 referral academic centers.\n\n\nMETHODS\nAll patients with ULMS who underwent treatment at the participating institutions between January 1, 2000, and December 31, 2010, were identified from the tumor registry database. In each case, the diagnosis was confirmed by a dedicated gynecologic pathologist following postsurgery pathology review. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox regression analysis.\n\n\nRESULTS\nAnalysis of 167 women with ULMS with adequate follow-up was performed. One hundred twenty-eight patients (77%) were initially managed at the participating institutions, and 39 (23%) were referred after initial management at a different institution. Ninety-two (55%) had stage I disease, 7 (4%) had stage II, 18 (11%) stage III, and 50 (30%) had stage IV disease. The median OS for women with stage I was 75 months, for stage II 66 months, stage III 34 months, and stage IV 20 months (P < 0.001). For patients with early stage (I and II), race, lower grade, smaller tumor size (<11 cm), low number of mitosis (<25/10 high-power field [HPF]), lymphovascular space invasion, and presence of necrosis were identified as variables with prognostic influence on survival in the univariate analysis. A Cox proportional hazards model identified size 11 cm or greater (hazard ratio, 5.9; P < 0.001) and mitotic count of 25/10 HPF or greater (hazard ratio, 2.3; P = 0.05) as independent predictors of OS. For patients with late stage (stage III and IV), race, stage III versus IV, lower grade, smaller tumor size (<11 cm), and low number of mitosis (<25/10 HPF) were all associated with significantly improved OS. A Cox proportional hazards model identified mitotic count of 25/10 HPF or greater (P = 0.01) as independent predictor of OS.\n\n\nCONCLUSIONS\nIn early stage, size of the tumor and number of mitosis were associated to survival. In contrast to late stage, only mitotic count was associated to survival.",
"affiliations": "Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.",
"authors": "Rauh-Hain|Jose Alejandro|JA|;Oduyebo|Titilope|T|;Diver|Elisabeth J|EJ|;Guseh|Stephanie H|SH|;George|Suzanne|S|;Muto|Micheal G|MG|;del Carmen|Marcela G|MG|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0b013e31829590dc",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "23(6)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007890:Leiomyosarcoma; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D014594:Uterine Neoplasms",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1036-43",
"pmc": null,
"pmid": "23714705",
"pubdate": "2013-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Uterine leiomyosarcoma: an updated series.",
"title_normalized": "uterine leiomyosarcoma an updated series"
} | [
{
"companynumb": "US-JNJFOC-20140507947",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Autoimmune thrombocytopenia is an uncommon but reported paraneoplastic manifestation of renal cell carcinoma (RCC). Treatment usually involves management of the underlying malignancy; however, steroids have shown a benefit in published case reports. Here, we describe a patient with profound thrombocytopenia secondary to metastatic RCC. It was refractory to steroid and intravenous immunoglobulin, but the platelet count improved markedly following initiation of everolimus. The possible explanation includes immunomodulation, tumour lysis or a combination of both effects. This is the first reported case of everolimus used in paraneoplastic thrombocytopenia from RCC. More studies are needed for further investigation of its potential use in secondary immune thrombocytopenia from RCC and perhaps other malignancies.",
"affiliations": "Department of Haematology, St Vincent's Hospital, Sydney, New South Wales, Australia.;Department of Oncology, St Vincent's Hospital, Sydney, New South Wales, Australia.;Department of Oncology, St Vincent's Hospital, Sydney, New South Wales, Australia.;Department of Haematology, St Vincent's Hospital, Sydney, New South Wales, Australia.",
"authors": "Zheng|S|S|;Chan|H|H|;Epstein|R J|RJ|;Joseph|J E|JE|",
"chemical_list": "D000970:Antineoplastic Agents; D000068338:Everolimus",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.12779",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "45(6)",
"journal": "Internal medicine journal",
"keywords": "everolimus; paraneoplastic thrombocytopenia; renal cell carcinoma",
"medline_ta": "Intern Med J",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D000068338:Everolimus; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D016553:Purpura, Thrombocytopenic, Idiopathic; D016896:Treatment Outcome",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "666-9",
"pmc": null,
"pmid": "26059878",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Resolution of paraneoplastic immune thrombocytopenia following everolimus treatment for metastatic renal cell carcinoma.",
"title_normalized": "resolution of paraneoplastic immune thrombocytopenia following everolimus treatment for metastatic renal cell carcinoma"
} | [
{
"companynumb": "AU-APOTEX-2015AP015433",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ≥ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ≥ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL.",
"affiliations": "Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;University College London Hospital, London, UK.;Blackpool Victoria Hospital, Blackpool, UK.;University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.;St James's Hospital, Leeds, UK.;Heart of England NHS Foundation Trust, Birmingham, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Division of Molecular Pathology, The Institute of Cancer Research, Surrey, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK.;Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK. david.cunningham@rmh.nhs.uk.",
"authors": "Kühnl|Andrea|A|;Peckitt|Clare|C|;Patel|Bijal|B|;Ardeshna|Kirit M|KM|;Macheta|Marian P|MP|;Radford|John|J|;Johnson|Rod|R|;Paneesha|Shankaranarayana|S|;Barton|Sarah|S|;Chau|Ian|I|;Begum|Ruwaida|R|;Valeri|Nicola|N|;Wotherspoon|Andrew|A|;Du|Yong|Y|;Zerizer|Imene|I|;Cunningham|David|D|",
"chemical_list": "D003841:Deoxycytidine; D000069283:Rituximab; C056507:gemcitabine; D008775:Methylprednisolone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03842-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(1)",
"journal": "Annals of hematology",
"keywords": "DLBCL; Lenalidomide; Second-line therapy",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D000069283:Rituximab; D015996:Survival Rate",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "105-112",
"pmc": null,
"pmid": "31776726",
"pubdate": "2020-01",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial.",
"title_normalized": "r gem lenalidomide versus r gem p as second line treatment of diffuse large b cell lymphoma results of the uk nrci phase ii randomised legend trial"
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"abstract": "To our knowledge, we conducted the first prospective oncologic clinical trial in Nepal aimed at providing state-of-the-art chemotherapy to patients with Ewing sarcoma. The efficacy of external-beam radiotherapy (RT) as the sole local treatment modality was explored and deemed justified as a result of the lack of available advanced tumor-orthopedic services in Nepal.\n\n\n\nTwenty patients, 11 female and 9 male patients between the ages of 6 and 37 years, with newly diagnosed Ewing sarcoma were enrolled. Neoadjuvant combination chemotherapy, comprising well-established drug combinations, was administered in five courses before external-beam RT, during which one course of etoposide and ifosfamide was given. After RT, six additional chemotherapy courses were scheduled.\n\n\n\nRT was tolerated well, providing rapid symptom relief and local tumor control, with no pathologic fractures observed among the 15 patients who received such treatment. Eleven patients completed the entire treatment protocol; seven patients were under continued follow-up, with no evidence of disease in six patients at a median follow-up time of 2.3 years (range, 1.3 to 3.1 years) and one patient alive but with a regional recurrence. Four patients experienced metastatic relapse and died as a result of their disease. Three treatment-related deaths linked to toxicity from chemotherapy occurred. Four of the six patients who refused to complete the treatment protocol and were lost to follow-up experienced progressive disease and were assumed dead.\n\n\n\nThis study was feasible with RT as the sole local treatment modality in combination with chemotherapy. As a result of the high number of patients lost to follow-up, no firm conclusions can be drawn, but the majority of the patients who completed treatment obtained durable long-term remissions.",
"affiliations": "BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal.;BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal.;Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.;BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal.;BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal.;BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal.;Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.;Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.",
"authors": "Jha|Anjani Kumar|AK|;Neupane|Pradeep|P|;Pradhan|Manohar|M|;Sharma|Krishna Sagar|KS|;Shrestha|Sadina|S|;Sigdel|Padma Raj|PR|;Smeland|Sigbjørn|S|;Bruland|Øyvind S|ØS|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1200/JGO.19.00015",
"fulltext": "\n==== Front\nJ Glob OncolJ Glob OncoljgojgoJGOJournal of Global Oncology2378-9506American Society of Clinical Oncology 190001510.1200/JGO.19.00015Radiation OncologySarcomasOriginal ReportEwing Sarcoma in Nepal Treated With Combined Chemotherapy and Definitive Radiotherapy Ewing sarcoma in Nepal treated with chemotherapy and radiotherapyJha Anjani Kumar MD1Neupane Pradeep MD1Pradhan Manohar MD, PhD2Sharma Krishna Sagar MD1Shrestha Sadina MD1Sigdel Padma Raj MD1Smeland Sigbjørn MD, PhD23Bruland Øyvind S. MD, PhD231 BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal2 Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway3 Institute of Clinical Medicine, University of Oslo, Oslo, NorwayA.K.J. and P.N. contributed equally to this work.\n\nØyvind S. Bruland, MD, PhD, Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway; Twitter: @BrulandYvind; e-mail: osb@ous-hf.no.2019 27 3 2019 5 JGO.19.0001522 2 2019 © 2019 by American Society of Clinical Oncology2019American Society of Clinical OncologyLicensed under the Creative Commons Attribution 4.0 License: https://creativecommons.org/licenses/by/4.0/PURPOSE\nTo our knowledge, we conducted the first prospective oncologic clinical trial in Nepal aimed at providing state-of-the-art chemotherapy to patients with Ewing sarcoma. The efficacy of external-beam radiotherapy (RT) as the sole local treatment modality was explored and deemed justified as a result of the lack of available advanced tumor-orthopedic services in Nepal.\n\nPATIENTS AND METHODS\nTwenty patients, 11 female and 9 male patients between the ages of 6 and 37 years, with newly diagnosed Ewing sarcoma were enrolled. Neoadjuvant combination chemotherapy, comprising well-established drug combinations, was administered in five courses before external-beam RT, during which one course of etoposide and ifosfamide was given. After RT, six additional chemotherapy courses were scheduled.\n\nRESULTS\nRT was tolerated well, providing rapid symptom relief and local tumor control, with no pathologic fractures observed among the 15 patients who received such treatment. Eleven patients completed the entire treatment protocol; seven patients were under continued follow-up, with no evidence of disease in six patients at a median follow-up time of 2.3 years (range, 1.3 to 3.1 years) and one patient alive but with a regional recurrence. Four patients experienced metastatic relapse and died as a result of their disease. Three treatment-related deaths linked to toxicity from chemotherapy occurred. Four of the six patients who refused to complete the treatment protocol and were lost to follow-up experienced progressive disease and were assumed dead.\n\nCONCLUSION\nThis study was feasible with RT as the sole local treatment modality in combination with chemotherapy. As a result of the high number of patients lost to follow-up, no firm conclusions can be drawn, but the majority of the patients who completed treatment obtained durable long-term remissions.\n\n SJS Export v1\n==== Body\nINTRODUCTION\nEwing sarcoma (ES) belongs to a rare family of tumors composed of small round cell tumors (SRCTs) arising primarily in the bone and most frequently affecting children, adolescents, and young adults.1-3 Epidemiologic studies have shown a lower incidence of ES in populations of African and East Asian origins compared with white populations.4 Information on the clinical characteristics of patients with ES in the developing world is sparse. Two epidemiologic studies are reported from Iran and India.5,6 To our knowledge, three studies, all with a retrospective design, have reported on clinical outcomes after multimodality treatment.7-9\n\nCONTEXT\nKey Objective Experiences and outcomes are reported from, to our knowledge, the first prospective oncologic clinical trial to be conducted in Nepal providing state-of-the-art chemotherapy to patients with Ewing sarcoma in combination with external-beam radiotherapy as the sole local treatment modality.\n\nKnowledge Generated Twenty patients were enrolled, including four patients with primary metastatic disease. Three treatment-related deaths were encountered during chemotherapy. Eleven patients completed the entire scheduled combined treatment. Six of these patients have experienced neither local relapse nor metastasis, with a median follow-up of 2.3 years.\n\nRelevance As a result of six patients who were lost to follow-up before having completed chemoradiotherapy, no firm conclusions can be made.\n\n\n\nIn Europe and North America, survival has substantially improved over the past couple of decades, with an expected 5-year overall survival rate of 65% to 75% for patients with localized disease at presentation and 30% for patients with primary metastatic ES.10,11 Multiagent chemotherapeutic regimens effectively eradicate systemic micrometastases in ES and most often induce a rapid response on the primary tumor site, with shrinkage of the soft tissue components.12,13 A randomized study comparing the vincristine, doxorubicin, cyclophosphamide, and actinomycin C regimen with the vincristine, doxorubicin, cyclophosphamide, and actinomycin C regimen plus ifosfamide and etoposide demonstrated that, in nonmetastatic patients, the six-drug regimen offered the best survival probability.14 The outcome for Scandinavian patients in the Italian Sarcoma Group (ISG)/Scandinavian Sarcoma Group (SSG) III protocol15 represents a substantial improvement compared with the previous trials SSG IV16 and SSG IX,17 comparing favorably with the results from other intergroups.14,18,19 In patients with limited metastatic disease at presentation, a more aggressive approach that included myeloablative treatment showed survival benefit.20\n\nThe current Nepali-Norwegian Ewing Sarcoma Study (NEWS) initiative was launched to explore the feasibility of implementing a prospective clinical study protocol providing multidisciplinary treatment to Nepalese citizens with ES and to report its outcomes. The study aimed to facilitate the referral of these patients to the BP Koirala Memorial Cancer Hospital (BPK) and to provide an evidence-based combination chemotherapy regimen administered at BPK. Another important goal was to gain systematic experience on the effectiveness of definitive external-beam radiotherapy (RT) as the sole local treatment modality to compensate for the lack of state-of-the-art limb-sparing tumor-orthopedic surgical service in Nepal. NEWS represents the collaboration between BPK and the Norwegian Radium Hospital, Oslo University Hospital, Norway. To our knowledge, this was the first prospective oncologic clinical study conducted in Nepal. The combination chemotherapy was adapted to the BPK experiences and resources, combining five effective drugs for ES that were successfully applied in the ISG/SSG III trial.15\n\nAdvances in both surgery and RT have resulted in better local control, fewer adverse effects, and the avoidance of amputation in the majority of patients.1,10 Patients with ES in the axial skeleton have a worse prognosis compared with those with tumors in the extremities.21 Surgical treatment of axial ES is often associated with considerable loss of function and difficulty in obtaining wide margins.22-24 Thus, postoperative RT is widely used when the histologic response to preoperative chemotherapy is unsatisfactory25 and/or surgical margins are regarded as inadequate.1 More recently, particle-beam RT with protons has been reported to yield favorable local control rates as single treatment of the primary tumor.26 The risk of a pathologic fracture after RT, when the primary tumor is localized in a weight-bearing bone, is an unsettled concern. Even the most sophisticated RT may have serious acute and late complications, including secondary malignancies,27,28 which are of particular concern among children with ES. Evidence regarding strategies for optimal local disease control is still somewhat contradictory; some institutions insist on attempting free-margin surgical resection whenever possible, whereas others propose definitive RT as an equally effective alternative.23,29 This article reports the first outcomes of the NEWS protocol related to patient compliance during treatment and follow-up; practical and logistical aspects; and the impacts of intensive polyagent chemotherapy and definitive RT on local tumor control, metastases-free survival, and adverse events.\n\nPATIENTS AND METHODS\nPatients\nOver a 2-year period, in total, 20 patients were invited to participate (Fig 1) and informed about the nature of the disease, as well as the treatment’s expected benefit and adverse effects. All 20 patients (11 females and nine males) accepted and signed the written informed consent form. The enrollment was from August 2014 to October 2016. Table 1 lists the patient age (at diagnosis) and sex distribution, the anatomic site of primary tumor with largest diameter, and the evidence of primary metastases.\n\nFIG 1 Overview of patients enrolled in the trial.\n\nTABLE 1 Demographic and Clinical Characteristics of Patients Enrolled in the Study\n\nThe inclusion criteria included histologically proven SRCT compatible with ES, age between 5 and 60 years, normal hepatic and renal functions, WBC count of 3.0 × 109/L or greater, and platelet count of 100 × 109/L or greater. Chemotherapy had to be started within 4 weeks of a conclusive histologic diagnosis. Chest x-ray and computed tomography images were mandatory, and in some cases, magnetic resonance imaging (MRI) of the primary tumor was used to estimate the largest tumor length.\n\nThe exclusion criteria included previous malignancy other than basal cell carcinoma of the skin or noninvasive carcinoma of the cervix, medical contraindications to the cytostatic agents and dose levels in question, major psychological or psychiatric disorders, and a priori expected lack of compliance to treatment and scheduled follow-ups. Patients with synchronous metastatic diseases were eligible if it was possible to include lesions in separate RT target volumes (see later discussion).\n\nCase report forms were developed on demographic and clinical variables at inclusion to document completion of chemotherapy cycles, capture RT details and adverse events, and document the clinical status on scheduled follow-up visits (Data Supplement). The clinical outcomes were classified as follows: no evidence of disease (NED), progressive disease (distant relapse or local recurrence), died of disease, or lost to follow-up (LFU).\n\nPathologic Diagnosis\nPathologic diagnosis was based on an open surgical biopsy or core-needle biopsies. Tissue was fixed in 10% buffered formalin for microscopic evaluation. Two experienced pathologists confirmed the diagnosis. Monoclonal antibodies were used for immunohistochemistry (IHC) analyses that comprised testing for expression of CD99 in all except one patient (Table 2). However, a standardized ES panel was not systematically used. Table 2 lists the IHC details of the 20 patients; IHC was performed at BPK in eight patients, with the remaining 12 patients having IHC performed at a private laboratory in India.\n\nTABLE 2 Pathologic Diagnosis With Immunohistologic Analyses Performed\n\nIn 12 patients, digital images from hematoxylin and eosin–stained and IHC slides were anonymously e-mailed to the Norwegian Radium Hospital for review to confirm a morphologic diagnosis and an IHC profile compatible with ES/SRCT. Molecular pathology, with the ES diagnostic translocation marker, was not applied in this study.\n\nChemotherapy\nFigure 2 presents the chemotherapy combinations with scheduling of the different combinations, as well as individual drug dosages based on the experiences from the ISG/SSG III trial cycles15 that combined vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Dactinomycin was excluded from the current chemotherapy regimen as a result of its significant addition to radiation toxicity and the sparse documentation on its antitumor effect on ES. A course of etoposide and ifosfamide chemotherapy was administered during the RT course. In total, 13 cycles of chemotherapy were planned over 36 weeks (Fig 2).\n\nFIG 2 Outline of the Nepali-Norwegian Ewing Sarcoma Study treatment protocol. C, cyclophosphamide (1,200 mg/m2 as a 30-minute intravenous [IV] infusion); Dox, doxorubicin (40 mg/m2/d as a 4-hour IV infusion on days 1 and 2; total dose, 80 mg/m2 in 2 days; total cumulative dose, 400 mg/m2); Eto, etoposide (150 mg/m2/d as 2-hour IV infusion; total dose, 450 mg/m2 in 3 days); Ifo, Ifosfamide (3,000 mg/m2 over 21 to 24 hours as 3-day continuous IV infusion; total dose, 9,000 mg/m2 in 3 days); V, vincristine (1.5 mg/m2 IV push; maximum, 2 mg).\n\nRT\nAn aim of NEWS was to explore the feasibility and effectiveness of RT as the sole local treatment modality with prospective registration of tumor control and normal tissue complications. The fractionation schedule was 1.5 Gy, given twice daily with a 6-hour minimum between fractions, for a total dose of 54 Gy interpolated between chemotherapy cycles15 (Fig 2). Because of the potential risk of pathologic fracture among patients whose primary tumor was located in weight-bearing bones, patients were instructed to avoid weight-bearing stress and to use crutches. A backup strategy, involving an orthopedic intervention in the event of a pathologic fracture, was in place at BPK.\n\nRT was documented in a separate case report form (Data Supplement). Acute toxicity and long-term sequelae of RT were documented. The radiation toxicity scoring was done according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Radiation Morbidity Scoring Schemes. Doses administered to critical organs were calculated based on the relevance of the actual RT administered, which should not exceed the following maximum values: spinal cord, 45 Gy; heart, 30 Gy to more than 50% of its volume; liver, 30 Gy to more than 50% of its volume; lung, 20 Gy to the whole lung; and kidney, 14 Gy to the whole kidney.\n\nRT was administered with high-energy 6-MV photons from a Varian 600 CD Linear Accelerator (Varian Medical Systems, Palo Alto, CA) with individual-dose planning to optimize treatment (eg, multiple beams with secondary-field shaping, individual filters, wedges). Computerizing the planning, using a map of isodose distribution on at least three slices, was required, including one central (reference plane) slice and two slices between the central and the peripheral planes. Whenever possible, some portion of the circumference of an extremity was excluded from the treatment volume to reduce the risk of distal or peripheral edema. A shrinking-field technique was applied, with target volume I encompassing the original tumor volume (gross tumor volume) with a 2-cm margin (clinical target volume) that received a dose of 42 Gy in 28 fractions. If a substantial shrinkage of the primary tumor during the first chemotherapy courses was observed, the initial soft tissue extensions seen at diagnosis were not part of the delineated boosted target volume II (eg, when the soft tissue mass expanded into thoracic or abdominal cavities). However, the entire bone or bone marrow extension at primary diagnosis was always used to guide the delineation of target volumes. An additional 12-Gy dose was given to target volume II, comprising the clinically and radiographically evident tumor at the start of RT (after neoadjuvant chemotherapy) with a 2-cm margin. A total accumulated dose of 54 Gy in 36 fractions was given to the gross tumor volume.\n\nFour patients (patients 2, 5, 12, and 16) had synchronous metastases. Three patients with skeletal lesions (suspected as metastasis but not biopsied) were administered RT as separate target volumes encompassing these lesions, similar to those for the expected primary tumor. Patient 12 had bilateral lung metastases and received 12 doses of 1.5 Gy to both lungs.\n\nFollow-Up Visits\nVisits were scheduled at 3, 6, and 9 months after completion of the chemotherapy cycle, with subsequent planned consultations every 6 months for up to 5 years of follow-up. Clinical examinations of the primary tumor site and the regional lymph nodes, as well as radiation toxicity scoring, were mandatory. In addition, x-rays of the affected bone or primary tumor site, conventional blood tests, and chest x-rays were planned. Computed tomography (or MRI if available) was performed in patients with suspected local relapse or metastases.\n\nEthical Aspects\nA formal protocol was written for this prospective study that was presented to and approved by the administration of BPK. The Ethical Review Board of the Nepal Health Research Council approved this study on August 14, 2014 (Registration No. 126/2014).\n\nRESULTS\nPatient Demographic and Disease-Related Information\nThe median age at diagnosis was 15 years (range, 6 to 37 years), with a 1.2 female predominance. The anatomic sites of the primary tumors were femur (n = 4), pubic bone (n = 1), fibula (n = 1), thoracic wall or costae (n = 4), clavicle (n = 1), craniofascial bone (n = 3), humerus (n = 3), and forearm (n = 1). Patient 15 may have had a large extraskeletal ES in the musculus sartorius, albeit with an invasion into the adjacent femur. Patient 10 had a primary tumor in her uterine cervix (ie, anticipated to be soft tissue ES; Table 1). However, in this patient, the panel of IHC analyses did not contain muscle markers (Table 2). Hence, a rhabdomyosarcoma diagnosis could not be ruled out. Table 1 also lists the available information on the largest tumor diameter for 17 patients, varying between 3 cm to 24 cm, but with no information for three patients.\n\nTable 2 lists the results of the IHC. All patients had tumor morphology with classic SRCTs on conventional hematoxylin and eosin staining. Unfortunately, the completeness of the tested IHC panel varied substantially. Hence, a definite ES diagnosis (eg, with the sound exclusion of rhabdomyosarcoma or primary bone lymphoma) could not be determined in eight patients.\n\nPatient 2 had his anticipated primary tumor in the left fibula and was diagnosed with synchronous, metastatic disease comprising two tumorous foci located in the contralateral extremity (foot and proximal femur). Patient 16 had a 10-cm primary tumor in the left mandibular ramus and an additional lesion suspected to be a metastasis involving costae 3 to 6. Both anatomic sites were administered RT as separate clinical target volumes. Patient 5 had an 11-cm tumor in her right clavicle and presented with possible metastases in both the manubrium of the sternum and a small lesion in the right parietal skull, diagnosed by MRI.\n\nCompliance With Protocol and Clinical Status During Follow-Up\nFigure 1 and the Data Supplement provide details on the enrollment, completeness of chemotherapy and RT according to the protocol, events during treatment, and available information on the clinical status during follow-up. All four patients enrolled with primary metastatic disease have died of disease.\n\nEleven patients completed the entire NEWS protocol as scheduled, without substantial delays or deviations regarding chemotherapy doses and RT (Figs 1 and 2). Four of these patients (patients 5, 12, 15, and 20) subsequently experienced metastases and died of disease. Patient 5 developed progression in the known metastatic sites of the manubrium of the sternum and the skull. Patient 12 experienced progression of his primary metastatic disease in both lungs. Patients 15 and 20 died as a result of disseminated metastases to both lungs diagnosed 12 and 3 months, respectively, after completion of NEWS.\n\nOne of the 11 patients (patient 19) who completed the entire NEWS protocol and had NED at the end of the therapy experienced a regional recurrence in her left inguinal region 6 months later. This was biopsied and showed SRCT morphology that this time tested positive for desmin expression. After response to second-line palliative chemotherapy, she remained symptom free at another 6-month follow-up.\n\nThe remaining six patients who had thus far not experienced a relapse all belonged to the subcohort of 11 patients who had complied with the entire NEWS protocol. The clinical data were updated in January 2018 (Fig 1 and Data Supplement). The median follow-up time was 2.3 years (range, 1.3 to 3.1 years) for the six patients with NED who were not LFU.\n\nAmong the six LFU patients, four had documented disease progression and were assumed to have died of disease. Patient 6 experienced progressive disease during chemotherapy and was found to be ineligible for RT as a result of massive lymphedema of the affected upper extremity. He was LFU after cycle 11 of chemotherapy. Five patients refused to comply with and complete the treatment and were LFU at various treatment stages. Despite various and repeated efforts to contact the patients and/or their families, no information on the state of their disease could be gathered.\n\nChemotherapy Compliance and Toxicity\nThe Data Supplement provides the number of completed chemotherapy cycles, information on substantial delays, and available information on serious adverse events. During the scheduled chemotherapy courses (Fig 2), three patients (patients 2, 3, and 16) experienced severe hematologic toxicity and died in a state of assumed febrile neutropenia (not at the treating hospital; Fig 1). Dose reductions in the 10% to 20% range were deemed necessary in three patients (Data Supplement).\n\nRT Experience\nAs shown in the Data Supplement, 15 of 20 patients received the scheduled RT, including the boost-volume RT, for the specified total accumulated 54-Gy dose. Patient 2 also received the same fractionated RT to the two assumed metastatic disease sites (right proximal femur and right foot).\n\nSystematic information on primary tumor control and normal tissue complications is far from complete because of the high number of patients LFU. However, among the patients who completed the entire treatment protocol, all had rapid and significant pain relief and considerable tumor shrinkage during the RT course. None of these patients experienced local tumor progression, and at the scheduled follow-up visits, no pathologic fractures were diagnosed at irradiated primary tumor sites.\n\nNo functional disability was observed, but most of the patients treated for ES in the lower limbs had mild peripheral distal edema, although it was of short duration. This observation is interesting because several patients had larger tumors, which posed considerable challenges in sparing a sufficient part of the circumference of the treated extremity from the full irradiation dose.\n\nDISCUSSION\nES is an RT-sensitive tumor,11,23,24,30 but surgery is considered the standard of care for local control.21,29,31 However, for inoperable tumors and tumors not operated with sufficient margins, RT adds substantial benefits to local control. In addition, RT techniques are rapidly evolving, improving the therapeutic index. To our knowledge, among patients with ES in the axial skeleton, no studies have proven a convincing benefit of surgery compared with RT regarding local control.\n\nWhen planning this study, advanced tumor-orthopedic surgery involving reconstructions with internal prostheses was not an available option in Nepal. Currently, only one hospital in Kathmandu offers such operations. However, the patient has to cover all expenses. Thus, this study’s exploratory hypothesis was that, in ES, external-beam RT would be as equally effective as surgery in local tumor control and overall survival when administered sequentially with an effective multidrug chemotherapy regimen. Given this setting, the clinical trial was deemed ethically acceptable. No a priori sample size calculations were made because no previous outcome data on ES outcome in Nepal were available.\n\nAn earlier timing of RT, provided sequentially with chemotherapy, and the introduction of hyperfractionated and accelerated RT as 1.5 Gy administered twice daily15 have composed the advocated strategy in the SSG and ISG. However, the true benefit of twice-daily RT has not been adequately studied, and most centers currently administer one fraction of 1.8 to 2.0 Gy/d.\n\nThe NEWS treatment protocol was feasible, and the oncologic outcomes were satisfactory for the 11 patients who completed the protocol, with no or minor dose reductions and without significant delays. Among these patients, six (55%) still had NED at a median follow-up of 2.3 years from the start of chemotherapy. Four of the 20 enrolled patients had primary metastatic disease, some of the primary tumors were of considerable size, and nine patients had axial tumors. These are all adverse prognostic factors for outcome.\n\nAll eligible patients seen at BPK during the actual period of accrual were invited to participate independent of economic capability. However, we cannot rule out a selection bias for patients who could afford flying to India and paying for their entire treatment costs.\n\nDespite the limited number of patients in this study, the fact that neither local disease progression nor any pathologic fracture was diagnosed is an important observation. This may also convey relevant information for sarcoma centers currently considering advanced surgical treatment of axial ES with significant functional disabilities as the best therapeutic option.\n\nThe NEWS study has several limitations. The high percentage of patients LFU (six of 20 patients) allows no sound conclusions on outcome to be drawn. As expected, given the socioeconomic situation in Nepal, tracing individual patients during follow-up turned out to be a major challenge, despite considerable efforts to re-establish contact by phone and postal mail.\n\nThe key message of this article is that it was feasible to conduct the ambitious clinical NEWS study at the BPK, with several patients still in first complete remission. This leads to the conclusion that international collaboration, as the advocated current approach in the Western world,11 might facilitate future collaborations in other cancer diagnoses for the benefit of both patients and oncologists in Nepal.\n\nSupported by the Radium Hospital Research Foundation, Oslo University Hospital (Norwegian Radium Hospital), which covered the expenses for the drugs composing the chemotherapy regimen.\n\nACKNOWLEDGMENT\nWe thank all doctors and nurses involved in the treatment administered at the BP Koirala Memorial Cancer Hospital. In particular, we acknowledge Chin Bahadur Pun, MD (head of the Pathology Department), Laxmi Narayan Singh, MD, PhD (radiologist), Bhola Rauniyar, MD (medical oncologist), Jaya Shrestha, MD (medical oncologist), Arun Sigdel, MS (orthopedic surgeon), Sushil Adhikari, MS (orthopedic surgeon), Shivaji Poudel, MD (radiation oncologist), Suresh Shrestha, MD (radiation oncologist), and Hari Prasad Dhakal, MD, PhD (pathologist). Special thanks are due to Prem Raj Kandel for secretarial assistance. Finally, we acknowledge the expert sarcoma pathology advice from Bodil Bjerkehagen, MD, PhD, of Oslo University Hospital.\n\nAUTHOR CONTRIBUTIONS\nConception and design: Anjani Kumar Jha, Øyvind S. Bruland\n\nFinancial support: Sigbjørn Smeland\n\nAdministrative support: Manohar Pradhan, Pradeep Neupane\n\nProvision of study materials or patients: Anjani Kumar Jha, Pradeep Neupane, Krishna Sagar Sharma, Sadina Shrestha, Padma Raj Sigdel\n\nCollection and assembly of data: Pradeep Neupane, Manohar Pradhan, Krishna Sagar Sharma,\n\nData analysis and interpretation: Manohar Pradhan, Sigbjørn Smeland, Øyvind S. Bruland\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jgo/site/misc/authors.html.\n\nNo potential conflicts of interest were reported.\n\nAppendix\nFinancial Aspects and External Funding\nExternal funding was provided by the Norwegian Radium Hospital Research Foundation to reimburse the patients without financial resources for their chemotherapy drug expenses.BP Koirala Memorial Cancer Hospital covered all other expenses for radiologic examinations, biopsies, administration of chemotherapy with hospital costs, management of adverse events, radiotherapy, and the planned outpatient follow-up visits. None of the 20 patients were able to raise sufficient money to pay for chemotherapy.\n==== Refs\nREFERENCES\n1. Bernstein M Kovar H Paulussen M et al Ewing’s sarcoma family of tumors: Current management Oncologist 11 503 519 2006 16720851 \n2. Balamuth NJ Womer RB Ewing’s sarcoma Lancet Oncol 11 184 192 2010 20152770 \n3. de Alava E, Lessnick SL, Sorenson PH: Ewing sarcoma, in Fletcher CDM, Bridge JA, Hogendoorn PCW, et al (eds): WHO Classification of Tumours of Soft Tissue and Bone (ed 4). Lyon, France, International Agency for Research on Cancer, 2013, pp 306-309 \n4. Worch J Matthay KK Neuhaus J et al Ethnic and racial differences in patients with Ewing sarcoma Cancer 116 983 988 2010 20052725 \n5. Solooki S Vosoughi AR Masoomi V Epidemiology of musculoskeletal tumors in Shiraz, south of Iran Indian J Med Paediatr Oncol 32 187 191 2011 22563150 \n6. Chakraborty D Rangamani S Kulothungan V et al Trends in incidence of Ewing sarcoma of bone in India: Evidence from the National Cancer Registry Programme (1982-2011) J Bone Oncol 12 49 53 2018 30237969 \n7. Tiwari A Gupta H Jain S et al Outcome of multimodality treatment of Ewing’s sarcoma of the extremities Indian J Orthop 44 378 383 2010 20924477 \n8. Puri A Gulia A Crasto S et al Does radiotherapy after surgery affect outcomes in Ewing’s sarcoma of the pelvis? Indian J Orthop 52 73 76 2018 29416173 \n9. Majeed SS Muhammad HA Ali JS et al Treatment Outcomes of Pediatric Patients With Ewing Sarcoma in a War-Torn Nation: A Single-Institute Experience From Iraq J Glob Oncol doi: 10.1200/JGO.18.00122\n10. Potratz J Dirksen U Jürgens H et al Ewing sarcoma: Clinical state-of-the-art Pediatr Hematol Oncol 29 1 11 2012 22295994 \n11. Gaspar N Hawkins DS Dirksen U et al Ewing sarcoma: Current management and future approaches through collaboration J Clin Oncol 33 3036 3046 2015 26304893 \n12. Bacci G Ferrari S Bertoni F et al Prognostic factors in nonmetastatic Ewing’s sarcoma of bone treated with adjuvant chemotherapy: Analysis of 359 patients at the Istituto Ortopedico Rizzoli J Clin Oncol 18 4 11 2000 10623687 \n13. Bacci G Mercuri M Longhi A et al Neoadjuvant chemotherapy for Ewing’s tumour of bone: Recent experience at the Rizzoli Orthopaedic Institute Eur J Cancer 38 2243 2251 2002 12441260 \n14. Grier HE Krailo MD Tarbell NJ et al Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone N Engl J Med 348 694 701 2003 12594313 \n15. Ferrari S Sundby Hall K Luksch R et al Nonmetastatic Ewing family tumors: High-dose chemotherapy with stem cell rescue in poor responder patients—Results of the Italian Sarcoma Group/Scandinavian Sarcoma Group III protocol Ann Oncol 22 1221 1227 2011 21059639 \n16. Nilbert M Saeter G Elomaa I et al Ewing’s sarcoma treatment in Scandinavia 1984-1990: Ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV Acta Oncol 37 375 378 1998 9743460 \n17. Elomaa I Blomqvist CP Saeter G et al Five-year results in Ewing’s sarcoma: The Scandinavian Sarcoma Group experience with the SSG IX protocol Eur J Cancer 36 875 880 2000 10785592 \n18. Oberlin O Deley MC Bui BN et al Prognostic factors in localized Ewing’s tumours and peripheral neuroectodermal tumours: The third study of the French Society of Paediatric Oncology (EW88 study) Br J Cancer 85 1646 1654 2001 11742482 \n19. Paulussen M Ahrens S Lehnert M et al Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study Ann Oncol 12 1619 1630 2001 11822764 \n20. Luksch R Tienghi A Hall KS et al Primary metastatic Ewing’s family tumors: Results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV study including myeloablative chemotherapy and total-lung irradiation Ann Oncol 23 2970 2976 2012 22771824 \n21. Schuck A Ahrens S Paulussen M et al Local therapy in localized Ewing tumors: Results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials Int J Radiat Oncol Biol Phys 55 168 177 2003 12504050 \n22. Indelicato DJ Keole SR Shahlaee AH et al Spinal and paraspinal Ewing tumors Int J Radiat Oncol Biol Phys 76 1463 1471 2010 19632062 \n23. Indelicato DJ Keole SR Shahlaee AH et al Definitive radiotherapy for Ewing tumors of extremities and pelvis: Long-term disease control, limb function, and treatment toxicity Int J Radiat Oncol Biol Phys 72 871 877 2008 18455323 \n24. La TH Meyers PA Wexler LH et al Radiation therapy for Ewing’s sarcoma: Results from Memorial Sloan-Kettering in the modern era Int J Radiat Oncol Biol Phys 64 544 550 2006 16198063 \n25. Picci P Rougraff BT Bacci G et al Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing’s sarcoma of the extremities J Clin Oncol 11 1763 1769 1993 8355043 \n26. Rombi B DeLaney TF MacDonald SM et al Proton radiotherapy for pediatric Ewing’s sarcoma: Initial clinical outcomes Int J Radiat Oncol Biol Phys 82 1142 1148 2012 21856094 \n27. Navid F Billups C Liu T et al Second cancers in patients with the Ewing sarcoma family of tumours Eur J Cancer 44 983 991 2008 18353632 \n28. Sultan I Rihani R Hazin R et al Second malignancies in patients with Ewing sarcoma family of tumors: A population-based study Acta Oncol 49 237 244 2010 20100158 \n29. DuBois SG Krailo MD Gebhardt MC et al Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: A report from the Children’s Oncology Group Cancer 121 467 475 2015 25251206 \n30. Donaldson SS Torrey M Link MP et al A multidisciplinary study investigating radiotherapy in Ewing’s sarcoma: End results of POG #8346 Int J Radiat Oncol Biol Phys 42 125 135 1998 9747829 \n31. Cotterill SJ Ahrens S Paulussen M et al Prognostic factors in Ewing’s tumor of bone: Analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group J Clin Oncol 18 3108 3114 2000 10963639\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2378-9506",
"issue": "5()",
"journal": "Journal of global oncology",
"keywords": null,
"medline_ta": "J Glob Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D009390:Nepal; D011446:Prospective Studies; D012512:Sarcoma, Ewing; D055815:Young Adult",
"nlm_unique_id": "101674751",
"other_id": null,
"pages": "1-10",
"pmc": null,
"pmid": "30917070",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20100158;29416173;21059639;8355043;10963639;20924477;12504050;18353632;19632062;20052725;10623687;26304893;22771824;12441260;11822764;12594313;10785592;30707662;18455323;9747829;21856094;25251206;20152770;11742482;22295994;16720851;22563150;16198063;9743460;30237969",
"title": "Ewing Sarcoma in Nepal Treated With Combined Chemotherapy and Definitive Radiotherapy.",
"title_normalized": "ewing sarcoma in nepal treated with combined chemotherapy and definitive radiotherapy"
} | [
{
"companynumb": "NP-PFIZER INC-2019148293",
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{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nTo report a case of rhabdomyolysis resulting from concomitant use of clarithromycin and simvastatin.\n\n\nMETHODS\nA 64-year-old African-American man was admitted to the hospital for worsening renal failure, elevated creatine phosphokinase, diffuse muscle pain, and severe muscle weakness. About three weeks prior to admission, the patient was started on clarithromycin for sinusitis. The patient had been receiving simvastatin for approximately six months. He was treated aggressively with intravenous hydration, sodium bicarbonate, and hemodialysis. A muscle biopsy revealed necrotizing myopathy secondary to a toxin. The patient continued to receive intermittent hemodialysis until his death from infectious complications that occurred three months after admission. There were several factors that could have increased his risk for developing rhabdomyolysis, including chronic renal failure.\n\n\nCONCLUSIONS\nClarithromycin is a potent inhibitor of CYP3A4, the major enzyme responsible for simvastatin metabolism. The concomitant administration of macrolide antibiotics and other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have resulted in previous reports of rhabdomyolysis. Other factors may increase the risk of this drug interaction, including the administration of other medications that are associated with myopathy, underlying renal insufficiency, and administration of high doses of HMG-CoA reductase inhibitors.\n\n\nCONCLUSIONS\nMacrolide antibiotics inhibit the metabolism of HMG-CoA reductase inhibitors that are metabolized by CYP3A4 (i.e., atorvastatin, cerivastatin, lovastatin, simvastatin). This interaction may result in myopathy and rhabdomyolysis, particularly in patients with renal insufficiency or those who are concurrently taking medications associated with myopathy.",
"affiliations": "University of the Pacific, Stockton, CA, USA. lee.audrey_J@sanfrancisco.va.gov",
"authors": "Lee|A J|AJ|;Maddix|D S|DS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000960:Hypolipidemic Agents; D019821:Simvastatin; D017291:Clarithromycin",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.10177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "35(1)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D004347:Drug Interactions; D006801:Humans; D006949:Hyperlipidemias; D000960:Hypolipidemic Agents; D008297:Male; D008875:Middle Aged; D012206:Rhabdomyolysis; D019821:Simvastatin; D012852:Sinusitis",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "26-31",
"pmc": null,
"pmid": "11197581",
"pubdate": "2001-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin.",
"title_normalized": "rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-01704",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"druga... |
{
"abstract": "Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1 gene. The most common clinical presentation in AT deficient patients includes venous thrombosis and pulmonary embolism, while the association of AT deficiency and its effect on the development of pregnancy complications has been less studied. The aim of our research was to evaluate the effect of AT deficiency types, determined by genotyping, on pregnancy outcomes.\n\n\n\nA retrospective cohort study included 28 women with AT deficiency, and their 64 pregnancies were analyzed.\n\n\n\nWith regard to live birth rate, a significant difference was observed among women who were carriers of different SERPINC1 mutations, as the rate varied from 100% in cases of type I to the extremely low rate of 8% for women with type II HBS (AT Budapest 3) in the homozygous variant, P = 0.0005. All pregnancies from the type I group, even untreated ones, resulted in live births. In women with AT Budapest 3 in homozygous variant the overall live birth rate increased to 28.5% in the treated pregnancies. In this group the highest incidence of fetal death was observed of 62%; repeated fetal losses in 30%; fetal growth restriction in 22% and placental abruption in 7% of all pregnancies.\n\n\n\nOur study results indicate a difference between type I and type II AT deficiency. The risk of pregnancy related VTE was equally present in both groups, except for AT Budapest 3 in the heterozygous variant, while adverse pregnancy outcomes were strictly related to type II, especially AT Budapest 3 in the homozygous variant.",
"affiliations": "Faculty of Medicine, University of Belgrade, Serbia; Blood Transfusion Institute of Serbia, Hemostasis Department, Belgrade, Serbia. Electronic address: mkovac008@gmail.com.;Institute of Laboratory Medicine, Clinical Center of Vojvodina, Faculty of Medicine Novi Sad, University of Novi Sad, Serbia.;Faculty of Medicine, University of Belgrade, Serbia; Gynecology and Obstetrics Clinic Narodni Front, Belgrade, Serbia.;Faculty of Medicine, University of Belgrade, Serbia; Gynecology and Obstetrics Clinic Narodni Front, Belgrade, Serbia.;Faculty of Medicine, University of Belgrade, Serbia; Clinic of Hematology, Clinical Center of Serbia, Serbia.;Faculty of Medicine, University of Belgrade, Serbia; Clinic of Hematology, Clinical Center of Serbia, Serbia.;Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.;Division of Clinical Laboratory Research, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.",
"authors": "Kovac|Mirjana|M|;Mitic|Gorana|G|;Mikovic|Zeljko|Z|;Mandic|Vesna|V|;Miljic|Predrag|P|;Mitrovic|Mirjana|M|;Tomic|Branko|B|;Bereczky|Zsuzsanna|Z|",
"chemical_list": "C542513:SERPINC1 protein, human; D000990:Antithrombin III",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2018.11.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "173()",
"journal": "Thrombosis research",
"keywords": "Antithrombin deficiency; Pregnancy outcome; SERPINC1 mutations",
"medline_ta": "Thromb Res",
"mesh_terms": "D000328:Adult; D000990:Antithrombin III; D005260:Female; D006801:Humans; D050498:Live Birth; D008875:Middle Aged; D009154:Mutation; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D019851:Thrombophilia; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "12-19",
"pmc": null,
"pmid": "30458337",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The influence of specific mutations in the AT gene (SERPINC1) on the type of pregnancy related complications.",
"title_normalized": "the influence of specific mutations in the at gene serpinc1 on the type of pregnancy related complications"
} | [
{
"companynumb": "RS-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-194505",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "Data on the outcome of allogenic hematopoietic stem cell transplantation (HSCT) in pediatric patients with a history of invasive fungal infection (IFI) are limited. The aim of this study was to report on the feasibility and outcome of allogenic HSCT in pediatric patients with an active or recently diagnosed IFI. In this retrospective, single-center study, 317 children underwent an allogenic HSCT (January 2012 to June 2020), of whom 23 had an active or recent (<6 months before transplantation) diagnosis of a probable or proven IFI before HSCT. Medical records were reviewed for data collection. Descriptive statistics were performed. One-year survival was described with Kaplan-Meier analysis. Four proven and 19 probable IFIs were diagnosed. The lungs were the main site of infection (22 out of 23 patients); brain involvement was diagnosed in six patients (26.1%). Aspergillus spp. were the most frequently identified organisms. Of the four patients diagnosed with mucormycosis, three had mixed infections with Aspergillus spp. One patient was diagnosed with Alternaria sinusitis and one patient with an infection with Curvularia spp. with both pulmonary and cutaneous involvement. One year after HSCT, 18 of the 23 patients (78.3%) were alive. Four of the five patients who did not survive died of non-IFI-related causes. One patient died due to a newly developed IFI post-transplant. Three patients showed non-fatal progression of their original IFIs that required prolonged antifungal treatment. Survival of this cohort of high-risk pediatric patients who underwent allogenic HSCT with an active or recently diagnosed IFI was favorable. An active IFI or recent history of IFI should not be a contraindication for proceeding to allogenic HSCT.",
"affiliations": "Pediatrics, Wilhelmina Children's Hospital, UMC Utrecht, University Utrecht, Utrecht, The Netherlands.;Pediatrics, Wilhelmina Children's Hospital, UMC Utrecht, University Utrecht, Utrecht, The Netherlands.;Hematopoietic Stem Cell Transplantation Unit, Princess Máxima Center for Pediatric Oncology, Wilhelmina Children's Hospital, UMC Utrecht, University Utrecht, Utrecht, The Netherlands.;Pediatrics, Wilhelmina Children's Hospital, UMC Utrecht, University Utrecht, Utrecht, The Netherlands. Electronic address: T.Wolfs@umcutrecht.nl.;Hematopoietic Stem Cell Transplantation Unit, Princess Máxima Center for Pediatric Oncology, Wilhelmina Children's Hospital, UMC Utrecht, University Utrecht, Utrecht, The Netherlands.",
"authors": "Rotte|Laura G Y|LGY|;Loeffen|Yvette G T|YGT|;Bierings|Marc B|MB|;Wolfs|Tom F W|TFW|;Lindemans|Caroline A|CA|",
"chemical_list": "D000935:Antifungal Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtct.2021.06.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2666-6367",
"issue": "27(9)",
"journal": "Transplantation and cellular therapy",
"keywords": "Allogenic; Hematopoietic stem cell transplantation; Invasive fungal infection; Outcome",
"medline_ta": "Transplant Cell Ther",
"mesh_terms": "D000935:Antifungal Agents; D002648:Child; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000072742:Invasive Fungal Infections; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101774629",
"other_id": null,
"pages": "781.e1-781.e5",
"pmc": null,
"pmid": "34153502",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Allogenic Hematopoietic Stem Cell Transplantation Is Feasible in Pediatric Patients with an Active or Recently Diagnosed Invasive Fungal Infection.",
"title_normalized": "allogenic hematopoietic stem cell transplantation is feasible in pediatric patients with an active or recently diagnosed invasive fungal infection"
} | [
{
"companynumb": "NL-GILEAD-2022-0576703",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nAA amyloidosis is the most serious potential complication of chronic inflammatory disorders. The main aim of treatment is to suppress inflammation thereby inhibiting serum amyloid A protein (SAA), which is the precursor of AA amyloid fibrils, to prevent or halt amyloid deposition. Interleukin (IL)-6 blockade is frequently effective in inflammatory conditions, however, there are few published data on its use in AA amyloidosis or the systemic autoinflammatory diseases (SAIDs) or chronic inflammatory conditions. We assessed clinical and serological responses and adverse events associated with tocilizumab (TCZ) use in 20 adult patients with inflammatory disorders refractory to other treatments, including 70% with AA amyloidosis and four with renal transplants.\n\n\nMETHODS\nIn addition to routine haematology and biochemistry (including SAA) blood panels, patients with AA amyloidosis underwent SAP scintigraphy to quantify amyloid load. Those with SAIDs underwent genetic analysis to identify mutations/variants in known associated genes. Quality of life (QoL) was surveyed using SF-36v2®.\n\n\nRESULTS\nWhole-cohort median pre-treatment SAA fell from 70 to 4 mg/L within 10 days of the first dose; this response has been maintained over an on-treatment follow-up period of 23 months (p<0.0001). AA amyloid deposits either regressed or remained stable. QoL improved in several domains. Infections were the predominant adverse effect experienced, but none resulted in permanent discontinuation of therapy.\n\n\nCONCLUSIONS\nThis small series shows that in patients with treatment-refractory chronic inflammatory conditions TCZ can be effective in suppressing inflammation, and in those with AA amyloidosis, can lead to regression of amyloid deposits. Longer follow-up is required to determined long-term safety and efficacy in these conditions.",
"affiliations": "National Amyloidosis Centre, University College London Division of Medicine, London, UK. t.lane@ucl.ac.uk.;National Amyloidosis Centre, University College London Division of Medicine, London, UK.;National Amyloidosis Centre, University College London Division of Medicine, London, UK.;National Amyloidosis Centre, University College London Division of Medicine, London, UK.;National Amyloidosis Centre, University College London Division of Medicine, London, UK.",
"authors": "Lane|Thirusha|T|;Gillmore|Julian D|JD|;Wechalekar|Ashutosh D|AD|;Hawkins|Philip N|PN|;Lachmann|Helen J|HJ|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000685:Serum Amyloid A Protein; C502936:tocilizumab",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "33(6 Suppl 94)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000686:Amyloidosis; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D002648:Child; D002908:Chronic Disease; D016208:Databases, Factual; D015536:Down-Regulation; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007249:Inflammation; D015850:Interleukin-6; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D011788:Quality of Life; D019947:Receptors, Interleukin-6; D012074:Remission Induction; D012307:Risk Factors; D000685:Serum Amyloid A Protein; D015398:Signal Transduction; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "S46-53",
"pmc": null,
"pmid": "26120866",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature.",
"title_normalized": "therapeutic blockade of interleukin 6 by tocilizumab in the management of aa amyloidosis and chronic inflammatory disorders a case series and review of the literature"
} | [
{
"companynumb": "PHHY2016GB069440",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Chronic lymphatic leukaemia (CLL) is the most common leukaemia in the Western world. Ibrutinib, a tyrosine kinase inhibitor, is the treatment of choice on relapse or p53-dysfunction. Richter's transformation to diffuse large B cell lymphoma is most often seen. However, transformation to other aggressive lymphomas as plasmablastic lymphoma (PBL) does occur. PBL is an extremely aggressive lymphoma and is usually treated using a CHOP-like regimen (cyclophosphamide, doxorubicin, vincristine and prednisone/dexamethasone), but with poor outcome. The only curative treatment is allogeneic stem cell transplant (ASCT).We report on a case of CLL treated with ibrutinib that underwent transformation to PBL. Due to high expression of CD138, we added daratumumab to the chemotherapy with a good, but transitory response. The case did not make it to an ASCT. Targeting CD138 by daratumumab may be added to chemoimmune therapy for PBL.",
"affiliations": "Department of Haematology, Sykehuset Østfold HF, Gralum, Østfold, Norway marvyin@gmail.com.;Department of Haematology, Sykehuset Østfold HF, Gralum, Østfold, Norway.;Department of Haematology, Sykehuset Østfold HF, Gralum, Østfold, Norway.;Department of Haematology, Oslo Universitetssykehus, Oslo, Norway.",
"authors": "Marvyin|Kristo|K|;Tjønnfjord|Eirik Brekka|EB|;Breland|Unni Mathilde|UM|;Tjønnfjord|Geir Erland|GE|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D010880:Piperidines; C508241:SDC1 protein, human; D053668:Syndecan-1; C551803:ibrutinib; C556306:daratumumab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000225:Adenine; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(9)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; haematology (incl blood transfusion)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000225:Adenine; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D002471:Cell Transformation, Neoplastic; D003520:Cyclophosphamide; D004317:Doxorubicin; D017809:Fatal Outcome; D006801:Humans; D007155:Immunologic Factors; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010880:Piperidines; D000069293:Plasmablastic Lymphoma; D011241:Prednisone; D053668:Syndecan-1; D014750:Vincristine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32994268",
"pubdate": "2020-09-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transformation to plasmablastic lymphoma in CLL upon ibrutinib treatment.",
"title_normalized": "transformation to plasmablastic lymphoma in cll upon ibrutinib treatment"
} | [
{
"companynumb": "NO-ACCORD-207612",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Small bowel intussusception in adults is rare. Unlike children, adults with intussusception generally have a causative lead point, of which a majority is benign. We report the case of a 55-year-old woman with systemic lupus erythematosus on steroids and nonsteroidal anti-inflammatory drugs who presented with intermittent melena. Contrast computed tomography revealed intussusception of the terminal ileum, with a low density mass which had advanced into the cecum as the lead point. The patient was diagnosed with ileocolic intussusception. The mass was observed in the terminal ileum on colonoscopy, indicating spontaneous reduction. As endoscopic treatment did not appear feasible, laparoscopic small bowel resection was performed with no complications. The resected specimen revealed a pedunculated mass over a healed ulcer. Pathology showed a deep ulcer reaching the subserosa with fibro-granulation, with no evidence of mesenteric vasculitis, thrombus, bacteria, fungi, granulomas, lipoma, or other tumors. The patient was diagnosed with ileocolic intussusception due to a fibro-granulation mass formed on a healed ulcer. Based on the patient's systemic lupus erythematosus being well controlled, the absence of other causative factors, and the discovery of several small bowel erosions on subsequent capsule endoscopy, the ulcer was strongly suspected to be drug induced. Both steroids and nonsteroidal anti-inflammatory drugs were reduced and proton pump inhibitors were discontinued by her rheumatologist after surgery. No recurrence has been observed during 4 months of follow-up.",
"affiliations": "Department of Gastroenterology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan. okamotot@luke.ac.jp.;Department of Gastroenterology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan.",
"authors": "Okamoto|Takeshi|T|http://orcid.org/0000-0001-9719-0282;Fukuda|Katsuyuki|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-020-01329-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(2)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Case report; Colonoscopy; Lipoma; Systemic lupus erythematosus",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D005260:Female; D006801:Humans; D007078:Ileal Neoplasms; D007443:Intussusception; D008067:Lipoma; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D014456:Ulcer",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "522-530",
"pmc": null,
"pmid": "33405177",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25333006",
"title": "Ileocolic intussusception caused by mass-forming fibro-granulation from healed ulcer masquerading as small bowel lipoma.",
"title_normalized": "ileocolic intussusception caused by mass forming fibro granulation from healed ulcer masquerading as small bowel lipoma"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1942061",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LOXOPROFEN"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nSince the initial recognition of coronavirus disease 2019 (COVID-19) in Wuhan, this infectious disease has spread to most areas of the world. The pathogenesis of COVID-19 is yet unclear. Hepatitis B virus (HBV) reactivation occurring in COVID-19 patients has not yet been reported.\n\n\nMETHODS\nA 45-year-old hepatitis B man with long-term use of adefovir dipivoxil and entecavir for antiviral therapy had HBV reactivation after being treated with methylprednisolone for COVID-19 for 6 d.\n\n\nCONCLUSIONS\nCOVID-19 or treatment associated immunosuppression may trigger HBV reactivation.",
"affiliations": "Department of Hepatobiliary and Pancreas Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Respiratory Disease and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Infectious Diseases, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Infectious Diseases, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Infectious Diseases, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Respiratory Disease and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Ophthalmology, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Laboratory Medicine, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Radiology, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Gastroenterology, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China.;Department of Hepatobiliary and Pancreas Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 315009, Zhejiang Province, China.;Department of Infectious Diseases, The Affiliated People's Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China. rmlixianpeng@nbu.edu.cn.",
"authors": "Wu|Yi-Feng|YF|;Yu|Wan-Jun|WJ|;Jiang|Yu-Hua|YH|;Chen|Yin|Y|;Zhang|Bo|B|;Zhen|Rui-Bing|RB|;Zhang|Jun-Tao|JT|;Wang|Yi-Ping|YP|;Li|Qiang|Q|;Xu|Feng|F|;Shi|Yan-Jun|YJ|;Li|Xian-Peng|XP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i19.5266",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i19.pg5266\n10.12998/wjcc.v9.i19.5266\nCase Report\nCOVID-19 or treatment associated immunosuppression may trigger hepatitis B virus reactivation: A case report\nWu YF et al. COVID-19 and HBV reactivation\nWu Yi-Feng Department of Hepatobiliary and Pancreas Surgery, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nYu Wan-Jun Department of Respiratory Disease and Critical Care Medicine, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nJiang Yu-Hua Department of Infectious Diseases, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nChen Yin Department of Infectious Diseases, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nZhang Bo Department of Infectious Diseases, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nZhen Rui-Bing Department of Respiratory Disease and Critical Care Medicine, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nZhang Jun-Tao Department of Ophthalmology, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nWang Yi-Ping Department of Laboratory Medicine, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nLi Qiang Department of Radiology, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nXu Feng Department of Gastroenterology, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China\n\nShi Yan-Jun Department of Hepatobiliary and Pancreas Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 315009, Zhejiang Province, China\n\nLi Xian-Peng Department of Infectious Diseases, The Affiliated People’s Hospital of Ningbo University, Ningbo 315040, Zhejiang Province, China. rmlixianpeng@nbu.edu.cn\n\nAuthor contributions: Wu YF, Yu WJ, Jiang YH, Chen Y, Zhang B, Zhen RB, Zhang JT, Wang YP, Li Q, Xu F, and Shi YJ cared for the patient; Wu YF and Li XP reviewed the literature and were primarily responsible for writing the manuscript; Li XP critically reviewed and edited the manuscript.\n\nCorresponding author: Xian-Peng Li, MD, PhD, Chief Doctor, Department of Infectious Diseases, The Affiliated People’s Hospital of Ningbo University, No. 251 Baizhang Road, Ningbo 315040, Zhejiang Province, China. rmlixianpeng@nbu.edu.cn\n\n6 7 2021\n6 7 2021\n9 19 52665269\n3 2 2021\n3 3 2021\n15 5 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/\nBACKGROUND\n\nSince the initial recognition of coronavirus disease 2019 (COVID-19) in Wuhan, this infectious disease has spread to most areas of the world. The pathogenesis of COVID-19 is yet unclear. Hepatitis B virus (HBV) reactivation occurring in COVID-19 patients has not yet been reported.\n\nCASE SUMMARY\n\nA 45-year-old hepatitis B man with long-term use of adefovir dipivoxil and entecavir for antiviral therapy had HBV reactivation after being treated with methylprednisolone for COVID-19 for 6 d.\n\nCONCLUSION\n\nCOVID-19 or treatment associated immunosuppression may trigger HBV reactivation.\n\nCOVID-19\nHepatitis B virus\nReactivation\nDiagnose\nTherapy\nCase report\n==== Body\nCore Tip: In this study, the authors found that coronavirus disease 2019 or treatment associated immunosuppression may trigger hepatitis B virus reactivation.\n\nINTRODUCTION\n\nHepatitis B virus (HBV) reactivation occurs primarily when body immunity declines due to the use of chemotherapy, long-term glucocorticoids, or immunosuppressive therapy[1]. Coronavirus disease 2019 (COVID-19) is an emerging global viral infectious disease. The pathogenesis of COVID-19 is still unclear[2]. Whether HBV reactivation occurs in COVID-19 patients has not yet been reported.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 45-year-old man was admitted to the hospital for fever and fatigue after his way back from Wuhan, China 2 d ago.\n\nHistory of present illness\n\nThe patient had a history of HBV infection for over 20 years. He was initially treated with adefovir dipivoxil and entecavir since then. Adfovir was discontinued 5 years ago.\n\nHistory of past illness\n\nThe patient had no history of high blood pressure, diabetes, heart disease, or tumor.\n\nPersonal and family history\n\nThe patient was married at the age of 25, with two sons. His wife was in good health and his family relations were harmonious. His parents were alive and healthy, and his two younger sisters were healthy.\n\nPhysical examination\n\nPhysical examination revealed no swelling of lymph nodes throughout the body, clear breath sounds in both lungs, and no rales.\n\nLaboratory examinations\n\nThe patient was positive for nucleic acid test for COVID-19. The initial laboratory results included: His blood lymphocyte count was 1.61 × 109/L, the percentage of CD4+ T cells was 32.82%, and alanine aminotransferase (ALT) and aspartate transaminase (AST) were 56 U/L and 30 U/L, respectively. After that, ALT was increased to 102 U/L, and AST was slightly increased to 48 U/L. HBV DNA was lower than the detection limit (30 IU/mL). Hepatitis B surface antigen was 1356 cutoff index (COI; < 1.000), hepatitis B surface antibody 2 iu/L (2-10 iu/L), hepatitis B e-antigen 0.34 COI (< 1.000), hepatitis B e-antibody 0.563COI (> 1.000), and hepatitis B c-antibody 0.416 COI (> 1.000).\n\nImaging examinations\n\nOn day 6, a chest computed tomography scan showed progressive pneumonia.\n\nFINAL DIAGNOSIS\n\nCOVID-19 and hepatitis B virus infection.\n\nTREATMENT\n\nAfter admission, the patient was treated with recombinant interferon-alpha-2b and lopinavir/ritonavir. Following this, he was treated with methylprednisolone (40 mg once daily). His lymphocyte count continued its downtrend to 0.89 × 109/L, CD4+ T cells further declined to 27.14%, and liver enzymes ALT and AST showed no significant changes. HBV DNA was increased to 1.11 × 102 IU/mL, although it was actually negative before this admission (Figure 1). Hence, tenofovir fumarate was added for possible HBV reactivation.\n\nFigure 1 Time-course of CD4+ T cells, lymphocyte count, alanine aminotransferase, aspartate transaminase, and hepatitis B virus DNA. A: CD4+ T cells, lymphocyte count, and hepatitis B virus (HBV) DNA; B: Alanine aminotransferase, aspartate transaminase, and HBV DNA. ALT: Alanine aminotransferase; AST: Aspartate transaminase; HBV: Hepatitis B virus.\n\nOUTCOME AND FOLLOW-UP\n\nThe patient started to be afebrile, and liver enzymes ALT and AST decreased to 42 U/L and 17 U/L, respectively. The nucleic acid test for COVID-19 became negative twice then. HBV DNA became lower than the detection limit (30 IU/mL). HBV drug resistance gene of the HBV P region was negative too. Then, the patient was discharged. Both liver enzymes and HBV DNA were within normal range after discharge from hospital.\n\nDISCUSSION\n\nAs we know, unstandardized administration of nucleos(t)ide analog, glucocorticoids, chemotherapy drugs, and new biological agents such as monoclonal antibodies and antiviral drugs of hepatitis B virus can cause HBV reactivation[1]. This patient had used adefovir dipivoxil and entecavir for antiviral therapy for a long time. His HBV DNA was negative before the development of COVID-19. He had elevated liver enzymes and increased HBV DNA during the treatment of COVID-19. Thus, according to American Association for the Study of Liver Diseases guideline about the definition of HBV reactivation, he met the criteria for HBV reactivation. Besides, the long term usage of antiviral drugs that may cause HBV resistance to NAs is also possible[3]. However, his HBV resistance gene was tested and negative for entecavir and adefovir dipivoxil. Noncompliance is another reason that causes HBV reactivation[3], but our patient was followed in the clinic regularly, and he did not discontinue or reduce dose without physician’s advice. Therefore, it could be possible that HBV reactivation in this patient was caused by COVID-19 or related treatment. The mechanism of HBV reactivation is not yet fully understood. Once the immune homeostasis between the virus and the body is disturbed, HBV reactivation may occur[4]. Previous studies have shown that COVID-19 patients may have impaired immune function and lower lymphocyte count, especially CD4+ T lymphocytes[2]. And glucocorticoid usage may decrease cellular immune function sharply. As a novel infectious disease, the pathogenesis of COVID-19 is yet unclear. This is the first case report of COVID-19 complicated with HBV reactivation.\n\nCONCLUSION\n\nFor COVID-19 patients complicated with hepatitis B, HBV reactivation may happen, and glucocorticoids need to be used cautiously.\n\nInformed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest to report.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist, and the manuscript was prepared and revised according to the CARE Checklist.\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: February 3, 2021\n\nFirst decision: February 28, 2021\n\nArticle in press: May 15, 2021\n\nSpecialty type: Infectious Diseases\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C\n\nGrade D (Fair): D, D\n\nGrade E (Poor): 0\n\nP-Reviewer: Hammad M, Lashen SA, Pavides M S-Editor: Wang JL L-Editor: Wang TQ P-Editor: Xing YX\n==== Refs\n1 Perrillo RP Gish R Falck-Ytter YT American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148: 221-244 e3\n2 Winker B [Remarks on the so-called feeling of hysteria] Nervenarzt 1988 59 752 753 3216940\n3 Ganem D Prince AM Hepatitis B virus infection--natural history and clinical consequences N Engl J Med 2004 350 1118 1129 15014185\n4 Loomba R Liang TJ Hepatitis B Reactivation Associated With Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions Gastroenterology 2017 152 1297 1309 28219691\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(19)",
"journal": "World journal of clinical cases",
"keywords": "COVID-19; Case report; Diagnose; Hepatitis B virus; Reactivation; Therapy",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "5266-5269",
"pmc": null,
"pmid": "34307577",
"pubdate": "2021-07-06",
"publication_types": "D002363:Case Reports",
"references": "15014185;25447852;28219691;3216940",
"title": "COVID-19 or treatment associated immunosuppression may trigger hepatitis B virus reactivation: A case report.",
"title_normalized": "covid 19 or treatment associated immunosuppression may trigger hepatitis b virus reactivation a case report"
} | [
{
"companynumb": "CN-GILEAD-2021-0541519",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome seen primarily in children. It is characterized by pathologic systemic hyper inflammation which in adults is easily overlooked due to non-specific clinical features. Most of the data available are on paedriatic population, making the diagnosis of HLH in adults challenging for the clinician. Here we report a case of HLH in a 48-year male who presented with pyrexia of unknown origin for 2 months but remained undiagnosed despite extensive workup. Due to a high index of suspicion, re-evaluation of bone marrow biopsy was done which showed hemophagocytosis, earlier reported as normal. It led to specific investigations, needed for establishing the diagnostic criteria of HLH. Even though chemotherapy was initiated, the patient did not survive. The aggressive nature of this disease makes it crucial for the physician to be aware of its signs and symptoms for the early diagnosis and immediate introduction of adequate treatment.",
"affiliations": "Department of Medicine, Liaquat National Hospital and Medical College, Karachi.;Department of Hematology, Liaquat National Hospital and Medical College, Karachi.;Department of Medicine, Liaquat National Hospital and Medical College, Karachi.",
"authors": "Bandhani|Asma|A|;Raza|Naila|N|;Ahmed|Kamal|K|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "26(6 Suppl)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D001706:Biopsy; D001853:Bone Marrow; D017809:Fatal Outcome; D005334:Fever; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "S56-8",
"pmc": null,
"pmid": "27376224",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemophagocytic Lymphohistiocytosis in an Adult: A Rapidly Progressive Disease with Grave Outcome.",
"title_normalized": "hemophagocytic lymphohistiocytosis in an adult a rapidly progressive disease with grave outcome"
} | [
{
"companynumb": "PK-FRESENIUS KABI-FK201706107",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nThe objective of this study was to evaluate the effect of a single intravenous dose of tocilizumab (TCZ) on pharmacokinetics (PK) of oral contraceptive (OC; norethindrone (NE) and ethinyl estradiol (EE)) and on sex hormone levels (progesterone (PG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)) in subjects with active rheumatoid arthritis (RA) who were on stable doses of methotrexate.\n\n\nMETHODS\nThis was an open-label, nonrandomized, multicenter, two-parallel group, one-sequence crossover study. In Group 1, Cycle 1 was a baseline cycle to determine the PK of OC and levels of sex hormones. At the start of Cycle 2, patients continued to receive OC and single TCZ dosing on Day 1. In Cycle 2, we determined the PK of OC and levels of sex hormones when OC and TCZ were combined. In Cycle 3, we determined the PK of OC and the levels of sex hormones after TCZ treatment was stopped. PK for EE and NE were analyzed serially on Day 7 when maximum TCZ effect on inflammation as indicated by C-reactiv protein (CRP) was expected. Hormone levels (PG, LH and FSH) were measured mid-cycle (cycle Days 12 - 16 and Day 21) during each cycle. Group 2 (healthy subjects) was studied to compare the levels of OC PK exposures with those in each cycle of Group 1 (RA subjects).\n\n\nRESULTS\nLevels of PG, LH and FSH were not affected by the combination of TCZ/OC treatment in RA patients studied. No breakthrough bleeding was attributed to the initiation of TCZ treatment in subjects receiving OCs. PK exposures of EE and NE were similar between RA and healthy subjects at baseline and were not affected by single-dose TCZ. Administration of OC with or without a single dose of TCZ was well tolerated.\n\n\nCONCLUSIONS\nData from this study indicated that the PK and sex hormone levels were not affected in RA subjects who had active disease and were on a stable regimen of methotrexate.",
"affiliations": null,
"authors": "Zhang|Xiaoping|X|;Rowell|Lucy|L|;Fettner|Scott|S|;Lau|Carol|C|;Teuber|Denise|D|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003276:Contraceptives, Oral; D019947:Receptors, Interleukin-6; D004997:Ethinyl Estradiol; D011374:Progesterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002097:C-Reactive Protein; C502936:tocilizumab; D009640:Norethindrone",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP201951",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "52(1)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid; D002097:C-Reactive Protein; D003276:Contraceptives, Oral; D018592:Cross-Over Studies; D004347:Drug Interactions; D004997:Ethinyl Estradiol; D005260:Female; D005640:Follicle Stimulating Hormone; D006801:Humans; D007986:Luteinizing Hormone; D009640:Norethindrone; D011374:Progesterone; D019947:Receptors, Interleukin-6",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "27-38",
"pmc": null,
"pmid": "24161161",
"pubdate": "2014-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Assessment of disease-drug-drug interaction between single-dose tocilizumab and oral contraceptives in women with active rheumatoid arthritis.",
"title_normalized": "assessment of disease drug drug interaction between single dose tocilizumab and oral contraceptives in women with active rheumatoid arthritis"
} | [
{
"companynumb": "US-JNJFOC-20140211303",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MESTRANOL\\NORETHINDRONE"
},
"drugadditional": nu... |
{
"abstract": "The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.",
"affiliations": "Faculty of Medicine, University of Melbourne, Victoria, Australia.;Weill Cornell Medical College, Doha, Qatar.;Department of Medicine, Royal North Shore Hospital, Saint Leonards, NSW, Australia.;Department of Medicine, Tauranga Hospital, Tauranga, New Zealand.;Department of Haematology, Palmerston North Hospital, Palmerston North, New Zealand.;Department of Medicine, Auckland Hospital, Auckland, New Zealand.;Department of Medicine, Middlemore Hospital, Auckland, New Zealand.;Department of Haematology, Gosford Hospital, North Gosford, NSW, Australia.;Department of Medicine, Border Medical Oncology, Albury-Wodonga, Vic., Australia.;Department of Medicine, Royal Perth Hospital, Perth, WA, Australia.;Department of Medicine, Concord Hospital, Concord, NSW, Australia.;Department of Medicine, Dunedin Hospital, Dunedin, New Zealand.;Faculty of Medicine, University of Melbourne, Victoria, Australia.;Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Victoria, Vic., Australia.;Celgene Corporation, Summit, NJ, USA.;Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Victoria, Vic., Australia.;Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.;Faculty of Medicine, University of Melbourne, Victoria, Australia.",
"authors": "Quach|Hang|H|;Fernyhough|Liam|L|;Henderson|Ross|R|;Corbett|Gillian|G|;Baker|Bart|B|;Browett|Peter|P|;Blacklock|Hilary|H|;Forsyth|Cecily|C|;Underhill|Craig|C|;Cannell|Paul|P|;Trotman|Judith|J|0000-0001-8009-4593;Neylon|Annette|A|;Harrison|Simon|S|;Link|Emma|E|;Swern|Arlene|A|;Cowan|Linda|L|;Dimopoulos|Meletios A|MA|;Miles Prince|H|H|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14562",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "177(3)",
"journal": "British journal of haematology",
"keywords": "dose-attenuation; elderly; frail; lenalidomide; multiple myeloma",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D013792:Thalidomide",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "441-448",
"pmc": null,
"pmid": "28197996",
"pubdate": "2017-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study.",
"title_normalized": "upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma final analysis of the phase ii revlite study"
} | [
{
"companynumb": "AU-CELGENEUS-AUS-2015082157",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection.\n\n\nMETHODS\nIn this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796.\n\n\nRESULTS\n700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI -1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, -6 to 8; p<0·001).\n\n\nCONCLUSIONS\nIf regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection.\n\n\nBACKGROUND\nGilead Sciences.",
"affiliations": "Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: psax@partners.org.;Orlando Immunology Center, Orlando, FL, USA.;Anthony Mills MD, Los Angeles, CA, USA.;Stanford University, Palo Alto, CA, USA.;Community Research Initiative of New England, Boston, MA, USA.;University of North Carolina, Chapel Hill, NC, USA.;University of North Carolina, Chapel Hill, NC, USA.;Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Gilead Sciences, Foster City, CA, USA.;Gilead Sciences, Foster City, CA, USA.;Gilead Sciences, Foster City, CA, USA.;Gilead Sciences, Foster City, CA, USA.;Gilead Sciences, Foster City, CA, USA.;Gilead Sciences, Foster City, CA, USA.;Gilead Sciences, Foster City, CA, USA.",
"authors": "Sax|Paul E|PE|;DeJesus|Edwin|E|;Mills|Anthony|A|;Zolopa|Andrew|A|;Cohen|Calvin|C|;Wohl|David|D|;Gallant|Joel E|JE|;Liu|Hui C|HC|;Zhong|Lijie|L|;Yale|Kitty|K|;White|Kirsten|K|;Kearney|Brian P|BP|;Szwarcberg|Javier|J|;Quirk|Erin|E|;Cheng|Andrew K|AK|;|||",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; D063065:Organophosphonates; D015363:Quinolones; D013844:Thiazoles; D003841:Deoxycytidine; C509700:elvitegravir; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz; D000069547:Cobicistat",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(12)60917-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "379(9835)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D002219:Carbamates; D000069547:Cobicistat; D003521:Cyclopropanes; D003841:Deoxycytidine; D004311:Double-Blind Method; D004338:Drug Combinations; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D015363:Quinolones; D000068698:Tenofovir; D013844:Thiazoles",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "2439-2448",
"pmc": null,
"pmid": "22748591",
"pubdate": "2012-06-30",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks.",
"title_normalized": "co formulated elvitegravir cobicistat emtricitabine and tenofovir versus co formulated efavirenz emtricitabine and tenofovir for initial treatment of hiv 1 infection a randomised double blind phase 3 trial analysis of results after 48 weeks"
} | [
{
"companynumb": "US-CIPLA (EU) LIMITED-2018US16723",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EFAVIRENZ\\EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
... |
{
"abstract": "Epigenetic regulators, including Jumonji domain 2 (JMJD2/KDM4) proteins are involved in post-translational modification of histone demethylation and have a major role in carcinogenesis of many solid tumors.\n\n\n\nWe assessed immunohistochemically the expression of lysine (K)-specific demethylase 4 (KDM4)A, KDM4B and KDM4D in tumors from 91 patients of adriamycin, bleomycin, vinblastine, darcabazine (ABVD)-treated classical Hodgkin lymphoma.\n\n\n\nStrong cytoplasmic KDM4B expression in the reactive cellular infiltrate and also in Reed-Sternberg (RS) cells predicted poor relapse-free survival (RFS) (p=0.020 and p=0.022, respectively) in patients with limited-stage disease. Strong KDM4B expression in RS cells was also related to B-symptoms (p=0.007) and advanced stage (p=0.024). Strong KDM4D expression in the cytoplasm of RS cells was also associated with poor RFS in limited-stage patients RFS (p=0.043) and, most significantly, in patients receiving involved-field radiotherapy (p=0.007).\n\n\n\nKDM4B and KDM4D expression may associate with an aggressive subtype of classical Hodgkin lymphoma and be linked with radioresistance.",
"affiliations": "Department of Oncology and Radiotherapy, Oulu University Hospital and University of Oulu, Oulu, Finland.;Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.;Department of Oncology and Radiotherapy, Oulu University Hospital and University of Oulu, Oulu, Finland.;Department of Oncology and Radiotherapy, Oulu University Hospital and University of Oulu, Oulu, Finland.;Department of Oncology, Cancer Center of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.;Department of Oncology, Cancer Center of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.;Department of Pathology and Forensic Medicine, University of Eastern Finland, Cancer Center of Eastern Finland, Kuopio, Finland.;Department of Oncology and Radiotherapy, Oulu University Hospital and University of Oulu, Oulu, Finland peeter.karihtala@oulu.fi.",
"authors": "Bur|Hamid|H|;Haapasaari|Kirsi-Maria|KM|;Turpeenniemi-Hujanen|Taina|T|;Kuittinen|Outi|O|;Auvinen|Päivi|P|;Marin|Katja|K|;Soini|Ylermi|Y|;Karihtala|Peeter|P|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; C521694:KDM4D protein, human",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(9)",
"journal": "Anticancer research",
"keywords": "Hodgkin lymphoma; KDM4B; KDM4D; radioresistance",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003593:Cytoplasm; D003606:Dacarbazine; D018572:Disease-Free Survival; D004317:Doxorubicin; D044127:Epigenesis, Genetic; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease; D006801:Humans; D007150:Immunohistochemistry; D056484:Jumonji Domain-Containing Histone Demethylases; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D014747:Vinblastine; D055815:Young Adult",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4677-83",
"pmc": null,
"pmid": "27630312",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Strong KDM4B and KDM4D Expression Associates with Radioresistance and Aggressive Phenotype in Classical Hodgkin Lymphoma.",
"title_normalized": "strong kdm4b and kdm4d expression associates with radioresistance and aggressive phenotype in classical hodgkin lymphoma"
} | [
{
"companynumb": "FI-JNJFOC-20161110929",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DACARBAZINE"
},
"drugadditional": null,
... |
{
"abstract": "We report the first New Zealand case of Anncaliia algerae myositis in a 55-year-old man with a history of psoriatic arthritis, treated with long-term immunosuppressive therapy. He resided in the city of Rotorua, which is famous for geothermal hot springs. A vastus lateralis muscle biopsy was performed to investigate the cause of an unexplained myositis. Light microscopy demonstrated a necrotizing myositis with scattered clusters of ovoid spores within the myocyte cytoplasm resembling microsporidia. DNA analysis by PCR and electron microscopy confirmed microsporidial myositis with features characteristic of A. algerae. Immunosuppressive drugs were stopped and the patient was treated with cholestyramine wash and albendazole. The patient deteriorated with involvement of bulbar and respiratory muscles requiring intensive care and ventilation. He died 3 weeks after diagnosis. Post-mortem examination of skeletal muscle from tongue and intercostal muscles also revealed numerous organisms confirming disseminated disease.",
"affiliations": "Department of Pathology, Waikato Hospital, Private Bag 3200, Hamilton 3240, New Zealand. Electronic address: Fouzia.Ziad@waikatodhb.health.nz.;Pathology Queensland, Royal Brisbane and Women's Hospital, Australia.;Centre for Infectious Diseases and Microbiology, Pathology West-ICPMR and Marie Bashir Institute, University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia.;Pathlab Bay of Plenty, New Zealand.;QE Health, Rotorua, New Zealand.;Dunedin School of Medicine, New Zealand.;St Vincent's Hospital, Darlinghurst, New South Wales, Australia.;Anatomical Pathology, LabPlus, Auckland City Hospital, New Zealand.;Anatomical Pathology, LabPlus, Auckland City Hospital, New Zealand.;Lakes District Health Board, Rotorua, New Zealand.",
"authors": "Ziad|Fouzia|F|;Robertson|Thomas|T|;Watts|Matthew R|MR|;Copeland|Justin|J|;Chiu|Graham|G|;Wang|David|D|;Stark|Damien|D|;Graham|Linda|L|;Turner|Clinton|C|;Newbury|Richard|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.nmd.2021.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8966",
"issue": "31(9)",
"journal": "Neuromuscular disorders : NMD",
"keywords": "Anncaliia Algerae; Immunocompromised; Microsporidia; Myositis",
"medline_ta": "Neuromuscul Disord",
"mesh_terms": null,
"nlm_unique_id": "9111470",
"other_id": null,
"pages": "877-880",
"pmc": null,
"pmid": "34391631",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal disseminated Anncaliia algerae myositis mimicking polymyositis in an immunocompromised patient.",
"title_normalized": "fatal disseminated anncaliia algerae myositis mimicking polymyositis in an immunocompromised patient"
} | [
{
"companynumb": "NZ-SA-2021SA276329",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Herpes simplex virus (HSV) is a common cause of viral encephalitis that can lead to refractory seizures. The primary treatment of HSV encephalitis is with acyclovir; however, surgery sometimes plays a role in obtaining tissue diagnosis or decompression in cases with severe mass effect. We report a unique case in which anterior temporal lobectomy was successfully used to treat refractory status epilepticus in HSV encephalitis.\n\n\n\nCase report and review of the literature.\n\n\n\nWe report a case of a 60-year-old man with HSV encephalitis, who presented with seizures originating from the right temporal lobe refractory to maximal medical management. Right anterior temporal lobectomy was performed for the purpose of treatment of refractory status epilepticus and obtaining tissue diagnosis, with ultimate resolution of seizures and excellent functional outcome.\n\n\n\nWe suggest that anterior temporal lobectomy should be considered in cases of HSV encephalitis with refractory status epilepticus with clear unilateral origin.",
"affiliations": "Department of Neurosurgery, Massachusetts General Hospital, Wang 021, 55 Fruit Street, Boston, MA, 02114, USA. sbick@partners.org.;Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.;Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.;Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.;Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.;Department of Neurosurgery, Massachusetts General Hospital, Wang 021, 55 Fruit Street, Boston, MA, 02114, USA.",
"authors": "Bick|Sarah K B|SK|0000-0003-0753-1720;Izzy|Saef|S|;Rubin|Daniel B|DB|;Zafar|Sahar F|SF|;Rosenthal|Eric S|ES|;Eskandar|Emad N|EN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12028-016-0302-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1541-6933",
"issue": "25(3)",
"journal": "Neurocritical care",
"keywords": "Epilepsy; HSV encephalitis; Status epilepticus; Temporal lobectomy",
"medline_ta": "Neurocrit Care",
"mesh_terms": "D038481:Anterior Temporal Lobectomy; D000069279:Drug Resistant Epilepsy; D020803:Encephalitis, Herpes Simplex; D006801:Humans; D008297:Male; D008875:Middle Aged; D013226:Status Epilepticus",
"nlm_unique_id": "101156086",
"other_id": null,
"pages": "458-463",
"pmc": null,
"pmid": "27473208",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "11488652;18173329;25462089;26543817;18580790;9328248;8323470;17621524;16675036;12614407;22527234;22543444;1592035;11511960;9040731;11834266;18826364;3001520;18430984;11395286;15699401;15270771;18773140;22674925;3675261",
"title": "Anterior Temporal Lobectomy for Refractory Status Epilepticus in Herpes Simplex Encephalitis.",
"title_normalized": "anterior temporal lobectomy for refractory status epilepticus in herpes simplex encephalitis"
} | [
{
"companynumb": "US-UCBSA-2017003539",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nTo present a case of the use of alteplase for the successful resolution of an upper extremity occlusion in a newborn receiving extracorporeal membrane oxygenation (ECMO).\n\n\nMETHODS\nA two-day-old full-term Hispanic girl receiving ECMO support developed a left upper extremity occlusion distal to the brachial artery. Alteplase therapy was initiated with a bolus dose of 0.48 mg/kg followed by a continuous infusion of 0.27 mg/kg/h for three hours. A repeat Doppler ultrasound revealed little improvement, resulting in continuation of alteplase therapy at an infusion rate of 0.27 mg/kg/h for an additional three hours. At the completion of the infusion, perfusion was greatly improved with palpable radial pulse present. While remaining on ECMO support, a brain ultrasound approximately 13 hours after alteplase therapy revealed a grade I right caudate head hemorrhage with normal ventricles. ECMO support was discontinued during the next 24 hours, with a repeat brain ultrasound three days later indicating no acute hemorrhage, normal ventricles, and almost complete resolution of the intraventricular hemorrhage. The neonate was discharged 19 days after discontinuing ECMO support.\n\n\nCONCLUSIONS\nPatients receiving ECMO support are at risk of hematologic complications, including thrombi formation. Moreover, limited information is available regarding the most appropriate thrombolytic therapy for patients receiving ECMO support. Alteplase is an attractive thrombolytic agent given its antigenicity, clot specificity, and pharmacokinetic profile. However, both ECMO support and thrombolytic therapy are risk factors for the development of intraventricular hemorrhage, which our patient developed. Therefore, close monitoring of patients receiving ECMO support and alteplase therapy is essential given the potential for hematologic adverse effects.\n\n\nCONCLUSIONS\nAlteplase is an effective thrombolytic agent in neonates receiving ECMO support. Additional experience with alteplase is necessary to determine the optimal dose and duration of therapy in this patient population.",
"affiliations": "Department of Pharmacy Practice, College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA.",
"authors": "Glover|M L|ML|;Camacho|M T|MT|;Wolfsdorf|J|J|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.18334",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "33(4)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D001132:Arm; D001157:Arterial Occlusive Diseases; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D007231:Infant, Newborn; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "416-9",
"pmc": null,
"pmid": "10332531",
"pubdate": "1999-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The use of alteplase in a newborn receiving extracorporeal membrane oxygenation.",
"title_normalized": "the use of alteplase in a newborn receiving extracorporeal membrane oxygenation"
} | [
{
"companynumb": "US-ROCHE-1898051",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo assess whether oral ketamine is safe at higher dosages for sedating children and whether it may be an option for the control of chronic pain in children.\n\n\nMETHODS\nA prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.25-1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment.\n\n\nRESULTS\nTwo participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, 2 with complete resolution of pain, lasting >4 weeks off ketamine treatment.\n\n\nCONCLUSIONS\nOral ketamine at dosages of 0.25-1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain.",
"affiliations": "Departments of Pediatrics and Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. bredlau@musc.edu",
"authors": "Bredlau|Amy-Lee|AL|;McDermott|Michael P|MP|;Adams|Heather R|HR|;Dworkin|Robert H|RH|;Venuto|Charles|C|;Fisher|Susan G|SG|;Dolan|James G|JG|;Korones|David N|DN|",
"chemical_list": "D000700:Analgesics; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "163(1)",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000700:Analgesics; D002648:Child; D059350:Chronic Pain; D005260:Female; D006801:Humans; D007649:Ketamine; D008297:Male; D010865:Pilot Projects; D011446:Prospective Studies; D055815:Young Adult",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "194-200.e1",
"pmc": null,
"pmid": "23403253",
"pubdate": "2013-07",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "7272143;23979309;21803783;15621359;19359097;2823161;15733628;10680109;22131399;12177794;8004881;11027905;22250028;22205203;10454501;7667557;19783371;21788321;17525784;19604642;8697554;12065445;18990467;10360847;2350571;22078064",
"title": "Oral ketamine for children with chronic pain: a pilot phase 1 study.",
"title_normalized": "oral ketamine for children with chronic pain a pilot phase 1 study"
} | [
{
"companynumb": "US-MYLANLABS-2017M1007252",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "Central nervous system lymphoproliferative disorder (CNS-PTLD) after organ transplant is a unique clinicopathological entity and is associated with poor survival rates. When the CNS is involved, intravenous rituximab might not be the treatment of choice, due to its poor CNS penetration. However, intrathecal (IT) administration of rituximab has shown to be safe and efficient in small studies and in case series. We report here the case of a patient with late development of CNS-PTLD after kidney-pancreas transplantation who achieved complete remission after surgical resection and four cycles of IT rituximab and we provide a review of the literature for this treatment option.",
"affiliations": "Oncology, Division Hematology, Hopitaux Universitaires de Geneve, Geneva, Switzerland maria.anastasiou@hcuge.ch.;Oncology, Division Hematology, Hopitaux Universitaires de Geneve, Geneva, Switzerland.;Oncology, Division Hematology, Hopitaux Universitaires de Geneve, Geneva, Switzerland.;Neuroradiology, Hopitaux Universitaires de Geneve, Geneva, Switzerland.;Nephrology, Hopitaux Universitaires de Geneve, Geneva, Switzerland.;Service of Clinical Pathology, Department of Genetic Medicine, Laboratory and Pathology, Hopitaux Universitaires de Geneve, Geneva, Switzerland.;Oncology, Division Hematology, Hopitaux Universitaires de Geneve, Geneva, Switzerland.",
"authors": "Anastasiou|Maria|M|;Mamez|Anne-Claire|AC|;Masouridi|Stavroula|S|;Vargas|Maria Isabel|MI|;Hadaya|Karine|K|;Egervari|Kristof|K|;Chalandon|Yves|Y|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238236",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "CNS cancer; haematology (drugs and medicines); haematology (incl blood transfusion); malignant disease and immunosuppression; neuroimaging",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D002490:Central Nervous System; D006801:Humans; D007668:Kidney; D008232:Lymphoproliferative Disorders; D010179:Pancreas; D000069283:Rituximab; D013234:Stem Cells",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34353823",
"pubdate": "2021-08-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of central nervous system lymphoproliferative disorder in a kidney-pancreas and stem cell transplanted patient using intrathecal rituximab.",
"title_normalized": "successful treatment of central nervous system lymphoproliferative disorder in a kidney pancreas and stem cell transplanted patient using intrathecal rituximab"
} | [
{
"companynumb": "FR-SHILPA MEDICARE LIMITED-SML-FR-2021-01117",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugaddi... |
{
"abstract": "Second primary diffuse large B cell lymphoma (spDLBCL) is defined as a metachronous tumor occurring after a first primary cancer. To date, while R-CHOP is the standard first-line treatment for de novo DLBCL, no available data show that R-CHOP is the optimal treatment for spDLBCL. This exploratory study aimed to investigate treatment of spDLBCL. From 2008 to 2015, the Poitou-Charentes general cancer registry recorded 68 cases of spDLBCL ≤ 80 years old, having received a first-line treatment with either R-CHOP (78%) or other regimens (22%). Patients without R-CHOP have worse overall survival in univariate (HR 2.89 [1.33-6.24], P = 0.007) and multivariate (HR 2.98 [1.34-6.67], P = 0.008) analyses. Patients without R-CHOP more frequently had PS > 1 (67% vs. 28%, P = 0.007) and prior chemotherapy (60% vs. 26%, P = 0.02), which suggests that both of these factors influence a clinician's decision to not use R-CHOP. Prior chemotherapy had no prognostic impact in univariate and multivariate analyses; this result could call into question the risk-benefit balance of not using R-CHOP to prevent toxicity. In our study, one DLBCL out of ten occurred after a first primary cancer, and as regards de novo DLBCL, R-CHOP appeared to be the best first-line treatment. Larger series are needed to confirm these results.",
"affiliations": "Poitou-Charentes General Cancer Registry, Université de Poitiers, 6 rue de la Milétrie, 86073, Poitiers Cedex 9, France. tsystchenko@orange.fr.;Poitou-Charentes General Cancer Registry, Université de Poitiers, 6 rue de la Milétrie, 86073, Poitiers Cedex 9, France.;INSERM CIC 1402, CHU de Poitiers, Poitiers, France.;Anatomy-pathology Department, CHU de Toulouse, Réseau Lymphopath, Toulouse, France.;Poitou-Charentes General Cancer Registry, Université de Poitiers, 6 rue de la Milétrie, 86073, Poitiers Cedex 9, France.;Anatomy-pathology Department, CHU de Poitiers, Poitiers, France.;Haematology Department, CHU de Poitiers, Poitiers, France.;Haematology Department, CHU de Poitiers, Poitiers, France.;INSERM CIC 1402, CHU de Poitiers, Poitiers, France.;INSERM CIC 1402, CHU de Poitiers, Poitiers, France.;Poitou-Charentes General Cancer Registry, Université de Poitiers, 6 rue de la Milétrie, 86073, Poitiers Cedex 9, France.",
"authors": "Systchenko|T|T|https://orcid.org/0000-0003-0507-1740;Defossez|G|G|;Guidez|S|S|;Laurent|C|C|;Puyade|M|M|;Debiais-Delpech|C|C|;Dreyfus|B|B|;Machet|A|A|;Leleu|X|X|;Delwail|V|V|;Ingrand|P|P|",
"chemical_list": "D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04100-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(7)",
"journal": "Annals of hematology",
"keywords": "Diffuse large B cell lymphoma; Prior chemotherapy; R-CHOP; Second primary neoplasms",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D005602:France; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016609:Neoplasms, Second Primary; D011241:Prednisone; D011379:Prognosis; D012042:Registries; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1605-1613",
"pmc": null,
"pmid": "32451709",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": "28761745;23558444;26314773;11807147;17389762;27377716;14504078;17105812;27909221;19689822;20414658;26223361;17654614;24220559;28524259;21266519;29439113",
"title": "R-CHOP appears to be the best first-line treatment for second primary diffuse large B cell lymphoma: a cancer registry study.",
"title_normalized": "r chop appears to be the best first line treatment for second primary diffuse large b cell lymphoma a cancer registry study"
} | [
{
"companynumb": "NVSC2020FR151155",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "A young woman with ulcerative colitis developed pneumonia, which responded to corticosteroids. Histological examination showed this to be bronchiolitis obliterans organising pneumonia.",
"affiliations": "Regional Cardiothoracic Unit, Freeman Hospital, Newcastle upon Tyne.",
"authors": "Swinburn|C R|CR|;Jackson|G J|GJ|;Cobden|I|I|;Ashcroft|T|T|;Morritt|G N|GN|;Corris|P A|PA|",
"chemical_list": "D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/thx.43.9.735",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-6376",
"issue": "43(9)",
"journal": "Thorax",
"keywords": null,
"medline_ta": "Thorax",
"mesh_terms": "D000328:Adult; D001989:Bronchiolitis Obliterans; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D008168:Lung; D011014:Pneumonia; D011239:Prednisolone; D011859:Radiography",
"nlm_unique_id": "0417353",
"other_id": null,
"pages": "735-6",
"pmc": null,
"pmid": "3194883",
"pubdate": "1988-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "5697529;1267553;7444824;2863097;6647749;3965933;4023983;7267968",
"title": "Bronchiolitis obliterans organising pneumonia in a patient with ulcerative colitis.",
"title_normalized": "bronchiolitis obliterans organising pneumonia in a patient with ulcerative colitis"
} | [
{
"companynumb": "GB-ALLERGAN-1640666",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "BACKGROUND\nAlthough gemcitabine is thought to play a critical role in the treatment of nasopharyngeal cancer, no research to evaluate the efficacy and toxicity of gemcitabine monotherapy has been conducted in Japan.\n\n\nMETHODS\nWe retrospectively reviewed eight nasopharyngeal carcinoma patients treated with gemcitabine monotherapy at National Cancer Center Hospital East between May 2015 and August 2016. The main eligibility criteria were (1) histopathologically proven NPC; (2) tumor recurrence or an initial M1 TNM stage diagnosis; (3) at least two other types of systemic chemotherapy prior to gemcitabine; (4) no other active malignant tumor during treatment.\n\n\nRESULTS\nAll patients were administered gemcitabine 800-1000 mg/m2 on days 1, 8, and 15, repeated every 4 weeks. Gemcitabine was given as third-line systemic chemotherapy in six (74%) patients, as fourth-line in one (13%) and as fifth-line in one (13%). One patient had a complete response and one had a partial response, giving an overall response rate of 25%; four patients (50%) had stable disease and two (25%) experienced disease progression. The main toxicity was myelosuppression, with grade 3 leukopenia in three (38%) patients and neutropenia in four (50%). There were no treatment-related deaths. Median dose intensity and relative dose intensity of gemcitabine were 620 mg/m2/week and 97.5%, respectively.\n\n\nCONCLUSIONS\nOur findings suggest that GEM monotherapy is well tolerated and has potential as an active agent in Japanese patients with recurrent/metastatic NPC who have been heavily pretreated.",
"affiliations": "Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Division of Pharmacy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.;Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. mataharas@east.ncc.go.jp.",
"authors": "Enokida|Tomohiro|T|;Uozumi|Shinya|S|;Fujisawa|Takao|T|;Ueda|Yuri|Y|;Okano|Susumu|S|;Tahara|Makoto|M|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-017-1152-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "22(6)",
"journal": "International journal of clinical oncology",
"keywords": "Gemcitabine; Locoregional; Nasopharyngeal cancer/DT; Neoplasm metastasis; Neoplasm recurrence",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D044466:Asians; D002277:Carcinoma; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D009503:Neutropenia; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "1009-1014",
"pmc": null,
"pmid": "28616753",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "25220842;27567279;17909810;11865813;22684794;10093695;10561261;12676255;15612023;20716628;22454646;22076785;7918127;22937482;20153243",
"title": "Gemcitabine monotherapy in patients with heavily treated nasopharyngeal cancer: a case series.",
"title_normalized": "gemcitabine monotherapy in patients with heavily treated nasopharyngeal cancer a case series"
} | [
{
"companynumb": "JP-TEVA-2018-JP-002017J",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "BACKGROUND\nLeprosy relapse/recurrence is a serious concern particularly in a leprosy-endemic nation such as India. It is believed that bacilli persisting even after multidrug therapy can cause relapse; recently, however, drug resistance as a cause for recurrences and chronic erythema nodosum leprosum (ENL) has been speculated.\n\n\nOBJECTIVE\nTo study drug-resistance patterns in cases of leprosy relapse and chronic/recurrent (c/r)ENL.\n\n\nMETHODS\nThis cross-sectional study conducted over a period of 1 year included patients diagnosed as having leprosy relapse and those with c/rENL. Skin biopsy specimens were examined by conventional PCR for resistance testing for rifampicin, dapsone and ofloxacin, respectively targeting the rpoB, folP and gyrA genes of Mycobacterium leprae.\n\n\nRESULTS\nIn total, 61 patients (25 smear-negative) were included in the study. Of these, 37 were diagnosed as having leprosy relapse and 24 as having c/rENL. Drug resistance to at least one drug was identified in 10 cases (16.4%). Rates of drug resistance were 5.4% (2 of 37) for dapsone, 10.8% (4 of 37) for rifampicin and 2.7% (1 of 37) for ofloxacin among cases of relapse, whereas it was 12.5% (3 of 24) and 8.3% (2 of 24) for dapsone and rifampicin respectively among those with c/rENL. Multidrug resistance was seen in 3.3% patients (2 of 61).\n\n\nCONCLUSIONS\nDrug-resistance rate among those with c/rENL was almost equalled that of relapse. Smear-negative leprosy relapse cases also had resistance to bactericidal drugs. These findings call for modifications in criteria for testing under leprosy drug-resistance surveillance and all cases of relapse and those with recalcitrant c/rENL should be tested.",
"affiliations": "Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Enteric Viruses Group, ICMR-National Institute of Virology, Pune, India.;Department of Molecular Biology, Stanley Browne Laboratory, TLM Community Hospital, New Delhi, India.;Department of Molecular Biology, Stanley Browne Laboratory, TLM Community Hospital, New Delhi, India.;Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Narang|T|T|https://orcid.org/0000-0002-0464-2989;Kamat|D|D|https://orcid.org/0000-0002-6526-9575;Thakur|V|V|https://orcid.org/0000-0003-0495-6571;Lavania|M|M|;Singh|I|I|;Ahuja|M|M|;Dogra|S|S|https://orcid.org/0000-0001-9912-0085",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ced.14884",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": null,
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": null,
"nlm_unique_id": "7606847",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34382256",
"pubdate": "2021-08-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Equal rates of drug resistance in leprosy cases with relapse and recurrent/chronic Type 2 reaction: time to revise the guidelines for drug-resistance testing in leprosy?",
"title_normalized": "equal rates of drug resistance in leprosy cases with relapse and recurrent chronic type 2 reaction time to revise the guidelines for drug resistance testing in leprosy"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2022-07581",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional":... |
{
"abstract": "Gemcitabine is a commonly used antimetabolite that has been effective in a broad spectrum of tumors so far. The main grade three and four known toxicity of this drug is myelosuppression. Cardiac adverse events have rarely been reported and gemcitabine-induced atrial-fibrillation (AF) has been described in only five previous cases so far. Here we report the 6th case of gemcitabine-related AF. A 68-year-old man diagnosed with metastatic nasopharyngeal cancer was referred to our oncology department. He started first line chemotherapy with gemcitabine and cisplatin. He presented poorly tolerated atrial fibrillation related to gemcitabine infusion that lasted for six days. The treatment was then withdrawn and the patient received best supportive care. We conclude that Medical oncologists and cardiologists should be aware of such toxicities of gemcitabine, especially in the elderly who seem to be at a higher risk of such adverse events and which may dictate discontinuation of the drug.",
"affiliations": "Department of medical oncology Faculty of medicine of Tunis, University Tunis El-Manar, Tunis. Tunisia.;Department of medical oncology Faculty of medicine of Tunis, University Tunis El-Manar, Tunis. Tunisia.;Department of cardiology, Faculty of medicine of Tunis, University Tunis El-Manar, Tunis. Tunisia.;Department of medical oncology Faculty of medicine of Tunis, University Tunis El-Manar, Tunis. Tunisia.;Department of medical oncology Faculty of medicine of Tunis, University Tunis El-Manar, Tunis. Tunisia.;Department of medical oncology Faculty of medicine of Tunis, University Tunis El-Manar, Tunis. Tunisia.;Department of medical oncology Faculty of medicine of Tunis, University Tunis El-Manar, Tunis. Tunisia.",
"authors": "ABdallah|Ichrak Ben|IB|;Nasr|Sonia Ben|SB|;Chourabi|Chadia|C|;Zribi|Aref|A|;Balti|Mehdi|M|;Fehri|Wafa|W|;Haddaoui|Abderrazek|A|",
"chemical_list": null,
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886316666210811155102",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": null,
"journal": "Current drug safety",
"keywords": "Gemcitabine; antimetabolites; arrhythmia; atrial fibrillation; chemotherapy; cisplatin.",
"medline_ta": "Curr Drug Saf",
"mesh_terms": null,
"nlm_unique_id": "101270895",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34382526",
"pubdate": "2021-08-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Gemcitabine-Related Atrial Fibrillation: A Case Report and Review of the Literature.",
"title_normalized": "gemcitabine related atrial fibrillation a case report and review of the literature"
} | [
{
"companynumb": "TN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-308881",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "A 67-year-old male with history of well controlled type 2 diabetes mellitus and hypertension developed acute interstitial nephritis (AIN) with nephrotic-range proteinuria during treatment with cefazolin for methicillin-sensitive Staphylococcus aureus and Group B Streptococcus (GBS) bacteremia. The patient received intravenous cefazolin 2 g every 8 h for 4 weeks prior to presentation to the emergency department with abdominal distension, nausea, and vomiting. Investigations revealed a serum ascites albumin gradient of 1.0 with total protein of 1.8 g/dL suggestive of nephrotic syndrome, which was confirmed with a spot urine protein/creatinine ratio that estimated 7.95 g of protein per day. Serum creatinine was elevated compared with baseline. Urine studies showed sterile pyuria with 3+ protein and eosinophiluria. The patient was diagnosed with AIN with nephrotic-range proteinuria associated with cefazolin use. Cefazolin was discontinued and, within a couple of days, the patient's creatinine stabilized. He was discharged with prednisone 60 mg once a day for 10 days with a taper over 2 weeks for his AIN. The patient's creatinine and proteinuria slowly decreased over the next couple of weeks, however, did not recover to baseline. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient's AIN with nephrotic-range proteinuria and his use of cefazolin.",
"affiliations": "Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. Ang.Xu@bcm.edu.;Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.;Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.",
"authors": "Xu|Ang|A|;Hyman|David|D|;Lu|Lee Bach|LB|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40800-018-0080-5",
"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 296330428010.1007/s40800-018-0080-5Case ReportCefazolin-Related Acute Interstitial Nephritis with Associated Nephrotic-Range Proteinuria: A Case Report Xu Ang 512-786-1309Ang.Xu@bcm.edu Hyman David Lu Lee Bach 0000 0001 2160 926Xgrid.39382.33Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030 USA 9 4 2018 9 4 2018 12 2018 5 16© The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.A 67-year-old male with history of well controlled type 2 diabetes mellitus and hypertension developed acute interstitial nephritis (AIN) with nephrotic-range proteinuria during treatment with cefazolin for methicillin-sensitive Staphylococcus aureus and Group B Streptococcus (GBS) bacteremia. The patient received intravenous cefazolin 2 g every 8 h for 4 weeks prior to presentation to the emergency department with abdominal distension, nausea, and vomiting. Investigations revealed a serum ascites albumin gradient of 1.0 with total protein of 1.8 g/dL suggestive of nephrotic syndrome, which was confirmed with a spot urine protein/creatinine ratio that estimated 7.95 g of protein per day. Serum creatinine was elevated compared with baseline. Urine studies showed sterile pyuria with 3+ protein and eosinophiluria. The patient was diagnosed with AIN with nephrotic-range proteinuria associated with cefazolin use. Cefazolin was discontinued and, within a couple of days, the patient’s creatinine stabilized. He was discharged with prednisone 60 mg once a day for 10 days with a taper over 2 weeks for his AIN. The patient’s creatinine and proteinuria slowly decreased over the next couple of weeks, however, did not recover to baseline. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient’s AIN with nephrotic-range proteinuria and his use of cefazolin.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nKey points\n\nPatients on cefazolin may develop acute interstitial nephritis (AIN) with associated nephrotic-range proteinuria.\t\nAlthough nephrotic-range proteinuria is rare with AIN, its presence should not delay discontinuation of the suspected drug if AIN is clinically suspected.\t\nGiven that AIN can present with minimal symptoms, it can be helpful to monitor creatinine when starting a new medication that has been implicated to cause AIN.\t\n\n\n\nIntroduction\nAcute interstitial nephritis (AIN) is an under-diagnosed cause of acute to subacute kidney injury. The most common etiology of AIN is drug induced. Many classes of drugs can cause AIN, including but not limited to antibiotics, antivirals, anticonvulsants, analgesics, proton pump inhibitors, and diuretics [1]. AIN with associated nephrotic-range proteinuria is very rare, occurring in < 1% of cases of AIN [2]. This is the first case report of a patient who developed AIN with nephrotic-range proteinuria during treatment with cefazolin.\n\nCase Report\nA 67-year-old male with history of well controlled type 2 diabetes mellitus and hypertension presented to the emergency department for abdominal distension with nausea and vomiting. One month prior to presentation, the patient was hospitalized for methicillin-sensitive Staphylococcus aureus (MSSA) and Group B Streptococcus (GBS) bacteremia and was discharged on intravenous cefazolin 2 g every 8 h. The patient’s creatinine and complete blood count were monitored weekly as an outpatient during his antibiotic therapy. Two weeks after being on home intravenous cefazolin, his creatinine increased from a baseline of 1.0 to 2.3 mg/dL. He developed progressively worsening nausea and vomiting with abdominal pain, eventually leading to inability to tolerate oral intake.\n\nOn physical exam, vitals were within normal limits except for blood pressure in the 180 s/90 s. No jaundice was noted. Abdominal exam showed a tense, distended abdomen that was diffusely tender to palpation with fluid waves. Extremities revealed bilateral 2+ pitting edema up to the thighs. The rest of the physical exam was unremarkable.\n\nThe patient had a normal leukocyte count with eosinophilia (white blood cell [WBC] 5600/μL: eosinophils 7.0%) thrombocytopenia (103,000/μL), and normocytic anemia (hemoglobin 9.3 g/dL; mean corpuscular volume [MCV] 95 pg). He had low albumin (2.2 g/dL), elevated blood urea nitrogen (56 mg/dL), and elevated creatinine (1.8 mg/dL with baseline creatinine of 1.0) but normal electrolytes and liver enzymes. Urinalysis displayed 3+ protein, 2+ blood, 19 WBC, and eosinophiluria. Urine sediment exam revealed many WBCs with WBC casts, red blood cells (RBCs) but no RBC casts. Urine spot protein/creatinine ratio gave an estimation of 7.95 g of protein per day. Diagnostic paracentesis showed 28 neutrophils and a serum albumin ascites gradient of 1.0 with a protein of 1.8 mg/dL, which suggested that the ascites was likely secondary to nephrotic syndrome (Table 1).Table 1 Interpretation of ascites fluid based on ascites fluid analysis (serum albumin ascites gradient of 1.0 with a protein of 1.8 mg/dL); our patient had fluid consistent with nephrotic syndrome\n\nInterpretation of ascites fluid\tSerum ascites albumin gradient\t\n< 1.1 g/dL\t ≥ 1.1 g/dL\t\nTotal protein (g/dL)\t\n< 2.5\tNephrotic syndrome\tCirrhosis\t\n ≥ 2.5\tCancer, tuberculosis\tHeart failure\t\n\n\nThe findings were consistent with AIN caused by cefazolin as the time course of the acute kidney injury coincided with the use of the antibiotic. This was further supported by the peripheral eosinophilia, eosinophiluria (not quantified) with sterile pyuria, and microhematuria. However, AIN very rarely causes nephrotic-range proteinuria so an extensive workup of the nephrotic syndrome was done. Although the patient had a history of type 2 diabetes mellitus and hypertension, diabetic and hypertensive nephropathies were less likely given the subacute process of the acute kidney injury. The patient had a stable creatinine with intermittent trace proteinuria for years including during his last admission for the MSSA/GBS bacteremia 4 weeks prior. Rapid plasma reagin (RPR) and HIV tests were negative. C4 was normal, C3 was mildly low (69 mg/dL). Serum and urine electrophoresis and Free Kappa/Lambda light chain tests were unremarkable. Renal ultrasound showed no hydronephrosis.\n\nThe patient refused a kidney biopsy for definitive diagnosis; however, given the clinical picture, we hypothesized that cefazolin was related to the AIN with nephrotic range proteinuria. The diagnosis was delayed because of a combination of factors: the nephrotic syndrome workup, consultation with infectious disease services to discuss the safety of discontinuing the antibiotic, and the fact that cefazolin causing AIN was incredibly rare in the literature. The patient was initially continued on cefazolin during which time his creatinine worsened from 1.8 to 2.6 mg/dL. Once the diagnosis was made, cefazolin was discontinued immediately, and his creatinine stabilized and decreased to 2.4 mg/dL on discharge (Fig. 1).Fig. 1 Plot of the patient’s serum creatinine throughout his clinical course from admission to primary-care outpatient follow up\n\n\n\n\nPatient was discharged with prednisone 60 mg once a day for 10 days with a subsequent taper to 40 mg to 30 mg-20 mg-10mg-5 mg once a day for 3 days for his AIN. Patient’s creatinine slowly decreased over the next couple of weeks, reaching a nadir of 1.7 mg/dL, however, did not recover to baseline. Unfortunately, the patient was lost to nephrology outpatient follow-up so a repeat urine spot protein/creatinine ratio was not repeated. Repeat urine dipstick done at a primary-care appointment showed improved proteinuria from 3+ (threshold of 300 mg/dL) to 2+ (threshold of 100 mg/dL) within 2 weeks of discharge.\n\nDiscussion\nAIN is primarily iatrogenic. Although other etiologies include infectious, autoimmune, and idiopathic, drug-induced AIN accounted for 71.1% of all cases of AIN according to a large retrospective pooled study by Baker and Pusey [3]. Methicillin was one of the first drugs to be implicated as a cause of AIN, with one study showing 17% of patients developing AIN if on methicillin for more than 10 days [4].\n\nAIN is classically thought to have a triad of rash, eosinophiluria, and fever; however, a recent retrospective pooled study showed that rash, eosinophiluria, and fever were only present 22, 35, and 36% of the time, respectively [2]. One study showed that eosinophiluria, by itself, only had a sensitivity of 40% and a positive predictive value of around 38% [5]. The more common abnormal studies were microhematuria and sterile pyuria, which were reported 67 and 82% of the time, respectively [2]. Our patient’s urinalysis revealed sterile pyuria, microhematuria, and eosinophiluria, all of which are present in AIN. Additionally, cefazolin was the only change that occurred prior to admission, and once cefazolin was discontinued, there was immediate stabilization and improvement in creatinine. This was highly suggestive that cefazolin caused the acute kidney injury.\n\nThis case report illustrates that AIN can commonly present with little to no symptoms. Although our patient’s creatinine rose from a baseline of 1.0 to 2.3 mg/dL within 2 weeks, the only reason that the patient presented to the emergency department was because of his tense ascites secondary to his nephrotic-range proteinuria. Physicians should have high index of suspicion for AIN, especially if the patient recently started a new medication.\n\nThere are dozens of classes of drugs that have been reported to cause AIN; however, only a select few have been known to cause AIN with nephrotic-range proteinuria, the most well established being non-steroidal anti-inflammatory drugs (NSAIDs). AIN causes interstitial edema that, over time, can spread to and damage the tubules causing proteinuria. Specifically, cephalosporins have been implicated in causing a hypersensitive allergic reaction and mitochondria injury to the tubular cells via inhibition of fatty acid and carnitine transport systems [6]. Although glomerular damage is rare, the interstitial inflammatory response, over time, can spread to Bowman’s capsule. NSAIDs are hypothesized to cause AIN via an alternative pathway by shunting arachidonic acid metabolites into immune-modifying pathways causing glomerular damage and nephrotic-range proteinuria [7]. Although cefazolin has not been implicated in a similar mechanism of action, we believe that the length of treatment (4 weeks) prior to diagnosis of AIN may have contributed to a more severe kidney injury with spread of the interstitial inflammatory response to the glomeruli causing nephrotic-range proteinuria.\n\nCefazolin has been associated with AIN in only a handful of reported cases, none of which had a nephrotic-range proteinuria. A case report by Fredericks et al. described a case of acute renal failure after initiation of cefazolin and gentamicin therapy [8]. Urine protein analysis only showed trace proteinuria. The patient fully recovered his renal function after discontinuation of both antibiotics.\n\nTreatment of drug-induced AIN consists primarily of discontinuing the offending agent and supportive care [9]. Our patient’s blood counts and renal function were monitored while on cefazolin, as per the Infectious Diseases Society of America (IDSA) guidelines. His nephrotic syndrome initially undermined the diagnosis of AIN, which led to the delay of cefazolin discontinuation. Steroids are often used to treat AIN; however, the evidence is mixed with one retrospective study in Spain showing significant improvement in serum creatinine with steroid use and another in the United States revealing no benefit [10, 11]. Unfortunately, 30–70% of all patients who developed AIN never regained their baseline kidney function [2].\n\nConclusion\nThis case report presents a patient with cefazolin-induced AIN with associated nephrotic-range proteinuria. AIN should be suspected whenever there is an unexplained increase in creatinine, especially after initiation of a new medication. Although nephrotic-range proteinuria is rare with AIN, its presence should not delay discontinuation of the causative drug if AIN is clinically suspected. Hence, for patients who need to be treated with outpatient parenteral antibiotic(s) for 4–6 weeks, it is imperative to monitor weekly laboratory studies as recommended by IDSA guidelines.\n\nAbbreviations\nAINAcute interstitial nephritis\n\nMSSAMethicillin-sensitive Staphylococcus aureus\n\nGBSGroup B streptococcus\n\nFunding source\nAng Xu, David Hyman, and Lee Bach Lu received no external funding for this manuscript.\n\nFinancial disclosure\nAng Xu, David Hyman, and Lee Bach Lu have no financial relationships relevant to this article to disclose.\n\nConflict of interest\nAng Xu, David Hyman, and Lee Bach Lu declare that they have no conflict of interest.\n\nInformed consent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent may be requested for review from the corresponding author.\n==== Refs\nReferences\n1. Perazella MA Markowitz GS Drug-induced acute interstitial nephritis Nat Rev Nephrol. 2010 6 8 461 470 10.1038/nrneph.2010.71 20517290 \n2. Praga M González E Acute interstitial nephritis Kidney Int. 2010 77 11 956 961 10.1038/ki.2010.89 20336051 \n3. Baker RJ Pusey CD The changing profile of acute tubulointerstitial nephritis Nephrol Dial Transplant. 2004 19 1 8 11 10.1093/ndt/gfg464 14671029 \n4. Nolan CM Abernathy RS Nephropathy associated with methicillin therapy. Prevalence and determinants in patients with staphylococcal bacteremia Arch Intern Med. 1977 137 8 997 1000 10.1001/archinte.1977.03630200007006 879956 \n5. Ruffing KA Hoppes P Blend D Cugino A Jarjoura D Whittier FC Eosinophils in urine revisited Clin Nephrol. 1994 41 3 163 166 10.1007/BF00860746 8187360 \n6. Tune BM Hsu CY Toxicity of cephaloridine to carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria: structure-activity relationships J Pharmacol Exp Ther. 1994 2702025 873 880 \n7. Murray MD Brater DC Renal toxicity of the nonsteroidal anti-inflammatory drugs Annu Rev Pharmacol Toxicol. 1993 33 1 435 465 10.1146/annurev.pa.33.040193.002251 8494347 \n8. Fredericks MR Dworkin R Ward DM Steiner RW Antibiotic-induced acute renal failure associated with an elevated serum lactic dehydrogenase level of renal origin West J Med. 1986 144 6 743 744 3727535 \n9. Whitman CB Wike MJ Possible case of nafcillin-induced acute interstitial nephritis Am J Health Syst Pharm. 2012 69 12 1049 1053 10.2146/ajhp110357 22644982 \n10. González E Gutiérrez E Galeano C Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis Kidney Int. 2008 73 8 940 946 10.1038/sj.ki.5002776 18185501 \n11. Clarkson MR Giblin L O’Connell FP Acute interstitial nephritis: Clinical features and response to corticosteroid therapy Nephrol Dial Transplant. 2004 19 11 2778 2783 10.1093/ndt/gfh485 15340098\n\n",
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"abstract": "Early-stage glioblastoma has few identifiable findings; clinical significance of its early diagnosis and treatment remains unclear as no report has described treatment and long-term follow-up for early-stage glioblastoma. Here, we report a case of a 69-year-old woman with early-stage glioblastoma treated by microsurgical resection and chemoradiotherapy. Magnetic resonance imaging (MRI) revealed a small high-intensity lesion in the right temporal lobe on T2-weighted imaging. Contrast-enhanced T1-weighted MRI revealed ring enhancement. On magnetic resonance spectroscopy, the lesion demonstrated increased choline and reduced N-acetyl-aspartate levels compared with the normal brain. Positron emission tomography with 11C-methionine (MET) revealed 11C-methionine uptake in the lesion. Microsurgical resection was performed, and glioblastoma was pathologically diagnosed. The patient was treated with local radiotherapy and temozolomide chemotherapy postoperatively. Eight years postoperatively, the patient is surviving without tumor recurrence, but progressive cognitive impairment developed 6 years' postoperatively. Aggressive treatment of early-stage glioblastoma may improve its extremely poor prognosis. Conversely, cognitive impairment may become a significant medical and social problem when effective therapies for glioblastoma are developed.",
"affiliations": "Department of Neurosurgery, Juntendo University Nerima Hospital, Tokyo, Japan.;Department of Pathology, Juntendo University Nerima Hospital, Tokyo, Japan.;Department of Neurosurgery, Juntendo University School of Medicine, Juntendo University, Tokyo, Japan.",
"authors": "Hishii|Makoto|M|;Matsumoto|Toshiharu|T|;Arai|Hajime|H|",
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"fulltext": "\n==== Front\nAsian J NeurosurgAsian J NeurosurgAJNSAsian Journal of Neurosurgery1793-54822248-9614Medknow Publications & Media Pvt Ltd India AJNS-14-58910.4103/ajns.AJNS_18_19Case ReportDiagnosis and Treatment of Early-Stage Glioblastoma Hishii Makoto Matsumoto Toshiharu 1Arai Hajime 2Department of Neurosurgery, Juntendo University Nerima Hospital, Tokyo, Japan1 Department of Pathology, Juntendo University Nerima Hospital, Tokyo, Japan2 Department of Neurosurgery, Juntendo University School of Medicine, Juntendo University, Tokyo, JapanAddress for correspondence: Dr. Makoto Hishii, Department of Neurosurgery, Juntendo University Nerima Hospital, 3-1-10, Takanodai, Nerima-Ku, Tokyo 177-8521, Japan. E-mail: m.hishii@juntendo-nerima.jpApr-Jun 2019 14 2 589 592 Copyright: © 2019 Asian Journal of Neurosurgery2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Early-stage glioblastoma has few identifiable findings; clinical significance of its early diagnosis and treatment remains unclear as no report has described treatment and long-term follow-up for early-stage glioblastoma. Here, we report a case of a 69-year-old woman with early-stage glioblastoma treated by microsurgical resection and chemoradiotherapy. Magnetic resonance imaging (MRI) revealed a small high-intensity lesion in the right temporal lobe on T2-weighted imaging. Contrast-enhanced T1-weighted MRI revealed ring enhancement. On magnetic resonance spectroscopy, the lesion demonstrated increased choline and reduced N-acetyl-aspartate levels compared with the normal brain. Positron emission tomography with 11C-methionine (MET) revealed 11C-methionine uptake in the lesion. Microsurgical resection was performed, and glioblastoma was pathologically diagnosed. The patient was treated with local radiotherapy and temozolomide chemotherapy postoperatively. Eight years postoperatively, the patient is surviving without tumor recurrence, but progressive cognitive impairment developed 6 years’ postoperatively. Aggressive treatment of early-stage glioblastoma may improve its extremely poor prognosis. Conversely, cognitive impairment may become a significant medical and social problem when effective therapies for glioblastoma are developed.\n\nCognitive impairmentearly diagnosisearly stageearly treatmentglioblastomalong-term survival\n==== Body\nIntroduction\nOne reason for the poor outcome of glioblastoma may be delayed diagnosis and treatment; however, knowledge about the early stage of glioblastoma is limited. Although small glioblastomas (with diameters of 8–14 mm) have been described as early- or initial-stage glioblastomas by several authors.[123] These were pathologically diagnosed and treated after tumor progression, not at an early stage. Here, we report the case of a glioblastoma that was diagnosed and surgically treated at an early stage. To the best of our knowledge, this is the first case report of a long-term follow-up of glioblastoma treated at an early stage.\n\nCase Report\nA 69-year-old Japanese woman presented with transient finger tremor. No abnormalities were detected in the neurological and general examinations, but T2-weighted images (T2WI) and fluid-attenuated inversion recovery magnetic resonance imaging (MRI) revealed a 12 × 10-mm hyperintense lesion in the right hippocampal body [Figure 1a], which was hypointense on T1-weighted images (T1WI) [Figure 1b] and diffusion-weighted imaging [Figure 1c]. Contrast-enhanced T1WI images demonstrated lesion ring enhancement [Figure 1d and e].\n\nFigure 1 Preoperative magnetic resonance imaging and 11C-methionine positron emission tomography. These studies demonstrated a 12 mm × 10 mm lesion in the right hippocampal body, showing hyperintense on T2-weighted magnetic resonance imaging (a) and hypointense on T1-weighted magnetic resonance imaging (b) and diffusion-weighted images (c). T1-weighted gadolinium-enhanced magnetic resonance imaging showed lesion ring enhancement (d: axial view; e: coronal view). 11C-methionine positron emission tomography image showing an area of 11C-methionine accumulation in the right temporal lesion (f)\n\nSingle-voxel magnetic resonance spectroscopy of the lesion revealed increased choline and decreased N-acetyl aspartate levels without high levels of lactate or lipids. 11C-methionine (MET) positron emission tomography (PET) showed increased MET uptake in the lesion [Figure 1f], with a maximum standardized uptake value of 1.73 and tumor/normal brain ratio of 1.45. No abnormal uptake was observed on whole body 18F-fluorodeoxyglucose PET. The diagnosis was that the lesion was likely to be a malignant glioma.\n\nGross total lesion removal was performed using the transcortical (middle temporal gyrus)–transventricular approach, guided by surgical navigation and the visual evoked potential. The lesion was a grayish, soft, and comparatively well-demarcated tissue, making it relatively easy to discriminate from the surrounding normal brain tissue [Figure 2a]. A rapid intraoperative pathological diagnosis indicated that the lesion was a glioblastoma and no tumor cells were detected in the brain tissue surrounding the tumor. We, therefore, chose resection of the tumor alone rather than an extensive resection.\n\nFigure 2 Intraoperative findings and postoperative studies. The lesion had grayish, soft, and relatively well-demarcated tissue (arrow) (a). Total lesion removal was confirmed on postoperative magnetic resonance imaging (b); T2-weighted magnetic resonance imaging (c); T1-weighted gadolinium-enhanced magnetic resonance imaging; and on 11C-methionine positron emission tomography (d)\n\nIn a pathological analysis, hematoxylin and eosin staining demonstrated extensive necrotic tissue surrounded by tumor cells [Figure 3a]. High-magnification microscopy revealed pleomorphic tumor cells with nuclear atypia [Figure 3b] and microvascular proliferation [Figure 3c]. Immunohistochemical staining was positive for glial fibrillary acidic protein [Figure 3d] and epidermal growth factor receptor [Figure 3e], and negative for isocitrate dehydrogenase (IDH) 1 R132H [Figure 3f] and p-53. These histopathological findings were consistent with features of glioblastoma. The MIB-1 proliferation index was 3%–5%.\n\nFigure 3 Pathological findings. Hematoxylin and eosin staining demonstrated a large necrotic area (star) surrounded by tumor cells (a), pleomorphic tumor cells with nuclear atypia (b), and microvascular proliferation (c). Immunohistochemical analyses demonstrated positive staining for glial fibrillary acidic protein (d) and epidermal growth factor receptor (e) and negative staining for isocitrate dehydrogenase 1 R132H mutation-specific antibody (f). Original magnifications: ×40 (a), ×200 (c), ×400 (b and d-f)\n\nGenetic analysis demonstrated the wild-type status of the IDH 1 and 2 genes and TERT promoter, as well as the absence of O6-methylguanine-DNA methyltransferase (MGMT) methylation and 1p19q codeletion. The final diagnosis was glioblastoma IDH-wild type.\n\nPostoperatively, the patient exhibited no neurological deficit, and no residual tumor was observed on MRI [Figure 2b and c] and MET-PET [Figure 2d]. The patient underwent focal radiation therapy (a total of 60 Gy over 30 days) and concomitant temozolomide (TMZ) chemotherapy (75 mg/m2/day), followed by six maintenance TMZ chemotherapy courses (150 mg/m2 for 5/28 days).\n\nNo tumor recurrence has been observed on follow-up MRI for 8 years’ postoperatively. However, the patient began suffering from memory disturbance 6 years’ postoperatively, at the age of 75 years. Her standard profile score on the Rivermead Behavioural Memory Test was 15/24, which was lower than the cutoff point for her age. Currently, the patient lives in a nursing home for the elderly because of her progressive memory disturbance.\n\nDiscussion\nOne reason for the poor outcomes experienced by patients with glioblastoma may be delayed diagnosis and treatment, but there are currently no standard diagnostic or therapeutic strategies for early-stage glioblastoma. Ideguchi et al. summarized the clinical characters of all previously reported early-stage glioblastoma cases (15 cases). They reported that the MRI findings of early-stage glioblastoma were a small, ill-defined, hyperintense lesion on T2WI, and subtle or no contrast enhancement on contrast-enhanced T1WI; thus, it was difficult to distinguish from nonneoplastic diseases, including ischemic and demyelinating diseases.[2] In our patient, ring enhancement on contrast-enhanced T1WI was characteristic of glioblastoma. In addition, increased choline and decreased N-acetyl aspartate levels on magnetic resonance spectroscopy and obvious MET uptake on MET-PET were useful indicators that the lesion was neither ischemic nor demyelinating disease but a neoplastic disease such as glioblastoma.\n\nEarly-stage glioblastomas can develop into bulky mass lesions within a few weeks, with dismal prognosis.[12] We therefore performed early-stage lesion treatment instead of careful MRI follow-up.\n\nThe 5-year survival of glioblastoma patients with unmethylated MGMT promoter has been reported to be 8.3%,[4] and the 10-year survival in glioblastoma has been estimated as 0.71%.[5] The 8-year recurrence-free survival of our patient is therefore a rare phenomenon. According to the established prognostic factors for glioblastoma,[6] our patient's age of 69 years and unmethylated MGMT promoter were negative factors, whereas her high Karnofsky Performance Status and the gross total resection (>98%) were positive factors. The early treatment may also have contributed to these positive factors, improving her survival. In addition, the patient's MIB-1 proliferation index of 3%–5% was low compared with that of other patients with glioblastoma, and this may have been related to her long-term survival. However, MIB-1 index values in glioblastoma vary widely (0%–76.4%), and an association with clinical outcome has not been demonstrated.[7] Although developed glioblastoma is generally an infiltrative tumor, the extent of the peripheral infiltrating margin shows great variability.[8] The low invasive character of the tumor in the present case, demonstrated by the intraoperative findings and pathological diagnosis, may be another factor in the patient's long-term survival.\n\nIt is unclear whether the low proliferation index and the low invasiveness of this tumor were because of the tumor stage or the biological nature of this specific tumor because there is little information available about early-stage glioblastoma. Further clinical and biological research on early-stage glioblastoma is necessary.\n\nDeterioration in mental status during adjuvant TMZ chemotherapy following concomitant chemoradiotherapy has been reported to affect 56% of elderly patients.[9] Postoperative radiotherapy may therefore have been the cause of the cognitive dysfunction in our patient.\n\nIdentifying early-stage glioblastomas remains difficult. However, the development of technologies such as liquid biopsy[10] and the detection of serum biomarker[11] may enable early diagnosis and early treatment of glioblastoma in the future and may improve the prognosis of glioblastoma. On the other hand, cognitive impairment resulting from treatment may become a significant medical and social problem.\n\nConclusion\nOpportunities to diagnose and treat early-stage glioblastomas will increase with the development of technologies. However, we have insufficient knowledge of early stage glioblastoma. Further biological and clinical studies on early-stage glioblastoma are required.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Faguer R Tanguy JY Rousseau A Clavreul A Menei P Early presentation of primary glioblastoma Neurochirurgie 2014 60 188 93 24856049 \n2 Ideguchi M Kajiwara K Goto H Sugimoto K Nomura S Ikeda E MRI findings and pathological features in early-stage glioblastoma J Neurooncol 2015 123 289 97 25939441 \n3 Oyama H Ando Y Aoki S Kito A Maki H Hattori K Glioblastoma detected at the initial stage in its developmental process -case report Neurol Med Chir (Tokyo) 2010 50 414 7 20505302 \n4 Stupp R Hegi ME Mason WP van den Bent MJ Taphoorn MJ Janzer RC Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial Lancet Oncol 2009 10 459 66 19269895 \n5 Tykocki T Eltayeb M Ten-year survival in glioblastoma. A systematic review J Clin Neurosci 2018 54 7 13 29801989 \n6 Adamson C Kanu OO Mehta AI Di C Lin N Mattox AK Glioblastoma multiforme: A review of where we have been and where we are going Expert Opin Investig Drugs 2009 18 1061 83 \n7 Moskowitz SI Jin T Prayson RA Role of MIB1 in predicting survival in patients with glioblastomas J Neurooncol 2006 76 193 200 16234986 \n8 Burger PC Heinz ER Shibata T Kleihues P Topographic anatomy and CT correlations in the untreated glioblastoma multiforme J Neurosurg 1988 68 698 704 2833587 \n9 Brandes AA Franceschi E Tosoni A Benevento F Scopece L Mazzocchi V Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: Correlation with MGMT promoter methylation status Cancer 2009 115 3512 8 19514084 \n10 Zachariah MA Oliveira-Costa JP Carter BS Stott SL Nahed BV Blood-based biomarkers for the diagnosis and monitoring of gliomas Neuro Oncol 2018 20 1155 61 29746665 \n11 Adachi-Hayama M Adachi A Shinozaki N Matsutani T Hiwasa T Takiguchi M Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas BMC Cancer 2014 14 452 24946857\n\n",
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"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nNecrotizing fasciitis has been reported as a complication secondary to bisphosphonate-related osteonecrosis of the jaw (BRONJ) in a low number of patients. The only report of such a case in an osteoporosis patient found in current literature was related to short-term bisphosphonate but long time corticosteroid and methotrexate treatment.\n\n\nMETHODS\nIn this article, we report a case of necrotizing fasciitis secondary to osteonecrosis of the jaw related to long-term oral bisphosphonate treatment in an osteoporosis patient additionally suffering from poorly controlled type 2 diabetes. Diabetes mellitus not only has been reported to be a systemic risk factor regarding BRONJ but also to be the most common comorbidity in patients presenting with necrotizing fasciitis and to increase mortality of this condition. Necrotizing fasciitis and BRONJ in the patient could eventually be resolved by a surgical approach and intravenous antibiotic therapy.\n\n\nCONCLUSIONS\nThe case presented suggests diabetes mellitus potentially having been an important factor in the particularly unfavorable course of therapy. It emphasizes the importance of an adequate therapy and surveillance of modifiable systemic risk factors like diabetes mellitus in patients being at risk for development of BRONJ. If necrotizing fasciitis is suspected, early diagnosis and aggressive surgical and medical management are essential to minimize morbidity and mortality.",
"affiliations": "Department of Oral and Craniomaxillofacial Surgery, Center for Dental Medicine, University Medical Center Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany. david.steybe@uniklinik-freiburg.de.;Department of Oral and Craniomaxillofacial Surgery, Center for Dental Medicine, University Medical Center Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.;Department of Oral and Craniomaxillofacial Surgery, Center for Dental Medicine, University Medical Center Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.;Department of Oral and Craniomaxillofacial Surgery, Center for Dental Medicine, University Medical Center Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.;Department of Oral and Craniomaxillofacial Surgery, Center for Dental Medicine, University Medical Center Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.;Department of Oral and Craniomaxillofacial Surgery, Center for Dental Medicine, University Medical Center Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.",
"authors": "Steybe|David|D|http://orcid.org/0000-0003-3885-6659;Voss|Pit Jacob|PJ|;Ermer|Michael Andreas|MA|;Fuessinger|Marc Anton|MA|;Schmelzeisen|Rainer|R|;Poxleitner|Philipp|P|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s10006-018-0725-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-1550",
"issue": "23(1)",
"journal": "Oral and maxillofacial surgery",
"keywords": "Bisphosphonates; Necrotizing fasciitis; Osteonecrosis of the jaw; Osteoporosis",
"medline_ta": "Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D019115:Fasciitis, Necrotizing; D005260:Female; D006801:Humans; D008336:Mandibular Diseases; D063175:Mandibular Reconstruction; D011862:Radiography, Panoramic",
"nlm_unique_id": "101319632",
"other_id": null,
"pages": "83-89",
"pmc": null,
"pmid": "30288621",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11491229;12627098;17179196;18022461;20015718;21122968;21676622;22336489;22822005;23830962;24338771;24480762;24711984;25234529;25414052;25541255;25726090;26412796;27639154;27956123;28875143;3304413;7087624",
"title": "Necrotizing fasciitis as a complication of osteonecrosis of the jaw related to oral bisphosphonate application in a patient with osteoporosis: a case report.",
"title_normalized": "necrotizing fasciitis as a complication of osteonecrosis of the jaw related to oral bisphosphonate application in a patient with osteoporosis a case report"
} | [
{
"companynumb": "DE-TEVA-2019-DE-1116014",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population.\n\n\n\nPlasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted.\n\n\n\nData from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%.\n\n\n\nDrug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.",
"affiliations": "*Department of Anaesthesiology and Intensive Care, Charité Universitätsmedizin Berlin-Campus Benjamin Franklin, Berlin, Germany; †Department of Clinical Pharmacy, Institute of Pharmacy, University of Regensburg, Regensburg, Germany; ‡Hospital pharmacy, University Hospital Regensburg, Regensburg, Germany; §Department of Pharmaceutical Biosciences, Uppsala Universitet, Uppsala, Sweden; ¶Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany; ‖Department of Pharmacology, University of Regensburg, Regensburg, Germany; and #Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.",
"authors": "Töpper|Christoph|C|;Steinbach|Cathérine L|CL|;Dorn|Christoph|C|;Kratzer|Alexander|A|;Wicha|Sebastian G|SG|;Schleibinger|Michael|M|;Liebchen|Uwe|U|;Kees|Frieder|F|;Salzberger|Bernd|B|;Kees|Martin G|MG|",
"chemical_list": "D018435:ATP Binding Cassette Transporter, Subfamily B; D000900:Anti-Bacterial Agents; D065693:Cytochrome P-450 Enzyme Inducers; D065607:Cytochrome P-450 Enzyme Inhibitors; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1097/FTD.0000000000000324",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4356",
"issue": "38(5)",
"journal": "Therapeutic drug monitoring",
"keywords": null,
"medline_ta": "Ther Drug Monit",
"mesh_terms": "D018435:ATP Binding Cassette Transporter, Subfamily B; D000900:Anti-Bacterial Agents; D065693:Cytochrome P-450 Enzyme Inducers; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006801:Humans; D007362:Intensive Care Units; D000069349:Linezolid; D008954:Models, Biological",
"nlm_unique_id": "7909660",
"other_id": null,
"pages": "573-8",
"pmc": null,
"pmid": "27631464",
"pubdate": "2016-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Variable Linezolid Exposure in Intensive Care Unit Patients-Possible Role of Drug-Drug Interactions.",
"title_normalized": "variable linezolid exposure in intensive care unit patients possible role of drug drug interactions"
} | [
{
"companynumb": "DE-PFIZER INC-2018118064",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "3",
... |
{
"abstract": "To describe the effect of in utero exposure to the buprenorphine+naloxone combination product in a rural and remote population.\n\n\n\nA district hospital that services rural and remote, fly-in communities in Northwestern Ontario, Canada.\n\n\n\nA retrospective cohort study was conducted of 855 mother infant dyads between 1 July 2013 and 30 June 2015. Cases included all women who had exposure to buprenorphine+naloxone during pregnancy (n=62). 2 control groups were identified; the first included women with no opioid exposure in pregnancy (n=618) and the second included women with opioid exposure other than buprenorphine+naloxone (n=159). Women were excluded if they had multiple pregnancy or if they were part of a methadone programme (n=16). The majority of women came from Indigenous communities.\n\n\n\nThe primary outcomes were birth weight, preterm delivery, congenital anomalies and stillbirth. Secondary neonatal outcomes included gestational age at delivery, Apgar scores at 1 and 5 min, NAS Score >7 and treatment for neonatal abstinence syndrome (NAS). Secondary maternal outcomes included the number of caesarean sections, postpartum haemorrhages, out of hospital deliveries and transfer of care to tertiary centres.\n\n\n\nNo difference was found in the primary outcomes or in the Apgar score and caesarean section rate between in utero buprenorphine+naloxone exposure versus no opioid exposure in pregnancy. Compared to women taking other opioids, women taking buprenorphine+naloxone had higher birthweight babies (p=0.001) and less exposure to marijuana (p<0.001) during pregnancy.\n\n\n\nRetrospective data suggest that there likely is no harm from taking buprenorphine+naloxone opioid agonist treatment in pregnancy. Larger, prospective studies are needed to further assess safety.",
"affiliations": "Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.;School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.;Anishinaabe Bimaadiziwin Research Program, Sioux Lookout, Ontario, Canada.;Integrated Pregnancy Program, Sioux Lookout Meno Ya Win Health Centre, Sioux Lookout, Canada.;Integrated Pregnancy Program, Sioux Lookout Meno Ya Win Health Centre, Sioux Lookout, Canada.;Anishinaabe Bimaadiziwin Research Program, Sioux Lookout, Ontario, Canada.",
"authors": "Jumah|Naana Afua|NA|;Edwards|Craig|C|;Balfour-Boehm|Jazmyn|J|;Loewen|Kassandra|K|;Dooley|Joseph|J|;Gerber Finn|Lianne|L|;Kelly|Len|L|",
"chemical_list": "D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine",
"country": "England",
"delete": false,
"doi": "10.1136/bmjopen-2016-011774",
"fulltext": "\n==== Front\nBMJ OpenBMJ OpenbmjopenbmjopenBMJ Open2044-6055BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bmjopen-2016-01177410.1136/bmjopen-2016-011774AddictionResearch150616811845172417191710Observational study of the safety of buprenorphine+naloxone in pregnancy in a rural and remote population Jumah Naana Afua 1Edwards Craig 2Balfour-Boehm Jazmyn 1Loewen Kassandra 3Dooley Joseph 4Gerber Finn Lianne 4Kelly Len 3\n1 Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada\n2 School of Public Health, University of Saskatchewan, Saskatoon, Saskatchewan, Canada\n3 Anishinaabe Bimaadiziwin Research Program, Sioux Lookout, Ontario, Canada\n4 Integrated Pregnancy Program, Sioux Lookout Meno Ya Win Health Centre, Sioux Lookout, CanadaCorrespondence to Dr Naana Afua Jumah; njumah@nosm.ca2016 31 10 2016 6 10 e0117749 3 2016 4 8 2016 1 9 2016 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/2016This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Objectives\nTo describe the effect of in utero exposure to the buprenorphine+naloxone combination product in a rural and remote population.\n\nSetting\nA district hospital that services rural and remote, fly-in communities in Northwestern Ontario, Canada.\n\nParticipants\nA retrospective cohort study was conducted of 855 mother infant dyads between 1 July 2013 and 30 June 2015. Cases included all women who had exposure to buprenorphine+naloxone during pregnancy (n=62). 2 control groups were identified; the first included women with no opioid exposure in pregnancy (n=618) and the second included women with opioid exposure other than buprenorphine+naloxone (n=159). Women were excluded if they had multiple pregnancy or if they were part of a methadone programme (n=16). The majority of women came from Indigenous communities.\n\nOutcomes\nThe primary outcomes were birth weight, preterm delivery, congenital anomalies and stillbirth. Secondary neonatal outcomes included gestational age at delivery, Apgar scores at 1 and 5 min, NAS Score >7 and treatment for neonatal abstinence syndrome (NAS). Secondary maternal outcomes included the number of caesarean sections, postpartum haemorrhages, out of hospital deliveries and transfer of care to tertiary centres.\n\nResults\nNo difference was found in the primary outcomes or in the Apgar score and caesarean section rate between in utero buprenorphine+naloxone exposure versus no opioid exposure in pregnancy. Compared to women taking other opioids, women taking buprenorphine+naloxone had higher birthweight babies (p=0.001) and less exposure to marijuana (p<0.001) during pregnancy.\n\nConclusions\nRetrospective data suggest that there likely is no harm from taking buprenorphine+naloxone opioid agonist treatment in pregnancy. Larger, prospective studies are needed to further assess safety.\n\nSafetyRural and remoteIndigenous healthPregnancyBuprenorphine + naloxone\n==== Body\nStrengths and limitations of this study\nOpioid misuse is epidemic in rural and remote areas of Northwestern Ontario, Canada, with up to 30% of women exposed during pregnancy. Community-based buprenorphine+naloxone programmes have engaged many rural women in treatment programmes who otherwise would not receive care.\n\nThis is the largest cohort of women exposed to buprenorphine+naloxone in pregnancy and contains detailed information about the daily dose, cumulative dose and exposure time with respect to each trimester of pregnancy.\n\nWhile 62 women had exposure to buprenorphine+naloxone in pregnancy, only 3 women had exposure throughout all three trimesters, a further 48 had exposure in the first trimester only and the remainder had variable lengths of exposure.\n\nData on illicit substances, smoking and alcohol use during pregnancy were determined by self-report and confirmed with urine drug screens. Data were not collected on other exposures or on the use of other medications such as antidepressants, anxiolytics and folic acid.\n\nData were collected retrospectively and were limited to antenatal, maternal and neonatal outcomes. Prospective data and long-term outcomes would provide more robust safety data.\n\nIntroduction\nOpioid dependence in pregnancy is an increasingly common occurrence in rural and remote areas such as Northwestern Ontario, Canada, where up to 28% of pregnancies are exposed to opioid use.1 Our catchment area of 30 000 patients includes 25 000 patients in remote communities who are mostly Indigenous and receive their initial pregnancy care at the nursing station in their community.2 Methadone treatment has the most evidence regarding safety and efficacy in pregnancy;3\n4 however, due to logistical and regulatory limitations, methadone is often not available in rural and remote areas.5 Community-based, sublingual buprenorphine+naloxone treatment programmes have been established in rural and remote, predominantly Indigenous communities in order to provide access to treatment in areas with high rates of opioid dependence and no access to methadone.5\n\nThe WHO and several national Obstetrics and Gynaecology associations recommend that, when pregnancy is diagnosed, women participating in a buprenorphine+naloxone treatment programme switch to the buprenorphine mono-product because the safety of buprenorphine+naloxone has not been demonstrated in pregnancy.6–8 A multicentred randomised controlled trial demonstrated that the buprenorphine mono-product has similar pregnancy outcomes and decreased severity of neonatal abstinence syndrome compared to methadone.9 Naloxone was added to buprenorphine as a deterrent to illicit use as it precipitates withdrawal from opioids when administered intravenously or intranasally but not via the buccal or sublingual routes.10\n11 Precipitated withdrawal has been shown to result in adverse pregnancy outcomes.12\n13\n\nThe caution against using buprenorphine+naloxone in pregnancy is not limited to concerns for withdrawal but also possible teratogenicity. However, to date, there have been no reports of teratogenicity in humans or animals.14 Congenital anomalies are only one marker of drug safety in pregnancy. The live birth rate, spontaneous abortion rate and stillbirth rates are also markers of safety, and among live births, preterm delivery, low birth weight and functional deficits are factors that may be affected by a medication.15 Further, the severity of pregnancy outcomes may be modified by the duration and intensity of the exposure to the medication.\n\nIn Canada, the buprenorphine mono-product is available only through a special access programme. In our setting, women are counselled to transition from buprenorphine+naloxone to either buprenorphine or long-acting morphine when they present for antenatal care. As a result of delays in obtaining buprenorphine through the special access programme, many women are exposed to buprenorphine+naloxone during early pregnancy and into the second trimester. In addition, for personal reasons, some women opt to remain on buprenorphine+naloxone throughout their pregnancy. This study documents the pregnancy outcomes of a cohort of women from rural and remote communities in Northwestern Ontario who continued to take buprenorphine+naloxone treatment during pregnancy as part of a community-based treatment programme.\n\nMethods\nParticipants\nMaternal and neonatal data were collected from outpatient antenatal clinic records and inpatient medical records for all pregnancies between 1 July 2010 and 31 July 2015. Cases included all women who had exposure to buprenorphine+naloxone during pregnancy. Two control groups were identified; the first included women with no opioid exposure in pregnancy and the second included women with opioid exposure other than buprenorphine+naloxone. All women who were receiving opioid agonist treatment with buprenorphine+naloxone were advised to switch to the buprenorphine mono-product when available, once pregnancy was diagnosed as per national guidelines.7 Cases represent those women who elected to stay on buprenorphine+naloxone during their pregnancy. Women were excluded if they had a multiple pregnancy or were taking methadone as part of a treatment programme. All infants room-in with their mother following delivery unless there is a medical or safety reason that precludes rooming-in. The majority of women came from Indigenous communities.\n\nData collection\nA standard case report form was used to collect maternal and neonatal data. The maternal case report form contained information on the health and pregnancy history; smoking, drug and alcohol exposure; and intrapartum data. Smoking was defined by self-reported daily use of cigarettes and was further characterised by the number of cigarettes smoked per day. Alcohol and drug exposure were determined by self-report. Drug exposure was characterised further by urine drug screen results. The neonatal case report form contained information on birth weight, gestational age, Apgars, congenital anomalies and stillbirths.\n\nThe primary outcomes for the study was an assessment of the safety of buprenorphine+naloxone, including birth weight, preterm delivery (delivery prior to 37+0 weeks gestational age), congenital anomalies and stillbirth. Secondary neonatal outcomes included gestational age at delivery, Apgar scores at 1 and 5 min, NAS Score >7 and treatment for NAS (two or more NAS Scores that are >7). NAS Scores were calculated using a modified Finnegan Scale at the bedside by nurses who have been trained to use this measure. Secondary maternal outcomes included the number of caesarean sections, postpartum haemorrhages, out of hospital deliveries and transfer of care to tertiary centres.\n\nStatistical analysis\nCategorical variables are presented as percentages while continuous variables are presented as a mean with SD. We compared cases to controls using a t-test for continuous variables and a Pearson χ2 test of independence or a Fisher's Exact test, as appropriate, for categorical data. ORs are presented with the 95% CI. Data analysis was performed with SPSS statistical software V.20 (SPSS, Chicago, Illinois, USA) and Microsoft Excel V.14.1.0 (Microsoft Corp, Redmond, Washington, USA). A p value<0.05 indicated statistical significance.\n\nEthics\nEthics approval was granted by the Sioux Lookout Meno Ya Win Health Centre Research Review and Ethics Committee.\n\nResults\nA total of 855 consecutive singleton births were included in the study, of these, 62 had exposure to buprenorphine+naloxone, 618 had no opioid exposure and 159 used illicit opioids during the pregnancy (figure 1). Sixteen women were excluded due to participation in a methadone treatment programme. Twenty-five women were excluded due to a multiple pregnancy. Maternal characteristics are described in table 1. The overall rate of opioid exposure in pregnancy is 27.8%. Data on the racial and ethnic make-up of our study participants as well as data on educational attainment were not collected. Previous studies of this population show that the majority (85%) of women are Indigenous.2 Educational attainment among Indigenous women living on reserve is low where 57% do not complete high school, 16% receive a high school diploma, 19% participate in postsecondary education and only 4% have a university degree.16\n\nTable 1 Maternal characteristics\n\n\tA\tB\tA–B\tC\tA–C\t\nVariable\tBup/Nalox (n=62)\tNo opioids (n=618)\tp Value\tIllicit opioids (n=159)\tp Value\t\nAge (years)\t25.9±4.4\t25.2±6.3\t0.21\t25.5±4.6\t0.63\t\nGravida\t4.1±2.4\t3.3±2.3\t0.009\t3.9±2.1\t0.54\t\nParity\t2.4±1.8\t1.8±2.0\t0.03\t2.2±1.7\t0.50\t\nComorbidities\t\n Type II diabetes\t5 (8.1%)\t26 (4.2%)\t0.19†\t3 (1.9%)\t0.04†\t\n Gestational diabetes\t7 (11.3%)\t63 (10.2%)\t0.79*\t14 (8.8%)\t0.57*\t\n Hypertension\t6 (9.7%)\t39 (6.3%)\t0.29†\t11 (6.9%)\t0.58†\t\n HIV\t0\t0\t\t0\t\t\n Hepatitis B\t0\t0\t\t1 (0.6%)\t>0.99†\t\n Hepatitis C\t3 (4.8%)\t2 (0.3%)\t0.006†\t12 (7.5%)\t0.566\t\nPrenatal smoking and alcohol exposure\t\n Smoking, cig/day\t\n None\t7 (11.3%)\t327 (52.9%)\t<0.001*\t20 (12.6%)\t0.79*\t\n 1–5\t33 (53.2%)\t208 (33.7%)\t0.002*\t61 (38.4%)\t0.045*\t\n 6–10\t15 (24.2%)\t51 (8.3%)\t<0.001*\t34 (21.4%)\t0.65*\t\n >10\t7 (11.3%)\t32 (5.2%)\t0.08†\t44 (27.7%)\t0.009†\t\n Alcohol\t11 (17.7%)\t134 (21.7%)\t0.47*\t41 (25.8%)\t0.21*\t\nData are n (%) or mean±SD unless otherwise specified.\n\n*χ2 test was used.\n\n†When assumptions for the χ2 test were not met, the Fisher's Exact test was used.\n\nFigure 1 Patient flow chart.\n\nA total of 62 women had exposure to buprenorphine+naloxone in pregnancy (see figure 1). Of these women, three women continued prepregnancy buprenorphine+naloxone throughout pregnancy and after delivery. A further 48 women who were taking buprenorphine+naloxone prior to pregnancy switched to buprenorphine alone after the first trimester as per national and international guidelines.6–8 Eleven women were induced onto buprenorphine+naloxone during pregnancy, and this occurred in the first trimester for 6 women. The average daily dose of buprenorphine+naloxone was 8.2±5.8 mg. Ongoing illicit opioid use was identified in 12 women (19.4%) through routine urine drug screening. Six cases had positive urine drug screens for marijuana. No other illicit substances were identified on urine drug screening. Data were not collected for other psychotropic medications or antidepressant medications.\n\nCases and controls were of similar age at the time of delivery. However, women who had no opioid exposure in pregnancy had fewer pregnancies and fewer births compared to cases. The OR of Hepatitis C infection for women taking buprenorphine+naloxone compared to no opioid use was OR 15.7, 95% CI 2.6 to 95.6. Women taking buprenorphine+naloxone were more likely to smoke 1–5 cigarettes per day compared to women in the control groups while women continuing to use illicit opioids were more likely to be heavy smokers (>10 cigarettes per day). There was no difference in alcohol consumption between the three groups.\n\nPrenatal patterns of substance use revealed a high number of women with polysubstance use defined as the use of at least one other illicit substance among women taking buprenorphine+naloxone (12.9%) and those continuing to use illicit opioids (53.5%) (table 2). Treatment with buprenorphine+naloxone decreased the odds of polysubstance use in pregnancy to 0.13 (0.06 to 0.29) compared to women with ongoing illicit opioid use. The most frequent non-opioid drug of abuse was marijuana followed by cocaine (see table 2). Among women continuing to use illicit opioids during pregnancy, the majority (59.7%) used morphine followed by oxycodone derivatives (30.8%). The route of administration for women continuing to use illicit opioids during pregnancy was predominantly intravenous (67.9%) and intranasal (30.8%). Data on the primary opioid of abuse and route of administration were largely missing for women taking buprenorphine+naloxone and as a result a valid comparison cannot be made.\n\nTable 2 Prenatal exposure to drugs of abuse\n\n\tA\tB\tA–B\tC\tA–C\t\n\tBup/Nalox (n=62)\tNo opioids (n=618)\tp Value\tIllicit opioids (n=159)\tp Value\t\nPrimary opioid of abuse, n (%)\t\n Morphine\t14 (22.6%)\t0\t\t95 (59.7%)\t<0.001*\t\n Oxycodone, Percocet and OxyNeo\t5 (8.1%)\t0\t\t50 (31.4%)\t<0.001†\t\n Hydromorphone\t4 (6.5%)\t0\t\t7 (4.4%)\t0.507†\t\n Tylenol+Codeine\t0\t0\t\t4 (2.5%)\t0.578†\t\n Methadone\t0\t0\t\t1 (0.6%)\t>0.999†\t\n Suboxone\t1 (1.6%)\t0\t\t9 (5.7%)\t0.289†\t\n Unknown\t39 (62.9%)\t0\t\t7 (4.4%)\t<0.001*\t\nRoute of opioid administration, n (%)\t\n Intravenous\t16 (25.8%)\t0\t\t108 (67.9%)\t<0.001*\t\n Snort/intranasal\t5 (8.1%)\t0\t\t49 (30.8%)\t<0.001†\t\n By mouth/per os\t0\t0\t\t9 (5.7%)\t0.064†\t\n Smoke/inhale\t1 (1.6%)\t0\t\t7 (4.4%)\t0.447†\t\n Not available\t42 (67.7%)\t0\t\t8 (5.0%)\t<0.001*\t\nFrequency of opioid use, n (%)\t\n Occasional (two times per week or less)\t1 (1.6%)\t0\t\t25 (15.7%)\t0.003†\t\n Regular (three times per week or more)\t5 (8.1%)\t0\t\t26 (16.4%)\t0.111†\t\n Daily\t11 (17.7%)\t0\t\t97 (61.0%)\t<0.001*\t\n Unknown\t45 (72.6%)\t0\t\t11 (6.9%)\t<0.001*\t\nOther drugs of abuse, n (%)\t\n Polysubstance use\t8 (12.9%)\t0\t<0.001†\t85 (53.5%)\t<0.001*\t\n Marijuana, reported\t8 (12.9%)\t60 (9.7%)\t0.424*\t58 (36.5%)\t0.001*\t\n Marijuana, positive urine screen\t6 (9.7%)\t36 (5.8%)\t0.261†\t44 (27.7)\t0.004†\t\n Benzodiazepines\t0\t0\t\t3 (1.9%)\t0.561†\t\n Cocaine\t1 (1.6%)\t0\t0.091†\t10 (6.3%)\t0.299†\t\n Ecstasy\t0\t0\t\t1 (0.6%)\t>0.999†\t\n*χ2 test was used.\n\n†When assumptions for the χ2 test were not met, the Fisher's Exact test was used.\n\nThe primary outcome of this study is the safety of in utero exposure to buprenorphine+naloxone (table 3). For the 62 women exposed to buprenorphine+naloxone during pregnancy, the duration of exposure (mean±SD) was 121.4±75.5 days with a daily dose of 8.2±5.8 mg. Among parameters used to define safety of the drug, there was no difference in the birth weight, number of preterm deliveries, number of congenital malformations or number of stillbirths in women taking buprenorphine+naloxone compared to women taking no opioids during pregnancy. Women who continued to use illicit opioids had a statistically significant reduction in birth weight of 262.7 g compared to women treated with buprenorphine+naloxone. There were no stillbirths among the cohort taking buprenorphine+naloxone, five among the women with no opioid exposure and one among the women taking illicit opioids.\n\nTable 3 Primary outcomes\n\n\tA\tB\tA–B\tC\tA–C\t\n\tBup/Nalox (n=62)\tNo opioids (n=618)\tp Value\tIllicit opioids (n=159)\tp Value\t\nPrimary outcomes\t\n Preterm delivery, n (%)‡\t2 (3.2%)\t26 (4.21%)\t>0.999†\t7 (4.4%)\t>0.999†\t\n Birth weight (g), mean±SD‡\t3541±540\t3553±569\t0.924*\t3274±551\t<0.001*\t\n Congenital anomalies, n (%)\t2 (3.2%)\t5 (0.8%)\t0.127†\t0\t0.078†\t\n Stillbirths\t0\t5 (0.8%)\t>0.999†\t1 (0.6%)\t>0.999†\t\n*χ2 test was used.\n\n†When assumptions for the χ2 test were not met, the Fisher's Exact test was used.\n\n‡Birth weight and gestational age were limited to live births that were >500 g and >20 weeks.\n\nThere were a total of five congenital malformations in the control group with no opioid exposure and none in the group with illicit opioid exposure. Two infants exposed to buprenorphine+naloxone had congenital malformations: one case of bilateral cleft palate and another case of atrial septal defect. The infant with the bilateral cleft palate had exposure to buprenorphine+naloxone from conception until the third trimester at which point the mother was switched to buprenorphine mono-product. The daily dose ranged from 2 to 4 mg, and the cumulative dose was 525 mg. There was alcohol exposure and smoking (>10 cigarettes per day) during the pregnancy but no other illicit opioids. The infant with the atrial septal defect had exposure to buprenorphine+naloxone from the first trimester until delivery. The daily dose ranged from 2 to 4 mg, and the cumulative dose was 564 mg. There was no other smoking, drug or alcohol exposure during this pregnancy, and there is no family history of congenital heart disease. Data on prepregnancy folic acid supplementation and prepregnancy body mass index were not available for either woman. Both women were diagnosed with gestational diabetes.\n\nSecondary neonatal outcomes (table 4) revealed no difference between cases and controls with respect to gestational age at the time of delivery, Apgar scores, NAS Scores and NAS treatment. Secondary maternal outcomes (table 4) showed that mothers exposed to buprenorphine+naloxone stayed in hospital an extra 1.1 days compared to mothers with no opioid exposure in pregnancy. There was no statistically significant difference in length of stay between cases and illicit opioid using controls. There was no difference in the number of caesarean sections, postpartum haemorrhages, out of hospital deliveries or transfers to tertiary care hospitals for cases compared to controls.\n\nTable 4 Secondary outcomes\n\n\tA\tB\tA–B\tC\tA–C\t\n\tBup/Nalox (n=62)\tNo opioids (n=618)\tp Value\tIllicit opioids (n=159)\tp Value\t\nNeonatal outcomes\t\n Gestational age at birth, mean±SD\t38.7±1.5\t38.9±1.5\t0.405\t38.6±1.5\t0.686\t\n Apgar 1 min, mean±SD\t8.7±0.8\t8.6±1.3\t0.780\t8.6±1.2\t0.407\t\n Apgar 5 min, mean±SD\t9.0±0.4\t8.9±0.8\t0.761\t8.9±0.8\t0.421\t\n # NAS Score >7\t1 (1.6%)\t0\t\t11 (6.9%)\t0.186†\t\n Treated for NAS\t1 (1.6%)\t0\t\t9 (5.7%)\t0.289†\t\n Males\t38 (61.3%)\t325 (52.6%)\t0.229*\t81 (50.9%)\t0.166*\t\nMaternal outcomes\t\n Caesarean section\t14 (22.6%)\t151 (24.4%)\t0.746*\t42 (26.4%)\t0.556†\t\n Postpartum haemorrhage\t10 (16.1%)\t61 (9.9%)\t0.124*\t14 (8.8%)\t0.116†\t\n Length of maternal stay in hospital\t3.1±1.5\t2.0±1.1\t<0.001\t2.8±1.9\t0.235\t\n Out of hospital deliveries\t1 (1.6%)\t11 (1.8%)\t>0.999†\t3 (1.9%)\t>0.999†\t\n Transfer to tertiary care centre\t2 (3.2%)\t13 (2.1%)\t0.639†\t5 (3.1%)\t>0.999†\t\n*χ2 test was used.\n\n†When assumptions for the χ2 test were not met, the Fisher's Exact test was used.\n\nDiscussion\nAlmost one-third of the study population were exposed to opioids during pregnancy, but only 5.6% were on opioid agonist treatment prior to pregnancy. There was no evidence of teratogenicity or adverse pregnancy outcomes in a cohort of 62 women exposed to buprenorphine+naloxone during pregnancy compared to women who had no opioid exposure during pregnancy. Two cases of congenital malformations were identified in women exposed to buprenorphine+naloxone. One case of bilateral cleft lip and palate included a significant confounder in the form of in utero alcohol exposure. The second was a case of an atrial septal defect—one of the most common congenital malformations occurring in 1 in 1500 live births.17 Data regarding other confounders such as folic acid supplementation, exposure to other medications and obesity were not available. In spite of these limitations, the rate of congenital malformations was not significantly different compared to the control group.\n\nWomen who continued to use illicit opioids during pregnancy did have babies with a statistically significant lower birth weight compared to those women taking buprenorphine+naloxone. The rate of congenital malformations was not above the rate in the general population although the cohort exposed to buprenorphine+naloxone is small and therefore may give a biased estimation of this risk. Exposure to buprenorphine+naloxone also had no observable impact on Apgar scores or treatment for NAS. The low rates of NAS observed in this study may be accounted for by several factors. First, the majority of community-based opioid agonist programmes included in the study use a low dose treatment protocol where the average maintenance dose of buprenorphine+naloxone is less than 8 mg daily. Second, for those women who continue to use illicit opioids, non-daily, binge use is the predominant pattern of opioid use and short acting opioids (morphine and oxycodone) are the most common opioids of abuse.17 Furthermore, opioid tapering during pregnancy, with long-acting morphine, is a common practice in this setting and results in lower doses of opioids at the time of delivery.18 Finally, all infants room-in with their mother after delivery and breastfeeding and supportive care are encouraged, all of which are beneficial in the management of NAS.\n\nThis study represents the largest cohort of women exposed to buprenorphine+naloxone in pregnancy and contains detailed information about the daily dose, cumulative dose and exposure time with respect to each trimester of pregnancy. We present an assessment of key safety parameters for mother and infant. A harm reduction strategy is applied in our catchment area as it has been shown that there are better pregnancy outcomes when a woman is part of a treatment programme compared to ongoing use of illicit opioids. Many of the women in this study were inducted on to buprenorphine+naloxone during pregnancy rather than the buprenorphine mono-product. In our jurisdiction, the buprenorphine mono-product is available through a special access programme with lengthy delays between applying for an exemption and receipt of the drug, whereas buprenorphine+naloxone is readily available in communities as part of community-based harm reduction programmes. As a result, women are induced onto buprenorphine+naloxone and maintained on this drug until such time that the buprenorphine mono-product becomes available.\n\nTwo small retrospective cohort studies are reported in the literature that look at the effect of buprenorphine+naloxone on pregnancy outcomes.19–21 The first compared 10 women who took buprenorphine+naloxone in pregnancy to women who took buprenorphine or methadone in six other studies with similar outcome measures. No differences in maternal outcomes or neonatal outcomes were observed with the exception of head circumference which was larger among infants exposed to buprenorphine+naloxone compared to infants who were exposed to methadone withdrawal in utero.19\n20 The second retrospective cohort study compared 31 women who took buprenorphine+naloxone in pregnancy to a control group of 31 women who took methadone in pregnancy. The study excluded stillbirth and congenital malformations as well as women who received treatment for <30 days prior to delivery. Again, no significant differences in maternal or neonatal outcomes were observed. Infants exposed to methadone were born at an earlier gestational age than buprenorphine+naloxone, but the average gestational age for both was >38 weeks.21\n\nBuprenorphine+naloxone is an efficacious treatment for opioid dependence with the advantage of a lower overdose risk and ease of prescribing when compared to methadone.22 Owing to these factors, it is being used widely in opioid treatment programmes in rural and remote settings where methadone treatment is not available.23 Currently women participating in buprenorphine+naloxone treatment programmes who become pregnant are advised to switch to the buprenorphine mono-product out of theoretical concerns of the risk of naloxone to the developing fetus. This study demonstrates no increase rate of congenital malformations, stillbirth or low birth weight for women exposed to buprenorphine+naloxone. Anecdotally women who are stable on buprenorphine+naloxone prior to pregnancy express concern about changing medications and often reluctantly switch to the buprenorphine mono-product on the recommendation of their care provider.\n\nResults from this study support the safety of buprenorphine+naloxone in pregnancy and provide evidence for inclusion of pregnancy as an indication for buprenorphine+naloxone therapy. A policy change of this nature would increase access to care for many women residing in rural and remote settings or where methadone is not an option. Ongoing research and postmarket surveillance would be required to assess rare outcomes. Furthermore, longitudinal studies of the infants exposed to buprenorphine in utero should be performed to assess developmental outcomes. This would add valuable information on the safety of this medication in pregnancy.\n\nContributors: NAJ and CE contributed to data analysis and manuscript preparation. JB-B and KL involved in data collection and provided approval of final draft. JD and LGF contributed to data collection and manuscript preparation. LK involved in data collection, data analysis and manuscript preparation.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nEthics approval: Sioux Lookout Meno Ya Win Health Centre.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: Source data will not be shared publicly as this was not stipulated in the original ethics approval. Data may be obtained by emailing lkelly@mcmaster.ca.\n==== Refs\nReferences\n1 Dooley R , Dooley J , Antone I \nNarcotic tapering in pregnancy using long-acting morphine: an 18 month year prospective study in Northwest Ontario . Can Fam Physician \n2015 ;61 :e88 –95 .25821873 \n2 Walker R , Cromarty H , Kelly L \nAchieving Cultural Safety in Aboriginal Health Services: implementation of a cross-cultural safety model in a hospital setting . Divers Health Care \n2009 ;6 :11 –22 .\n3 Jones HE , Martin PR , Heil SH \nTreatment of opioid-dependent pregnant women: clinical and research issues . J Subst Abuse Treat \n2008 ;35 :245 –59 . 10.1016/j.jsat.2007.10.007 18248941 \n4 Winklbaur B , Kopf N , Ebner N \nTreating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates . Addiction \n2008 ;103 :1429 –40 . 10.1111/j.1360-0443.2008.02283.x 18783498 \n5 Katt M , Chase C , Samokhvalov A \nFeasibility and outcomes of a community-based taper-to-low-dose-maintenance suboxone treatment program for prescription opioid dependence in a remote First Nations community in Northern Ontario . J Aborig Health \n2012 ;9 :52 –9 .\n6 World Health Organization . Guidelines for the identification and management of substance use and substance use disorders in pregnancy . Geneva, Switzerland : World Health Organization , 2014 :14 .\n7 Wong S , Ordean A , Kahan M \nSubstance abuse in pregnancy . J Obstet Gynaecol Can \n2011 ;33 :367 –84 . 10.1016/S1701-2163(16)34855-1 21501542 \n8 American College of Obstetricians and Gynecologists . Opioid abuse, dependence and addiction in pregnancy. Committee opinion 524 . Obstet Gynecol \n2012 ;119 :1070 –1 . 10.1097/AOG.0b013e318256496e 22525931 \n9 Jones HE , Kaltenbach K , Heil SH \nNeonatal abstinence syndrome after methadone or buprenorphine exposure . N Engl J Med \n2010 ;363 :2320 –31 . 10.1056/NEJMoa1005359 21142534 \n10 Daily Med . Suboxone tablet (product monograph) . Bethesda (MD) : National Institutes of Health , 2013 \nhttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4b9b43c4-293e-4323-a1a1-9a2f6a16ac39 (accessed 23 Aug 2013 ).\n11 Daily Med . Suboxone soluble film (product monograph) . Bethesda (MD) : National Institutes of Health , 2013 \nhttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8a5edcf9-828c-4f97-b671-268ab13a8ecd (accessed 23 Aug 2013 ).\n12 Rementeriá JL , Nunag NN \nNarcotic withdrawal in pregnancy: stillbirth incidence with a case report . Am J Obstet Gynecol \n1973 ;116 :1152 –6 . 10.1016/0002-9378(73)90953-8 4721145 \n13 Stern R \nThe pregnant addict: a study of 66 case histories, 1950–1959 . Am J Obstet Gynecol \n1966 ;94 :253 –7 . 10.1016/0002-9378(66)90472-8 5948036 \n14 Daily Med . Naloxone hydrochloride (product monograph) . Bethesda (MD) : National Institutes of Health , 2013 \nhttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d524c0e5-a7c2-40b2-9eed-2caf71c787dc (accessed 23 Aug 2013 ).\n15 Food and Drug Administration . Reviewer guidance evaluating the risks of drug exposure in human pregnancies . Rockville (MD) : Food and Drug Administration , 2005 :4 .\n16 Indigenous and Northern Affairs Canada . Aboriginal women in Canada: a statistical profile from the 2006 census . Ottawa (ON) : Government of Canada , 2012 \nhttps://www.aadnc-aandc.gc.ca/eng/1331664678840/1331838092221 \n17 Porter CJ , Feldt RH , Edwards WD \nChapter 27: atrial septal defects . In: Allen HD , Gutgesell HP , Clark EB et al eds. Moss & Adams’ heart disease in infants, children & adolescents: including the fetus and young adults . 8th edn \nPhiladelphia (PA) : Lippincott, Williams and Wilkins , 2013 (accessed 29 May 2016 ).\n18 Kelly L , Guilfoyle J , Dooley J \nincidence of narcotic abuse during pregnancy in Northwestern Ontario: three-year prospective cohort study . Can Fam Physician \n2014 ;60 :e493 –8 .25316764 \n19 Debelak K , Morrone WR , O'Grady KE \nBuprenorphine+naloxone in the treatment of opioid dependence during pregnancy—initial patient care and outcome data . Am J Addict \n2013 ;22 :252 –4 . 10.1111/j.1521-0391.2012.12005.x 23617867 \n20 Lund IO , Fisher G , Welle-Strand G \nA Comparison of buprenorphine+naloxone to buprenorphine and methadone in the treatment of opioid dependence during pregnancy: maternal and neonatal outcomes . Subst Abuse \n2013 ;7 :61 –74 . 10.4137/SART.S10955 23531704 \n21 Wiegand SL , Stringer EM , Stuebe AM \nBuprenorphine and naloxone compared with methadone treatment in pregnancy . Obstet Gynecol \n2015 ;125 :363 –8 . 10.1097/AOG.0000000000000640 25569005 \n22 Mattick RP , Breen C , Kimber J \nBuprenorphine maintenance versus placebo or methadone maintenance for opioid dependence . Cochrane Database Syst Rev \n2014 ;(2) :CD002207 \n10.1002/14651858.CD002207.pub4 24500948 \n23 Jumah NA , Graves L , Kahan M \nThe management of opioid dependence in pregnancy in rural and remote settings . CMAJ \n2015 ;187 :E41 –6 . 10.1503/cmaj.131723 25288311\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2044-6055",
"issue": "6(10)",
"journal": "BMJ open",
"keywords": "Buprenorphine + naloxone; Indigenous health; Pregnancy; Rural and remote; Safety",
"medline_ta": "BMJ Open",
"mesh_terms": "D000328:Adult; D001034:Apgar Score; D001724:Birth Weight; D002047:Buprenorphine; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D009270:Naloxone; D009292:Narcotic Antagonists; D009357:Neonatal Abstinence Syndrome; D009864:Ontario; D009293:Opioid-Related Disorders; D011247:Pregnancy; D011248:Pregnancy Complications; D037841:Pregnant Women; D012189:Retrospective Studies; D012424:Rural Population; D016896:Treatment Outcome",
"nlm_unique_id": "101552874",
"other_id": null,
"pages": "e011774",
"pmc": null,
"pmid": "27799240",
"pubdate": "2016-10-31",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "18248941;21142534;21501542;5948036;25316764;22525931;24500948;25821873;18783498;23617867;23531704;4721145;25288311;25569005",
"title": "Observational study of the safety of buprenorphine+naloxone in pregnancy in a rural and remote population.",
"title_normalized": "observational study of the safety of buprenorphine naloxone in pregnancy in a rural and remote population"
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"abstract": "In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years.\n\n\n\nPatients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed.\n\n\n\nOf 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups.\n\n\n\nAdvancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients.\n\n\n\nNCT01345682 (ClinicalTrials.gov).",
"affiliations": "Department of Oncology, KU Leuven, Leuven Department of General Medical Oncology, UZ Leuven, Leuven, Belgium paul.clement@uzleuven.be.;Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany.;Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium.;Departmant of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, USA.;Departmant of Medical Oncology, Léon Bérard Center, University of Lyon, Lyon, France.;Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, USA.;Service d'Oncologie Médicale, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier, France.;Department of Medical Oncology, Hospital Clínic and University of Barcelona, Barcelona, Spain.;Department of Medical Oncology, Gustave Roussy, Villejuif Centre Antoine Lacassagne, Nice, France.;Department of Melanoma, Soft Tissues, Muscolo Scheletal, Head and Neck, Head and Neck Medical Oncology, National Tumor Institute of Naples, Naples, Italy.;Oncologia Clinica, Instituto do Câncer do Estado de São Paulo, São Paulo.;Department of Medical Oncology, Hospital de Câncer de Barretos, São Paulo, Brazil.;Charité Comprehensive Cancer Center, Berlin, Germany.;Department of Medical Oncology, Hospital Universitario Vall D'Hebron, Barcelona, Spain.;Biometrics and Data Management, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA.;Division of Oncology, Boehringer Ingelheim Danmark A/S, Copenhagen, Denmark.;Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium.",
"authors": "Clement|P M|PM|;Gauler|T|T|;Machiels|J P|JP|;Haddad|R I|RI|;Fayette|J|J|;Licitra|L F|LF|;Tahara|M|M|;Cohen|E E W|EE|;Cupissol|D|D|;Grau|J J|JJ|;Guigay|J|J|;Caponigro|F|F|;de Castro|G|G|;de Souza Viana|L|L|;Keilholz|U|U|;Del Campo|J M|JM|;Cong|X J|XJ|;Ehrnrooth|E|E|;Vermorken|J B|JB|;|||",
"chemical_list": "D011799:Quinazolines; D000077716:Afatinib; D010984:Platinum; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdw151",
"fulltext": "\n==== Front\nAnn OncolAnn. OncolannoncannoncAnnals of Oncology0923-75341569-8041Oxford University Press 10.1093/annonc/mdw151mdw151Original ArticlesHead and Neck TumorsAfatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial† Clement P. M. 12*Gauler T. 3Machiels J. P. 4Haddad R. I. 5Fayette J. 6Licitra L. F. 7Tahara M. 8Cohen E. E. W. 9Cupissol D. 10Grau J. J. 11Guigay J. 1213Caponigro F. 14de Castro G. Jr15de Souza Viana L. 16Keilholz U. 17del Campo J. M. 18Cong X. J. 19Ehrnrooth E. 20Vermorken J. B. 21on behalf of the LUX-H&N 1 investigators1 Department of Oncology, KU Leuven, Leuven2 Department of General Medical Oncology, UZ Leuven, Leuven, Belgium3 Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany4 Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium5 Departmant of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, USA6 Departmant of Medical Oncology, Léon Bérard Center, University of Lyon, Lyon, France7 Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy8 Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan9 Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, USA10 Service d'Oncologie Médicale, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier, France11 Department of Medical Oncology, Hospital Clínic and University of Barcelona, Barcelona, Spain12 Department of Medical Oncology, Gustave Roussy, Villejuif13 Centre Antoine Lacassagne, Nice, France14 Department of Melanoma, Soft Tissues, Muscolo Scheletal, Head and Neck, Head and Neck Medical Oncology, National Tumor Institute of Naples, Naples, Italy15 Oncologia Clinica, Instituto do Câncer do Estado de São Paulo, São Paulo16 Department of Medical Oncology, Hospital de Câncer de Barretos, São Paulo, Brazil17 Charité Comprehensive Cancer Center, Berlin, Germany18 Department of Medical Oncology, Hospital Universitario Vall D'Hebron, Barcelona, Spain19 Biometrics and Data Management, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA20 Division of Oncology, Boehringer Ingelheim Danmark A/S, Copenhagen, Denmark21 Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium* Correspondence to: Dr Paul M. Clement, Department of Oncology, KU Leuven, Herestraat 49, Leuven 3000, Belgium. Tel: +32-16-34-69-03; E-mail: paul.clement@uzleuven.be† Presented, in part, at the International Conference on Innovative Approaches in Head and Neck Oncology Meeting; 12–14 February 2015, Nice, France. Abstract No. OC-005.\n\n8 2016 15 4 2016 15 4 2016 27 8 1585 1593 6 1 2016 15 3 2016 21 3 2016 © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comIn the LUX-Head & Neck 1 study, older age (≥65 years) did not adversely affect the benefit in patient-reported outcomes and antitumor activity observed with afatinib over methotrexate, which was consistent with findings from the overall population. Safety in older patients was also consistent with the overall population, favoring afatinib in terms of fewer dose reductions and discontinuations.\n\nBackground\nIn the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years.\n\nPatients and methods\nPatients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m2/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed.\n\nResults\nOf 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45–1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62–1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54–1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76–1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%–77%) and diarrhea (70%–80%) with afatinib, and stomatitis (43%) and fatigue (31%–34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups.\n\nConclusions\nAdvancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients.\n\nClinical trial registration\nNCT01345682 (ClinicalTrials.gov).\n\nafatinibmethotrexateHNSCCsecond-linephase IIIolderBoehringer Ingelheim\n==== Body\nintroduction\nHead and neck squamous cell carcinoma (HNSCC), including cancers of the lip, oral cavity, larynx, and pharynx, represents the seventh most common malignancy worldwide, with >650 000 cases diagnosed in 2012 [1]. Of these cases, 37% were older patients (≥65 years), 15% aged ≥75 years. These statistics are consistent with the EUROCARE-5 population-based study (1999–2007), which also reported decreased survival for head and neck cancer patients of advancing age at diagnosis (5-year relative survival: 56%, 38%, and 34% in patients aged ≤44, 65–74, and ≥75 years, respectively) [2]. There are no specific therapy guidelines for older patients with HNSCC, and treatment is often suboptimal due to poor functional status, high comorbidity burden and limited tolerability of standard therapies [3, 4]. For recurrent and/or metastatic (R/M) HNSCC patients progressing on/after first-line platinum therapy, these age-associated factors add to an already dismal prognosis and limited treatment options. Second-line treatment for R/M HNSCC primarily consists of single-agent or combination chemotherapy (e.g. methotrexate, taxanes) [5, 6]. However, older patients often do not receive these therapies due to the high risk of chemotherapy-induced toxicities, which can lead to treatment intolerance and poorer outcomes [3, 4].\n\nDespite advancements in the development of targeted therapies as similarly efficacious and potentially less toxic options compared with chemotherapy, only one targeted therapy, the anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, is approved for second-line R/M HNSCC, and only in the United States [7]. There are no published studies evaluating cetuximab in older R/M HNSCC patients, although subgroup analyses in a phase II study of cetuximab following the failure of a platinum-based therapy reported similar efficacy outcomes in patients aged <65 or ≥65 years; safety was not analyzed according to age [7]. In contrast, a phase III study of cetuximab combined with platinum-based therapy for first-line R/M disease reported reduced clinical benefit in subgroup analyses of patients aged ≥65 years [8]. In light of these limited data, there remains significant need to identify effective and manageable treatments for older HNSCC patients.\n\nAfatinib, an oral, irreversible ErbB family blocker, binds to human EGFR 1, 2, and 4 and inhibits signaling from all ErbB family members [9]. In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) and patient-reported outcomes versus methotrexate in R/M HNSCC patients progressing on/after platinum-based therapy [10]. Afatinib was associated with a predictable and manageable adverse event (AE) profile, with fewer treatment-related dose reductions, discontinuations and fatal events compared with methotrexate. This report evaluates the efficacy and safety of afatinib in prespecified age subgroups of ≥65 and <65 years in LHN1.\n\nmaterials and methods\npatients\nComplete eligibility criteria were previously reported [10]. Eligible patients were aged ≥18 years, had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, and histologically or cytologically confirmed squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx or larynx, which had recurred or metastasized and were not amenable for salvage surgery or radiotherapy. Patients had documented progression based on investigator assessment [Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)] following ≥2 cycles of cisplatin or carboplatin for R/M disease; treatment with >1 systemic regimen in this setting was not allowed. Prior EGFR-targeted antibody therapy, but not EGFR tyrosine kinase inhibitors, was allowed.\n\nstudy design\nIn this global, phase III, open-label trial, patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m2/week intravenous methotrexate, stratified by ECOG PS (0/1) and prior EGFR-targeted antibody therapy for R/M disease (yes/no). Details on dose modifications were reported [10]. Treatment continued until disease progression, unacceptable toxicity, or withdrawal.\n\nThe primary end point was PFS (independent central review); overall survival (OS) was the key secondary end point. Other end points included objective response, tumor shrinkage, patient-reported outcomes of disease symptoms and quality of life [QoL; European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire C30 and its head and neck cancer-specific module], and safety; disease control was also assessed.\n\nThe study protocol, designed in accordance with the Declaration of Helsinki, the International Conference on Harmonization Guideline for Good Clinical Practice, and applicable region-specific regulatory requirements, was approved by Independent Ethics Committees at each center. All patients provided written informed consent.\n\nassessments\nTumor response was assessed by investigators and independent central review (RECIST v1.1) every 6 weeks for the first 24 weeks, and every 8 weeks thereafter [10]. Safety was monitored weekly, with incidence and intensity of AEs graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3.0).\n\nstatistical analysis\nComplete details on statistical analyses were reported [10]. Efficacy analyses included all randomized patients (intent-to-treat population); safety analyses included all treated patients (randomized patients receiving ≥1 dose of study drug). PFS and OS were analyzed following a hierarchical testing procedure consisting of a stratified log-rank test with strata used for randomization on PFS followed by OS. The Kaplan–Meier method was used to estimate PFS and OS, and hazard ratios (HRs) for afatinib versus methotrexate were derived using a stratified Cox proportional hazards model. Predefined age subgroups included ≥65 and <65 years; a Cox proportional hazards model was used to explore subgroup by treatment interaction. Statistical analyses were performed with SAS (version 9.2).\n\nresults\npatients\nOf 483 randomized patients, 128 (27%) were aged ≥65 years (afatinib, n = 83; methotrexate, n = 45), and 355 (73%) aged <65 years (afatinib, n = 239; methotrexate, n = 116) (supplementary Figure S1, available at Annals of Oncology online), further described as ‘older’ and ‘younger’, respectively. The median (range) age was 71 (65–82) and 71 (65–88) years for patients treated with afatinib and methotrexate in the older subgroup, and 57 (32–64) and 55 (32–64) years in the younger subgroup. Approximately 15% (n = 71) of patients were aged ≥70 years (afatinib, n = 47; methotrexate, n = 24) and 7% (n = 32) aged ≥75 years (afatinib, n = 22; methotrexate, n = 10) due to small patient numbers; no further analyses were conducted in these exploratory age subgroups.\n\nBaseline disease characteristics were generally well balanced (Table 1). A larger proportion of older patients randomized to methotrexate had an ECOG PS of 1 compared with the afatinib arm, although patient numbers in this arm were small. Compared with the younger subgroup, a larger proportion of older patients had oral cavity primary tumor site, and fewer received prior cisplatin for R/M disease. More patients in the older subgroup received prior radiotherapy with curative intent and fewer received chemoradiation. Slightly higher incidences of diabetes and hypertension were noted in older patients (supplementary Table S1, available at Annals of Oncology online). There were no notable differences in baseline concomitant medications (data on file).Table 1. Patients’ demographic and baseline characteristics by age subgroup\n\nCharacteristic\tPatients aged ≥65 years\tPatients aged <65 years\t\nAfatinib (N = 83)\tMethotrexate (N = 45)\tAfatinib (N = 239)\tMethotrexate (N = 116)\t\nGender, n (%)\t\n Male\t68 (82)\t37 (82)\t207 (87)\t100 (86)\t\n Female\t15 (18)\t8 (18)\t32 (13)\t16 (14)\t\nAge (years)\t\n Median (range)\t71 (65–82)\t71 (65–88)\t57 (32–64)\t55 (32–64)\t\nAge category, n (%)\t\n <75 years\t61 (73)\t35 (78)\t239 (100)\t116 (100)\t\n ≥75 years\t22 (27)\t10 (22)\t0 (0)\t0 (0)\t\nECOG PS, n (%)\t\n 0\t23 (28)\t7 (16)\t66 (28)\t35 (30)\t\n 1\t60 (72)\t38 (84)\t173 (72)\t81 (70)\t\nSmoking habits, n (%)a\t\n Median (range) pack years\t50.0 (4.5–156.0)\t43.0 (3.7–156.0)\t40.0 (1.0–130.0)\t36.0 (0.6–225.0)\t\n <10 pack years\t18 (22)\t8 (18)\t38 (16)\t23 (20)\t\n ≥10 pack years\t60 (72)\t34 (76)\t195 (82)\t92 (79)\t\n Unknown\t5 (6)\t3 (7)\t6 (3)\t1 (1)\t\nAlcohol consumption, n (%)a\t\n ≤7 units/week\t65 (78)\t40 (89)\t185 (77)\t84 (72)\t\n >7 units/week\t15 (18)\t5 (11)\t43 (18)\t28 (24)\t\n Unknown\t3 (4)\t0 (0)\t11 (5)\t4 (3)\t\nWeight loss in prior 3 months, n (%)a\t\n None\t59 (71)\t27 (60)\t161 (67)\t80 (69)\t\n ≤5%\t12 (14)\t8 (18)\t35 (15)\t19 (16)\t\n >5% and ≤10%\t6 (7)\t4 (9)\t27 (11)\t10 (9)\t\n >10%\t4 (5)\t3 (7)\t5 (2)\t3 (3)\t\n Unknown\t2 (2)\t3 (7)\t11 (5)\t4 (3)\t\nPrimary tumor site, n (%)a\t\n Oral cavity\t29 (35)\t17 (38)\t65 (27)\t25 (22)\t\n Oropharynx\t26 (31)\t10 (22)\t73 (31)\t44 (38)\t\n Hypopharynx\t12 (14)\t9 (20)\t51 (21)\t21 (18)\t\n Larynx\t16 (19)\t9 (20)\t50 (21)\t26 (22)\t\nMedian time since first diagnosis, years (range)a\t2.3 (0.4–27.1)\t1.7 (0.6–21.7)\t1.9 (0.3–21.0)\t2.4 (0.5–18.2)\t\n <2, n (%)\t37 (45)\t24 (53)\t126 (53)\t47 (41)\t\n ≥2, n (%)\t46 (55)\t21 (47)\t112 (47)\t68 (59)\t\n Unknown, n (%)\t0 (0)\t0 (0)\t1 (<1)\t1 (1)\t\nRecurrence and metastases, n (%)a\t\n Recurrent only\t28 (34)\t22 (49)\t78 (33)\t39 (34)\t\n Metastatic only\t10 (12)\t8 (18)\t36 (15)\t10 (9)\t\n Both\t43 (52)\t15 (33)\t121 (51)\t62 (53)\t\n Unknown\t2 (2)\t0 (0)\t4 (2)\t5 (4)\t\np16 status,b\nn (%)a\t\n Positive\t10 (12)\t8 (18)\t21 (9)\t10 (9)\t\n Negative\t25 (30)\t16 (36)\t116 (49)\t51 (44)\t\n Not performed\t48 (58)\t21 (47)\t102 (43)\t55 (47)\t\nPrior platinum-based therapy for R/M disease, n (%)\t\n Cisplatin\t35 (42)\t18 (40)\t133 (56)\t65 (56)\t\n Carboplatin\t38 (46)\t17 (38)\t81 (34)\t30 (26)\t\n Cisplatin and carboplatin\t8 (10)\t9 (20)\t22 (9)\t19 (16)\t\n Other\t2 (2)\t1 (2)\t3 (1)\t2 (2)\t\nPrior use of anti-EGFR mAb for R/M disease, n (%)c\t49 (59)\t30 (67)\t140 (59)\t68 (59)\t\nPrior surgery, n (%)\t62 (75)\t32 (71)\t182 (76)\t90 (78)\t\nPrior curative anticancer therapy,d\nn (%)\t\n CT only\t0 (0)\t1 (2)\t8 (3)\t5 (4)\t\n RT only\t28 (34)\t14 (31)\t49 (21)\t23 (20)\t\n CRT\t31 (37)\t14 (31)\t114 (48)\t59 (51)\t\n CRT + anti-EGFR mAb\t5 (6)\t2 (4)\t20 (8)\t6 (5)\t\n Other\t4 (5)\t2 (4)\t8 (3)\t2 (2)\t\naPercentages may not total 100% due to rounding.\n\nbBased on either local or central test results.\n\ncOne patient (aged <65 years in the afatinib group) received prior panitumumab; all remaining patients received cetuximab.\n\ndInvestigator-reported anticancer therapies with curative intent.\n\nCRT, chemoradiation therapy; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; mAb, monoclonal antibody; PS, performance status; R/M, recurrent and/or metastatic; RT, radiation therapy.\n\n\n\ntreatment exposure\nMedian (range) treatment durations with afatinib and methotrexate were 84 (6–512) and 43 (1–337) days in older patients, and 80 (2–546) and 43 (1–442) days in younger patients. The majority of older (afatinib, 82%; methotrexate, 82%) and younger (afatinib, 86%; methotrexate, 85%) patients received ≥80% of the assigned study medication. The majority of afatinib-treated patients received the drug in tablet form (older, 80%; younger, 73%) compared with feeding tube administration (older, 13%; younger, 22%) or oral dispersion (older, 7%; younger, 5%).\n\nefficacy\nTreatment effects on survival outcomes were similar between subgroups. The median PFS with afatinib versus methotrexate was 2.8 versus 2.3 months {HR = 0.68 [95% confidence interval (CI) 0.45–1.03], P = 0.061} in older patients and 2.6 versus 1.6 months [HR = 0.79 (0.62–1.01), P = 0.052] in younger patients (Figure 1A). The median OS with afatinib and methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54–1.31), P = 0.436] in older patients and 6.7 versus 6.2 months [HR = 0.98 (0.76–1.28), P = 0.910] in younger patients (Figure 1B).Figure 1. Kaplan–Meier estimates of (A) PFS and (B) OS by age subgroup. aStratified log-rank test. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.\n\n\n\nObjective response rates (ORRs) with afatinib versus methotrexate were 10.8% versus 6.7% [odds ratio (OR) = 1.7 (95% CI 0.44–6.64)] in older patients, and 10.0% versus 5.2% [OR = 2.0 (0.81–5.15)] in younger patients. Disease control rates (DCRs) with afatinib versus methotrexate were 53.0% versus 37.8% [OR = 1.9 (0.89–3.90)] in older patients and 47.7% versus 38.8% [OR = 1.4 (0.92–2.26)] in younger patients. A higher percentage of patients in each subgroup experienced tumor shrinkage from baseline with afatinib versus methotrexate, with no notable differences between the subgroups (Figure 2).Figure 2. Waterfall plot of maximum percentage tumor shrinkage in subgroups of patients aged (A) ≥65 years and (B) <65 years.\n\n\n\nApproximately 50% of patients in each subgroup received subsequent anticancer therapy following discontinuation of study treatment, with the majority (∼92% in each subgroup) receiving subsequent chemotherapy as monotherapy or in combination (supplementary Table S2, available at Annals of Oncology online).\n\nsafety\nThe safety profiles of afatinib and methotrexate were similar in older and younger patients (Table 2). Treatment-related AEs occurred in ≥85% of patients across treatment groups in each age subgroup, with grade 3/4 AEs in 32%–40% of patients (Table 2). In each subgroup, the most frequent grade 3/4 treatment-related AEs consisted of rash/acne, diarrhea, stomatitis, and fatigue with afatinib, and stomatitis and hematologic AEs (e.g. anemia, neutropenia, thrombocytopenia, and leukopenia) with methotrexate. There were no notable differences with either treatment between subgroups in change from baseline in body weight or ECOG PS (data on file).Table 2. Treatment-related AEs in ≥5% of patients (in any group) by age subgroup\n\nEvent, n (%)\tPatients aged ≥65 years\tPatients aged <65 years\t\nAfatinib (N = 83)\tMethotrexate (N = 44)\tAfatinib (N = 237)\tMethotrexate (N = 116)\t\nAny AE\tAny grade\tGrade 3/4a\tAny grade\tGrade 3/4a\tAny grade\tGrade 3/4b\tAny grade\tGrade 3/4b\t\n80 (96)\t31 (37)\t39 (89)\t15 (34)\t223 (94)\t94 (40)\t98 (85)\t37 (32)\t\nDiarrhea\t66 (80)\t9 (11)\t6 (14)\t2 (5)\t165 (70)\t21 (9)\t13 (11)\t1 (1)\t\nRash/acnec\t64 (77)\t6 (7)\t4 (9)\t0 (0)\t174 (73)\t25 (11)\t9 (8)\t0 (0)\t\nStomatitisd\t40 (48)\t3 (4)\t19 (43)\t1 (2)\t85 (36)\t17 (7)\t50 (43)\t12 (10)\t\nFatiguee\t19 (23)\t7 (8)\t15 (34)\t2 (5)\t60 (25)\t11 (5)\t36 (31)\t3 (3)\t\nNausea\t14 (17)\t3 (4)\t5 (11)\t0 (0)\t50 (21)\t2 (1)\t31 (27)\t1 (1)\t\nParonychiaf\t10 (12)\t1 (1)\t0 (0)\t0 (0)\t36 (15)\t2 (1)\t0 (0)\t0 (0)\t\nDry skin\t10 (12)\t0 (0)\t0 (0)\t0 (0)\t26 (11)\t0 (0)\t0 (0)\t0 (0)\t\nPruritus\t10 (12)\t1 (1)\t0 (0)\t0 (0)\t16 (7)\t3 (1)\t0 (0)\t0 (0)\t\nVomiting\t9 (11)\t0 (0)\t0 (0)\t0 (0)\t32 (14)\t4 (2)\t14 (12)\t0 (0)\t\nWeight decreased\t9 (11)\t1 (1)\t2 (5)\t0 (0)\t17 (7)\t1 (<1)\t3 (3)\t0 (0)\t\nDecreased appetite\t8 (10)\t0 (0)\t5 (11)\t1 (2)\t35 (15)\t10 (4)\t16 (14)\t0 (0)\t\nEpistaxis\t6 (7)\t0 (0)\t0 (0)\t0 (0)\t11 (5)\t0 (0)\t1 (1)\t0 (0)\t\nDyspepsia\t5 (6)\t0 (0)\t0 (0)\t0 (0)\t18 (8)\t0 (0)\t0 (0)\t0 (0)\t\nAnemia\t5 (6)\t1 (1)\t8 (18)\t5 (11)\t17 (7)\t3 (1)\t22 (19)\t5 (4)\t\nCheilitis\t5 (6)\t0 (0)\t0 (0)\t0 (0)\t9 (4)\t0 (0)\t2 (2)\t0 (0)\t\nMuscle spasms\t5 (6)\t0 (0)\t0 (0)\t0 (0)\t3 (1)\t0 (0)\t0 (0)\t0 (0)\t\nHypokalemia\t4 (5)\t2 (2)\t1 (2)\t0 (0)\t9 (4)\t5 (2)\t3 (3)\t1 (1)\t\nDysgeusia\t4 (5)\t0 (0)\t0 (0)\t0 (0)\t8 (3)\t0 (0)\t2 (2)\t0 (0)\t\nBlood creatinine increased\t4 (5)\t0 (0)\t0 (0)\t0 (0)\t4 (2)\t0 (0)\t1 (1)\t0 (0)\t\nDehydration\t4 (5)\t2 (2)\t0 (0)\t0 (0)\t3 (1)\t3 (1)\t0 (0)\t0 (0)\t\nDizziness\t4 (5)\t0 (0)\t0 (0)\t0 (0)\t3 (1)\t0 (0)\t0 (0)\t0 (0)\t\nConjunctivitisg\t2 (2)\t1 (1)\t1 (2)\t0 (0)\t16 (7)\t1 (<1)\t1 (1)\t0 (0)\t\nPalmar-plantar erythrodysethesia\t2 (2)\t0 (0)\t1 (2)\t0 (0)\t15 (6)\t2 (1)\t1 (1)\t0 (0)\t\nLeukopenia\t1 (1)\t0 (0)\t4 (9)\t1 (2)\t0 (0)\t0 (0)\t9 (8)\t7 (6)\t\nALT increased\t0 (0)\t0 (0)\t3 (7)\t1 (2)\t1 (<1)\t0 (0)\t12 (10)\t2 (2)\t\nNeutropenia\t0 (0)\t0 (0)\t15 (34)\t4 (9)\t1 (<1)\t1 (<1)\t16 (14)\t7 (6)\t\nThrombocytopenia\t0 (0)\t0 (0)\t3 (7)\t2 (5)\t0 (0)\t0 (0)\t5 (4)\t2 (2)\t\naThere were no grade 5 drug-related AEs observed in ≥5% of patients. In the subgroup of patients aged ≥65 years, there were no patients with grade 5 AEs in the afatinib group and one patient with grade 5 renal failure and pancytopenia in the methotrexate group not included in the table.\n\nbIn the subgroup of patients aged <65 years, there were two patients with grade 5 AEs in the afatinib group (one aspiration, one septic shock) and four patients with grade 5 AEs in the methotrexate group (one aspiration, one septic shock, one sepsis, and one general physical health deterioration) not included in the table.\n\ncGrouped term including acne, dermatitis, dermatitis acneiform, erythema, exfoliative rash, folliculitis, rash, rash erythematous, rash macular, rash maculopapular, rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, and skin ulcer.\n\ndGrouped term including aphthous stomatitis, mucosal erosion, mucosal inflammation, mouth ulceration, and stomatitis.\n\neGrouped term including asthenia, chronic fatigue syndrome, fatigue, and malaise.\n\nfGrouped term including nail bed infection and paronychia.\n\ngGrouped term including conjunctivitis.\n\nAE, adverse event; ALT, alanine aminotransferase.\n\n\n\nIncidences of treatment-related serious AEs were similar for afatinib and methotrexate in older (10% and 9%) and younger (15% and 12%) patients. In both subgroups, afatinib was associated with fewer treatment-related dose reductions (older, 36% versus 43%; younger, 31% versus 41%) and discontinuations (older, 7% versus 16%; younger, 7% versus 16%). There were no deaths related to afatinib and one related to methotrexate in older patients; fewer treatment-related deaths were observed with afatinib [n = 2 (1%)] compared with methotrexate [n = 4 (3%)] in younger patients.\n\npatient-reported outcomes\nIn the older and younger subgroups, respectively, ≥90% and ≥95% completed EORTC QoL questionnaires at baseline, and ≥65% and ≥71% across treatment groups completed questionnaires at assessment time points during the first 24 weeks of treatment. There were no notable differences in baseline questionnaire scores between subgroups (data on file). A trend toward improved time to deterioration in global health status and pain was observed with afatinib versus methotrexate in both subgroups; a significant benefit with afatinib was observed for time to deterioration in swallowing in older patients (Figure 3). A significant improvement in change in pain over time (P = 0.015) was observed with afatinib versus methotrexate in older patients (data on file).Figure 3. Time to deterioration of patient-reported outcomesa by age subgroup. aAssessed using EORTC questionnaire QLQ-C30 and QLQ-H&N35 for pain (composite of items 31–34) and swallowing (composite of items 35–38). CI, confidence interval; EORTC, European Organization for Research and Treatment of Cancer; GHS, global health status; HR, hazard ratio; QLQ-C30, quality-of-life questionnaire C30; QLQ-H&N35, quality-of-life questionnaire head and neck cancer-specific module.\n\n\n\ndiscussion\nThe PFS benefit with afatinib over methotrexate was similarly present in R/M HNSCC patients aged ≥65 or <65 years, and was associated with a trend toward improvement in some disease-related symptoms. Although patient numbers in the older subgroup were smaller than the overall population and younger subgroup (particularly the methotrexate arm due to the 2:1 randomization scheme), and the study was not powered for formal statistical comparison of predefined subgroups, there is no indication that the benefit observed with afatinib would be adversely affected by advancing age. Median OS, percentage of patients with tumor shrinkage, ORR, and DCR were also numerically higher with afatinib versus methotrexate in both subgroups, with >50% of older patients achieving disease control with afatinib. Similar to the previous phase III trials in this setting [8, 11], the 65-year age cutoff was predefined in this study, and patient numbers in exploratory subgroups aged ≥70 years were too small for meaningful analyses.\n\nIn both predefined age subgroups, afatinib was associated with a trend toward improved patient-reported time to deterioration of global health status, pain and swallowing, reflecting the improvements observed in the overall population [10]. In older patients, significant benefit with afatinib was observed for time to deterioration in swallowing and improvement in pain over time. Patient-reported outcomes were not analyzed by primary tumor site, which can impact swallowing ability. In this context, a larger proportion of older patients had oral cavity primary site, while more patients in the younger subgroup had oropharynx primary site. In the previous phase III studies of R/M HNSCC, EGFR-targeted agents have not significantly improved global health status over chemotherapy, although some improvements in disease-related symptoms were reported with first-line cetuximab plus chemotherapy; no studies evaluated QoL or disease-related symptoms specifically in older patients [11–13]. While some caution is warranted when interpreting the patient-reported outcomes data for older patients in this study due to smaller patient numbers, findings suggest that afatinib may provide some QoL benefit over methotrexate in these patients.\n\nTreatment compliance is an important factor for clinical outcomes in older patients, as they are vulnerable to nonadherence due to health-related and socioeconomic factors (e.g. logistical complications and hospital transportation) [14]. In this study, treatment exposure with afatinib was similar in older and younger patients, and compliance rates were high with afatinib versus methotrexate in both subgroups. Further, no unexpected safety findings with afatinib were observed in older patients, with an AE profile that was predictable and manageable, and generally similar to younger patients. Of note, there were some differences in baseline prior therapies that may impact tolerability, including less intensive therapy in the curative setting in the older subgroup (i.e. more patients received radiotherapy alone and fewer received chemoradiation compared with younger patients), although no analysis of timing of curative therapy was performed, and a greater proportion of older patients receiving carboplatin over cisplatin in the first-line R/M setting compared with younger patients. Consistent with the overall study, fewer treatment-related dose reductions and discontinuations were observed with afatinib versus methotrexate in both subgroups, with no afatinib-related deaths occurring in older patients. These findings suggest that advancing age did not adversely affect the favorable safety profile of afatinib in this study.\n\nThere are some study limitations that should be considered when interpreting these findings, particularly for patients aged ≥65 years. There is no standard definition for ‘older’ or ‘elderly’; however, much of the literature defines patients aged ≥65 years as ‘older’, with subcategories of ‘young old’ (65–74 years), ‘old’ (75–85 years), and ‘oldest old’ (>85 years) [3, 4]. In this study, 25% of patients included in the ≥65 years subgroup were aged ≥75 years, categorizing the majority as ‘young old’. This is not unexpected, as patients aged ≥75 years are often underrepresented in clinical trials due to exclusion criteria preventing enrollment of patients with high comorbidity burden and poor functional status, which are routinely observed with advancing age, particularly in HNSCC patients. In this trial, patients with ECOG PS ≥2 (due to the lack of prior experience with afatinib in R/M HNSCC patients with ECOG PS >1) and/or significant comorbidities (e.g. cardiovascular abnormalities, gastrointestinal disorders) were excluded, resulting in similar functional status and baseline medical conditions between subgroups. Further, there was no formal geriatric assessment to define frailty of the patients enrolled; thus, patients in the ≥65 years subgroup are considered to be relatively fit, warranting a certain degree of caution when considering treatment of a frailer population. Despite these limitations, patients aged ≥65 years represented a substantial proportion (27%) of the total study population, with a ∼15-year difference in median age observed between subgroups. This allowed for meaningful comparison of clinical outcomes based on the age cutoff of ≥65 years, ultimately demonstrating similar treatment effects of afatinib and methotrexate in these subgroups. These findings support the concept that chronological age alone should not be a determining factor in treatment choice, and other factors including functional status, comorbidities, and frailty should be considered [4]. Ongoing trials in HNSCC patients aged ≥70 years have incorporated geriatric evaluation to define patient frailty and deliver more personalized treatment (ELAN trials) [15].\n\nIn summary, effective anticancer treatment and management of tolerability in older R/M HNSCC patients is a significant challenge. In the LHN1 study, similar outcomes with regard to efficacy and patient-reported outcomes of QoL and disease-related symptoms were observed with afatinib versus methotrexate in the second-line R/M HNSCC patients aged ≥65 and <65 years. Further, afatinib demonstrated a predictable and manageable safety profile in both subgroups.\n\nfunding\nThis work was supported by Boehringer Ingelheim. There is no applicable grant number for this work.\n\ndisclosure\nTG has stock ownership or options in Bayer AG; has participated in advisory boards for Boehringer Ingelheim, Merck Serono, Novartis, and MSD; and has received honoraria from Novartis, Merck Serono, Boehringer Ingelheim, and Roche. J-PHM has participated in noncompensated advisory boards for Boehringer Ingelheim. RIH has participated in advisory boards for BMS, Merck, Celgene, and Bayer and corporate-sponsored research for BMS, Merck, Boehringer Ingelheim, Celgene, and AstraZeneca. LFL has participated in advisory boards for Eisai, BMS, GlaxoSmithKline, Lilly, Merck Serono, Amgen, Boehringer Ingelheim, Debiopharm, VentiRX, SOBI, Novartis, AstraZeneca, and Bayer. MT has participated in advisory boards for Merck Serono, Eisai, and Bayer; has participated in corporate-sponsored research for Eisai and MSD; and has received honoraria from Merck Serono, BMS, Eisai, Otsuka, and Bayer. JG has participated in advisory boards for BMS and Merck Serono, and has received research grants from BMS, Boehringer Ingelheim, Chugai, GlaxoSmithKline, MSD, Merck Serono, and Sanofi. GdC Jr has participated in advisory boards and corporate-sponsored research for Boehringer Ingelheim, Roche, MSD, AstraZeneca, Merck Serono, and Eurofarma; has also participated in corporate-sponsored research for BMS; and has received honoraria from Roche, MSD, AstraZeneca, Merck Serono, and Eurofarma. XJC and EE are employees of Boehringer Ingelheim Pharmaceuticals, Inc. JBV has participated in advisory boards for Merck Serono, Innate Pharma, Synthon Biopharmaceuticals, MSD and Vaccinogen; has received honoraria from Merck Serono and Vaccinogen; and is on the steering committee for the LUX-Head & Neck studies. All remaining authors have declared no conflicts of interest.\n\nSupplementary Material\nSupplementary Data\n acknowledgments\nWe thank the patients, their families, and all of the investigators who participated in the study. We also thank Liz Svensson (Boehringer Ingelheim) for her contributions to the study. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Katie McClendon, PhD, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.\n==== Refs\nreferences\n1 Ferlay J , Soerjomataram I , Ervik M et al \nGLOBOCAN 2012 v1.0: Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 . 2012 .\n2 Gatta G , Botta L , Sanchez MJ et al \nPrognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study . Eur J Cancer \n2015 ; 51 : 2130 –2143 .\n3 Mountzios G \nOptimal management of the elderly patient with head and neck cancer: issues regarding surgery, irradiation and chemotherapy . World J Clin Oncol \n2015 ; 6 : 7 –15 .25667910 \n4 Sarris EG , Harrington KJ , Saif MW , Syrigos KN \nMultimodal treatment strategies for elderly patients with head and neck cancer . Cancer Treat Rev \n2014 ; 40 : 465 –475 .24238923 \n5 National Comprehensive Cancer Network . NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers, Version 1.2015 . 2015 In http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf (11 March 2016, date last accessed) .\n6 Grégoire V , Lefebvre JL , Licitra L , Felip E , and on behalf of the EHNS–ESMO–ESTRO Guidelines Working Group . Squamous cell carcinoma of the head and neck: EHNS-ESM–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol \n2010 ; 21 : v184 –v186 .20555077 \n7 Vermorken JB , Trigo J , Hitt R et al \nOpen-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy . J Clin Oncol \n2007 ; 25 : 2171 –2177 .17538161 \n8 Vermorken JB , Mesia R , Rivera F et al \nPlatinum-based chemotherapy plus cetuximab in head and neck cancer . N Engl J Med \n2008 ; 359 : 1116 –1127 .18784101 \n9 Solca F , Dahl G , Zoephel A et al \nTarget binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker . J Pharmacol Exp Ther \n2012 ; 343 : 342 –350 .22888144 \n10 Machiels JP , Haddad RI , Fayette J et al \nAfatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial . Lancet Oncol \n2015 ; 16 : 583 –594 .25892145 \n11 Machiels JP , Subramanian S , Ruzsa A et al \nZalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial . Lancet Oncol \n2011 ; 12 : 333 –343 .21377930 \n12 Stewart JS , Cohen EE , Licitra L et al \nPhase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected] . J Clin Oncol \n2009 ; 27 : 1864 –1871 .19289630 \n13 Mesia R , Rivera F , Kawecki A et al \nQuality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck . Ann Oncol \n2010 ; 21 : 1967 –1973 .20335368 \n14 Gellad WF , Grenard JL , Marcum ZA \nA systematic review of barriers to medication adherence in the elderly: looking beyond cost and regimen complexity . Am J Geriatr Pharmacother \n2011 ; 9 : 11 –23 .21459305 \n15 Joel Guigay J , Le Caer H , Mertens C et al \nElderly Head and Neck Cancer (ELAN) study: personalized treatment according to geriatric assessment in patients age 70 or older: first prospective trials in patients with squamous cell cancer of the head and neck (SCCHN) unsuitable for surgery . J Clin Oncol \n2014 ; 32 \n(15_suppl): abstract TPS6099 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0923-7534",
"issue": "27(8)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "HNSCC; afatinib; methotrexate; older; phase III; second-line",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008727:Methotrexate; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D010984:Platinum; D011799:Quinazolines; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1585-93",
"pmc": null,
"pmid": "27084954",
"pubdate": "2016-08",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "26421817;22888144;19289630;21459305;25892145;20555077;21377930;20335368;24238923;18784101;17538161;25667910",
"title": "Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.",
"title_normalized": "afatinib versus methotrexate in older patients with second line recurrent and or metastatic head and neck squamous cell carcinoma subgroup analysis of the lux head neck 1 trial"
} | [
{
"companynumb": "BE-MYLANLABS-2016M1043189",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nImproved psychopharmacologic treatment of posttraumatic stress disorder (PTSD) is needed. Accruing evidence implicates pain-conducting signals in PTSD pathophysiology.\n\n\nMETHODS\nFour combat-related PTSD patients from the wars in Iraq and Afghanistan were treated with open-label tramadol hydrochloride (HCL), an atypical analgesic with opioid and non-opioid mechanisms of antinociception. Tramadol also inhibits neuronal reuptake of norepinephrine and serotonin.\n\n\nRESULTS\nThe clinical outcomes show evidence of a positive effect of twice-daily immediate-release tramadol HCL in men with combat-related PTSD. Total daily doses were 200 to 300 mg/d, with individual doses ranging from 100 to 200 mg.\n\n\nCONCLUSIONS\nGiven its unique mechanism of action, relatively low abuse potential, and ability to double as an analgesic for minor to moderate pain, tramadol is a promising candidate for clinical use in PTSD.",
"affiliations": "Veterans Affairs Medical Center, Cincinnati Department of Psychiatry and Behavioral Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA. E-mail: thomas.geracioti@uc.edu.",
"authors": "Geracioti|Thomas D|TD|",
"chemical_list": "D000701:Analgesics, Opioid; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D014147:Tramadol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-1237",
"issue": "26(3)",
"journal": "Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists",
"keywords": null,
"medline_ta": "Ann Clin Psychiatry",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D006801:Humans; D008297:Male; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D013313:Stress Disorders, Post-Traumatic; D014147:Tramadol; D016896:Treatment Outcome; D014857:Warfare",
"nlm_unique_id": "8911021",
"other_id": null,
"pages": "217-21",
"pmc": null,
"pmid": "25166484",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Tramadol treatment of combat-related posttraumatic stress disorder.",
"title_normalized": "tramadol treatment of combat related posttraumatic stress disorder"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2015-02367",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional":... |
{
"abstract": "Purpuric skin lesions have only rarely been reported in patients receiving epidermal growth factor receptor inhibitors. However, their clinical and histopathologic presentations have varied considerably.\n\n\n\nTo characterize purpuric skin eruptions caused by epidermal growth factor receptor inhibitors.\n\n\n\nThis prospective study enrolled 32 patients who presented to an integrated dermato-oncologic clinic in a tertiary referral medical center with purpuric skin lesions after using epidermal growth factor receptor inhibitors from January 1, 2013, through December 31, 2015.\n\n\n\nEpidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, erlotinib, and afatinib.\n\n\n\nClinical presentations, histopathologic features, laboratory examinations, and treatment outcomes of patients with purpuric drug eruptions.\n\n\n\nThirty-two patients, 14 with purpuric drug eruptions without pustules (mean [SD] age, 60 [11] years; 12 female and 2 male) and 18 with purpuric drug eruptions with pustules (mean [SD] age, 64 [11] years; 12 female and 6 male), were identified. The median time to development of skin lesions was 3.5 months. The clinical presentations were characterized by purpuric macules, papules, and confluent plaques predominantly on the lower extremities. Pustules in various sizes could be found in 18 patients (56%). Eleven patients (34%) had skin lesions that covered places other than the lower extremities. Eczema craquelé-like features developed in 13 patients (41%). Bacterial pathogens were frequently identified in these skin lesions. Among them, Staphylococcus aureus was the most predominant and was found in 20 patients (63%), commonly in those with cutaneous pustules. Epidermal dysmaturation, neutrophil exocytosis, perivascular infiltration of lymphocytes and neutrophils, red blood cell extravasation, and plumping endothelium were the main histopathologic features. The expressions of filaggrin and human β-defensin 2 in lesional skin of these patients were markedly reduced. All patients improved after receiving at least 1 week of systemic antibiotic treatment; the doses of epidermal growth factor receptor inhibitors were also changed for 14 patients (44%).\n\n\n\nPurpuric drug eruptions caused by epidermal growth factor receptor inhibitors are uncommon and have characteristic clinical and histopathologic presentations. The role of bacterial pathogens in this reaction is important and requires further exploration.",
"affiliations": "Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.",
"authors": "Cho|Yung-Tsu|YT|;Chen|Kai-Lung|KL|;Sheen|Yi-Shuan|YS|;Yang|Che-Wen|CW|;Liau|Jau-Yu|JY|;Cheng|Yu-Pin|YP|;Chu|Chia-Yu|CY|",
"chemical_list": "D000970:Antineoplastic Agents; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib",
"country": "United States",
"delete": false,
"doi": "10.1001/jamadermatol.2017.0903",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6068",
"issue": "153(9)",
"journal": "JAMA dermatology",
"keywords": null,
"medline_ta": "JAMA Dermatol",
"mesh_terms": "D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D003875:Drug Eruptions; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D000091344:Filaggrin Proteins; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011799:Quinazolines",
"nlm_unique_id": "101589530",
"other_id": null,
"pages": "906-910",
"pmc": null,
"pmid": "28538945",
"pubdate": "2017-09-01",
"publication_types": "D016428:Journal Article",
"references": "10601294;23966300;18283195;25959005;21149656;20709888;24831548;22783433;15864276;20007525;26649681;27248048;23602600;24401788",
"title": "Purpuric Drug Eruptions Caused by Epidermal Growth Factor Receptor Inhibitors for Non-Small Cell Lung Cancer: A Clinicopathologic Study of 32 Cases.",
"title_normalized": "purpuric drug eruptions caused by epidermal growth factor receptor inhibitors for non small cell lung cancer a clinicopathologic study of 32 cases"
} | [
{
"companynumb": "TW-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-053311",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "BACKGROUND\nThe aggressive and timely treatment of post-traumatic fungal infections is the most efficacious way to reduce morbidity and mortality. Compared to the military trauma population, studies reporting on fungal infections in civilian trauma are not well described. The purpose of this study was to describe characteristics of civilian trauma patients who developed fungal infections and to identify common risk factors and report any delays between injury and treatment.\n\n\nMETHODS\nThis was a five-year (1/1/2013-3/1/2018) retrospective, descriptive study across six level 1 trauma centers. All consecutively admitted trauma patients (≥18 years) with laboratory-confirmed fungal wound infections were included. Patients with solely candida wound isolates were excluded. Patient demographics, clinical wound and infection characteristics, organisms cultured, treatment modalities, length of stay, in-hospital mortality, and any diagnostic or treatment delays were described.\n\n\nRESULTS\nOf the 54,521 trauma patients screened for fungal infection, 12 were identified. All patients suffered major injuries after blunt trauma (abbreviated injury score 3-5) and sustained wound contamination, and in nine patients, the cause of injury was motor vehicle. Six had open wounds/fractures on admission. The geographical region with the highest rate of fungal infection was Texas (n = 7), followed by Kansas (N = 3), then Missouri (N = 2). First symptoms of infection (leukocytosis or fever (n = 10)) presented a median of 6.3 (4.1-9.8) days after injury. Wound management entailed a combination of debridements (n = 8), negative pressure wound therapy (n = 9), amputation (n = 6), and antifungal treatment (n = 10). All fungal isolates identified from the wound site were hyphomycetes. A median of 2.1 (1.8-4.0) days passed from diagnosis to first antifungal treatment, and 3 patients died.\n\n\nCONCLUSIONS\nOur study shows the challenges surrounding diagnosis and treatment of fungal infections secondary to trauma. Non-specific fungal infection symptoms, such as leukocytosis and fever, typically presented a week after injury. Vigilance for investigating risk factors and infection symptoms may help clinicians with more timely management of trauma patients with a severe fungal infection.",
"affiliations": "Medical City Plano, Trauma Research Department, Plano, TX, United States; Wesley Medical Center, Trauma Research Department, Wichita, KS, United States; Research Medical Center, Trauma Research Department, Kansas City, MO, United States; St. Anthony Hospital, Trauma Research Department, Lakewood, CO, United States; Penrose Hospital, Trauma Research Department, Colorado Springs, CO, United States; Swedish Medical Center, Trauma Research Department, Englewood, CO, United States.;Medical City Plano, Trauma Services Department, Plano, TX, United States.;Wesley Medical Center, Trauma Services Department, Wichita, KS, United States.;Wesley Medical Center, Trauma Services Department, Wichita, KS, United States.;Research Medical Center, Trauma Services Department, Kansas City, MO, United States.;Medical City Plano, Trauma Research Department, Plano, TX, United States; Wesley Medical Center, Trauma Research Department, Wichita, KS, United States; Research Medical Center, Trauma Research Department, Kansas City, MO, United States; St. Anthony Hospital, Trauma Research Department, Lakewood, CO, United States; Penrose Hospital, Trauma Research Department, Colorado Springs, CO, United States; Swedish Medical Center, Trauma Research Department, Englewood, CO, United States.;St. Anthony Hospital, Trauma Services Department, Lakewood, CO, United States.;Penrose Hospital, Trauma Services Department, Colorado Springs, CO, United States.;Penrose Hospital, Trauma Services Department, Colorado Springs, CO, United States.;Swedish Medical Center, Trauma Services Department, Englewood, CO, United States.;Medical City Plano, Trauma Research Department, Plano, TX, United States; Wesley Medical Center, Trauma Research Department, Wichita, KS, United States; Research Medical Center, Trauma Research Department, Kansas City, MO, United States; St. Anthony Hospital, Trauma Research Department, Lakewood, CO, United States; Penrose Hospital, Trauma Research Department, Colorado Springs, CO, United States; Swedish Medical Center, Trauma Research Department, Englewood, CO, United States. Electronic address: davidbme49@gmail.com.",
"authors": "McGraw|Constance|C|;Carrick|Matthew|M|;Ekengren|Francie|F|;Berg|Gina|G|;Lieser|Mark|M|;Orlando|Alessandro|A|;Madayag|Robert|R|;Tanner Ii|Allen|A|;Kelly|Michael|M|;Banton|Kaysie|K|;Bar-Or|David|D|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.injury.2019.10.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-1383",
"issue": "50(12)",
"journal": "Injury",
"keywords": "Blunt trauma; Fungal infection; Management; Post-traumatic; Risk factors",
"medline_ta": "Injury",
"mesh_terms": "D000328:Adult; D000671:Amputation; D000935:Antifungal Agents; D003646:Debridement; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D015601:Injury Severity Score; D007902:Length of Stay; D008297:Male; D003904:Mitosporic Fungi; D009181:Mycoses; D054843:Negative-Pressure Wound Therapy; D012307:Risk Factors; D014193:Trauma Centers; D014481:United States; D014946:Wound Infection; D014949:Wounds, Nonpenetrating",
"nlm_unique_id": "0226040",
"other_id": null,
"pages": "2234-2239",
"pmc": null,
"pmid": "31630781",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe fungal infections following blunt traumatic injuries: A 5-year multicenter descriptive study.",
"title_normalized": "severe fungal infections following blunt traumatic injuries a 5 year multicenter descriptive study"
} | [
{
"companynumb": "US-PFIZER INC-2019551793",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Drugs are an uncommon but well-recognised cause of acute pancreatitis and new agents of drug-induced pancreatitis continue to be reported. We describe only the 10th reported case of lisinopril-induced pancreatitis in a young female patient.",
"affiliations": "Department of General Surgery, Frimley Park Hospital, Portsmouth Road, Frimley, Camberley, Surrey. katevbrown@aol.com",
"authors": "Brown|K V|KV|;Khan|A Z|AZ|;Paterson|I M|IM|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril",
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"abstract": "OBJECTIVE\nVoriconazole (VCZ) is a new-generation triazol antifungal agent. CYP2C19 mutations have been reported to cause variability in VCZ pharmacokinetics, and thus lead to undesirable effects of pharmacotherapy. We observed four Caucasian patients who underwent allogenic hematopoietic stem cell transplantation, treated with voriconazole for prevention of fungal infections, to establish the impact of CYP2C19*2/*17 genotype on side effect occurrence.\n\n\nMETHODS\nGenetic testing for CYP2C19 allele*2 and*17 was performed using two PCR-RFLP methods established by Goldstein and Blaisdell, and Sim et al. All four patients presented CYP2C19*2/*17 genotype.\n\n\nRESULTS\nThe patients suffered from gastrointestinal, dermatological, neurological, hepatobiliary and renal adverse drug reactions (ADR). ADR could be best described by the use of VCZ. Other drugs potentially causing side effects were also taken into consideration. The presented complications were temporary and did not force dosage regimen adjustments or discontinuation of pharmacotherapy. After 2 months, the patients were discharged from hospital.\n\n\nCONCLUSIONS\nDrug-drug interactions and ADR may occur even if an agent is used for prophylaxis only. We, therefore, should use any available tools for pharmacotherapy optimization-also genetic testing.",
"affiliations": "Department of Clinical Pharmacology, Faculty of Pharmacy, Wrocław Medical University, 211a Borowska St., 50-556, Wrocław, Poland. beata.sienkiewicz@gmail.com.;Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, 4 Wybrzeże Pasteura St., 50-367, Wrocław, Poland.;Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, 4 Wybrzeże Pasteura St., 50-367, Wrocław, Poland.;Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, 4 Wybrzeże Pasteura St., 50-367, Wrocław, Poland.;Department of Clinical Pharmacology, Faculty of Pharmacy, Wrocław Medical University, 211a Borowska St., 50-556, Wrocław, Poland.",
"authors": "Beata|Sienkiewicz|S|http://orcid.org/0000-0003-1912-0873;Donata|Urbaniak-Kujda|UK|;Jarosław|Dybko|D|;Tomasz|Wróbel|W|;Anna|Wiela-Hojeńska|WH|",
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"fulltext": "\n==== Front\nJ Cancer Res Clin OncolJ. Cancer Res. Clin. OncolJournal of Cancer Research and Clinical Oncology0171-52161432-1335Springer Berlin Heidelberg Berlin/Heidelberg 235710.1007/s00432-017-2357-yOriginal Article – Clinical OncologyInfluence of CYP2C19*2/*17 genotype on adverse drug reactions of voriconazole in patients after allo-HSCT: a four-case report http://orcid.org/0000-0003-1912-0873Beata Sienkiewicz beata.sienkiewicz@gmail.com 1Donata Urbaniak-Kujda 2Jarosław Dybko 2Tomasz Wróbel 2Anna Wiela-Hojeńska 11 0000 0001 1090 049Xgrid.4495.cDepartment of Clinical Pharmacology, Faculty of Pharmacy, Wrocław Medical University, 211a Borowska St., 50-556 Wrocław, Poland 2 0000 0001 1090 049Xgrid.4495.cDepartment and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, 4 Wybrzeże Pasteura St., 50-367 Wrocław, Poland 28 2 2017 28 2 2017 2017 143 6 1103 1106 23 1 2017 27 1 2017 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nVoriconazole (VCZ) is a new-generation triazol antifungal agent. CYP2C19 mutations have been reported to cause variability in VCZ pharmacokinetics, and thus lead to undesirable effects of pharmacotherapy. We observed four Caucasian patients who underwent allogenic hematopoietic stem cell transplantation, treated with voriconazole for prevention of fungal infections, to establish the impact of CYP2C19*2/*17 genotype on side effect occurrence.\n\nMethods\nGenetic testing for CYP2C19 allele*2 and*17 was performed using two PCR-RFLP methods established by Goldstein and Blaisdell, and Sim et al. All four patients presented CYP2C19*2/*17 genotype.\n\nResults\nThe patients suffered from gastrointestinal, dermatological, neurological, hepatobiliary and renal adverse drug reactions (ADR). ADR could be best described by the use of VCZ. Other drugs potentially causing side effects were also taken into consideration. The presented complications were temporary and did not force dosage regimen adjustments or discontinuation of pharmacotherapy. After 2 months, the patients were discharged from hospital.\n\nConclusions\nDrug–drug interactions and ADR may occur even if an agent is used for prophylaxis only. We, therefore, should use any available tools for pharmacotherapy optimization—also genetic testing.\n\nKeywords\nCYP2C19*2/*17VoriconazoleAdverse drug reactionsGenotypeHematologyissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2017\n==== Body\nIntroduction\nVoriconazole (VCZ) is a new-generation triazol antifungal agent. The drug is approved mainly for treatment of invasive aspergillosis, candidiasis and infections caused by Scedosporium spp. and Fusarium spp. (SPC Vfend 2016). As it is more effective in the prevention of mold infections than fluconazole (FCZ) and itraconazole, VCZ is also used in prophylaxis of invasive fungal infections (IFI) among immunocompromised patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) (Xu et al. 2013).\n\nThe drug is metabolized in the liver by CYP2C19, CYP3A4 and CYP2C9. Only mutations of the first isoenzyme have been reported to cause variability in voriconazole pharmacokinetics (Moriyama et al. 2015). This is why many scientists postulate the need for CYP2C19 genotyping for therapeutic drug monitoring of VCZ (Trubiano et al. 2014).\n\nThe concomitant use of other medicines in the therapy of haematological malignancies leads to drug–drug interactions. Especially the co-administration of voriconazole with phenytoin, fluconazole or cyclosporine A is reported to cause adverse effects due to changes in pharmacokinetic parameters (Purkins et al. 2003; Damle et al. 2011, SPC Sandimmun 2013).\n\nIn this paper, we present the case of more severe adverse drug reactions of VCZ in four patients with CYP2C19*2/*17 genotype after allo-HSCT and a concomitant drug–drug interaction analysis.\n\nCase reports\nAnamnesis\nFour Caucasian patients, two males (aged 62 and 50) and two females (aged 61 and 63), with normal BMI were admitted to the Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation for allogenic hematopoietic stem cell transplantation. The primary diseases were acute myeloid leukemia (AML) in two cases, myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL). Three patients were treated with reduced-intensity conditioning (RIC) and one, suffering from ALL, with myeloablative conditioning (MAC). The treatment protocols are described below.\n\nDuring RIC, mega-dose chemotherapy was performed using fludarabine I.V. on days −6 to −2, busulfan I.V. on days −5 to −2 inclusive and thymoglobulin I.V. on days −3 to −1. For MAC, the regimen consisted of TBI (2 × 2.0 Gy/day) and cyclophosphamide I.V. The patients received graft versus host disease (GVHD) prophylaxis combining cyclosporine A (CyA) I.V. with methotrexate I.V. To avoid infections, a co-medication with trimethoprim (TMP) p.o., acyclovir (ACV) p.o., and fluconazole (FCZ) p.o. was started. The decontamination was performed using ciprofloxacin p.o. Three days before transplantation, ACV and FCZ administrations have been suspended and voriconazole I.V. with ganciclovir I.V. was introduced into therapy as IFI and viral infection prophylaxis. After allo-HSCT, omeprazole I.V. was included as ulcer prevention. The dose regiments were established according to the particular summaries of product characteristics (SPC).\n\nResults\nDuring VCZ pharmacotherapy, we observed adverse drug reactions (ADR) in frequency that was not noticed in other patients treated with the same protocols. One female demonstrated nausea and dizziness. The second one suffered from vomiting, constipation, rush, exfoliative dermatitis, vertigo, ataxia and aphasia. Among male patients, elevation of GGT (gamma-glutamyl transpeptidase) and in one male nausea, vomiting, rush, erythema, pneumonia, nephritis as well as hematuria were observed.\n\nWe performed genetic testing for CYP2C19 allele *2 and *17 determination, using two PCR-RFLP methods established by Goldstein and Blaisdell (1996) and Sim et al. (2006). All of the patients presented CYP2C19*2/*17 genotype. To our knowledge there is no definite information in the literature on the impact of this diplotype on voriconazole pharmacokinetic properties, but there is evidence suggesting a poor metabolizer (PM) phenotype, causing adverse drug reactions due to higher VCZ serum levels (Cervinski et al. 2013).\n\nOn the other hand, there are drug–drug interactions between voriconazole, cyclosporine A and omeprazole. This type of co-medication also leads to increased VCZ concentrations and is, therefore, a factor influencing ADR occurrence (SPC Sandimmun 2013; Wood et al. 2003).\n\nTreatment and progression\nThese presented complications were temporary and did not force dosage regimen adjustments or discontinuation of pharmacotherapy. After 2 months, the patients were discharged from hospital.\n\nDiscussion\nIn the presented case report, adverse drug reactions of VCZ treatment occurred in patients with the CYP2C19*2/*17 diplotype, suggesting rather a poor metabolizer phenotype. The frequency of this genotype in the Caucasian population and the influence on voriconazole pharmacokinetic properties are unknown yet. On one hand, Weiss et al. (2009) reported that patients carrying this genetic variant demonstrated the same pharmacokinetic properties of VCZ as the ones with CYP2C19*1/*17 genotype. On the other hand, Chung et al. (2015) stated in their article that patients with CYP2C19*2/*17 variant were rather IM (intermediate metabolizers), but they also underlined the need for further research on this topic.\n\nIn another study conducted by Harmsze et al. (2012), the influence of CYP2C19 mutations on clopidogrel on-treatment platelet reactivity was established. Clopidogrel is a prodrug that needs to be metabolized to its active form. In patients demonstrating the CYP2C19*2/*17 genotype, the on-treatment platelet reactivity was increased compared with wild type, *1/*17 and *17/*17 diplotypes suggesting that CYP2C19*2/*17 genetic variant is associated with lower enzymatic activity. This may lead to the hypothesis that in the presented cases, the genotype led to decreased enzymatic activity, higher VCZ serum levels and as a result to its adverse reactions.\n\nAnother factor that has to be taken into account is the concomitant use of omeprazole. The drug is a competitive inhibitor of CYP2C19 isoenzyme. Its influence on the pharmacokinetic properties of voriconazole was established. Wood et al. (2003) showed that the co-administration of omeprazole leads to increased VCZ blood concentrations, what in case of our patients, considered to be PM, could have led to a greater elevation of voriconazole serum levels, and as a consequence to noticeable side effects (Boyd et al. 2012).\n\nCertainly, the presented adverse effects may occur due to other drugs used in the patients’ treatment. Apart from gastrointestinal disturbances, such as nausea, vomiting and constipation, that are very frequent ADR during pharmacotherapy at all, hepatobiliary (GGT elevation), skin (exfoliative dermatitis, erythema), nervous system (ataxia) and renal disorders (nephritis) are undesirable effects common during VCZ treatment (SPC Vfend 2016).\n\nOther observed ADR such as dizziness, vertigo, aphasia and pneumonia are more likely connected with methotrexate and cyclosporine A administration (SPC Sandimmun 2013, SPC Methotrexat-Ebewe 2016). This conclusion is based on the investigation of Mori et al. (2009) who demonstrated that voriconazole inhibits P-gp (P-glycoprotein) and increases CyA blood concentrations leading to adverse drug reactions, as cyclosporine A has a narrow therapeutic window, and the frequently noticed ADR during MTX treatment (SPC Methotrexat-Ebewe 2016).\n\nConclusion\nBy reporting these cases, we would like to emphasize that drug–drug interactions and side effects may occur even if an agent is used for prophylaxis only. The definite identification of the medication causing ADR during polypharmacotherapy, e.g., accompanying allogenic hematopoietic stem cell transplantation, is challenging. Therefore, any available tools for pharmacotherapy optimization should be used including genetic testing.\n\nIn the presented case, previous determination of CYP2C19 mutation may have helped to avoid, at least partially, undesirable effects connected with voriconazole administration.\n\nCompliance with ethical standards\nFunding\nThe authors declare that no funding was received.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nEthical approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nInformed consent\nInformed consent was obtained from all individual participants included in the study.\n==== Refs\nReferences\nBoyd NK Zoellner CL Swancutt MA Bhavan KP Utilization of omeprazole to augment subtherapeutic voriconazole concentrations for treatment of Aspergillus infections Antimicrob Agents Chemother 2012 56 6001 6002 10.1128/AAC.00700-12 22890768 \nCervinski MA Schwab MC Lefferts JA Lewis LD Lebel KA Tyropolis AM Pflueger SM Tsongalis GJ Establishment of a CYP2C19 genotyping assay for clinical use Am J Clin Pathol 2013 139 202 207 10.1309/AJCP9K2KDOCPCBSV 23355205 \nChung H Lee H Han H An H Lim KS Lee YJ Cho JY Yoon SH Jang IJ Yu KS Pharmacokinetic comparison of two voriconazole formulations and the effect of CYP2C19 polymorphism on their pharmacokinetic profiles Drug Des Develop Ther 2015 9 2609 2616 10.2147/DDDT.S80066 \nDamle B Varma MV Wood N Pharmacokinetics of voriconazole administered concomitantly with fluconazole and population-based simulation for sequential use Antimicrob Agents Chemother 2011 55 5172 5177 10.1128/AAC.00423-11 21876043 \nGoldstein JA Blaisdell J Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism Methods Enzymol 1996 272 210 218 10.1016/S0076-6879(96)72025-6 8791779 \nHarmsze AM van Werkum JW Hackeng CM Ruven HJT Kelder JC Bouman HJ Breet NJ ten Berg JM Klungel OH de Boer A Deneer VHM The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting Pharmacogenet Genom 2012 22 169 175 10.1097/FPC.0b013e32834ff6e3 \nMori T Aisa Y Kato J Nakamura Y Ikeda Y Okamoto S Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients Bone Marrow Transplant 2009 44 371 374 10.1038/bmt.2009.38 19270729 \nMoriyama B Kadri S Henning SA Danner RL Walsh TJ Therapeutic drug monitoring and genotypic screening in the clinical use of voriconazole Curr Fungal Infect Rep 2015 9 74 87 10.1007/s12281-015-0219-0 26918067 \nPurkins L Wood N Ghahramani P Love ER Eve MD Fielding A Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration Br J Clin Pharmacol 2003 56 37 44 10.1046/j.1365-2125.2003.01997.x 14616412 \nSim SC Risinger C Dahl ML Aklillu E Christensen M Bertilsson L Ingelman-Sundberg M A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants Clin Pharmacol Ther 2006 79 103 113 10.1016/j.clpt.2005.10.002 16413245 \nSummary of Product Characteristics. Sandimmun: Novartis Pharma GmbH (2013)\nSummary of Product Characteristics. Methotrexat: Ebewe Pharma Ges.m.b.H. Nfg. KG (2016a)\nSummary of Product Characteristics. Vfend: Pfizer, Inc. (2016b)\nTrubiano JA Crowe A Worth LJ Thursky KA Slavin MA Putting CYP2C19 genotyping to the test: Utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort J Antimicrob Chemother 2014 70 1161 1165 \nWeiss J Ten Hoevel MM Burhenne J Walter-Sack I Hoffmann MM Rengelshausen J Haefeli WE Mikus G CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole J Clin Pharmacol 2009 49 196 204 10.1177/0091270008327537 19033450 \nWood N Tan K Purkins L Layton G Hamlin J Kleinermans D Nichols D Effect of omeprazole on the steady-state pharmacokinetics of voriconazole J Clin Pharmacol 2003 56 56 61 10.1046/j.1365-2125.2003.02000.x \nXu S-X Shen J-L Tang X-F Feng B Newer antifungal agents for fungal infection prevention during hematopoietic cell transplantation: a meta-analysis Transplant Proc 2013 45 407 414 10.1016/j.transproceed.2012.07.149 23375330\n\n",
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"keywords": "Adverse drug reactions; CYP2C19*2/*17; Genotype; Hematology; Voriconazole",
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"mesh_terms": "D065731:Cytochrome P-450 CYP2C19; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D065819:Voriconazole",
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"title": "Influence of CYP2C19*2/*17 genotype on adverse drug reactions of voriconazole in patients after allo-HSCT: a four-case report.",
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"abstract": "Early T-cell precursor (ETP) leukemia represents a new subtype of T-lymphoblastic leukemia/lymphoma with unique immunophenotypes expressing T-cell and one or more of the myeloid/stem cell markers. Here, we report a young patient who had primary mediastinal mass and pleural effusion without bone marrow involvement. A CT-guided mediastinal biopsy and flow cytometry analysis of the pleural effusion revealed the blast cells to have complicated immunophenotypes: strongly expressed T-cell antigen CD7, myeloid-lineage antigens CD33 and CD13 and stem cell markers cTdT, CD34, and HLA-DR; dimly expressed myeloid-lineage specific antigen cMPO and B-cell antigen cCD79a; but did not express T-cell specific antigen cytoplasmic CD3 and B-cell specific antigen CD19. Clonal T-cell receptor rearrangement eventually determined the cell of origin from ETPs, not myeloblasts. The patient showed primary resistance to lymphoid and myeloid-directed induction therapy. Finally, low-dose decitabine combined with modified-CAG regimen induced a complete remission and allogeneic stem cell transplantation was performed as consolidation. The case indicates a primary mediastinal neoplasm from ETP with distinctive immunophenotype from leukemia type. Low-dose decitabine and modified-CAG regimen in combination with allogeneic stem cell transplantation may improve the outcome of patient.",
"affiliations": "Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Central Laboratory, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.;Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.",
"authors": "Yang|Yuhuan|Y|;Yao|Shuna|S|;Zhang|Jiuyang|J|;Yan|Zheng|Z|;Chu|Junfeng|J|;Wang|Haiying|H|;Yao|Zhihua|Z|;Zhang|Fan|F|;Xia|Qingxin|Q|;Liu|Yanyan|Y|",
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"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOTTottOncoTargets and therapy1178-6930Dove 21490510.2147/OTT.S214905Case ReportDecitabine-containing G-CSF priming regimen overcomes resistance of primary mediastinal neoplasm from early T-cell precursors to conventional chemotherapy: a case report Yang et alYang et alYang Yuhuan 1Yao Shuna 1Zhang Jiuyang 1Yan Zheng 1Chu Junfeng 1Wang Haiying 1Yao Zhihua 1Zhang Fan 2Xia Qingxin 3Liu Yanyan 11 Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China2 Department of Central Laboratory, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China3 Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Yanyan LiuDepartment of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, 127 Dong Ming Road, Zhengzhou, Henan450008, People’s Republic of ChinaEmail yyliu@zzu.edu.cnQingxin XiaDepartment of Pathology, Affiliated Cancer Hospital of Zhengzhou University, 127 Dong Ming Road, Zhengzhou, Henan450008, People’s Republic of ChinaEmail 13838173710@139.com* These authors contributed equally to this work\n\n29 8 2019 2019 12 7039 7044 08 5 2019 06 8 2019 © 2019 Yang et al.2019Yang et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nEarly T-cell precursor (ETP) leukemia represents a new subtype of T-lymphoblastic leukemia/lymphoma with unique immunophenotypes expressing T-cell and one or more of the myeloid/stem cell markers. Here, we report a young patient who had primary mediastinal mass and pleural effusion without bone marrow involvement. A CT-guided mediastinal biopsy and flow cytometry analysis of the pleural effusion revealed the blast cells to have complicated immunophenotypes: strongly expressed T-cell antigen CD7, myeloid-lineage antigens CD33 and CD13 and stem cell markers cTdT, CD34, and HLA-DR; dimly expressed myeloid-lineage specific antigen cMPO and B-cell antigen cCD79a; but did not express T-cell specific antigen cytoplasmic CD3 and B-cell specific antigen CD19. Clonal T-cell receptor rearrangement eventually determined the cell of origin from ETPs, not myeloblasts. The patient showed primary resistance to lymphoid and myeloid-directed induction therapy. Finally, low-dose decitabine combined with modified-CAG regimen induced a complete remission and allogeneic stem cell transplantation was performed as consolidation. The case indicates a primary mediastinal neoplasm from ETP with distinctive immunophenotype from leukemia type. Low-dose decitabine and modified-CAG regimen in combination with allogeneic stem cell transplantation may improve the outcome of patient.\n\nKeywords\nearly T-cell precursordecitabineG-CSF primingT-lymphoblastic lymphoma\n==== Body\nIntroduction\nT-lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a precursor lymphoid neoplasm that occurs in bone marrow and blood (T-ALL) or involves the thymus, lymph nodes, or extranodal sites (T-LBL). The thymus is the most common site involved by T-LBL, which is located in the anterior mediastinum and holds the key to T-cell development. There are four stages of intrathymic differentiation related to T-ALL/LBL according to the antigens expressed: 1) pro-T/T-I, 2) pre-T/T-II, 3) cortical T/T-III, and 4) medullary T/T-IV.1 Early T-cell precursors (ETPs) usually belong to pro-T and pre-T cells and retain multiple potentials for T-cells and natural killer cells as well as myeloid lineage and dendritic cell differentiation.2,3 ETP-ALL, as a neoplasm from ETP, has been defined to be a new subtype of T-ALL/LBL in 2016 WHO classification.4 The diagnosis of ETP-ALL is mainly based on a set of unique immunophenotypes: expresses CD7, cytoplasmic CD3 (cCD3), and one or more of the myeloid/stem cell markers CD34, CD117, HLA-DR, CD33, CD13, CD11b, and CD65, but lacks CD8, CD1a, and MPO.5 The mutation profiling of ETP-ALL is more similar to that of myeloid leukemia than to those of other T-cell leukemias.4 Recent studies have shown that patients with ETP-ALL have a similar clinical outcome as those with other T-ALL phenotypes, although initial studies suggested a very poor prognosis.6\n\nHere we reported a patient having a clear primary lesion in the mediastinum and pleural effusion without bone marrow involvement. He possessed detectable multi-lineage antigens of stem cells, T-cells, B-cells, myeloid cells, and dendritic cells. Although there was a similar immunophenotypic feature to myeloid sarcoma with dim expression of cMPO and without cCD3, he was diagnosed as ETP-LBL depending on clonal T-cell receptor (TCR) rearrangement. The case presented with primary resistance to lymphoid and myeloid-directed induction therapy. Fortunately, novel myeloid-directed salvage therapy, decitabine-containing G-CSF priming regimen, induced a complete remission and allogeneic stem cell transplantation further improved the outcome.\n\nCase presentation\nA 22-year-old male was admitted to our hospital for chest pain and dyspnea in November 2017. He has gotten a continuous pain in anterior chest since July 2017. After comprehensive CT scan was done at his local hospital, a large mediastinal mass was found. A CT-guided mediastinal biopsy in combination with immunohistochemistry showed that T-cell, stem cell, and myeloid-lineage antigens were present in the neoplasm tissues: LCA+, TdT+, CD7+, CD34+, Ki-67 (80%), MPO+, CD33+, CD8-, CD1a-, CD117-, CD15-, cCD3-, CD2-, CD10-, CD19-, PAX5-, CK-, S-100- (Figure 1). Since bone marrow was not involved by the analysis of aspiration and biopsy with routine staining and flow cytometry, he was diagnosed as T-LBL with myeloid differentiation. CHOP (cyclophosphamide, vincristine, epirubicin, and prednisone) and DICE (dexamethasone, ifosfamide, etoposide, and cisplatin) regimens were given at the local hospital, but the neoplasm continued to deteriorate.Figure 1 The immunohistochemical staining of the mediastinum mass (magnification, ×200). (A) H&E staining. The neoplasm expressed TdT (B), CD7 (C), MPO (E), Ki67 (80%) (F), CD34 (G), CD33 (H), and LCA (I), while it did not express cCD3 (D), CD8 (J), PAX5 (K), and CD1a (L).\n\n\n\nMultiple supraclavicular lymph node swellings were palpated with a maximal diameter of about 2 cm at our hospital. The patient had weak respiratory sounds and large amounts of hydrothorax in left chest cavity were observed by ultrasound. After the pleural effusion was drained, PET-CT scan was performed, which revealed a bulky mass in anterior superior mediastinum (SUVmax 8.1) and many enlarged lymph nodes in bilateral cervical, supraclavicular, subclavian, hilar, axillary, and retroperitoneal regions (SUVmax from 3.0 to 4.6) (Figure 2). Bone marrow was also negative by the examination of aspiration and biopsy. Comprehensive blood tests revealed elevated lactate dehydrogenase and erythrocyte sedimentation rate. The immunohistochemistry slides were assessed by our pathologists. Flow cytometry analysis of blast cells in the pleural effusion found a single population expressing multi-lineage markers (Figure 3). Bright expression of T-cell antigen CD7 and dim expression of B-cell antigen cCD79a were seen, though T-cell specific antigen cCD3 and B-cell specific antigen CD19 were negative. Myeloid-lineage specific antigen cMPO was dimly expressed while myeloid-lineage antigens CD33 and CD13 were brightly expressed. We also found bright expression of stem cell markers cTdT, CD34, HLA-DR, and CD38, and dim expression of blastic plasmacytoid dendritic cell marker CD123. Other specific markers were negative, including stem cell marker CD117, monocyte markers CD15 and CD11c, T-cell markers CD1a, CD2, CD4 and CD8, NK cell markers CD16 and CD56, and B-cell markers CD10, CD19, and CD22. At first sight, the neoplasm met the criteria for myeloid sarcoma due to having cMPO expression, but not cCD3. However, clonal TCR gene rearrangement was found, which suggested an origin of T-cell precursor (Figure 4). ETP neoplasm was postulated to originate from a subset of cells that immigrated from the bone marrow into the thymus but were not yet irreversibly committed to the T-cell lineage and retained the potential for myeloid/dendritic cell differentiation. In contrast to definitive ETP-ALL, the patient did not have the bone marrow involvement. Some markers were consistent with ETP-ALL phenotype, including positive CD7, CD34, HLA-DR, CD33, and CD13, and negative CD1a and CD8, whereas others were not consistent, such as positive cMPO and negative cCD3. Eventually, the case was considered to be ETP-LBL with some distinctive features from ETP-ALL.Figure 2 The PET-CT imaging of the lesions before and after treatment. In comparison with before treatment (A, B, E, F), the masses disappeared in left cervix, mediastinum, and peritoneal cavity after the completion of therapy (C, D, G, H).\n\nFigure 3 Flow cytometry analysis of lineage antigens of blast cells in pleural effusion. The blast cells brightly expressed CD7, CD33, CD13, cTdT, CD34, HLA-DR, and CD38, dimly expressed cCD79a, cMPO, and CD123, but did not express cCD3, CD19, CD20, CD117, CD2, CD5, CD8, CD10, CD15, CD16, and CD56.\n\nFigure 4 Conal T-cell receptor (TCR) rearrangement of blast cells. Clonal gene rearrangement was observed in TCR beta VJII (A) and TCR delta VD/DD/DJ (B) fragments. In panel (A), the arrow indicates the monoclonal peak of TCR beta VJII. In Panel (B), the arrow indicates the monoclonal peak of TCR delta VD/DD/DJ.\n\n\n\nA 4-week hybrid regimen of myeloid and lymphoid-directed therapy, DA (daunorubicin and cytarabine) plus VLP (vindesine, pegaspargase, and prednisone), was given at our hospital. Nevertheless, the masses did not shrink significantly after the completion of the 4-week schedule. So far, the optimal treatment for patients with a neoplasm from ETP remains elusive, especially for those with primary resistance to conventional chemotherapy. Since the case was positive for myeloid-lineage antigens, myeloid-directed salvage regimens might be a suitable choice. CAG regimen (cytarabine 10 mg/m2 q12h for 10–14 days and aclarubicin 20 mg/d for 4 days with G-CSF priming) had been reported to produce responses in refractory patients with acute myeloid leukemia.7 CAG regimen in combination with decitabine, a DNA methyltransferase inhibitor approved to treat patients with myelodysplasia syndrome, had also been reported to improve CR rate in patients with newly diagnosed MDS-EB and AML-MRC.8 However, the optimal dosage and schedule of decitabine were rather challenging when used in combination with other drugs. Due to the patient’s poor performance status, low-dose decitabine (10 mg/d subcutaneous injection, twice a week for three times) combined with modified-CAG regimen (cytarabine of 10 mg/m2 q12h for 10 days and aclarubicin of 20 mg/d for 4 days with pegylated 6 mg G-CSF priming) was given. Encouragingly, superficial masses disappeared following a treatment cycle. After two cycles of treatment, the patient achieved a CR as evaluated by PET/CT scan (Figure 2). Generally, adverse effects were tolerable and reversible, including grade IV neutropenia, anemia, thrombocytopenia, and grade I transaminase lift. Four cycles of high-dose methotrexate-based regimens were then taken as the prophylaxis of the central nervous system and intensification therapy and then additional two cycles of low-dose decitabine plus modified-CAG regimen were administered as re-induction and consolidation therapy. Since HLA-identical donor was not found, the patient’s father was selected for mismatched-allogeneic stem cell transplantation. A successful operation was performed in June 2018. By the end of June 2019, the patient had been maintaining a CR status.\n\nDiscussion and conclusion\nThe classical model of hematopoiesis postulates that pluripotent hematopoietic stem cells of bone marrow differentiate into common myeloid-erythroid progenitors and common lymphoid progenitors. Some lymphoid progenitors migrate to the thymus for T-cell development. However, further studies have found that the myeloid-lineage potential persists even as the lineage branches segregate toward T- or B-cells.2,3 ETP-ALL has been considered as a neoplasm originated from ETP, indicating a limited early T-cell differentiation with frequent expression of the markers of stem cells and myeloid cells.4 The case represents an alternative neoplasm from ETP, referred to as ETP-LBL, with different immunophenotypic features from ETP-ALL. Owing to expressing cMPO, but not cCD3, the neoplasm should be differentiated with myeloid sarcoma. For myeloid sarcoma, the expression of CD7 is usually weak, but cMPO is often strong in granulocytic sarcoma. The dim expression of cMPO weakens the significance of diagnosing myeloid sarcoma. Anti-MPO antibodies have been shown to react with B-lymphoblastic leukemia/lymphoma on flow cytometry or immunohistochemistry as a non-specific staining.9,10 In fact, the dim expression of B-cell antigen cCD79a was seen in the case. Mediastinal myeloid sarcoma is a rare disease. According to the definition of 2015 WHO classification of thymus tumors, mediastinal myeloid sarcoma should be considered to exclude if lymphoid-antigens are coexpressed with myeloid-lineage antigens. Eventually, clonal TCR gene rearrangement confirmed the diagnosis of ETP neoplasm.\n\nT-LBL originates from a thymic lymphocytes and presents with a primary mass in the anterior mediastinum, which often grows rapidly and sometimes leads to respiratory failure. T-LBL usually has a better prognosis than T-ALL, however, its prognostic factors remain ambiguous compared to T-ALL.11 Previous studies did not show its association of T-LBL with clinical features, such as age, LDH level, and extranodal lesion, except the involvement of the central nervous system.12 One or both of the myeloid-associated antigens CD13 and CD33 are expressed in 19–32% of the patients with T-LBL.13,14 Till now, studies on the prognostic significance of myeloid-lineage markers are limited. Our case indicates a poorer outcome of ETP-LBL in the setting of conventional therapy. As a novel therapy for myeloid neoplasms, CAG regimen alone or with decitabine has achieved an obvious response in patients with refractory acute lymphoblastic leukemia.15,16 However, the predominant subtype who benefited from it is unclear. The successful treatment of the present case with low-dose decitabine in combination with modified-CAG regimen indicates the significance of this novel regimen for treating the ETP neoplasms. Finally, allogeneic stem cell transplantation eventually extended the survival time of the patient.\n\nIn conclusion, comprehensive lineage antigens should be examined to make the diagnosis of neoplasms from ETP due to their complicated immunophenotypes. Sometimes, the examination of antigen receptor genes plays a critical role in differential diagnosis. We speculate that ETP neoplasm should be a heterogeneous disease in clinical characteristics, immunophenotypic features, and prognosis. Novel myeloid-directed novel therapy with allogeneic stem cell transplantation may improve the outcome in patients with primary resistance to conventional therapy.\n\nThe patient has provided written informed consent for publication. This case report does not require institutional approval to publish the case details.\n\nAcknowledgments\nThe authors thank the patient and his families and all of physicians and nurses who took care of the patient. This report was supported by the National Natural Science Foundation of China (No. 81071938) and the Science and Technology Projects of Henan Province Education Department (No. 81470365).\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Bene \nMC , Castoldi \nG , Knapp \nW , et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL) . Leukemia . 1995 ;9 (10 ):1783 –1786 .7564526 \n2. Bell \nJJ , Bhandoola \nA . The earliest thymic progenitors for T cells possess myeloid lineage potential . Nature . 2008 ;452 (7188 ):764 –767 . doi:10.1038/nature06840 18401411 \n3. Luc \nS , Luis \nTC , Boukarabila \nH , et al. The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential . Nat Immunol . 2012 ;13 (4 ):412 –419 . doi:10.1038/ni.2255 22344248 \n4. Arber \nDA , Orazi \nA , Hasserjian \nR , et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia . Blood . 2016 ;127 (20 ):2391 –2405 . doi:10.1182/blood-2016-03-643544 27069254 \n5. Coustan-Smith \nE , Mullighan \nCG , Onciu \nM , et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia . Lancet Oncol . 2009 ;10 (2 ):147 –156 . doi:10.1016/S1470-2045(08)70314-0 19147408 \n6. Jain \nN , Lamb \nAV , O’Brien \nS , et al. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype . Blood . 2016 ;127 (15 ):1863 –1869 . doi:10.1182/blood-2015-08-661702 26747249 \n7. Xu \nJ , Lv \nTT , Zhou \nXF , Huang \nY , Liu \nDD , Yuan \nGL . Efficacy of common salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia: a retrospective cohort study . Medicine (Baltimore) . 2018 ;97 (39 ):e12102 . doi:10.1097/MD.0000000000012102 30278488 \n8. Liu \nJ , Jia \nJS , Gong \nLZ , et al. [Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in MDS-EB and AML-MRC] . Zhonghua Xue Ye Xue Za Zhi . 2018 ;39 (9 ):734 –738 . doi:10.3760/cma.j.issn.0253-2727.2018.09.006 30369183 \n9. Leong \nCF , Kalaichelvi \nAV , Cheong \nSK , Hamidah \nNH , Rahman \nJ , Sivagengei \nK . Comparison of myeloperoxidase detection by flow cytometry using two different clones of monoclonal antibodies . Malays J Pathol \n2004 ;26 (2 ):111 –116 .16329563 \n10. Nakase \nK , Sartor \nM , Bradstock \nK . Detection of myeloperoxidase by flow cytometry in acute leukemia . Cytometry . 2015 ;34 (4 ):198 –202 .\n11. Marks \nDI , Rowntree \nC . Management of adults with T-cell lymphoblastic leukemia . Blood . 2017 ;129 (9 ):1134 –1142 . doi:10.1182/blood-2016-07-692608 28115371 \n12. Goldberg \nJM , Silverman \nLB , Levy \nDE , et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience . J Clin Oncol . 2003 ;21 (19 ):3616 –3622 . doi:10.1200/JCO.2003.10.116 14512392 \n13. Uckun \nFM , Sather \nHN , Gaynon \nPS , et al. Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children’s Cancer Group . Blood . 1997 ;90 (1 ):28 –35 .9207434 \n14. Khalidi \nHS , Chang \nKL , Medeiros \nLJ , et al. Acute lymphoblastic leukemia. Survey of immunophenotype, French-American-British classification, frequency of myeloid antigen expression, and karyotypic abnormalities in 210 pediatric and adult cases . Am J Clin Pathol . 1999 ;111 (4 ):467 –476 . doi:10.1093/ajcp/111.4.467 10191766 \n15. Zhou \nK , Song \nY , Zhang \nY , et al. Efficacy and safety of G-CSF, low-dose cytarabine and aclarubicin in combination with l-asparaginase, prednisone in the treatment of refractory or relapsed acute lymphoblastic leukemia . Leuk Res . 2017 ;62 :29 –33 . doi:10.1016/j.leukres.2017.09.016 28982056 \n16. Qin \nT , Youssef \nEM , Jelinek \nJ , et al. Effect of cytarabine and decitabine in combination in human leukemic cell lines . Clin Cancer Res . 2007 ;13 (14 ):4225 –4232 . doi:10.1158/1078-0432.CCR-06-2762 17634552\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "12()",
"journal": "OncoTargets and therapy",
"keywords": "G-CSF priming; T-lymphoblastic lymphoma; decitabine; early T-cell precursor",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "7039-7044",
"pmc": null,
"pmid": "31507324",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10191766;14512392;16329563;17634552;18401411;19147408;22344248;26747249;27069254;28115371;28982056;30278488;30369183;7564526;9207434;9725460",
"title": "Decitabine-containing G-CSF priming regimen overcomes resistance of primary mediastinal neoplasm from early T-cell precursors to conventional chemotherapy: a case report.",
"title_normalized": "decitabine containing g csf priming regimen overcomes resistance of primary mediastinal neoplasm from early t cell precursors to conventional chemotherapy a case report"
} | [
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"companynumb": "CN-OTSUKA-2019_032563",
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"activesubstancename": "DECITABINE"
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{
"abstract": "BACKGROUND\nLow-molecular weight heparin (LMWH) was shown to be effective and safe in treating venous thromboembolism, and generally used for stroke in cancer patients, but its effects on stroke are unclear. We compared clinical outcomes between LMWH and new oral anticoagulant (NOAC) in patients with cancer-related stroke.\n\n\nMETHODS\nWe enrolled patients with cryptogenic ischemic stroke with active cancer who were treated with LMWH or NOAC between May 2012 and June 2015. The clinical outcomes, including early neurologic deterioration, early radiologic recurrence, 3-month modified Rankin scale score, 90-day mortality, cardio-cerebrovascular recurrence, and bleeding complications, were compared.\n\n\nRESULTS\nAmong 48 patients, 7 patients were treated with NOAC, and the remaining 41 patients with LMWH. Overall, the participants presented poor outcomes, including 20 (42%) early neurologic deteriorations, 28 (58%) early radiologic recurrences, 34 (71%) poor modified Rankin scale scores, 27 (56%) 90-day mortality events, 24 (50%) cardio-cerebrovascular recurrences, and 18 (38%) bleeding complications, that led to a change or temporary hold in medication in 12 cases. No statistical differences were found between the 2 groups in terms of demographic, clinical, or cardiovascular risk factors and clinical outcomes.\n\n\nCONCLUSIONS\nNOAC showed the similar clinical outcomes and safety compared with LMWH in the treatment of cryptogenic ischemic stroke in active cancer patients.",
"affiliations": "Department of Neurology, Seoul National University Hospital and Seoul National University College of Medicine, 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 and Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital and Seoul National University College of Medicine, 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 and Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: bwyoon@snu.ac.kr.",
"authors": "Nam|Ki-Woong|KW|;Kim|Chi Kyung|CK|;Kim|Tae Jung|TJ|;An|Sang Joon|SJ|;Oh|Kyungmi|K|;Ko|Sang-Bae|SB|;Yoon|Byung-Woo|BW|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D000069552:Rivaroxaban; D000069604:Dabigatran; D017985:Dalteparin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2017.07.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "26(12)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Ischemic stroke; NOAC; anticoagulation; cancer; hypercoagulability; prognosis",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001777:Blood Coagulation; D000069604:Dabigatran; D017985:Dalteparin; D004185:Disability Evaluation; D017984:Enoxaparin; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012008:Recurrence; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D000069552:Rivaroxaban; D066106:Seoul; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "2976-2980",
"pmc": null,
"pmid": "28843806",
"pubdate": "2017-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Treatment of Cryptogenic Stroke with Active Cancer with a New Oral Anticoagulant.",
"title_normalized": "treatment of cryptogenic stroke with active cancer with a new oral anticoagulant"
} | [
{
"companynumb": "KR-JNJFOC-20171219618",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
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"activesubstancename": "RIVAROXABAN"
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"abstract": "Bedaquiline and delamanid used to treat extensively drug-resistant tuberculosis are known to cause prolonged QTc. Two children with extensively drug-resistant tuberculosis were put on bedaquiline and delamanid and had prolonged QTc on the Bazett formula but normal QTc by the Fridericia formula. Both had no adverse effects. Correct formula for monitoring QTc should be used thereby preventing unnecessary withholding of medicines.",
"affiliations": "From the Pediatric TB Clinic, Department of Pediatric Infectious Diseases, B J Wadia Hospital for Children, Mumbai, India.",
"authors": "Shah|Ira|I|;Gandhi|Srushti|S|;Shetty|Naman S|NS|",
"chemical_list": "D000995:Antitubercular Agents; D064687:Diarylquinolines; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; C493870:bedaquiline",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000002601",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "39(6)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000293:Adolescent; D000995:Antitubercular Agents; D002648:Child; D064687:Diarylquinolines; D054908:Extensively Drug-Resistant Tuberculosis; D005260:Female; D006801:Humans; D008297:Male; D009593:Nitroimidazoles; D010080:Oxazoles; D013183:Sputum; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "512-513",
"pmc": null,
"pmid": "32032176",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bedaquiline and Delamanid in Children With XDR Tuberculosis: What is prolonged QTc?",
"title_normalized": "bedaquiline and delamanid in children with xdr tuberculosis what is prolonged qtc"
} | [
{
"companynumb": "NVSC2021IN116226",
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"occurcountry": "IN",
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"activesubstancename": "BEDAQUILINE"
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{
"abstract": "Diarrhea after hematopoietic stem cell transplantation (HSCT) can be life-threatening, and its etiology includes conditioning regimens, graft-versus-host disease (GVHD), infections, and transplantation-associated microangiopathy (iTAM). Cord colitis syndrome (CCS) has been described as a syndrome of culture-negative and antibiotic-responsive persistent watery and non-bloody diarrhea of uncertain pathogenesis and occurs in umbilical cord blood transplantation (UCBT) recipients. We encountered a case similar to CCS that developed severe watery diarrhea after UCBT without any signs of GVHD or infection and responded well to metronidazole (MNZ) treatment. Since CCS is very rare, we herein describe a case of MNZ-effective diarrhea after UCBT.",
"affiliations": "Department of Hematology and Oncology, Tosei General Hospital, Japan.;Department of Hematology and Oncology, Tosei General Hospital, Japan.;Division of Cell Therapy, National Hospital Organization, Nagoya Medical Center, Japan.;Department of Pathology, Japanese Red Cross Nagoya First Hospital, Japan.;Department of Hematology and Oncology, Tosei General Hospital, Japan.",
"authors": "Sakemura|Reona|R|;Hayakawa|Hiroshi|H|;Iida|Hiroatsu|H|;Ito|Masafumi|M|;Kajiguchi|Tomohiro|T|",
"chemical_list": "D008795:Metronidazole",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.8948-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2902146610.2169/internalmedicine.8948-17Case ReportSuccessful Treatment of a Case of Late-onset Colitis after Umbilical Cord Transplantation with Metronidazole: A Case Report and Literature Review Sakemura Reona 1Hayakawa Hiroshi 1Iida Hiroatsu 2Ito Masafumi 3Kajiguchi Tomohiro 1\n1 Department of Hematology and Oncology, Tosei General Hospital, Japan\n2 Division of Cell Therapy, National Hospital Organization, Nagoya Medical Center, Japan\n3 Department of Pathology, Japanese Red Cross Nagoya First Hospital, JapanCorrespondence to Dr. Tomohiro Kajiguchi, tomokaji@med.nagoya-u.ac.jp\n\n11 10 2017 1 12 2017 56 23 3219 3223 28 1 2017 27 3 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Diarrhea after hematopoietic stem cell transplantation (HSCT) can be life-threatening, and its etiology includes conditioning regimens, graft-versus-host disease (GVHD), infections, and transplantation-associated microangiopathy (iTAM). Cord colitis syndrome (CCS) has been described as a syndrome of culture-negative and antibiotic-responsive persistent watery and non-bloody diarrhea of uncertain pathogenesis and occurs in umbilical cord blood transplantation (UCBT) recipients. We encountered a case similar to CCS that developed severe watery diarrhea after UCBT without any signs of GVHD or infection and responded well to metronidazole (MNZ) treatment. Since CCS is very rare, we herein describe a case of MNZ-effective diarrhea after UCBT. \n\ncord colitis syndrome (CCS)umbilical cord blood (UCB)metronidazole (MNZ)watery diarrhea\n==== Body\nIntroduction\nDespite the emergence of numerous novel therapies (1, 2), allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective treatment strategy for hematological malignancies in the post-remission state. In the absence of an appropriate donor, umbilical cord blood (UCB) is often selected as an alternative source. The number of patients undergoing umbilical cord blood transplantation (UCBT) has markedly increased in Japan over the past few years. Due to its improved safety profile, UCB is now regarded as an appropriate source for HSCT (3).\n\nThe risk of severe graft-versus-host disease (GVHD) is generally considered to be lower with UCBT than with other graft sources. However, previous findings have indicated that the incidence of diarrhea caused by GVHD is relatively high in patients who undergo UCBT (4). Cord colitis syndrome (CCS) was recently described as a syndrome of culture-negative and antibiotic-responsive persistent watery and non-bloody diarrhea of uncertain pathogenesis; this syndrome affects the recipients of UCBT (5). CCS shows an atypical histopathological manifestation because it typically occurs in the upper and lower gastrointestinal tract and is associated with granulomatous inflammation. Diarrhea is a common but serious complication of HSCT and is caused by various etiologies. An early and accurate diagnosis results in appropriate therapeutic approaches and better outcomes for patients.\n\nWe herein report a case of a 60-year-old man diagnosed with acute monocytic leukemia (AML M5a) who underwent UCBT and developed severe watery diarrhea without any evidence of gut GVHD, intestinal transplantation-associated microangiopathy (iTAM), or cytomegalovirus (CMV) colitis. The diarrhea responded well to treatment with metronidazole (MNZ). We herein describe the clinical course and examination findings of this case, together with a literature review.\n\nCase Report\nA 60-year-old man diagnosed with intermediate-risk AML M5a showed an increased level of Wilms tumor 1 (WT1) mRNA and elevation in the blast percentage in bone marrow 6 months after the completion of 4 courses of consolidation chemotherapy. HSCT was planned, but there were neither human leukocyte antigen (HLA)-matched siblings nor unrelated donors available. UCB was selected as an alternative donor source. The clinical course is shown in Fig. 1. The patient was treated with a reduced-intensity conditioning regimen consisting of 125 mg/m2 fludarabine, 140 mg/m2 melphalan and total-body irradiation (TBI) 4 Gy, followed by the infusion of a single unit of cord blood. GVHD prophylaxis consisted of tacrolimus and short-term methotrexate (MTX). The dose of MTX was 15 mg/m2 intravenously (i.v.) on day 1, followed by 10 mg/m2 i.v. on days 3 and 6. Neutrophil engraftment was achieved on day 19. A fever, vomiting, diarrhea, abdominal pain, and a skin rash developed on day 20. The frequency of diarrhea is shown in Fig. 1. On day 22, endoscopic biopsies of the stomach and duodenum were performed, and the pathological findings supported a diagnosis of acute GVHD. The patient was treated with 1 mg/kg of methylprednisolone (mPSL). Despite improvements in the skin rash and fever after systemic corticosteroid therapy, the diarrhea and abdominal pain remained unchanged. Morphine was administered in order to relieve the severe abdominal pain.\n\nFigure 1. Clinical course. The frequency of diarrhea is shown as a black wave. The diarrhea responded well to treatment with MNZ. Flu: fludarabine, MEL: melphalan, TBI: total body irradiation, CBT: cord blood transplantation, MTX: methotrexate, ACV: acyclovir, GCV: ganciclovir, MNZ: metronidazole, PSL: prednisone, TAC: tacrolimus\n\nOn day 42, computed tomography (CT) of the abdomen revealed large bowel ileus, which was attributed to the use of opioids. Therefore, opioids were slowly tapered, and a prokinetic agent was initiated. Thereafter, the abdominal pain and image findings of ileus gradually improved. However, the frequency of diarrhea remained unchanged. CT on day 72 revealed diffuse thickness of the colon wall and the retention of ascites (Fig. 2a and b). Laboratory data showed increased levels of transaminase and biliary enzymes without elevations in bilirubin. In addition, his serum albumin level markedly decreased due to its leakage into the intestine and undernutrition (Table). As an immunological study using an anti-CMV monoclonal antibody (C10, C11) demonstrated that cells were positive for CMV antigen, preemptive CMV treatment was initiated on day 42. On day 76, colonoscopy was performed and revealed that the surface of the intestine was edematous, pale, and rough, but with no signs of ulcers (Fig. 2c).\n\nFigure 2. Abdominal CT scan and colonoscopy findings before the MNZ treatment. (a, b) A CT scan shows the thickness of the colon wall and retention of ascites. (c) Colonoscopy performed before the MNZ treatment revealed that the mucosa of the colon was rough and pale but had no signs of ulcers. (d, e) Colonoscopy biopsy samples stained with Hematoxylin and Eosin staining indicate the retention of normal epithelium tissues and weak invasion of lymphocytes. MNZ: metronidazole\n\nTable. Laboratory Findings before Administering MNZ.\n\nTP\t3.0\t(g/dL)\t\nAlbumin\t1.9\t(g/dL)\t\nT-Bil\t0.52\t(mg/dL)\t\nD-Bil\t0.10\t(mg/dL)\t\nAST\t83\t(U/L)\t\nALT\t120\t(U/L)\t\nLDH\t238\t(U/L)\t\nALP\t593\t(U/L)\t\nγ-GTP\t228\t(U/L)\t\nTP: total protein, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase\n\nA tissue culture obtained during colonoscopy identified Enterococcus faecium, which is an enterobacterium. In addition, a stool culture was negative with no signs of clostridium toxin. A pathological examination of colonoscopy biopsies revealed that the lamina propria mucosa of the colon was edematous and showed slight invasion of lymphocytes but no signs of ulceration or nuclear inclusions (Fig. 2d and e), suggesting the absence of GVHD. Since the history of this patient was similar to the diarrheal presentation reported by Herrera et al. (5), MNZ (1.5 g daily) was administered for 14 days. After starting MNZ, his diarrhea gradually improved, as shown in Fig. 1. However, the diarrhea relapsed after the cessation of MNZ. Therefore, MNZ was administered for another 14 days. Similar to the initial administration of MNZ, the diarrhea markedly improved within a few days after restarting MNZ. The patient was discharged from the hospital on day 134. On day 139, soon after being discharged, he presented to the outpatient clinic with watery diarrhea at a frequency of more than 10 times a day. Since this was similar to his initial presentation, a third course of MNZ was administered for 14 days. As expected, the watery diarrhea improved after restarting MNZ. CT performed after the third course of MNZ treatment showed improvements in wall thickening and the disappearance of ascites (Fig. 3). This was the last occurrence of MNZ-responsive diarrhea, with no subsequent recurrence being reported to the present date.\n\nFigure 3. Abdominal CT scan findings after the MNZ treatment. (a, b) A CT scan showing improvements in wall thickening and the disappearance of ascites. MNZ: metronidazole\n\n\nDiscussion\nThe differential diagnosis of diarrhea after HSCT includes conditioning regimen toxicity, GVHD, infectious causes such Clostridium difficile infection, CMV reactivation, iTAM (6), drug effects, chemoradiation toxicity, and peptic ulcer disease. It is extremely important to make a precise and specific diagnosis of diarrhea after hematopoietic transplantation, as the treatment strategies differ markedly based on the cause and this complication can be life-threatening.\n\nWe herein report a case of a recipient of UCBT who developed severe but culture-negative and MNZ-responsive diarrhea. Although diarrhea relapsed several times after the discontinuation of MNZ, it was easily treated by restarting MNZ. CCS was first described by Herrera et al., and is caused by unknown pathogens, but may be treated with antibiotics, such as MNZ or fluoroquinolone. A common presentation of patients with CCS is watery and non-bloody diarrhea lasting for more than seven days. The median time of the onset of diarrhea after UCBT was reported to be 131 days and is frequently accompanied by a fever and weight loss. CT often shows diffuse thickening or an increased CT value of panniculitis of the colon wall. Erythematous mucosa is a major colonoscopic finding of this syndrome. Colon biopsy findings have indicated the association of granulomas with inflammatory cell infiltration (5). Previous studies on MNZ-effective diarrhea in UCBT recipients have indicated that Bradyrhizobium enterica is a pathogen of CCS. Indeed, Bhatt et al. performed shotgun DNA sequencing and detected the genome of B. enterica in colon biopsy samples obtained from patients who underwent UCBT (7). In addition, other studies have identified Bacteroides fragilis in colon biopsy samples and proposed that this bacterium is a candidate pathogen of chronic colitis after UCBT (7). In addition to these clinical findings, B. fragilis is known to secrete an enterotoxin in animal models (8). B. fragilis is a commensal and anaerobic bacterium found in the normal flora of the human gut. It has two variations: non-enterotoxigenic (NTBF) and enterotoxigenic (ETBF) (9), with the latter regarded as a pathogen of diarrhea or colon cancer. However, the relationship between ETBF and CCS remains unclear. Based on previous findings, CCS may be related to enterococci pathogens.\n\nA major question regarding MNZ-effective diarrhea is why it only occurs after UCBT. Herrera et al. reported that only 1 out of 381 patients who underwent non-UCBT had findings suggestive of granulomatous colitis. However, this patient's diarrhea was related to eosinophilia and responded well to immunosuppressants. Therefore, none of the non-UCBT patients developed granulomatous colitis after hematopoietic transplantation (5). In contrast, Shimoji et al. (10) and Milano et al. (11) found that granuloma and Paneth cell metaplasia changes after chronic colitis were not always a unique feature of patients who underwent UCBT. Milano et al. also suggested that CCS might be caused by a geographically limited pathogen restricted to the northeast part of the United States. Both these and the Boston researchers who first reported CCS have advocated a multicentric study to clarify these suspicions. In addition, the Kyushu and Seattle groups asserted that this type of chronic colitis is caused by intestinal GVHD and not by infectious pathogens. Patients were treated with immunosuppressant agents rather than antibiotics in their cohort. Nevertheless, Herrera et al. also suggested a relationship between GVHD and CCS because patients with a history of grade 2 or higher GVHD were more likely to develop this type of diarrhea in their institute than those without such a history.\n\nAnother major question is why the Boston patients or our patient, who had immunotherapy-refractory diarrhea, responded well to MNZ therapy. Milano et al. made the following proposal (11): Antibiotics exert therapeutic effects against enteric organisms, which are the pathogens of CCS; the administration of MNZ modifies the microflora, which is altered due to the damage associated with acute GVHD; mycophenolate mofetil (MMF)-related colitis is often difficult to distinguish from the presentation of gut GVHD; and CCS may not consist of a simple or single etiology. MNZ is sometimes used in the treatment of chronic inflammatory bowel disease, such as Crohn's disease or ulcerative colitis (12). Therefore, MNZ may exert immunomodulatory effects under inflammatory conditions. Magenau et al. reported that CCS is a variant type of GVHD that is accelerated by B. enterica. Therefore, MNZ is effective for late-onset diarrhea in patients after UBCT (13). In our case, the patient was diagnosed with acute GVHD and treated with systemic corticosteroids. He may have had severe intestinal damage caused by GVHD, and his intestinal microflora may have been obliterated. Therefore, colitis was caused by bacterial translocation via the destruction of the mucosal barrier. The administration of MNZ may have altered his microflora and eventually led to the remission of diarrhea. However, there is no direct evidence to support this hypothesis because no pathogens were detected in cultures. Regarding the relapse of diarrhea, Herrera et al. reported that 45% of patients had recurrence of diarrhea within a median of 7 days after the discontinuation of MNZ, and the relapse of diarrhea was well controlled by restarting MNZ. Nevertheless, the courses and duration of MNZ treatment were not described (5). The optimum dose and course of MNZ treatment for CCS has not yet been established. CCS might be a syndrome that is triggered by various pathogens and not by a single factor alone. As discussed above, since diarrhea after HSCT can be caused by many factors, a close examination needs to be performed, and extensive efforts must be made to determine the cause of diarrhea.\n\nConclusions\nThis case report indicates that antibiotic-responsive colitis after UCBT needs to be considered as a possible cause of diarrhea in patients who undergo UCBT. An early and appropriate diagnosis will lead to good patient outcomes without the need for unnecessary immunosuppressant agents. Since this is a single case report, we need to accumulate similar cases of watery, non-bloody, culture-negative, and antibiotic-responsive diarrhea following hematopoietic transplantation.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nDavila ML , Bouhassira DC , Park JH , et al \nChimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies . Int J Hematol \n99 : 361 -371 , 2014 .24311149 \n2. \nKenderian SS , Porter DL , Gill S \nChimeric Antigen Receptor T Cells and Hematopoietic Cell Transplantation: How Not to Put the CART before the Horse . Biol Blood Marrow Transplant \n2016 .\n3. \nTerakura S , Atsuta Y , Tsukada N , et al \nComparison of outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation and single unit cord blood transplantation in adults with acute leukemia . Biol Blood Marrow Transplant \n22 : 330 -338 , 2016 .26476205 \n4. \nAlsultan A , Giller RH , Gao D , et al \nGVHD after unrelated cord blood transplant in children: characteristics, severity, risk factors and influence on outcome . Bone Marrow Transplant \n46 : 668 -675 , 2011 .20676147 \n5. \nHerrera AF , Soriano G , Bellizzi AM , et al \nCord colitis syndrome in cord-blood stem-cell transplantation . N Engl J Med \n365 : 815 -824 , 2011 .21879899 \n6. \nFujino M , Kim Y , Ito M \nIntestinal thrombotic microangiopathy induced by FK506 in rats . Bone Marrow Transplant \n39 : 367 -372 , 2007 .17277791 \n7. \nBhatt AS , Freeman SS , Herrera AF , et al \nSequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome . N Engl J Med \n369 : 517 -528 , 2013 .23924002 \n8. \nRhee KJ , Wu S , Wu X , et al \nInduction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice . Infect Immun \n77 : 1708 -1718 , 2009 .19188353 \n9. \nWick EC , Sears CL \nBacteroides spp. and diarrhea . Curr Opin Infect Dis \n23 : 470 -474 , 2010 .20697287 \n10. \nShimoji S , Kato K , Eriguchi Y , et al \nEvaluating the association between histological manifestations of cord colitis syndrome with GVHD . Bone Marrow Transplant \n48 : 1249 -1252 , 2013 .23749110 \n11. \nMilano F , Shulman HM , Guthrie KA , Riffkin I , McDonald GB , Delaney C \nLate-onset colitis after cord blood transplantation is consistent with graft-versus-host disease: results of a blinded histopathological review . Biol Blood Marrow Transplant \n20 : 1008 -1013 , 2014 .24704386 \n12. \nRosén A , Ursing B , Alm T , et al \nA comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. I. Design and methodologic considerations . Gastroenterology \n83 : 541 -549 , 1982 .6124473 \n13. \nMagenau J , Reddy P \nThe difficulty in diagnosing cord colitis . Biol Blood Marrow Transplant \n20 : 906 -907 , 2014 .24838030\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "cord colitis syndrome (CCS); metronidazole (MNZ); umbilical cord blood (UCB); watery diarrhea",
"medline_ta": "Intern Med",
"mesh_terms": "D003092:Colitis; D036101:Cord Blood Stem Cell Transplantation; D003967:Diarrhea; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008795:Metronidazole; D008875:Middle Aged; D016896:Treatment Outcome; D014470:Umbilical Cord",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3219-3223",
"pmc": null,
"pmid": "29021466",
"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23924002;20697287;24838030;20676147;27638367;21879899;17277791;19188353;24311149;23749110;24704386;26476205;6124473",
"title": "Successful Treatment of a Case of Late-onset Colitis after Umbilical Cord Transplantation with Metronidazole: A Case Report and Literature Review.",
"title_normalized": "successful treatment of a case of late onset colitis after umbilical cord transplantation with metronidazole a case report and literature review"
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"abstract": "Tacrolimus is an immunosuppressive drug mainly used to lower the risk of transplant rejection in individuals who are post solid organ or hematopoietic transplantation. It is a macrolide which reduces peptidyl-propyl isomerase activity and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and interleukin-2 (IL-2) transcription. It has been associated with Posterior Reversible Encephalopathy Syndrome (PRES), a disease of sudden onset that can present as a host of different symptoms, depending on the affected area of the brain. While infectious causes of encephalopathy must always be entertained, the differential diagnosis should also include PRES in the appropriate context. We report three cases of PRES in patients with acute myeloid leukemia (AML) placed on tacrolimus after receiving a bone marrow transplant (BMT). The focus of this review is to enhance clinical recognition of PRES as it is related to an adverse effect of Tacrolimus in the setting of hematopoietic transplantation.",
"affiliations": "Internal and Hospital Medicine, Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida 33612-9497, USA.;Internal and Hospital Medicine, Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida 33612-9497, USA.;Department of Neurology, Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida 33612-9497, USA.;Department of Infectious Diseases. University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida 33612-9497, USA.;Infectious Diseases and Hospital Epidemiologist, Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, FOB-3, Tampa, Florida 33612-9497, USA.",
"authors": "Apuri|Susmitha|S|;Carlin|Kristin|K|;Bass|Edward|E|;Nguyen|Phuong Thuy|PT|;Greene|John N|JN|",
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"doi": "10.4084/MJHID.2014.014",
"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 2467839110.4084/MJHID.2014.014mjhid-6-1-e2014014Case ReportTacrolimus Associated Posterior Reversible Encephalopathy Syndrome – A Case Series and Review Apuri Susmitha 1Carlin Kristin 1Bass Edward 2Nguyen Phuong Thuy 3Greene John N. 4\n1 Internal and Hospital Medicine, Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida 33612-9497, USA\n2 Department of Neurology, Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida 33612-9497, USA\n3 Department of Infectious Diseases. University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, Florida 33612-9497, USA\n4 Infectious Diseases and Hospital Epidemiologist, Moffitt Cancer Center, University of South Florida College of Medicine, 12902 Magnolia Drive, FOB-3, Tampa, Florida 33612-9497, USACorrespondence to: John N. Greene, M.D. F.A.C.P. Chief, Infectious Diseases and Hospital Epidemiologist, Moffitt Cancer Center. Professor of Internal Medicine & Oncological Sciences. University of South Florida College of Medicine, 12902 Magnolia Drive, FOB-3, Tampa, Florida 33612-9497, USA. Tel.: (813) 745-8565, Fax: (813) 745-8468. E-mail: john.greene@moffitt.org2014 18 2 2014 6 1 e201401430 8 2013 07 1 2014 2014This 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.Tacrolimus is an immunosuppressive drug mainly used to lower the risk of transplant rejection in individuals who are post solid organ or hematopoietic transplantation. It is a macrolide which reduces peptidyl-propyl isomerase activity and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and interleukin-2 (IL-2) transcription. It has been associated with Posterior Reversible Encephalopathy Syndrome (PRES), a disease of sudden onset that can present as a host of different symptoms, depending on the affected area of the brain. While infectious causes of encephalopathy must always be entertained, the differential diagnosis should also include PRES in the appropriate context. We report three cases of PRES in patients with acute myeloid leukemia (AML) placed on tacrolimus after receiving a bone marrow transplant (BMT). The focus of this review is to enhance clinical recognition of PRES as it is related to an adverse effect of Tacrolimus in the setting of hematopoietic transplantation.\n==== Body\nIntroduction\nTacrolimus is a macrolide lactone derived from the bacteria Streptomyces tsukubaensis, which is used in the treatment of various immune-mediated disorders. This drug binds with cyclosporine to form a drug-receptor complex. This complex then competitively binds to and inhibits calcineurin. It functions by inhibiting the transcription of Interleukin-2 (IL-2) by T-helper lymphocytes, as well as inhibiting T-helper lymphocyte growth and proliferation.17–18 Unfortunately, tacrolimus is associated with renal and neural toxicity, among its other side effects of immunosuppression. One of the more uncommon presentations of neurotoxicity is posterior reversible encephalopathy syndrome (PRES). PRES was initially described by Hinchey et al1 in 1996 as a clinical neuroradiological entity. It is characterized by generalized seizures, headache, vision changes, coma, paresis, hemianopsia, nausea, altered mental status, and/or focal neurological deficits.2 There are varying reports of neurotoxicity related to tacrolimus ranging from 7 to 32% in solid organ transplants (SOT).47 The overall incidence of PRES occurs in 0.5%–5% of SOT recipients and is most commonly associated with tacrolimus.50 We are describing 3 cases of neurotoxicity related to tacrolimus in the hematopoietic transplant population.\n\nPatient One\nOur patient is a 36-year-old white female with a history of AML, who underwent allogeneic BMT 41 days prior to the onset of her neurologic symptoms. Her posttransplant course was complicated by mild graft versus host disease (GVHD) of the gastrointestinal tract and skin, for which she was placed on tacrolimus on day 16. On day 29, she was also started on prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) for pneumocystis jiroveci pneumonia (PCP). Additionally, she was diagnosed with cytomegalovirus (CMV) reactivation and BK virus hemorrhagic cystitis. She was placed on valgancyclovir (day 19) and Cidofovir (day 27) respectively. She subsequently developed acute renal failure with creatinine levels peaking at 3.7 mg/dL and BUN peaking at 88 mg/dL on day 34. Cidofovir was presumed to be the likely causative agent for the acute kidney injury; although she had recently been placed on multiple additional nephrotoxic agents, including the aforementioned tacrolimus, TMP-SMX, and pyridium.\n\nOn day 41, she presented with sudden onset of altered mental status manifesting as staring into space and right gaze preference. Tonic-clonic activity, incontinence, or tongue biting was not observed, but concern was raised for new onset of seizures given the episode of unresponsiveness with fixed gaze. She was started on treatment with 2 mg of intravenous lorazepam (AtivanTM) and 500 mg of levetiracetam (KeppraTM). She underwent imaging of the brain with a non-contrast computed tomography (CT). The CT scan did not demonstrate any acute findings. A non-contrast magnetic resonance imaging (MRI) was then obtained. The MRI study showed increased FLAIR and T2 signal in the cortex of the infero-posterior, posterior temporal and occipital lobe with absence of diffusion abnormality consistent with PRES (Figure 1). An EEG was negative for epileptiform activity. Cerebrospinal fluid analysis was performed for possible encephalitis as well as lepto-meningeal recurrence with negative results.\n\nInterestingly, the patient was taken off of tacrolimus on day 34 at the onset of acute renal failure, prior to the onset of PRES. The tacrolimus levels were within the desired range of 10–15 ng/ml throughout this course.\n\nShe was switched to sirolimus one week after the onset of PRES, maintaining serum levels within the desired range of 8–12 ng/ml. At this time her neurological symptoms had improved although not completely resolved. Three weeks following the diagnosis of PRES, a repeat MRI with gadolinium was performed showing resolution of the posterior areas and a small focus on FLAIR in the right frontal lobe. Levetiracetam was discontinued and sirolimus was maintained. The patient was followed for an additional year. She had a complete recovery from this event. No additional seizures or new neurological findings occurred during this time.\n\nPatient Two\nAltered mental status and severe headache developed in a 54 year old female, previously diagnosed with acute myeloid leukemia, four weeks after admission for high dose chemotherapy followed by matched unrelated donor stem cell transplant. Following her conditioning chemotherapy, which consisted of busulfan and fludarabine and subsequent bone marrow transplant, she developed a nodular pneumonia thought to be fungal in nature but culture negative by bronchoscopy specimens. During this time, the patient was on tacrolimus for graft versus host disease prophylaxis. This was started 25 days prior to the onset of mental status changes. Tacrolimus levels were maintained in a therapeutic target range of 10–15ng/ml during this time frame. On day 27 of the admission, she complained of severe headache which was followed by confusion. Also of note, the patient developed accelerated hypertension in the 48 hours surrounding the episode of confusion. Neither visual disturbance nor seizure activity was noted. Prior to this event, the patient was fairly normotensive with a systolic blood pressure range of 120–130 mmHg. At the peak of confusion, she was noted to have blood pressure of 188/90 mmHg. Calcium channel blocker therapy was then started and normotension was achieved.\n\nCranial T2-weighted MRI showed increased FLAIR and signal in the left and right cerebellar hemispheres that did not enhance or show restricted diffusion. There was also increased flair signal in the left and right posterior parietal occipital cortex consistent with posterior reversible leukoencephalopathy. Tacrolimus was discontinued and mycophenaolate mofetil was initiated. Within 24 hours of discontinuation of the tacrolimus, the neurologic symptoms began to resolve and the patient was again normotensive. Subsequent to this, she did develop grade II graft versus host disease of skin requiring high dose steroids and sirolimus was then added to the regimen. Because of the concern for potential worsening of the nodular pneumonia, steroid taper was initiated as soon as clinically feasible. Ultimately, she recovered and was discharged from the hospital in stable condition, with resolution of all neurologic findings.\n\nPatient Three\nOur third patient with a history of AML, refractory to chemotherapy, underwent a matched unrelated donor BMT. On transplant day 2, the patient was started on tacrolimus for graft versus host prophylaxis. Tacrolimus levels were maintained between 15.2 ng/ml and 17.3 ng/ml. Concurrently, she was found to have confusion, visual hallucinations, headaches, gait disturbances, nausea and vomiting. CT scan of the head showed no acute findings. These complaints were soon attributed to hyponatremia of 121mEq/L. As the sodium was gently corrected, her mental status returned to normal baseline within three days.\n\nOn transplant day 6, the patient again developed neurologic changes including visual disturbances, cerebellar ataxia, and headache. The visual disturbance consisted of seeing flashing lights as well as the inability to distinguish faces or colors. She had labile blood pressure throughout the hospital stay with systolic blood pressures ranging from 120mmHg to 180mmHg. CT scan of the head showed decreased attenuation in the bilateral mesial aspect of posterior parietal cortex as well as occipital cortex. MRI showed new areas of increased signal on the cortical gyral surfaces of both occipital lobes and portions of the temporal lobes. There was no diffusion restriction. There was no evidence of hemorrhage or acute stroke. These findings were consistent with PRES. EEG showed moderately severe slowing of the background rhythm, consistent with encephalopathy. There was no evidence of focal abnormalities or epileptiform discharges.\n\nGiven the diagnosis of PRES, the tacrolimus was discontinued cyclosporine and mycophenalate mofetil were initiated. By the time of her discharge on transplant day 20, her mental status improved significantly however she was left with a broad based gate. This was thought to be due to busulfan toxitcity. Mycophenalate mofetil was discontinued once engrafted and rapamune initiated. Cyclosporine was continued upon discharge. On day 46, she was readmitted to the hospital with alteration in mental status, hyponatremia and was found to have GVHD grade 1 of the duodenum and Grade 1–2 GVHD of the rectum. Infectious work up was negative as a cause of encephalopathy. During this admission, the patient remained normotensive. Repeat MRI showed evidence of recurrent PRES and was thought to be now related to cyclosporine. Unfortunately, the patient continued to decline and enrolled in hospice services, dying shortly thereafter.\n\nDiscussion\nAML is a disease of the bone marrow where abnormal cancer cells grow rapidly and replace healthy marrow. This process increases the susceptibility for bone pain, bleeding and infections, anemia and recurrent fevers. Initial treatment almost always consists of chemotherapy regimen, such as duanorubicin and cytarabine. BMT is an option often reserved for chemotherapy failure. Three distinct modalities of BMT include autologous transplant, allogeneic transplant and umbilical cord transplant. In allogeneic transplant, hematopoietic stem cells are collected from a donor and ultimately infused into a patient after high-dose chemotherapy. Complications from this procedure include immunosuppression, anemia, bleeding, fever, and infections as well as rejection or GVHD.19\n\nThe primary role of tacrolimus (also FK-506, or Fujimycin) is to prevent GVHD in the post-allogeneic solid organ transplant patient. In recent years, it has been increasingly used as an immunosuppressive agent in hematopoietic stem cell transplantation as well. Neurotoxicity secondary to tacrolimus has been well described, particularly in solid organ transplant recipients.15\n\nPRES, as the name suggests, is a constellation of symptoms associated with vasogenic edema, most commonly, of the posterior cerebral vasculature, often affecting the parietaloccipital region. Other vascular territories can also be affected in PRES, such as the posterior portion of frontal lobe and temporal lobe.23 The abnormalities primarily affect white and gray matter, but the cortex can also be involved. Although the diagnosis may be suggested by CT, MRI of the brain is the most sensitive diagnostic tool.3 Distinguishing between vasogenic edema in PRES and cytotoxic edema in the setting of cerebral ischemia can be reliably determined by diffusion weighted MR imaging.46 PRES is typically a reversible phenomenon, as indicated by the name, but if not recognized early and treated appropriately, permanent brain injury may ensue.8 Many agents and etiologies have been linked to PRES (Table 1).\n\nPRES is an increasingly recognized neurologic disorder with characteristic image findings. Clinically, its presentation can be variable and the differential is wide (Table 2). The pathophysiology of PRES still remains unclear. The mechanism of action of Tacrolimus induced PRES may be similar to Cyclosporine. Neurotoxicity associated with Cyclosporine was thought to be facilitated by hypomagnesemia, hypocholesterolemia, hypertension and the vasoactive agent endothelin.53 Cyclosporine is also believed to exacerbate hypertension by inhibiting nitric oxide production.54 The mechanism of cellular injury is thought to be secondary to mitochondrial dysfunction as the symptoms of Cyclosporine induced neurotoxicity and mitochondrial encephalopathy appear to be similar.55 Schwartz et al assessed sixteen patients by evaluating the factors responsible for the neurotoxic effects of Cyclosporine using neuroimaging as well as clinical and laboratory data. The only major factor associated with neurotoxic effects of Cyclosporine was systemic hypertension although thrombocytopenia, microangiopathic hemolytic anemia and hypoalbuminemia are common.56 The syndrome is likely initiated by a breakdown in the blood brain barrier leading to a leakage of fluid into the interstitium of the brain tissue and the development of vasogenic edema.9 In addition, immunosuppressant drugs exert cytotoxic effects on the vascular endothelium.10,11 It is unknown whether vasospasm plays a clear role in the genesis of local ischemia.12 Sympathetic innervation regulates the vessels of the brain during acute elevations in blood pressure. Because auto-regulatory mechanisms are dependent on the neurogenic response, the more poorly innervated areas in the posterior circulation are more vulnerable to increased blood pressure.12,13 As PRES may occur in patients with hypertensive encephalopathy where the limits of autoregulation are exceeded, hypertension has been suggested as a potential risk factor for neurotoxicity induced by tacrolimus and other drug related cases of PRES. It is important to exclude unrecognized increases in blood pressure that can be overlooked or occur in the outpatient setting. Two of our three patients were hypertensive surrounding the PRES event and a careful review of the chart records failed to show any elevations in the third case.\n\nUnfortunately, immune suppressant blood levels do not appear to correlate with severe neurotoxicity or PRES, but discontinuation or change in the offending immunosuppressant can lead to clinical improvement. Grimbert et al reported significant levels of Tacrolimus in the CSF which suggests that this molecule can cross the blood brain barrier. Demyelination was noted in two cerebral biopsies associated with leukoencephalopathy in patients who underwent liver and lung transplantation.57\n\nImmune challenges post-transplant (i.e. transplant rejection, GVHD), effects of chemotherapy, and the risks of infection in the immunosuppressed state may further contribute to toxicity. Clearly, a balance exists between adequate immunosuppression and infection risk.14 The diagnosis of tacrolimus-associated PRES was made by the following criteria: (1) characteristic clinical findings (headache, mental status changes, seizures, visual abnormalities and/or focal neurological deficits) with the exclusion of other possible causes (i.e. infection, metabolic disturbances and structural neurological lesions) and (2) characteristic findings of subcortical white matter lesions on CT or MRI of the brain.16\n\nOur patients presented with classic MRI findings of PRES at the onset of symptoms, and had appropriate response to treatment in the expected timeframe. Patients affected by PRES may experience some or all of the following: visual disturbances, altered mental status, seizures, and headaches. Of note, the association of hypertension with PRES is well reported; however is not always a component of PRES in patients on immunosuppressive therapy.49\n\nThese cases demonstrate the challenge of understanding the pathophysiology of PRES, since tacrolimus use would appear to be the main contributor. However, in the first case, PRES did not appear until four days after this medication was withheld secondary to acute renal failure. Although subtherapeutic levels of immunosuppressants have been reported as causing PRES, observations of the onset of this disease at the time of declining levels is seemingly paradoxical. There exists the possibility of delayed onset of symptoms, or perhaps the confounding factor was related to the acute renal failure itself. Proteinuria and hypoalbuminemia are known to be associated contributors to the development of PRES. The time course of developing PRES from the onset of beginning immunosuppressant therapy is particularly variable; therefore, the development of PRES, even while maintaining therapeutic levels, is not surprising.\n\nIn addition, our third patient had recurrent PRES with the second event likely related to cyclosporine. Interim images had revealed resolution of PRES once the offending Tacrolimus had been discontinued. Cyclosporine was subsequently initiated and maintained in the therapeutic target range. Cyclosporine has been reported in the literature to be an inciting factor in PRES events.51 There have been published case reports documenting recurrent episodes of PRES with varying inciting factors.52\n\nConclusions\nTacrolimus-associated PRES is an uncommon, but serious complication after BMT, especially with matched-unrelated or mismatched transplants, where higher levels of immunosuppression are required to prevent rejection. It should also be noted that supratherapeutic levels of tacrolimus need not be present to cause a PRES event.48\n\nThis syndrome should be promptly recognized as it is potentially reversible and generally responds to withholding or decreasing the dose of tacrolimus in addition to controlling hypertension and seizures.\n\nAlthough there are common yet heterogeneous etiologies that surround the onset of PRES, more research into the mechanisms surrounding PRES is needed to understand this disease process. The compilation of these diseases and a study of the time course of the patient’s history leading up to and during the presentation of PRES may better elucidate the means by which we treat and diagnose this disease.\n\nCompeting interests: The authors have declared that no competing interests exist.\n\nFigure 1 Table 1 Common causes of PRES\n\nMedications\tChemotherapy agents\tCytokines and Immunoglobulin’s\tOthers\t\n\n\t\nLinezolid20\tCyclosporine4,5\tRituximab37\tBlood transfusion44\t\nAntiretroviral21\tCisplatin29\tInfliximab38\tIV contrast agents23\t\nErythropoietin22\tOxaliplatin30\tInterferon-alpha39\tHypertension23\t\nCocaine23\tCarboplatin31\tInterleukin-240\tPre-eclampsia23\t\nEphedra24\tGemcitabine29\tEtanarcept41\tEclampsia23\t\nLysergic acid\tCytarabine32\tAnti-lymphocyte\tTumor lysis syndrome8\t\nAmide25\tMethotrexate33\tglobulin42\tSepsis8\t\nCarbamazepine26\tVincristine34\tTacrolimus1,23\tSLE*23\t\nIntravenous\tIrinotecan\tSirolimus43\tTTP*23\t\nCaffeine27\tHydrochloride35\t\tITP*23\t\nCorticosteroids23,28\tBevazicumab35\t\tAnti-depressants8\t\n\tSunitinib36\t\tRenal Failure8\t\n* SLE = Systemic lupus erthythematosus; TTP = Thrombotic thrombocytopenic purpura; ITP = Idiopathic thrombocytopenic purpura.\n\nTable 2 Differential Diagnosis of PRES:\n\nEmergent- Ischemia, Thrombosis, Mass effect, Hemorrhage, Hydrocephalus, Seizures, Trauma.\t\nInfectious- Encephalitis, HIV*,PML*,SSPE*, Toxoplasmosis, Neurosyphilis, Septic Cerebral Embolism,Rubella, Lyme Disease.\t\nInflammatory- SLE*, Scleroderma, Vasculitis, Multiple sclerosis.\t\nOther- Toxic white matter demyelination, Adrenoleukodystrophy, Uremic encephalopathy.\t\n* HIV-Human Immunodeficiency Virus; PML=Progressive Multifocal Leukoencephalopathy; SSPE=Subacute Sclerosing Panencephalitis; SLE=Systemic Lupus erythematosus45\n==== Refs\nReferences\n1 Hinchey J Chaves C Appignani B A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 10.1056/NEJM199602223340803 8559202 \n2 Hodnett P Coyle J O_Regan K Maher MM Fanning N PRES (posterior reversible encephalopathy syndrome), a rare complication of tacrolimus therapy Emerg Radiol 2009 16 493 496 10.1007/s10140-008-0782-6 19096887 \n3 Nakamura M Fuchinoue S Sato S Clinical and radiological features of two cases of tacrolimus-related posterior leukoencephalopathy in living related liver transplantation Transplant Proc 1998 30 1477 1478 10.1016/S0041-1345(98)00323-6 9636600 \n4 Jarosz JM Howlett DC Cox TC Bingham JB Cyclosporine-related reversible posterior leukoencephalopathy: MRI Neuroradiology 1997 39 711 715 10.1007/s002340050492 9351107 \n5 Saeed B Abou-Zor N Amer Z Kanani I Hilal M Cyclosporin-A induced posterior reversible encephalopathy syndrome Saudi J Kidney Dis Transpl 2008 19 439 442 18445907 \n6 Bartynski WS Posterior reversible encephalopathy syndrome, part 1: Fundamental imaging and clinical features Am J Neuroradiol 2008 29 1036 1042 10.3174/ajnr.A0928 18356474 \n7 Feske SK Posterior reversible encephalopathy syndrome: a review Semin Neurol 2011 31 2 202 215 10.1055/s-0031-1277990 21590625 \n8 Hedna VS Stead LG Bidari S Patel A Gottipati A Posterior reversible encephalopathy syndrome (PRES) and CT perfusion changes Int J Emerg Med 2012 5 12 10.1186/1865-1380-5-12 22377097 \n9 Provenzale JM Petrella JR Cruz LC Jr Wong JC Engelter S Barboriak DP Quantitative assessment of diffusion abnormalities in posterior reversible encephalopathy syndrome Am J Neuroradiol 2001 22 1455 1461 11559490 \n10 Dinsdale HB Robertson DM Haas RA Cerebral bloodflow in acute hypertension Arch Neurol 1974 31 80 87 10.1001/archneur.1974.00490380028002 4365987 \n11 Johansson BB The blood-brain barrier and cerebral blood flow in acute hypertension Acta Med Scand Suppl 1983 678 107 112 6584009 \n12 Edvinsson L Owman C Sjöberg NO Autonomic nerves, mast cells, and amine receptors in human brain vessels. A histochemical and pharmacological study Brain Res 1976 115 377 393 10.1016/0006-8993(76)90356-5 184880 \n13 Beausang-Linder M Bill A Cerebral circulation in acute arterial hypertension - protective effects of sympathetic nervous activity Acta Physiol Scand 1981 111 193 199 10.1111/j.1748-1716.1981.tb06724.x 7282395 \n14 Bartynski WS Posterior Reversible Encephalopathy Syndrome, Part 1: Fundamental Imaging and Clinical Features Am J Neuroradiol 2008 29 6 1036 1042 10.3174/ajnr.A0928 18356474 \n15 Hodnett P Coyle J O’Regan K Maher MM Fanning N PRES (posterior reversible encephalopathy syndrome), a rare complication of tacrolimus therapy Emerg Radiol 2009 16 6 493 496 10.1007/s10140-008-0782-6 19096887 \n16 Wong R Beguelin GZ de Lima M Giralt SA Hosing C Ippoliti C Forman AD Kumar AJ Champlin R Couriel D Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation Br J Haematol 2003 122 1 128 134 10.1046/j.1365-2141.2003.04447.x 12823354 \n17 Wiederrecht G Lam E Hung S Martin M Sigal N The mechanism of action of FK-506 and cyclosporine A Ann N Y Acad Sci 1993 696 9 19 10.1111/j.1749-6632.1993.tb17137.x 7509138 \n18 Schreiber SL Crabtree GR The mechanism of action of cyclosporine A and FK506 Immunol Today 1992 13 4 136 142 10.1016/0167-5699(92)90111-J 1374612 \n19 Acute Myeloid Leukemia U.S National Library of Medicine 1 2001 Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001569/ Accessed February 13, 2013 \n20 Nagel S Kohrmann M Huttner HB Storch-Hagenlocher B Schwab S Linezolid induced posterior reversible leukoencephalopathy syndrome Arch Neurol 2007 64 5 746 748 10.1001/archneur.64.5.746 17502475 \n21 Ridolfo AL Resta F Milazzo L Reversible posterior leukoencephalopathy syndrome in 2 HIV-infected patients receiving antiretroviral therapy Clin Infect Dis 2008 46 2 e19 22 10.1086/524740 18171242 \n22 Delanty N Vaughan C Frucht S Stubgen P Erythropoietin-associated hypertensive Posterior leukoencephalopathy Neurology 1997 49 3 686 689 10.1212/WNL.49.3.686 9305323 \n23 McKinney AM Short J Truwit CL Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings Am J Roentgenol 2007 189 4 904 912 10.2214/AJR.07.2024 17885064 \n24 Moawad FJ Hartzell JD Biega TJ Lettieri CJ Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose South Med J 2006 99 5 511 514 10.1097/01.smj.0000215739.90211.3b 16711314 \n25 Legriel S Bruneel F Spreux-Varoquaux O Lysergic acid amide-induced posterior reversible encephalopathy syndrome with status epilepticus Neurocrit Care 2008 9 2 247 252 10.1007/s12028-008-9096-5 18446448 \n26 Furuta N Fujita Y Sekine A Ikeda M Okamoto K Reversible posterior leukoencephalopathy syndrome associated with carbamazepine-induced hypertension Rinsho Shinkeigaku 2009 49 4 191 193 10.5692/clinicalneurol.49.191 19462818 \n27 Ortiz GA Bianchi NA Tiede MP Bhatia RG Posterior reversible encephalopathy syndrome after intravenous caffeine for post-lumbar puncture headaches Am J Neuroradiol 2009 30 3 586 587 10.3174/ajnr.A1321 18945799 \n28 McKinney AM Short J Truwit CL Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings Am J Roentgenol 2007 189 4 904 912 10.2214/AJR.07.2024 17885064 \n29 Kwon EJ Kim SW Kim KK Seo HS Kim DY A case of gemcitabine and cisplatin associated posterior reversible encephalopathy syndrome Cancer Res Treat 2009 41 1 53 55 10.4143/crt.2009.41.1.53 19688073 \n30 Nagata Y Omuro Y Shimoyama T A case of colon cancer with reversible posterior leukoencephalopathy syndrome following 5-FU and oxaliplatin (FOLFOX regime) Gan To Kagaku Ryoho 2009 36 1163 1166 19620809 \n31 Vieillot S Pouessel D de Champfleur NM Becht C Culine S Reversible posterior leukoencephalopathy syndrome after carboplatin therapy Ann Oncol 2007 18 608 609 10.1093/annonc/mdl436 17164233 \n32 Saito B Nakamaki T Nakashima H Reversible posterior leukoencephalopathy syndrome after repeat intermediate-dose cytarabine chemotherapy in a patient with acute myeloid leukemia Am J Hematol 2007 82 304 306 10.1002/ajh.20772 16947320 \n33 Dicuonzo F Salvati A Palma M Posterior reversible encephalopathy syndrome associated with methotrexate neurotoxicity: conventional magnetic resonance and diffusion-weighted imaging findings J Child Neurol 2009 24 1013 1018 10.1177/0883073809332705 19307676 \n34 Hualde Olascoaga J Molins Castiella T Souto Hernandez S Reversible posterior leukoencephalopathy: report of two cases after vincristine treatment An Pediatr (Barc) 2008 68 3 282 285 10.1157/13116711 18358142 \n35 Allen JA Adlakha A Bergethon PR Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer Arch Neurol 2006 63 10 1475 1478 10.1001/archneur.63.10.1475 17030665 \n36 Cumurciuc R Martinez-Almoyna L Henry C Husson H de Broucker T Posterior reversible encephalopathy syndrome during sunitinib therapy Rev Neurol (Paris) 2008 164 6–7 605 607 10.1016/j.neurol.2008.03.007 18565360 \n37 Zito JA Lee CC Johnson S Singer A Vacirca J Reversible posterior leukoencephalopathy syndrome after rituximab Am J Emerg Med 2010 28 4 537.e1 537.e2 \n38 Zamvar V Sugarman ID Tawfik RF Macmullen-Price J Puntis JW Posterior reversible encephalopathy syndrome following infliximab infusion J Pediatr Gastroenterol Nutr 2009 48 1 102 105 10.1097/MPG.0b013e31818aedb4 19172132 \n39 Kamar N Kany M Bories P Reversible posterior leukoencephalopathy syndrome in hepatitis C virus-positive long-term hemodialysis patients Am J Kidney Dis 2001 37 4 E29 h 10.1016/S0272-6386(01)90015-0 11273899 \n40 Karp BI Yang JC Khorsand M Wood R Merigan TC Multiple cerebral lesions complicating therapy with interleukin-2 Neurology 1996 47 417 424 10.1212/WNL.47.2.417 8757014 \n41 Kastrup O Diener HC TNF-antagonist etanercept induced reversible posterior leukoencephalopathy syndrome J Neurol 2008 255 3 452 453 10.1007/s00415-008-0732-y 18283400 \n42 Greaves P Oakervee H Kon SS Jones R Farah N Posterior reversible encephalopathy syndrome following anti-lymphocyte globulin treatment for severe aplastic anemia Br J Haematol 2006 134 3 251 10.1111/j.1365-2141.2006.06157.x 16848767 \n43 Bodkin CL Eidelman BH Sirolimus-induced posterior reversible encephalopathy Neurology 2007 68 23 2039 2040 10.1212/01.wnl.0000264428.76387.87 17548556 \n44 Huang YC Tsai PL Yeh JH Chen WH Reversible posterior leukoencephalopathy syndrome caused by blood transfusion: a case report Acta Neurol Taiwan 2008 17 258 262 19280871 \n45 Siebert E Liman T Bohner G Differential diagnoses in posterior reversible encephalopathy syndrome (PRES) - a critical reassessment of falsely positive diagnosed cases European Society of Radiology 2011 Available at: http://ipp.myesr.org/esr/ecr2011/index.php?v=posterd&poid=100468&ippwwwsid=9q9us9eogkb09is7geptmj7h86 Accessed February 13, 2013 \n46 Covarrubias Diego J Luetmer Patrick H Campeau Norbert G Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images AJNR Am J Neuroradiol 2002 23 1038 1048 12063238 \n47 Qisi Wu Christian Marescaux Valerie Wolff Mi-Young Jeung Romain Kessler Valerie Lauer Yangmei Chen Tacrolimus-Associated Posterior Reversible Encephalopathy Syndrome after Solid Organ Transplantation Eur Neurol 2010 64 169 177 10.1159/000319032 20699617 \n48 Aimee Hammerstrom Joshua Howell Alison Gulbis Gabriela Rondon Richard Champlin Uday Popat Tacrolimus-Associated posterior reversible encephalopathy syndrome in hematopoietic allogenic stem cell transplantation Am. J Hematol 2013 88 301 305 10.1002/ajh.23402 23460378 \n49 Dimitre Staykov Stefan Schwab Posterior reversible encephalopathy syndrome Journal of Intensive Care Medicine 2012 27 1 11 24 10.1177/0885066610393634 21257628 \n50 Barbas AS Rege AS Castelberry AW Gommer J Ellis J Brennen TV Collins BH Martin AE Ravindra KV Vikraman DS Sudan DL Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation American Journal of Transplantation 2013 13 808 810 10.1111/ajt.12061 23331705 \n51 Bassam Saeed Najet Abou-Zor Ziad Amer Issam Kanani Mahmoud Hilal Cyclosporin-A induced posterior reversible encephalopathy syndrome Saudi Journal of Kidney Diseases and Transplantation 2008 19 3 439 442 18445907 \n52 Jon Sweany Walter Bartynski John Boardman “Recurrent” posterior reversible encephalopathy syndrome: report of 3 cases- Pres can strike twice! J Comput Assist Tomogr 2007 31 148 156 17259848 \n53 Kou R Greif D Michel T Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A J Biol Chem 2002 277 33 29669 10.1074/jbc.M204519200 12050171 \n54 Beal MF Mitochondrial dysfunction in neurodegenerative diseases Biochem Biophys Acta 1998 1366 1–2 211 10.1016/S0005-2728(98)00114-5 9714810 \n55 Glusker P Recht L Lane B Reversible posterior leukoencephalopathy syndrome and bevacizumab N Engl J Med 2006 354 9 980 10.1056/NEJMc052954 \n56 Schwartz RB Bravo SM Klufas RA Hsu L Barnes PD Robson CD Antin JH Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases AJR Am J Roentgenol 1995 165 3 627 10.2214/ajr.165.3.7645483 7645483 \n57 Grimbert Philippe Azema Christine Pastural Myriam Dhamane Djamel Remy Philippe Salomon Laurent Schrotgen Frederique Baron Christophe Lang Philippe Tacrolimus (FK-506) induced severe and late encephalopathy in a renal transplant recipient Nephrol Dial Transplant 1999 14 2489 2491 10.1093/ndt/14.10.2489 10528682\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2035-3006",
"issue": "6(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": null,
"medline_ta": "Mediterr J Hematol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101530512",
"other_id": null,
"pages": "e2014014",
"pmc": null,
"pmid": "24678391",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "21257628;12050171;16711314;21590625;19620809;19096887;23331705;8757014;19307676;7509138;9305323;19462818;18283400;10528682;20466257;19172132;18945799;7645483;22377097;9636600;18565360;184880;18445907;16947320;18446448;17030665;17502475;17885064;7282395;4365987;18171242;9351107;12063238;23460378;1374612;11273899;20699617;16510760;17164233;6584009;11559490;17548556;17259848;18356474;9714810;12823354;18358142;19688073;19280871;8559202;16848767",
"title": "Tacrolimus associated posterior reversible encephalopathy syndrome - a case series and review.",
"title_normalized": "tacrolimus associated posterior reversible encephalopathy syndrome a case series and review"
} | [
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"companynumb": "US-GILEAD-2014-0108870",
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"activesubstancename": "VALGANCICLOVIR"
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... |
{
"abstract": "Necrotizing fasciitis is a devastating, rapidly pro-gressive soft tissue infection. We present an unusual case of Escherichia coli necrotizing fasciitis following renal transplant. The patient was a 50-year-old woman previously on long-term hemodialysis who presented with left thigh erythema adjacent to the site of a central venous catheter 5 days after renal transplant. The classical features of necrotizing fasciitis were initially absent, and, despite aggressive resuscitation and debridement, she did not survive. Monomicrobial E. coli necrotizing fasciitis is rare, especially in this cohort of patients. Immunosuppression is a known risk factor for infection, and patients may present atypically. Shock and erythema may be the only clues to infection. Necrotizing fasciitis must be considered in acutely unwell renal transplant recipients so that immediate and life-saving surgical debridement can be delivered.",
"affiliations": "From Whittington Health, London, United Kingdom.",
"authors": "Cruddas|Lucinda|L|;Al-Midani|Ammar|A|;Banga|Neal|N|;Jones|Gareth|G|;Butler|Peter E M|PEM|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2018.0316",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "18(4)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D004926:Escherichia coli; D004927:Escherichia coli Infections; D019115:Fasciitis, Necrotizing; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008875:Middle Aged; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "519-521",
"pmc": null,
"pmid": "30674239",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Rare Presentation of Escherichia coli Necrotizing Fasciitis in Renal Transplantation.",
"title_normalized": "a rare presentation of escherichia coli necrotizing fasciitis in renal transplantation"
} | [
{
"companynumb": "GB-ACCORD-200837",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
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{
"abstract": "BACKGROUND\nCryoglobulinemia is an immune-complex-mediated small vessel vasculitis that classically involves the skin, kidneys and peripheral nerves. Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder which causes blood vessel thrombosis. It can present as a multi-organ microthrombotic disorder which is called catastrophic APS.\n\n\nOBJECTIVE\nIn this case series we aim to describe the diagnostic and management challenges that arise when these two severe disorders simultaneously present in the same patient.\n\n\nMETHODS\nWe describe four patients who were admitted to our hospital due to multi-organ life threatening damage mediated by cryoglobulinemic vasculitis with concurrent APS.\n\n\nRESULTS\nClinical manifestations included leg ulcers, livedo reticularis, renal failure, and peripheral neuropathy. Suggested etiologies for the combined syndromes were hepatitis C, systemic lupus erythematosus and myeloproliferative disease rectal maltoma. All of our patients were treated with anticoagulation, high-dose corticosteroids, rituximab, intravenous gammaglobulins and plasma exchange.\n\n\nCONCLUSIONS\nThe rare association of severe or catastrophic APS with cryoglobulinemia in patients should be considered by physicians who treat patients with multi-organ ischemia or necrosis.",
"affiliations": "Rheumatology Unit, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: sofereret@gmail.com.;Rheumatology Unit, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Shachaf|Shiber|S|;Yair|Molad|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2255-5021",
"issue": "56(1)",
"journal": "Revista brasileira de reumatologia",
"keywords": "Antiphospholipid syndrome; Crioglobulinemia; Cryoglobulinemia; Síndrome antifosfolipídica; Vasculite; Vasculitis",
"medline_ta": "Rev Bras Reumatol Engl Ed",
"mesh_terms": "D016736:Antiphospholipid Syndrome; D003449:Cryoglobulinemia; D006801:Humans; D007166:Immunosuppressive Agents; D010951:Plasma Exchange; D000069283:Rituximab",
"nlm_unique_id": "101672232",
"other_id": null,
"pages": "2-7",
"pmc": null,
"pmid": "27267327",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "The correlation between antiphospholipid syndrome and cryoglobulinemia: case series of 4 patients and review of the literature.",
"title_normalized": "the correlation between antiphospholipid syndrome and cryoglobulinemia case series of 4 patients and review of the literature"
} | [
{
"companynumb": "PHHY2018IL001867",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
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"activesubstancename": "PREDNISONE"
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"drugadditional": "3",
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{
"abstract": "Posterior reversible encephalopathy syndrome (PRES) is a rare clinical-radiographic syndrome that has been expanding rapidly in the world of clinical medical oncology and hematology. In this article, we provide a unique patient case of delayed gemcitabine-induced PRES.\n\n\n\nA 60-year-old African American female with significant past medical history of ER+/PR+/HER2- invasive ductal carcinoma of the left breast is seen in the medical oncology clinic with vague, mild complaints of lightheadedness. She had progressed on multiple lines of chemotherapy and was ultimately switched to gemcitabine. One month after her third dose of gemcitabine, she developed acute vision loss and soon developed generalized tonic-clonic seizure. Extensive workup was unrevealing other than PRES and she slowly improved with supportive care and withdrawal of the medication.\n\n\n\nMultiple case reports have described PRES in the context of combination chemotherapy with gemcitabine and a platinum agent in the treatment of gastrointestinal malignancies. With growing evidence, this case is consistent with the hypothesis that gemcitabine as monotherapy has a direct association with PRES. This case highlights a unique aspect in that PRES can occur at a delayed time interval, much further than the expected hours to days after the previous treatment.",
"affiliations": "Cancer Center and Research Institute, University of Mississippi Medical Center Guyton Research Building, MS, USA.;Cancer Center and Research Institute, University of Mississippi Medical Center Guyton Research Building, MS, USA. Electronic address: stang2@umc.edu.",
"authors": "Schaub|John R|JR|;Tang|Shou-Ching|SC|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2020.10.030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "361(6)",
"journal": "The American journal of the medical sciences",
"keywords": "Gemcitabine; Oncology; PRES",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D013997:Time Factors",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "795-798",
"pmc": null,
"pmid": "33888263",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Delayed Gemcitabine-Induced Posterior Reversible Encephalopathy Syndrome.",
"title_normalized": "delayed gemcitabine induced posterior reversible encephalopathy syndrome"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/21/0135566",
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"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
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... |
{
"abstract": "Cryptococcus gattii are closely related species of encapsulated yeast-like fungi involved in the etiology of cryptococcosis, especially in immunocompetent individuals. Dissemination with involvement of many organ systems is common. On the other hand, cellulitis in an immunossupressed patient caused by C. gattii is rare. We present a case of disseminated disease caused by Cryptococcus gattii in a lung transplant recipient who manifested cellulitis. The disease was also complicated by a lung carcinoma. We emphasize that cryptococcal cellulitis related to C. gattii in solid organ transplant (SOT) recipients should be considered in the differential diagnosis of acute bacterial skin infections.",
"affiliations": "Conselho Nacional de Desenvolvimento Científico Tecnológico.",
"authors": "Dall Bello|Aline Gehlen|AG|;Severo|Cecilia Bittencourt|CB|;Schio|Sadi|S|;Severo|Luiz Carlos|LC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "19(11)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000230:Adenocarcinoma; D002481:Cellulitis; D003453:Cryptococcosis; D056285:Cryptococcus gattii; D003586:Cytomegalovirus Infections; D017809:Fatal Outcome; D006801:Humans; D007165:Immunosuppression Therapy; D008175:Lung Neoplasms; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "20395",
"pmc": null,
"pmid": "24314772",
"pubdate": "2013-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First reported case of cellulitis due to Cryptococcus gattii in lung transplantation recipient: a case report.",
"title_normalized": "first reported case of cellulitis due to cryptococcus gattii in lung transplantation recipient a case report"
} | [
{
"companynumb": "PHHY2015BR080054",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Co-trimoxazole (CTX) causes various forms of severe cutaneous adverse reactions (SCARs). This case-control study was conducted to investigate the involvement between genetic variants of human leukocyte antigen (HLA) and CYP2C9 in CTX-induced SCARs, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in Thai patients. Thirty cases of CTX-induced SCARs were enrolled and compared with 91 CTX-tolerant controls and 150 people from the general Thai population. Cases comprised 18 SJS/TEN and 12 DRESS patients. This study demonstrated that genetic association of CTX-induced SCARs was phenotype-specific. HLA-B*15:02 and HLA-C*08:01 alleles were significantly associated with CTX-induced SJS/TEN, whereas the HLA-B*13:01 allele was significantly associated with CTX-induced DRESS. In addition, a significant higher frequency of HLA-A*11:01-B*15:02 and HLA-B*13:01-C*03:04 haplotypes were detected in the group of CTX-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and DRESS cases, respectively. Genetic association of CTX-induced SCARs is phenotype-specific. Interestingly, these association was observed only in HIV-infected patients but not in non-HIV-infected patients.",
"affiliations": "Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;The Thai Severe Cutaneous Adverse Drug Reaction (THAI-SCAR) Research Group.;The Thai Severe Cutaneous Adverse Drug Reaction (THAI-SCAR) Research Group.;The Thai Severe Cutaneous Adverse Drug Reaction (THAI-SCAR) Research Group.;The Thai Severe Cutaneous Adverse Drug Reaction (THAI-SCAR) Research Group.;Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;Pharmacy Unit, Udon Thani Hospital, Udon Thani, Thailand.;Pharmacy Unit, Udon Thani Hospital, Udon Thani, Thailand.;The Thai Severe Cutaneous Adverse Drug Reaction (THAI-SCAR) Research Group.;The Thai Severe Cutaneous Adverse Drug Reaction (THAI-SCAR) Research Group.;Pharmacy Department, Khon Kaen Hospital, Khon Kaen, Thailand.;Pharmacy Unit, Udon Thani Hospital, Udon Thani, Thailand.;Department of Pathology, Faculty of Medicine, Khon Kaen University, Thailand.;Pharmacy Unit, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand.;School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.;Genomic Medicine Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Molecular and Clinical Pharmacology, The Royal Liverpool, Broadgreen University Hospitals NHS Trust, MRC Centre for Drug Safety Science, Liverpool Health Partners, University of Liverpool, Liverpool, UK.",
"authors": "Sukasem|Chonlaphat|C|;Pratoomwun|Jirawat|J|;Satapornpong|Patompong|P|;Klaewsongkram|Jettanong|J|;Rerkpattanapipat|Ticha|T|;Rerknimitr|Pawinee|P|;Lertpichitkul|Pattamon|P|;Puangpetch|Apichaya|A|;Nakkam|Nontaya|N|;Konyoung|Parinya|P|;Khunarkornsiri|Usanee|U|;Disphanurat|Wareeporn|W|;Srisuttiyakorn|Chutika|C|;Pattanacheewapull|Oranuch|O|;Kanjanawart|Sirimas|S|;Kongpan|Thachanan|T|;Chumworathayi|Pansu|P|;Saksit|Niwat|N|;Bruminhent|Jackrapong|J|;Tassaneeyakul|Wichittra|W|;Chantratita|Wasun|W|;Pirmohamed|Munir|M|0000-0002-7534-7266",
"chemical_list": "D000900:Anti-Bacterial Agents; D006680:HLA Antigens; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": "10.1002/cpt.1915",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9236",
"issue": "108(5)",
"journal": "Clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016022:Case-Control Studies; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015658:HIV Infections; D006680:HLA Antigens; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013262:Stevens-Johnson Syndrome; D013785:Thailand; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D055815:Young Adult",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "1078-1089",
"pmc": null,
"pmid": "32452529",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Genetic Association of Co-Trimoxazole-Induced Severe Cutaneous Adverse Reactions Is Phenotype-Specific: HLA Class I Genotypes and Haplotypes.",
"title_normalized": "genetic association of co trimoxazole induced severe cutaneous adverse reactions is phenotype specific hla class i genotypes and haplotypes"
} | [
{
"companynumb": "TH-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-272861",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
... |
{
"abstract": "Rabbit antithymocyte globulin (rATG) is increasingly used in nonmyeloablative hematopoetic stem cell transplant (HSCT). Elevated liver function tests (LFTs) have been reported for antithymocyte globulin in the treatment of aplastic anemia, but not when used in a conditioning regimen for HSCT. We describe two cases of patients receiving a conditioning regimen for HSCT containing rATG who developed a transient, severe transaminase elevation. In the first case, a 66-year-old woman with a history of acute myeloid leukemia received the first dose of rATG and the patient's transaminases were found to be extremely elevated within a few hours. The aspartate transaminase (AST) peaked at 1286 U/L and alanine transaminase (ALT) peaked at 991 U/L and both resolved within a week. In the second case, a 72-year-old woman with a history of non-Hodgkin lymphoma received the first dose of rATG and the AST and ALT were found to be 1212 U/L and 689 U/L, respectively, 1 h after finishing the infusion. Like the previous case, the transaminase elevation resolved within a week. LFT abnormalities induced by rATG during conditioning therapy for HSCT may be transient and have a rapid onset after the first dose, but quickly subside without any complications or sequelae. It is important to follow the LFTs closely, as well as monitor for any signs and symptoms of acute liver failure.",
"affiliations": "Department of Pharmacy, Stanford Hospital and Clinics, Stanford, CA, USA abrahamwchang@gmail.com.;Department of Pharmacy, Stanford Hospital and Clinics, Stanford, CA, USA.;Department of Pharmacy, Stanford Hospital and Clinics, Stanford, CA, USA.;Department of Pharmacy, Stanford Hospital and Clinics, Stanford, CA, USA.",
"authors": "Chang|Abraham|A|;Lee-Lam|Fu-Ying|FY|;Wang|Joanna|J|;Cheng|Ya-Hwei|YH|",
"chemical_list": "D000961:Antilymphocyte Serum; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": "10.1177/1078155213517583",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "21(1)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Rabbit antithymocyte globulin; adverse effect; nonmyeloablative hematopoietic stem cell transplant; transaminitis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000410:Alanine Transaminase; D000818:Animals; D000961:Antilymphocyte Serum; D001219:Aspartate Aminotransferases; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008099:Liver; D008111:Liver Function Tests; D016393:Lymphoma, B-Cell; D011817:Rabbits",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "67-71",
"pmc": null,
"pmid": "24395543",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient liver function abnormality following treatment with rabbit antithymocyte globulin for nonmyeloablative hematopoetic stem cell transplant: two case reports.",
"title_normalized": "transient liver function abnormality following treatment with rabbit antithymocyte globulin for nonmyeloablative hematopoetic stem cell transplant two case reports"
} | [
{
"companynumb": "US-SA-2015SA005836",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "To report a rare paradoxical development of systemic sarcoidosis in a patient taking adalimumab manifesting as multifocal choroidal infiltrates and seventh nerve palsy.\nThis was a single patient case report.\nA 30-year-old man with a history of psoriatic arthritis on adalimumab presented with intermittent fevers and headaches. Initial infectious serology and initial ophthalmic examination were within normal limits. Over the next month, he developed a seventh nerve palsy, unilateral decreased visual acuity, and bilateral multifocal choroidal infiltrates. The patient was diagnosed with systemic sarcoidosis secondary to tumor necrosis factor alpha (TNFα) inhibitor use after a hilar lymph node biopsy. Upon treatment with high-dose oral corticosteroids, the patient's symptoms and choroidal lesions significantly improved.\nThis case report illustrates a rare presentation of ocular, neurologic, and systemic sarcoidosis presenting as a bilateral multifocal choroiditis and seventh nerve paresis in a patient treated with adalimumab. We highlight the importance of obtaining an ophthalmic evaluation in the management of this rare adverse effect of TNFα inhibitors.",
"affiliations": "Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA.;Department of Ophthalmology, Stroger Eye Clinic/Cook County Health, Chicago, IL, USA.;Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA.;Department of Neurology, Weill Cornell Medicine, Cornell University, New York, NY, USA.;Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Wilkins|Carl Stanley|CS|;Ashourian|Kristen Taylor|KT|;Sobol|Ethan Kyle|EK|;Fink|Matthew|M|;Saltzman|Brian|B|;Teich|Steven|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2452-2325.312161",
"fulltext": "\n==== Front\nJ Curr Ophthalmol\nJ Curr Ophthalmol\nJCO\nJournal of Current Ophthalmology\n2452-2325\nWolters Kluwer - Medknow India\n\nJCO-33-205\n10.4103/2452-2325.312161\nCase Report\nSarcoid-Associated Bilateral Multifocal Choroiditis Secondary to Adalimumab\nWilkins Carl Stanley 1\nAshourian Kristen Taylor 2\nSobol Ethan Kyle 1\nFink Matthew 3\nSaltzman Brian 4\nTeich Steven 4\n1 Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA\n2 Department of Ophthalmology, Stroger Eye Clinic/Cook County Health, Chicago, IL, USA\n3 Department of Neurology, Weill Cornell Medicine, Cornell University, New York, NY, USA\n4 Icahn School of Medicine at Mount Sinai, New York, NY, USA\nAddress for correspondence: Carl Stanley Wilkins, New York Eye and Ear Infirmary Retina Center, 310 East 14th Street, New York, NY, USA. E-mail: Carl.Wilkins@mountsinai.org\nApr-Jun 2021\n05 7 2021\n33 2 205208\n13 10 2020\n24 12 2020\n04 2 2021\nCopyright: © 2021 Journal of Current Ophthalmology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nPurpose:\n\nTo report a rare paradoxical development of systemic sarcoidosis in a patient taking adalimumab manifesting as multifocal choroidal infiltrates and seventh nerve palsy.\n\nMethods:\n\nThis was a single patient case report.\n\nResults:\n\nA 30-year-old man with a history of psoriatic arthritis on adalimumab presented with intermittent fevers and headaches. Initial infectious serology and initial ophthalmic examination were within normal limits. Over the next month, he developed a seventh nerve palsy, unilateral decreased visual acuity, and bilateral multifocal choroidal infiltrates. The patient was diagnosed with systemic sarcoidosis secondary to tumor necrosis factor alpha (TNFα) inhibitor use after a hilar lymph node biopsy. Upon treatment with high-dose oral corticosteroids, the patient's symptoms and choroidal lesions significantly improved.\n\nConclusion:\n\nThis case report illustrates a rare presentation of ocular, neurologic, and systemic sarcoidosis presenting as a bilateral multifocal choroiditis and seventh nerve paresis in a patient treated with adalimumab. We highlight the importance of obtaining an ophthalmic evaluation in the management of this rare adverse effect of TNFα inhibitors.\n\nAdalimumab\nDrug reaction\nMultifocal choroiditis\nSarcoidosis\nTumor necrosis factor alpha inhibitor\nUveitis\n==== Body\nINTRODUCTION\n\nTumor necrosis factor alpha (TNFα) inhibitors are biologic agents that are commonly used in the treatment of many rheumatologic and autoimmune diseases including sarcoidosis. Adalimumab (Humira, AbbVie Ltd.) is a Food and Drug Administration-approved humanized monoclonal antibody to TNFα that inhibits both soluble and transmembrane moieties, thereby inhibiting multiple downstream proinflammatory pathways.1\n\nThe adverse effects of anti-TNFα agents have been well described in the literature and most frequently include risk of infection, malignancy, demyelinating disorders, and cardiovascular disease.2 Interestingly, there have been several cases reported of paradoxical sarcoid granulomatous reactions developing after the initiation of TNFα inhibitor therapy. We describe pulmonary, neurologic, and ocular sarcoidosis associated with adalimumab therapy, first manifesting as bilateral multifocal choroidal infiltrates detected on ophthalmologic examination.\n\nCASE REPORT\n\nA 30-year-old man with a medical history significant for psoriatic arthritis, hereditary spherocytosis, and cutaneous herpes zoster infection presented to an infectious disease specialist with intermittent fevers and headaches over the course of 2 weeks. He had also reported an unintentional 10-pound weight loss over the last 9 months. For the last 6 years, the patient was receiving adalimumab for psoriatic arthritis with adequate suppression.\n\nThe patient discontinued adalimumab and underwent an extensive workup for an infectious etiology. Serologies for syphilis, Lyme, and toxoplasmosis were negative, chest X-ray was normal, and an ophthalmic examination was within normal limits. Laboratory studies showed an erythrocyte sedimentation rate of 2 mm/h and a C-reactive protein of 0.4 mg/L. Complete blood count and comprehensive metabolic profile were normal, except for elevations in bilirubin, lactate dehydrogenase, and reticulocyte count, consistent with hereditary spherocytosis. The patient was given a trial of doxycycline 200 mg twice daily and valacyclovir 1 g three times daily for 2 weeks and restarted on adalimumab.\n\nThe patient traveled to Mexico and returned 1 month later with complaints of worsening headache, left facial paresis, ageusia, and persistent fever. Examination revealed a visual acuity of 20/20 in the right eye (OD) and 20/50 in the left eye (OS) and a left seventh nerve paresis. Anterior segment examination was significant only for exposure keratopathy OS without anterior chamber cell or flare in either eye. Funduscopic examination now showed dozens of multifocal 100–200 micron-sized circular creamy, yellow-white choroidal infiltrates disseminated throughout the fundus of each eye. There was no vitritis, vasculitis, or optic nerve edema [Figure 1a and b]. Optical coherence tomography revealed the choroidal lesions to be hyporeflective and showed no macular cysts or thickening. Enhanced depth imaging was unavailable. Given the patient's history of immunosuppressive therapy and travel to Mexico, he was admitted for urgent evaluation for suspected fungal or mycobacterial meningitis, as well as possible lymphoma. Serum testing for Lyme, syphilis, tuberculosis (TB), and West Nile virus was negative. Comprehensive metabolic panel and complete blood count testing were within normal limits. Cerebrospinal fluid examination was similarly negative for organisms including cryptococcal antigen but revealed 8 white blood cells (91% lymphocytes) and normal chemistries. Magnetic resonance imaging of the brain and orbits revealed enhancement of the left facial nerve. Due to concerns for possible lymphoma, a chest computed tomography (CT) was performed, which demonstrated mediastinal lymphadenopathy. Histopathology of a transbronchial hilar lymph node biopsy showed noncaseating granulomatous inflammation without organisms, consistent with sarcoidosis. Special stains for mycobacterial and fungal organisms were negative. At this time, a diagnosis of sarcoid granulomatosis secondary to TNFα inhibitor use was made. Treatment with 40 mg daily of oral prednisone was initiated with resolution of the patient's fever, headache, and left facial paresis.\n\nFigure 1 (a and b) Color fundus photograph of the right (a) and left (b) eyes demonstrating diffuse, well-circumscribed, round, yellow-white choroidal lesions in the posterior pole representing multifocal choroiditis\n\nFunduscopic examination 1 month after his admission and completion of a 2-week course of prednisone revealed the choroidal lesions to be more sharply demarcated, paler, and partly regressed from prior examination. Follow-up fluorescein angiography demonstrated diffuse, multifocal, hypofluorescent choroidal lesions without late staining, and no macular edema or vascular leakage [Figure 2a and b]. Rheumatologic evaluation with possible initiation of alternative immunosuppressive therapy was planned.\n\nFigure 2 (a and b) Mid-phase fluorescein angiography of the right (a) and left (b) eyes demonstrating many areas of well-circumscribed hypofluroescence in the posterior pole due to blockage from the choroidal lesions, including more numerous lesions in the macula than seen on ophthalmoscopy. There is notable absence of optic nerve edema, macular edema, or vascular leakage\n\nDISCUSSION\n\nWe describe a case of multifocal choroiditis with neurologic and pulmonary sarcoidosis developing in a patient treated with the TNFα inhibitor, adalimumab. Our patient presented with constitutional symptoms which prompted suspicion for an infectious etiology, given his chronic immunosuppression and recent travel to a TB-endemic area. The development of bilateral disseminated multifocal choroidal lesions with a seventh nerve palsy and worsening systemic symptoms in a patient on a TNFα inhibitor heightened suspicion of infection, especially a fungal or mycobacterial etiology. Chest radiography was normal; however, a chest CT was performed due to high suspicion, and hilar lymphadenopathy was seen. A subsequent endobronchial lymph node biopsy confirmed sarcoidosis, and the patient improved upon initiation of oral corticosteroids. Lymphoma and birdshot chorioretinopathy (BSC) are important masquerades for sarcoid-associated choroiditis; however, workup for lymphoma was negative and retinal imaging and examination did not support a diagnosis of BSC. Of interest, in this case, the sarcoidosis progressed to choroidal and neurologic involvement despite the cessation of adalimumab, suggesting that, once the sarcoid reaction develops, discontinuation of the TNFα inhibitor may not prevent the inflammatory reaction from advancing.\n\nAlthough adalimumab may be used itself as a treatment for sarcoidosis, it is also associated with the paradoxical development of sarcoidosis in patients being treated for other autoimmune disorders. TNFα inhibitor-associated sarcoidosis is a rare occurrence estimated to occur in 0.04% of patients on these agents.3 This immune response has been rarely associated with all classes of anti-TNFα, suggesting that the reaction occurs primarily due to dysregulation of the inflammatory cytokines.4 One review of the literature found that the most commonly reported inciting agent for paradoxical sarcoidosis was etanercept in 59% of cases, followed by adalimumab (23%) and infliximab (18%). Regarding uveitis, this review found that only 12/90 (13%) reports of paradoxical sarcoid reactions included intraocular inflammation.5 A recent review also indicates that etanercept is the agent most associated with paradoxical reaction, frequently in patients with concomitant spondyloarthritis.6 To our knowledge, this is the first report of diffuse multifocal choroidal infiltrates in this setting.\n\nThough rare, isolated descriptions of TNFα inhibitor-associated sarcoid uveitis exist with manifestations in all subtypes of uveitis.7 The mean time from TNFα inhibitors initiation to development of sarcoid-like granulomatosis is thought to be 18 months (range 1–51).3 Though this patient was on adalimumab for roughly 6 years, his rheumatologist stopped and re-started the medication while undergoing initial workup for infection, and therefore, this reaction developed in our patient a little more than 4 weeks after initiation. There are two prior reports of panuveitis that resolved with cessation of biologic therapy and initiation of high-dose oral steroids, like the course of our patient. The chorioretinal lesions in these cases, however, were restricted to the periphery.89 Another report of panuveitis was shown to partially resolve upon cessation of etanercept and completely resolve 10 months later after initiation of adalimumab.10 Interestingly, a similar report of response after switch from adalimumab to etanercept led to regression of bilateral anterior uveitis.3 These case reports suggest variable, patient-dependent immunogenicity to these agents related to a “class–effect” among various medications with anti-TNFα activity. One case of intermediate uveitis resolved with cessation of etanercept and initiation of the antimetabolite methotrexate.11 Our patient presented with obvious warning signs of systemic disease, which lead to highest suspicion of sarcoidosis, including unilateral facial nerve palsy. Only one case has been published to date of uveitis and facial nerve palsy in this context, and those authors reported resolution of anterior uveitis and systemic disease with cessation of the agent and initiation of high-dose corticosteroids and methotrexate.12 Based upon this case and other prior reports, patient-dependent–isolated cessation of treatment with adjuvant oral steroids, switching immunosuppression within the same class, or switching to an anti-metabolite medication are all reasonable options.\n\nUltimately, this case report demonstrates the importance of ophthalmic examination among patients with systemic disease and highlights the importance of including sarcoidosis in the differential diagnosis of multifocal choroiditis in patients treated with TNFα inhibitors. Conclusive evidence of the etiology of this paradoxical reaction is not yet available, and we may only make a putative hypothesis of an immune dysregulation among a select subset of patients. In addition, this case shows that the granulomatous lesions can regress with cessation of the TNFα inhibitor and the initiation of corticosteroid treatment. As the use of biologic agents increases, the incidence of adverse effects and secondary syndromes may also increase, and ophthalmologists should play an important role in the early diagnosis and management of these potentially fatal conditions.\n\nEthics approval and consent to participate\n\nPatient was consented and all pictures are anonymous in compliance with HIPAA standards. This report is in compliance with the Declaration of Helsinki.\n\nConsent for publication\n\nPatient was consented for publication of images and case description.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Lis K Kuzawińska O Bałkowiec-Iskra E Tumor necrosis factor inhibitors – State of knowledge Arch Med Sci 2014 10 1175 85 25624856\n2 Ramos-Casals M Brito-Zerón P Muñoz S Soria N Galiana D Bertolaccini L Autoimmune diseases induced by TNF-targeted therapies: Analysis of 233 cases Medicine (Baltimore) 2007 86 242 51 17632266\n3 Daïen CI Monnier A Claudepierre P Constantin A Eschard JP Houvenagel E Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases Rheumatology (Oxford) 2009 48 883 6 19423648\n4 Massara A Cavazzini L Corte RL Trotta F Sarcoidosis appearing during anti-tumor necrosis factor α therapy: A new “Class Effect” paradoxical phenomenon. Two case reports and literature review Sem Arthritis Rheum 2010 39 313 9\n5 Decock A Van Assche G Vermeire S Wuyts W Ferrante M Sarcoidosis-like lesions: Another Paradoxical Reaction to Anti-TNF Therapy? J Crohns Colitis 2017 11 378 83 27591675\n6 Nicolela Susanna F Pavesio C A review of ocular adverse events of biological anti-TNF drugs J Ophthalmic Inflamm Infect 2020 10 11 32337619\n7 Cunningham ET Jr Pasadhika S Suhler EB Zierhut M Drug-induced inflammation in patients on TNFα inhibitors Ocul Immunol Inflamm 2012 20 2 5 22324894\n8 Seve P Varron L Broussolle C Denis P Kodjikian L Sarcoid-related uveitis occurring during adalimumab therapy Ocul Immunol Inflamm 2012 20 59 60 22017197\n9 Moisseiev E Shulman S Certolizumab-induced uveitis: A case report and review of the literature Case Rep Ophthalmol 2014 5 54 9 24707273\n10 Dragnev D Barr D Kulshrestha M Shanmugalingam S Sarcoid panuveitis associated with etanercept treatment, resolving with adalimumab BMJ Case Rep 2013 2013 bcr2013200552\n11 Fonollosa A Artaraz J Les I Martinez-Berriotxoa A Izquierdo JP Lopez AS Sarcoid intermediate uveitis following etanercept treatment: A case report and review of the literature Ocul Immunol Inflamm 2012 20 44 8 22017171\n12 Durel CA Feurer E Pialat JB Berthoux E Chapurlat RD Confavreux CB Etanercept may induce neurosarcoidosis in a patient treated for rheumatoid arthritis BMC Neurol 2013 13 212 24373564\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2452-2325",
"issue": "33(2)",
"journal": "Journal of current ophthalmology",
"keywords": "Adalimumab; Drug reaction; Multifocal choroiditis; Sarcoidosis; Tumor necrosis factor alpha inhibitor; Uveitis",
"medline_ta": "J Curr Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101678509",
"other_id": null,
"pages": "205-208",
"pmc": null,
"pmid": "34409234",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "25624856;27591675;17632266;19147181;22017197;22324894;19423648;24373564;24707273;32337619;24005973;22017171",
"title": "Sarcoid-Associated Bilateral Multifocal Choroiditis Secondary to Adalimumab.",
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"abstract": "There are 525 drugs that have been identified by the World Health Organization (WHO) as having the potential to cause pancreatitis. The most well-known drugs include mesalamine, azathioprine, and simvastatin, all of which have been well described in the literature. However, drug-induced pancreatitis only used to account for about 1%-2% of cases in the 1990s; this number has increased to up to 5% in some studies. By accounting for over 100,000 cases per year in the United States alone, it is important to be able to recognize these cases and act rapidly and appropriately to remove the offending agent. The vast majority of cases occur within six weeks of initiating or increasing the dosage of such medications. Here we present an interesting case of meloxicam-induced pancreatitis.",
"affiliations": "Internal Medicine, Unity Health, Searcy, USA.;Internal Medicine, Unity Health, Searcy, USA.;Internal Medicine, Brooklyn Hospital, Brooklyn, USA.;Internal Medicine, Unity Health, Searcy, USA.;Internal Medicine, Unity Health, Searcy, USA.",
"authors": "Landa|Eric|E|;Ganim|Ismail|I|;Vigandt|Erika|E|;Siraj|Talhah|T|;Zhu|Ying|Y|",
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"doi": "10.7759/cureus.12976",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12976\nInternal Medicine\nMedical Education\nGastroenterology\nMeloxicam-Induced Pancreatitis\nMuacevic Alexander Adler John R Landa Eric 1 Ganim Ismail 1 Vigandt Erika 2 Siraj Talhah 1 Zhu Ying 1 \n1 \nInternal Medicine, Unity Health, Searcy, USA \n\n2 \nInternal Medicine, Brooklyn Hospital, Brooklyn, USA \n\nEric Landa erlanda21@hotmail.com\n28 1 2021 \n1 2021 \n13 1 e1297628 1 2021 Copyright © 2021, Landa et al.2021Landa et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/50652-meloxicam-induced-pancreatitisThere are 525 drugs that have been identified by the World Health Organization (WHO) as having the potential to cause pancreatitis. The most well-known drugs include mesalamine, azathioprine, and simvastatin, all of which have been well described in the literature. However, drug-induced pancreatitis only used to account for about 1%-2% of cases in the 1990s; this number has increased to up to 5% in some studies. By accounting for over 100,000 cases per year in the United States alone, it is important to be able to recognize these cases and act rapidly and appropriately to remove the offending agent. The vast majority of cases occur within six weeks of initiating or increasing the dosage of such medications. Here we present an interesting case of meloxicam-induced pancreatitis.\n\npancreaspancreatitismeloxicamgastrointestinaldrug induced pancreatitisThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nPancreatitis is the leading cause of gastrointestinal-related hospitalizations in the United States. Although the etiology may vary slightly depending on what part of the world you find yourself in, the top three causes include gallstone induced, alcohol intake, and hypertriglyceridemia. Other less common but important etiologies include trauma, medication-induced, and medical procedures such as endoscopic retrograde cholangiopancreatography (ERCP). There are well-documented cases of medication-induced pancreatitis even though the mechanism of action by which this occurs is not fully understood by a majority of them. In addition, some of these medications have not been well documented. To the best of our knowledge, the number of meloxicam-induced pancreatitis reports is few. Herein we report such a case.\n\nCase presentation\nA 59-year-old Caucasian male with a past medical history of diabetes mellitus type II presented to the emergency department complaining of abdominal pain. He reported the pain started three days prior after having finished eating his dinner; it started suddenly and was localized to his epigastrium with radiation to his back. He described the pain as sharp and constant, rated it a 9/10, and was associated with nausea and three episodes of non-bloody, non-bilious emesis. Moving seemed to make the pain worse and nothing made it better. He denied any fever, chills, changes in bowel movement. He also denied any previous similar episodes in the past. The pain became progressively worse through the days which is what made him come into the hospital. On admission, his vitals were stable and labs were remarkable for leukocytosis and elevated pancreatic enzymes (Table 1).\n\nTable 1 Laboratory values upon admission\n \tValues\tNormal Range\t\nWhite blood cell count\t29.6\t(4.8-10.8)\t\nLipase\t522\t(8-78)\t\nCalcium\t9.3\t(8.4-10.2)\t\nAST (Aspartate Aminotransferase)\t19\t(5-34)\t\nALT (Alanine Transaminase)\t26\t(11-55)\t\nTotal Bilirubin\t1.0\t(0.1-1.3)\t\nDirect Bilirubin\t0.5\t(0.0-0.4)\t\nAlkaline Phosphatase\t108\t(38-126)\t\nCholesterol\t120\t(130-200)\t\nTriglycerides \t78\t(10-150)\t\nLDL (low-density lipoprotein)\t67\t(83-210)\t\nCOVID-19 Antigen\tNegative\tNegative\t\nAn ultrasound of the abdomen was performed which showed a normal gallbladder without cholelithiasis and a lack of evaluation of the pancreas secondary to obscuration by overlying bowel gas. A computed tomography (CT) of the abdomen without contrast was then obtained which demonstrated diffuse peri-pancreatic stranding suggestive of acute pancreatitis (Figure 1).\n\nFigure 1 CT abdomen without contrast demonstrating diffuse peripancreatic stranding\nHe was subsequently made NPO, started on normal saline at 125 ml/hr, and given morphine 2 mg PRN Q4. After ruling out the main causes of pancreatitis and upon chart review of his medications, it was found that his meloxicam dose had just been doubled from 7.5 mg to 15 mg two weeks prior to presentation. Meloxicam was withheld during his hospital stay and discontinued upon discharge. Of note, the patient did spike a fever two nights in a row with some increase in his pain, both of which resolved on their own. But due to these events, a follow-up CT of the abdomen and pelvis was conducted which ruled out any complications such as fluid collection or pancreatic necrosis. The patient remained stable and was able to go home six days after admission. \n\nDiscussion\nWithin the field of gastroenterology, pancreatitis continues to maintain its position as one of the most common causes of hospitalizations secondary to a gastrointestinal disturbance in the developed world [1]. Pancreatitis is represented as inflammation of the pancreas through a specific path of physiologic mechanisms that cause the destruction of pancreatic acinar cells. Pancreatic acinar cell destruction may cascade into further inflammation secondary to activation of pro-inflammatory cell lines including granulocytes and macrophages. The physiology of pro-inflammatory cytokines depends on the acuity of pancreatitis. Pancreatitis typically is characterized as either chronic, acute, or acute on chronic [2]. In regards to this particular presentation, drug-induced pancreatitis usually presents as acute pancreatitis. In order to diagnose pancreatitis, several criteria must be met including two or more of the following: abdominal pain consistent with acute pancreatitis; this typically includes abdominal pain with radiation toward the back. The second criteria includes serum amylase and/or lipase which must be greater than three times the normal upper limit, the third criteria are suggestive findings seen on abdominal imaging such as pancreatic inflammation on abdominal CT scan.\n\nWithin the United States, the two most prevalent etiologies of acute pancreatitis are secondary to gallstones (which represented 35%-40% of cases), as well as ethanol (EtOH) use which represents approximately 30% of cases. Although these two factors account for the majority of cases, there is a plethora of other etiology such as hypertriglyceridemia, autoimmune pancreatitis, and drug-induced mechanism systems which may contribute to acute pancreatitis [3]. This particular case presentation represents acute pancreatitis secondary to a drug-induced mechanism. In order to diagnose drug-induced pancreatitis, the clinician must rule out all other etiologies which may contribute to pancreatitis including the mentioned gallstones, elevated triglycerides, and alcohol abuse. Then, a thorough review of the patient's lifestyle and medications must be achieved to observe for any particular inciting factors. This particular patient was noted to be taking meloxicam which was recently increased in dosage two weeks prior to presentation. This suspicious increase of the dosage of this nonsteroidal anti-inflammatory drug (NSAID) in combination with the lack of other known inciting etiologies which may contribute to pancreatitis helped determine that a drug-induced mechanism was likely the etiology. Although the mechanism to explain why NSAIDs may be implicated in acute pancreatitis has not been thoroughly confirmed, there has been speculation that NSAIDs may cause a lack of appropriate response directed against oxidative stress secondary to a reduction in systemic glutathione that results from decreased superoxide dismutase activity, as well as a possible destabilization effect of the NSAID on the pancreatic cell membrane secondary to their effects on prostaglandins [4]. A direct hypersensitivity and/or immune-mediated response directly from the NSAID in a particular individual who developed drug-induced pancreatitis cannot be completely ruled out [5].\n\nThe best treatment approach in these particular individuals is early identification of the pancreatitis and prompt discontinuation of the offending agent in order to mitigate the deleterious effects of continuous pancreatic inflammation [6]. Typically, drug-induced pancreatitis improves upon cessation of the offending agent, this leads to decreased morbidity and mortality from advanced pancreatitis including the possibility of developing a pancreatic pseudocyst, chronic pancreatitis as well necrotizing pancreatitis [7]. For these reasons, it is crucial to keep a high index of clinical suspicion for drug-induced etiologies when evaluating a patient with pancreatitis in whom all other common scenarios have been ruled out.\n\nConclusions\nThough not uncommon, we are starting to see more and more cases of drug-induced pancreatitis across the world. Although physicians might not think about such an etiology right away, it is important to keep it in mind and do a thorough review of the patient's medications. We present this case in order to bring attention to an important etiology that might not be very obvious at first.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n1 Evaluation and management of acute pancreatitis World J Clin Cases Chatila AT Bilal M Guturu P 1006 1020 7 2019 31123673 \n2 Pathogenic mechanisms of pancreatitis World J Gastrointest Pharmacol Ther Manohar M Verma AK Venkateshaiah SU Sanders NL Mishra A 10 25 8 2017 28217371 \n3 Pancreatitis Mohy-ud-din N Morrissey S Treasure Island (FL) StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK538337/ \n4 Non-steroidal anti-inflammatory drug-induced acute pancreatitis: a case report Cureus Reyes JV Patel BM Malik F Gonzalez MO 0 11 2019 \n5 Drug-induced pancreatitis: a potentially serious and underreported problem P T Kaufman MB 349 38 2013 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737994/ 23946630 \n6 Drug-induced acute pancreatitis: a review Ochsner J Jones MR Hall OM Kaye AM Kaye AD 45 51 15 2015 http://www.ochsnerjournal.org/content/15/1/45.abstract 25829880 \n7 Drug-induced necrotizing pancreatitis with a focus on canagliflozin Am J Ther Patel KM Pikas E George T 0 24 2017\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(1)",
"journal": "Cureus",
"keywords": "drug induced pancreatitis; gastrointestinal; meloxicam; pancreas; pancreatitis",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pages": "e12976",
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"pmid": "33654637",
"pubdate": "2021-01-28",
"publication_types": "D002363:Case Reports",
"references": "25829880;31788383;28217371;28639964;31123673;23946630",
"title": "Meloxicam-Induced Pancreatitis.",
"title_normalized": "meloxicam induced pancreatitis"
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"abstract": "Wilson's disease can have varied clinical manifestations and initial presentation can be misleading as in our case. Our case depicts the necessity of suspicion of WD in variable presentation of liver disorders, especially in pediatrics population.",
"affiliations": "Nepalese Army Institute of Health Sciences College of Medicine Kathmandu Nepal.;Nepalese Army Institute of Health Sciences College of Medicine Kathmandu Nepal.;Department of Pediatrics Shree Birendra Hospital Kathmandu Nepal.;Department of Pediatrics Shree Birendra Hospital Kathmandu Nepal.",
"authors": "Malbul|Kiran|K|https://orcid.org/0000-0002-1690-2629;Katwal|Srijana|S|https://orcid.org/0000-0003-1644-2666;Khetan|Saurav|S|;Aryal|Nirjala|N|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4178\nCCR34178\nCase Report\nCase Reports\nA case report on serendipitous diagnosis of wilson’s disease in a child with brucellosis and pseudomonal infection\nMALBUL et al.\nMalbul Kiran https://orcid.org/0000-0002-1690-2629\n1 kiran.malbul04@naihs.edu.np\n\nKatwal Srijana https://orcid.org/0000-0003-1644-2666\n1\nKhetan Saurav 2\nAryal Nirjala 2\n1 Nepalese Army Institute of Health Sciences College of Medicine Kathmandu Nepal\n2 Department of Pediatrics Shree Birendra Hospital Kathmandu Nepal\n* Correspondence\nKiran Malbul, Nepalese Army Institute of Health Sciences College of Medicine, Sanobharyang, Kathmandu, Nepal.\nEmail: kiran.malbul04@naihs.edu.np\n\n06 5 2021\n6 2021\n9 6 10.1002/ccr3.v9.6 e0417828 3 2021\n25 10 2020\n31 3 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nWilson's disease can have varied clinical manifestations and initial presentation can be misleading as in our case. Our case depicts the necessity of suspicion of WD in variable presentation of liver disorders, especially in pediatrics population.\n\nWilson's disease can have varied clinical manifestations and initial presentation can be misleading as in our case. Our case depicts the necessity of suspicion of WD in variable presentation of liver disorders, especially in pediatrics population.\n\n\n\nbrucellosis\ncoinfection\nD‐penicillamine\npediatric\nrifampin\nwilson's disease\nsource-schema-version-number2.0\ncover-dateJune 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.06.2021\nMalbul K , Katwal S , Khetan S , Aryal N . A case report on serendipitous diagnosis of wilson’s disease in a child with brucellosis and pseudomonal infection. Clin Case Rep. 2021;9 :e04178. 10.1002/ccr3.4178\n==== Body\n1 INTRODUCTION\n\nWilson's disease (WD) is a rare inherited autosomal recessive genetic defect of the copper metabolism. It frequently leads to progressive hepatolenticular degeneration and characterized mainly by hepatic and neurological manifestations. 1 The prevalence is approximately one case per 30,000 live births 2 with estimated high prevalence in the East Asian region. 3 There is a mutation in ATP7B gene that encodes a copper transport protein on chromosome 13 4 , 5 leading to accumulation of copper into different tissues, 1 resulting in various clinical manifestations predominantly hepatic, neurological, and psychiatric with at times the presence of Kayser‐Fleischer (KF) rings on the cornea, patients often present with a combination of symptoms. 6 , 7 , 8 Early clinical features are nonspecific and sometimes maybe misleading in establishing a definitive diagnosis especially in younger patients and with concurrent other infections. Therefore, in young patients with unclear liver disease, hematologic or neurologic disorders, a differential diagnosis of Wilson's disease must be excluded. 6 We report a case of Wilson's disease in a 9 year‐old girl presented initially with fever and progressive yellowish discoloration of the body, later confirmed to be having acute on chronic hepatic Wilson's disease with brucellosis and culture‐positive Pseudomonas infection and also illustrate the complexity of diagnosing Wilson's disease in the early stages of a clinical course complicated with infection.\n\n2 CASE PRESENTATION\n\nA 9 year‐old girl was admitted to this hospital for evaluation of fever and jaundice. Two days before this admission, the patient was taken to a local hospital where she was found to have severe anemia with a hemoglobin of 3.4 gm/dl. She was suspected and worked up on the line of hemolytic condition for which two units of packed RBCs were transfused, and she was referred to our center for further evaluation.\n\nThe patient had been in her usual state of health until 10 days before this admission, when she was noted to have intermittent fever with chills and rigor, maximum documented being 38.9°C, yellowish discoloration of skin, and dark‐colored urine. She also had right upper abdominal pain but no nausea, vomiting, hematemesis, hemoptysis, pruritus, passage of clay‐/dark‐colored stool, skin rashes, or joint pain.\n\nThe patient had been delivered vaginally at full term. Subsequent growth and development were reportedly normal, and her immunizations were up to date. She had no known medical conditions, was not taking any medications, and had no known allergies to medications. She lived in a family with no history of consanguinity, and they were involved in cattle rearing.\n\nOn examination, she was ill appearing and appeared tired. The temperature was 38.3°C, the heart rate 92 per minute, the blood pressure 90/60 mmHg, the respiratory rate 22 per minute, and the oxygen saturation 98% while breathing ambient air. The weight was 26 kg (25.78th percentile), and height was 134 cm (55.5th percentile). She had conjunctival icterus and pallor but no clubbing, palmar erythema, cyanosis, lymphadenopathy, and edema. The lungs were clear on auscultation. The abdomen was soft, with mild right upper quadrant tenderness, and liver was palpable 6 cm below the coastal margin with a span of 14 cm. Abdominal guarding, rebound tenderness, and Murphy's sign were absent. The spleen tip was palpated one cm below the left coastal margin. There was no fluid thrill or shifting dullness. The skin examination revealed no lesions, rash, abnormal pigmentation, or abnormality of the nails. She was alert and oriented and followed commands. The remainder of the examination was normal.\n\n3 INVESTIGATIONS\n\nRoutine laboratory testing obtained 2 days after original blood transfusion revealed a hemoglobin of 8.2 gm/dl, total bilirubin of 16.3 mg/dl, prothrombin time of 18.3 seconds, and activated partial thromboplastin time (aPTT) of 65 seconds. Blood levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, and albumin were normal. A direct Coombs test was positive, and tests for hepatitis A, B, and C viruses were negative. Remainder of the laboratory test results are shown in (Table 1). Ultrasound of abdomen revealed an enlarged liver with coarse echotexture, mild splenomegaly, and minimal ascites (Figure 1). Intravenous fluids and empiric antibiotics were started for fever, jaundice, and abdominal pain of unknown causation.\n\nTABLE 1 Clinical laboratory results\n\nLaboratory investigations\tIllness Day 10, Hospital Day 1\n\n\tIllness Day 12, Hospital Day 3\n\n\tIllness Day 14, Hospital Day 5\n\n\tIllness Day 19, Hospital Day 10\n\n\tIllness Day 23, Hospital Day 14\n\n(rifampin withdrawn)\n\n\tIllness Day 26, Hospital Day 17\n\n\tIllness Day 32, Hospital Day 23\n\n(D‐penicillamine started)\n\n\tIllness Day 49, Hospital Day 40\n\n\tReference range\t\nWhite blood cell count (cells/μl)\t7000\t7400\t8100\t8600\t9500\t6700\t4300\t6020\t4500‐11000\t\nHemoglobin (g/dl)\t8.2↓\t7.5↓\t8.4↓\t9.5↓\t10↓\t9.9↓\t9.6↓\t11\t11.5‐15.5\t\nBilirubin, total (mg/dl)\t16.3↑\t2.1↑\t2.17↑\t2.77↑\t5.13↑\t2.91↑\t1.92↑\t1.3↑\t0.2‐1.0\t\nBilirubin, conjugated (mg/dl)\t6.9↑\t1.1↑\t1.4↑\t1.88↑\t3.27↑\t1.82↑\t1.13↑\t0.5↑\t<0.35\t\nAspartate aminotransferase (U/L)\t28\t76↑\t75↑\t86.6↑\t336↑\t263↑\t113↑\t60↑\t15‐40\t\nAlanine aminotransferase (U/L)\t25\t52↑\t64↑\t68.7↑\t237↑\t205↑\t89↑\t40↑\t10‐36\t\nAlkaline phosphatase (U/L)\t29↓\t53\t57\t117.2\t158↑\t130↑\t137↑\t114\t30‐120\t\nProthrombin time (sec)\t18.3↑\t20↑\t24.6↑\t26.4↑\t28.3↑\t36.1↑\t40↑\t22↑\t12.2‐15.5\t\nInternational normalized ratio\t1.2\t1.4↑\t1.6↑\t1.8↑\t1.9↑\t2.3↑\t2.6↑\t1.5↑\t0.8‐1.2\t\nPlatelet count (/mm3)\t249 × 103\t191 × 103\t200 × 103\t240 × 103\t320 × 103\t300 × 103\t343 × 103\t182 × 103\t150‐450 × 103\t\nActivated partial thromboplastin time (sec)\t65↑\t63↑\t68↑\t70↑\t73.6↑\t53.5↑\t86↑\t63.3↑\t26.5‐35.5\t\nNote\n\n↑ The value in the patient was above normal reference range.↓ The value in the patient was below normal reference range.\n\nJohn Wiley & Sons, Ltd\n\nFIGURE 1 Ultrasonography showing hepatomegaly with coarse echotexture as compared to renal cortex\n\nOn day three of admission, Brucella serology was reported to be high at 1:160 (significant titer >=1:80) and blood culture grew Pseudomonas aeruginosa. At that moment, her AST was 76 U/L, ALT 52 U/L, and total bilirubin 2.1 mg/dl. The PT and aPTT were also elevated at 20 seconds and 63 seconds, respectively. Antibiotics were switched to cefepime, doxycycline, and rifampin. On day five of admission, she was transfused with another two units of packed RBC for a hemoglobin of 8.4 gm/dl. Total bilirubin decreased briefly after starting antibiotics but later on liver function continued to worsen with rising total bilirubin, indirect bilirubin, transaminases, and PT/INR. Because of worsening liver function, rifampin was discontinued on day fourteen of admission.\n\nOn day twenty second of admission, serum ceruloplasmin was found to be low at 9.18 mg/dl (reference range, 23‐51 mg/dl). The urinary copper excretion was elevated at 2069 microgram/day (reference range, 3‐50 microgram/day). Eye examination did not reveal KF ring. Results of ANA (Anti‐Nuclear Antibody) and anti‐dsDNA (double‐stranded deoxyribonucleic acid) were unremarkable. A diagnosis of Wilson's disease was made based on low ceruloplasmin and high urinary copper excretion, and she was started on D‐penicillamine at 20 mg/kg/day along with zinc and pyridoxine. Subsequent Fibroscan showed a fibrosis score of 24.4 kPa suggestive of advanced liver scarring (Figure 2). Following treatment with D‐penicillamine, liver function continued to improve, and she was discharged on day 40.\n\nFIGURE 2 Fibroscan of liver showing advanced liver scarring\n\n4 OUTCOME AND FOLLOW‐UP\n\nPatient's clinical conditions improved with normalization of laboratory parameters mainly liver function tests. Subsequently, she was discharged with medical therapy with a plan to follow up after 3 months. They were counseled on nature of this disease, dietary restrictions, importance of extra vaccination, and side effects of the medications. Parents were advised for laboratory and genetic screening; however, they refused because of economical constraint, though they were screened for KF rings which were absent.\n\n5 DISCUSSION\n\nWilson's disease is a rare autosomal recessive disorder usually presenting as early as 3 years to as late as 55 years of age 9 and has varied clinical manifestations ranging from asymptomatic to hepatic, neurological, psychiatric, hematological, and ophthalmological symptoms. 1 , 8 , 9 Given this wide variability in presentation, diagnosis of Wilson's disease can be challenging.\n\nChildren with Wilson's disease are usually normal at birth and may remain for a variable period of time. 10 , 11 Given defective protein resulting from ATPB7 gene mutation, copper transport across hepatocytes and subsequent biliary excretion becomes impaired. 4 This leads to progressive copper accumulation within the hepatocytes, eventually exceeding hepatic storage capacity resulting in spillage of copper out of liver into the circulation which then gets gradually deposited in extrahepatic tissues like brain and Descemet's membrane of cornea. 12 , 13 Thus, liver manifestations are more common in first decade of life whereas neurological manifestations are common in third decades. 1 , 14 Liver is presumed to have considerable capacity to store excess copper, hence clinical manifestations are barely observed before 3 years of age. 9 , 15 Data from numerous pediatric series have shown 9–10 years as the average age of diagnosis of the disease. 7\n\nNot all cases of Wilson's disease have KF ring or present with typical hepatic, neurological, and psychiatric manifestations. Various studies have suggested that clinical and laboratory parameters only are not sufficient to make a diagnosis of Wilson's disease in patients with liver disease of unknown origin. 9 , 13 , 16 In a series of cases studied by Nina Manolakit et al (2009), out of 57 cases, 25% presented with jaundice, 12% with acute Coombs negative hemolytic anemia, and only 38% of patient had KF ring. 17 Similarly in a study done by Steindl et al (1997), out of 55 cases, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. KF rings were detected only in 55% of cases. In contrast to patients with neurological disease (90% KF rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. 16\n\nIn some cases, Wilson's disease becomes an incidental finding being discovered during work‐up of other health issues like infections. 7 Our patient presented with acute onset of fever, jaundice, right upper quadrant abdominal pain and was found to have hepatosplenomegaly on physical exam. Initial laboratory work was positive for DCT negative hemolytic anemia, Pseudomonas bacteremia, and positive Brucella serology. Exposure to milked animals including a bovine calf raised the suspicion of Brucellosis whereas source of Pseudomonas bacteremia was not entirely clear. Nevertheless, she was treated with antibiotics targeting both Brucella and Pseudomonas, following which she defervesced, icterus diminished but she experienced few episodes of nausea, vomiting, and loss of appetite in between. Liver function continued to get worse despite appropriate antibiotic treatment which raised the possibility of other causes of liver failure including autoimmune liver disease and Wilson's disease. Based on a low serum ceruloplasmin and high urinary copper excretion, diagnosis of Wilson's disease was established and improvement of liver function test following treatment with D‐penicillamine and zinc gave further credence to the diagnosis of Wilson's disease. Similar therapeutic response has been reported in the study done by Chaudhari S et al wherein 45 out of 50 cases showed satisfactory response to D‐ penicillamine and zinc therapy. 14\n\nIn children, hemolysis may be an initial presentation of Wilson's disease which might apparently get precipitated by infections or drugs and mostly is transient and self‐limiting, resulting in brief episodes of jaundice. 7 Our patient might have been in latent phase of Wilson's disease till she got infected with brucellosis. The infection might have triggered DCT negative hemolytic anemia resulting in progressive jaundice, and antibiotics treatment might have initially lowered the severity of hemolysis leading to apparent decrease in initial bilirubin but later worsening of liver function test could have been from use of hepatotoxic drugs like doxycycline 18 , 19 and rifampin. 20 , 21 She had significant fibrosis of liver on Fibroscan suggestive of chronic liver damage and was likely more susceptible to hepatotoxic effect of medications. She had no neurological symptoms, and KF rings were also absent. This is in accordance with the study done by Kalamar et al where a patient presented with hepatic lesions but did not have KF ring and neurological manifestations. 22\n\nA positive family history, detectable KF rings, low ceruloplasmin level (<20mcg/dL), elevated free copper >25 mcg/dL, and 24 hours urine copper >100 mcg/24 hours are some parameters which can help to make a diagnosis of Wilson's disease. 23 Hepatic copper concentration and ATP7B gene sequencing are the gold standard tests for definitive diagnosis of Wilson's disease. 24 However, diagnosis is mainly based on combination of clinical features, laboratory results, and mutation analysis. 13 , 17 Scoring systems like modified Leipzig score can be useful in patients presenting with liver disease with inconclusive diagnosis where a cumulative score of four or above establishes the diagnosis of Wilson's disease. 8 Findings suggestive of chronic liver inflammation on ultrasound abdomen and Fibroscan along with a score of five on modified Leipzig score strongly suggested the diagnosis of Wilson's disease. 25 , 26 , 27 Ultrasound and Fibroscan findings, however, need to be interpreted with caution. Ultrasound of liver can be useful in differentiating acute hepatitis from chronic one as an irregular liver capsule, and coarse echotexture may suggest chronic liver disease, as opposed to acute severe hepatitis. Noninvasive tests like Fibroscan assessing the degree of liver scarring can be a reliable method of detecting liver fibrosis and thereby helping to differentiate acute and chronic hepatitis but accuracy of such scan in pediatric population with age less than 12 years remains uncertain.\n\n6 CONCLUSION\n\nIn summary, Wilson's disease is a treatable disease which needs clinical focus with combined investigations to diagnose it on time and prevent mortality and morbidity from it, especially in pediatrics population with variable presentation of liver disorders. It also encourages us to be more cautious in using hepatotoxic medications in cases of diagnosed or suspected liver disorders like Wilson's disease.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nKiran Malbul and Srijana Katwal were involved in conception of the study, acquisition of data, drafting and reshaping the initial manuscript, and revising the contents.\n\nSaurav Khetan was involved in acquisition of data and reshaping the manuscript whereas Nirjala Aryal helped in revising the manuscript critically for important intellectual content.\n\nAll authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nETHICAL APPROVAL\n\nNeed for ethical approval waived. Consent from the patient's parents deemed to be enough.\n\nINFORMED CONSENT\n\nWritten informed consent was taken from the patient's parents before writing the manuscript.\n\nACKNOWLDGMENTS\n\nWe would like to acknowledge Dr Udip Dahal and Dr Nischinta Thapa for their support and revising the manuscript for important intellectual content.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 Ala A , Walker AP , Ashkan K , Dooley JS , Schilsky ML . Wilson's disease. Lancet. 2007;369 (9559 ):397‐408. 10.1016/S0140-6736(07)60196-2.17276780\n2 Gollan JL , Gollan TJ . Wilson disease in 1998: genetic, diagnostic and therapeutic aspects. J Hepatol. 1998;28 (Suppl 1 ):28‐36. 10.1016/s0168-8278(98)80373-5.9575447\n3 Sandahl TD , Ott P . Epidemiology of Wilson Disease. In: Weiss KH Schilsky MBT‐WD ed. Academic Press; 2019:85‐94. 10.1016/B978-0-12-811077-5.00007-4.\n4 Bull PC , Thomas GR , Rommens JM , Forbes JR , Cox DW . The Wilson disease gene is a putative copper transporting P‐type ATPase similar to the Menkes gene. Nat Genet. 1993;5 (4 ):327‐337. 10.1038/ng1293-327.8298639\n5 Roberts EA , Schilsky ML . Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47 (6 ):2089‐2111. 10.1002/hep.22261.18506894\n6 Stremmel W , Meyerrose K‐W , Niederau C , Hefter H , Kreuzpaintner G , Strohmeyer G . Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115 (9 ):720‐726. 10.7326/0003-4819-115-9-720.1929042\n7 Roberts EA , Socha P . Wilson disease in children. Handb Clin Neurol. 2017;142 :141‐156. 10.1016/B978-0-444-63625-6.00012-4.28433098\n8 Nagral A , Sarma MS , Matthai J , et al. Wilson's disease: clinical practice guidelines of the Indian national association for study of the liver, the Indian society of pediatric gastroenterology, hepatology and nutrition, and the movement disorders society of India. J Clin Exp Hepatol. 2019;9 (1 ):74‐98. 10.1016/j.jceh.2018.08.009.30765941\n9 Gitlin JD , EASL clinical practice guidelines: wilson's disease. J Hepatol. 2012;56 (3 ):671‐685. 10.1016/j.jhep.2011.11.007.22340672\n10 Esezobor CI , Banjoko N , Rotimi‐Samuel A , Lesi FEA . Wilson disease in a Nigerian child: a case report. J Med Case Rep. 2012;6 (1 ):200. 10.1186/1752-1947-6-200.22800610\n11 Saito T . Presenting symptoms and natural history of wilson disease. Eur J Pediatr. 1987;146 (3 ):261‐265. 10.1007/BF00716470.3595645\n12 Report C , Kaur H , Kaur K , Sharma N , Kumar K . Wilson's disease ‐ a case report. Int J Contemp Med Res. 2019;6 (7 ):G42‐G44.\n13 Ferenci P , Caca K , Loudianos G , et al. Diagnosis and phenotypic classification of wilson disease1. Liver Int. 2003;23 (3 ):139‐142. 10.1034/j.1600-0676.2003.00824.x.12955875\n14 Chaudhuri S . Wilson's disease in children – experience from a tertiary care centre. J Med Sci Clin Res. 2018;06 (06 ):170‐174. 10.18535/jmscr/v6i6.29.\n15 Walshe JM Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty‐seven patients. Q J Med. 1989;70 (3 ):253‐263. 10.1093/oxfordjournals.qjmed.a068320.2602537\n16 Steindl P , Ferenci P , Dienes HP , et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology. 1997;113 (1 ):212‐218. 10.1016/s0016-5085(97)70097-0.9207280\n17 Manolaki N , Nikolopoulou G , Daikos G , et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr. 2009;48 :72‐77. 10.1097/MPG.0b013e31817d80b8.19172127\n18 Lienart F , Morissens F , Jacobs P , Ducobu J . Doxycycline and Hepatotoxicity. Acta Clin Belg. 1992;47 (3 ):205‐208. 10.1080/17843286.1992.11718230.1332350\n19 Heaton PC , Fenwick SR , Brewer DE . Association between tetracycline or doxycycline and hepatotoxicity: a population based case‐control study. J Clin Pharm Ther. 2007;32 (5 ):483‐487. 10.1111/j.1365-2710.2007.00853.x.17875115\n20 Ichai P , Saliba F , Antoun F , et al. Acute liver failure due to antitubercular therapy: strategy for antitubercular treatment before and after liver transplantation. Liver Transpl. 2010;16 (10 ):1136‐1146. 10.1002/lt.22125.20879012\n21 Centers for Disease Control and Prevention (CDC) . Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection‐‐New York and Georgia, 2000. MMWR Morb Mortal Wkly Rep. 2001;50 (15 ):289‐291.11330495\n22 Kalamar V . Childhood Onset of Wilson's Disease A Case Report. Published online. 2014. https://urn.nsk.hr/urn:nbn:hr:105:142560.\n23 de Sócio SA , Ferreira AR , Fagundes EDT , et al. Wilson's disease in children and adolescents: diagnosis and treatment. Rev Paul Pediatr. 2010;28 :134‐140.\n24 Bennett J , Hahn SH . Clinical molecular diagnosis of Wilson disease. Semin Liver Dis. 2011;31 (3 ):233‐238. 10.1055/s-0031-1286054.21901653\n25 de Lédinghen V , Le Bail B , Rebouissoux L . et al., Liver stiffness measurement in children using fibroScan: Feasibility study and comparison with fibrotest, aspartate transaminase to platelets ratio index, and liver biopsy. Journal of Pediatric Gastroenterology & Nutrition. 2007;45 (4 ):443‐450. 10.1097/mpg.0b013e31812e56ff.18030211\n26 Stefanescu AC , Pop TL , Stefanescu H , Miu N . Transient elastography of the liver in children with Wilson's disease: Preliminary results. Journal of Clinical Ultrasound. 2016;44 (2 ):65‐71. 10.1002/jcu.22281.26177868\n27 Behairy BE , Sira MM , Zalata KR , Salama EE , Abd‐Allah MA . Transient elastography compared to liver biopsy and morphometry for predicting fibrosis in pediatric chronic liver disease: Does etiology matter? World Journal of Gastroenterology. 2016;22 (16 ):4238. 10.3748/wjg.v22.i16.4238.27122674\n\n",
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"keywords": "D‐penicillamine; brucellosis; coinfection; pediatric; rifampin; wilson's disease",
"medline_ta": "Clin Case Rep",
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"title": "A case report on serendipitous diagnosis of wilson's disease in a child with brucellosis and pseudomonal infection.",
"title_normalized": "a case report on serendipitous diagnosis of wilson s disease in a child with brucellosis and pseudomonal infection"
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"abstract": "BACKGROUND\nMany central nervous system disorders result in hypothalamic-pituitary (HP) axis dysfunction. Alternating Hemiplegia of Childhood (AHC) is usually caused by mutations in the ATP1A3 subunit of the Na+/K+ ATPase, predominantly affecting GABAergic interneurons. GABAergic interneurons and the ATP1A3 subunit are both important for function of the hypothalamus. However, whether HP dysfunction occurs in AHC and, if so, how such dysfunction manifests remains to be investigated.\n\n\nMETHODS\nWe conducted a retrospective review of a cohort of 50 consecutive AHC patients for occurrence of HP related manifestations and analyzed the findings of the 6 patients, from that cohort, with such manifestations.\n\n\nRESULTS\nSix out of 50 AHC patients manifested HP dysfunction. Three of these patients were mutation positive and 3 were mutation negative. Of the 6 patients with HP dysfunction, 3 had central precocious puberty. A fourth had short stature due to growth hormone deficiency. Two other patients had recurrent episodes of fever of unknown origin (FUO) diagnosed, after workups, as being secondary to central fever. All patients were evaluated and co-managed by pediatric neurology and endocrinology or rheumatology.\n\n\nCONCLUSIONS\nAHC was associated with HP dysfunction in about 12% of patients. Awareness of such dysfunction is important for anticipatory guidance and management particularly in the case of FUO which often presents a diagnostic dilemma. Our findings are also consistent with current understandings of the underlying pathophysiology of AHC and of the HP axis.",
"affiliations": "Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, 2301 Erwin Rd, Durham, NC, 27710, USA. Electronic address: keri.register@duke.edu.;Division of Pediatric Endocrinology, Duke Children's Health Center, 2301 Erwin Rd, Durham, NC, 27710, USA. Electronic address: elizabeth.greene@duke.edu.;Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, 2301 Erwin Rd, Durham, NC, 27710, USA. Electronic address: mary.mendez@duke.edu.;Division of Pediatric Endocrinology, Duke Children's Health Center, 2301 Erwin Rd, Durham, NC, 27710, USA. Electronic address: michael.freemark@duke.edu.;Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, 2301 Erwin Rd, Durham, NC, 27710, USA. Electronic address: lyndsey.prange@duke.edu.;Division of Pediatric Neurology and Developmental Medicine, Duke Children's Health Center, 2301 Erwin Rd, Durham, NC, 27710, USA. Electronic address: mohamad.mikati@duke.edu.",
"authors": "Wallace|Keri|K|;Greene|Elizabeth|E|;Moya-Mendez|Mary|M|;Freemark|Michael|M|;Prange|Lyndsey|L|;Mikati|Mohamad A|MA|",
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"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Alternating hemiplegia of childhood; Fever of unknown origin; Growth hormone deficiency; Hypothalamus; Precocious puberty",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D006429:Hemiplegia; D006801:Humans; D007027:Hypothalamic Diseases; D007030:Hypothalamo-Hypophyseal System; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055815:Young Adult",
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"pages": "1-7",
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"pmid": "33756210",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypothalamic-pituitary dysfunction in alternating hemiplegia of childhood.",
"title_normalized": "hypothalamic pituitary dysfunction in alternating hemiplegia of childhood"
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"abstract": "Posterior reversible encephalopathy syndrome (PRES) is a rare reversible neurological syndrome that causes subcortical vasogenic brain edema and which is associated with the use of target-specific agents. Lenvatinib is a target-specific agent that was recently approved for inoperable thyroid cancer. We herein describe the case of a 66-year-old woman with anaplastic thyroid cancer (ATC) who was treated with lenvatinib and who subsequently developed PRES. The clinical and radiological findings improved after suspending therapy for 1 week, and there was no recurrence with intermittent lower-dose lenvatinib treatment. Lenvatinib may prolong survival in patients with ATC and can be administered intermittently, even after PRES onset.",
"affiliations": "Department of Otorhinolaryngology, Fukui Red Cross Hospital, Japan.;Department of Otorhinolaryngology, Fukui Red Cross Hospital, Japan.;Department of Otorhinolaryngology, Fukui Red Cross Hospital, Japan.;Department of Neurology, Fukui Red Cross Hospital, Japan.;Department of Radiology, Fukui Red Cross Hospital, Japan.;Department of Otorhinolaryngology, Fukui Red Cross Hospital, Japan.",
"authors": "Osawa|Yoko|Y|;Gozawa|Rikako|R|;Koyama|Keisuke|K|;Nakayama|Takeo|T|;Sagoh|Tadashi|T|;Sunaga|Hiroshi|H|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011804:Quinolines; C531958:lenvatinib",
"country": "Japan",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2922526510.2169/internalmedicine.9593-17Case ReportPosterior Reversible Encephalopathy Syndrome after Lenvatinib Therapy in a Patient with Anaplastic Thyroid Carcinoma Osawa Yoko 1Gozawa Rikako 1Koyama Keisuke 1Nakayama Takeo 2Sagoh Tadashi 3Sunaga Hiroshi 1\n1 Department of Otorhinolaryngology, Fukui Red Cross Hospital, Japan\n2 Department of Neurology, Fukui Red Cross Hospital, Japan\n3 Department of Radiology, Fukui Red Cross Hospital, JapanCorrespondence to Dr. Yoko Osawa, oosawa@fukui-med.jrc.or.jp\n\n8 12 2017 1 4 2018 57 7 1015 1019 29 5 2017 27 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Posterior reversible encephalopathy syndrome (PRES) is a rare reversible neurological syndrome that causes subcortical vasogenic brain edema and which is associated with the use of target-specific agents. Lenvatinib is a target-specific agent that was recently approved for inoperable thyroid cancer. We herein describe the case of a 66-year-old woman with anaplastic thyroid cancer (ATC) who was treated with lenvatinib and who subsequently developed PRES. The clinical and radiological findings improved after suspending therapy for 1 week, and there was no recurrence with intermittent lower-dose lenvatinib treatment. Lenvatinib may prolong survival in patients with ATC and can be administered intermittently, even after PRES onset. \n\nanaplastic thyroid carcinomalenvatinibposterior reversible encephalopathy syndrometyrosine kinase inhibitor\n==== Body\nIntroduction\nAnaplastic thyroid cancer (ATC) represents approximately 2% of all thyroid tumors; the outcome is almost always fatal. The treatment of ATC has not been standardized as most patients die within 6 months of the diagnosis, primarily due to asphyxiation caused by local tumor invasion (1-3). Lenvatinib is a tyrosine kinase inhibitor (TKI) that inhibits the vascular endothelial growth factor receptors and platelet-derived growth factor receptors, leading to the inhibition of tumor angiogenesis (4, 5). In 2015, lenvatinib was approved for the treatment of inoperable thyroid cancer in Japan. Lenvatinib therapy can prolong the survival of patients with ATC for 1 year or more (6). Lenvatinib therapy is associated mild side effects; however, adverse events including hypertension, bleeding, arterial thrombosis embolism, vein thrombus embolism, hepatopathy, nephropathy, gastrointestinal perforation and fistulation, posterior reversible encephalopathy syndrome, cardiac disorder, hand-foot syndrome, infectious disease, myelosuppression, hypocalcemia, delayed wound healing, diarrhea, and fatigue have been reported (7).\n\nPosterior reversible encephalopathy syndrome (PRES) was first described by Hinchey et al. in 1996; PRES is a reversible clinical-radiological syndrome that is characterized by the acute onset of headache, nausea, dizziness, changes in consciousness, convulsions, transient visual disturbances such as cortical blindness, and white matter edema mainly localized to the occipital-parietal lobe (8). PRES can be caused by hypertension, immunosuppressant use, exposure to cytotoxic agents, and the use of molecular target-specific agents; however, the exact cause of PRES is unknown (9). The present report describes the case of a patient with ATC and papillary thyroid cancer who received a total thyroidectomy and right neck dissection followed by lenvatinib treatment for inoperable ATC and subsequently developed PRES.\n\nCase Report\nThe patient, a 66-year-old woman, provided her written informed consent for treatment. She had undergone a total thyroidectomy and right conservative neck dissection to treat bilateral thyroid cancer with right neck lymph node metastasis, right papillary thyroid cancer (pT3 N1b M0), and left ATC (pT4b N0 M0). Preoperative fine needle aspiration biopsy identified suspicious papillary cancer cells (class V) in the right thyroid lobe and suspicious carcinoma cells of unknown histological type (class V) in the left thyroid lobe. The ATC had infiltrated the constrictor pharyngeal and cervical esophagus muscles; however, the patient elected not to undergo the removal of her larynx; thus, it was not possible to completely resect the ATC. Her relevant medical history included, type II diabetes mellitus, hypercholesterolemia, angina, and transient cerebral ischemia. Her blood pressure was controlled to within the normal range (130-140/70-80 mmHg) with antihypertensive agents. The patient's HbA1c level was 6.3% with the self-administration of subcutaneous insulin. Her performance status was 0 and a physical examination revealed no relevant physical abnormalities.\n\nNine days after the operation, we confirmed that all skin wounds were closed and subsequently initiated lenvatinib therapy (24 mg/day) to treat the remaining cancer of the constrictor pharyngeal and cervical esophagus muscles. Initially, the patient did not experience any adverse events; however, 19 days after the initiation of treatment, she presented with hypertension. The dose of lenvatinib was reduced (20 mg/day) and an antihypertensive drug was added to her treatment regimen.\n\nTwenty-nine days after the initiation of lenvatinib treatment (10 days after the dose reduction), the patient noticed a defect in the upper left side of her visual field while she was self-administering insulin. She went to the nearest ophthalmological clinic, but the ophthalmologist suggested that her symptoms were related to a central nervous system disorder. On the same day, the patient consulted with our emergency department. Cranial computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA) were performed. No evidence of acute cerebral bleeding or infarction was identified on CT, MRI, or MRA images. The next day (30 days after the initiation of lenvatinib treatment), she visited our department accompanied by her husband and son because of the appearance of additional symptoms, including forgetfulness, incoherent speech, and restlessness mimicking dementia as well as difficulty in self-administering medications. Her blood pressure was elevated (172/83 mmHg) and her neurological status had deteriorated. The patient had a Glasgow Coma Scale (GCS) score of 12 (E4, V3, M5). The patient's heart rate was 81 beats per minute and the electrocardiography findings were within the normal limits. A laboratory analysis revealed that her blood sugar level was 164 mg/dL and her HbA1c level was 5.8%. We consulted with neurologists who noted that the patient's previous MRI scan showed abnormal findings. Upon re-examination, T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI scans that had been obtained on the previous day and the same day revealed bilateral areas of increased signal intensity in the white matter of the occipital lobes (Fig. 1A, C and E). PRES was suspected based on the MRI findings. There were no notable findings on T1-weighted or diffusion-weighted images (Fig. 1B, F and D) or in the other white matter areas (data not shown). MRA performed on the previous day did not indicate the presence of lesions of cerebral angiostenosis or cerebral angiectasis, or any regional differences in the cerebral blood flow (data not shown). There was no abnormal stenosis of the main arteries, including stenosis of the large arteries in the trunk of the body on preoperative enhanced CT images (data not shown). Moreover, there were no enhancing lesions in the area that showed high intensity on T2-weighted imaging and the dural sinus was patent in the whole brain on gadolinium diethylenetriamine pentaacetic acid contrast-enhanced imaging (Fig. 1G).\n\nFigure 1. Axial T2-weighted and fluid-attenuated inversion recovery images showing bilateral (right>left) areas of increased signal intensity in the white matter of the occipital lobes on days 0 (A) and 1 (C, E) after the onset of the visual defect. There were no significant findings on T1-weighted (F) or diffusion-weighted imaging (B, D) or in other white matter areas (data not shown). There was no evidence of enhancing lesions in the area of high signal intensity on T2-weighted imaging, and the dural sinus was patent in the whole brain on gadolinium diethylenetriamine pentaacetic acid contrast-enhanced imaging (G, white arrow). T2WI: T2-weighted imaging, DWI: diffusion weighted imaging, FLAIR: fluid-attenuated inversion-recovery imaging, T1WI: T1-weighted imaging, Gd-DTPA: gadolinium diethylenetriamine pentaacetic acid\n\nThe patient was admitted to our hospital and treated with antihypertensive agents including an angiotensin II receptor antagonist and a calcium antagonist. Type-II diabetes mellitus was treated with the injection of rapid-acting insulin, which had previously been suspended due to the patient's impaired consciousness. The next day, the patient recovered from her confused mental state, but remained disoriented and continued to complain of a defect in the upper left side of her visual field. On day 4 after the onset of the visual defect, the visual disturbance resolved and FLAIR images showed a reduction of edema (decreased signal intensity) in the white matter of the occipital lobes (Fig. 2B). On day 8 after the onset of the visual defect, the patient was found to have completely recovered from her consciousness disturbance (GCS score: 15), and FLAIR images showed that areas of high signal intensity in the occipital lobes had completely resolved (Fig. 2C).\n\nFigure 2. Follow-up fluid-attenuated inversion recovery imaging showing the reduction of edema (decreased signal intensity) in the white matter of the occipital lobes on day 4 (B) after the onset of the visual defect in comparison to day 1 (A). Fluid-attenuated inversion recovery imaging shows the progressive reduction of edema and normalization by day 8 after the onset of the visual defect (C); normal findings were observed 1 month (D) and 8 months (E) later, during intermittent lenvatinib treatment.\n\nIn accordance with the LENVIMA guidebook, which contains information about the proper use of lenvatinib, we reduced the patient's dose of lenvatinib to 14 mg/day at 8 days after the onset of the visual defect. After 13 days of treatment with lenvatinib at a dose of 14 mg/day (day 21 after the onset of the visual defect), the patient presented with hypertension and hepatopathy with increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and increased urinary levels of protein. Lenvatinib therapy was discontinued; 4 days later, adverse effects related to lenvatinib treatment completely disappeared and the patient resumed lenvatinib therapy at a lower dose (10 mg/day). Follow-up cranial MRI did not reveal any areas of high signal intensity (Fig. 2D). Nine days after resuming lenvatinib therapy (day 34 after the onset of the visual defect), the patient again presented with hypertension, hepatopathy, increased serum levels of ALT/AST, and increased urinary levels of protein. Lenvatinib was again discontinued and the adverse effects disappeared after 7 days. The patient resumed lenvatinib therapy at a dose of 8 mg/day. The patient eventually died due to rupture of the left common carotid artery, 12 months after the first medical examination (9 months after the diagnosis of ATC was established); she did not experience any other episodes impaired consciousness. Cranial MRI scans obtained 7 days before her death (7 months after the onset of the visual defect), revealed no areas of high signal intensity, confirming the absence of PRES (Fig. 2E).\n\nDiscussion\nWe reported the case of a patient with ATC who developed PRES after treatment with lenvatinib. Our case shows the outcome of repeated treatment with decreasing doses of lenvatinib after the onset of PRES. No other study to date has described the outcome of repeated treatment with a TKI after the appearance of PRES.\n\nPRES-associated visual disturbances can become obvious as the disease evolves, whereas hypertension typically presents early after the onset of PRES, although some cases involving normal blood pressure have been reported (9, 10). The lesions of PRES are normally localized to the posterior regions of the brain and can affect both the white and grey matter; however, these lesions are usually reversible (9). The development of MRI technology has made it easier to diagnose PRES. In the present case, our patient experienced visual disturbance and hypertension in the early stage of PRES and later developed mental dysfunction with areas of increased signal intensity in the white matter of the bilateral occipital lobes on T2-weighted and FLAIR MRI. A 7-day interruption in lenvatinib treatment (20 mg/day) allowed the patient to recover from the visual and consciousness disturbances; during this time, the white matter lesions completely disappeared. This finding indicated that lenvatinib induced typical PRES in the present case.\n\nThe medications that have been associated with PRES primarily include immunosuppressant agents and molecular target-specific agents, including a number of TKIs (cediranib, sunitinib, sorafenib, pazopanib, and regorafenib) (11-18). Lenvatinib is a TKI that has been approved for the treatment of inoperable thyroid cancer, including ATC, in Japan. According to the LENVIMA guidebook, no Japanese patients developed PRES in phase II and phase III trials of lenvatinib treatment. In a phase III trial from another country, only 1 of 261 patients developed PRES after lenvatinib treatment (7). Thus, the present case represents the first reported case of PRES associated with lenvatinib use in a Japanese patient.\n\nThe concentration of lenvatinib may persist in the body for more than 7 days (19). In the present case, a 7-day interruption in therapy allowed for the resolution of PRES symptoms and MRI findings, suggesting that lenvatinib treatment was the cause of PRES. One study suggested that severe hypertension causing vasogenic edema can also precipitate PRES (20). It is unlikely that PRES was directly caused by severe hypertension - independent of lenvatinib use - in the present case, as the PRES symptoms disappeared during the suspension of lenvatinib treatment and reappeared after its re-initiation, despite the patient's recurrent severe hypertension. Lenvatinib inhibits vascular endothelial growth factor receptors (VEGFR) 1-3 in order to disrupt tumor angiogenesis and thus tumor invasion and metastasis (21). It is known that vascular endothelial growth factor (VEGF) regulates vasomotor tonus and maintains the blood pressure by dilating small arterioles and venules (22). The LENVIMA guidebook reported that 70% of patients treated with lenvatinib developed hypertension in a phase III trial (7). Thus, it is possible that hypertension related to lenvatinib use contributed to the appearance of PRES.\n\nIn the present case, we repeatedly administered lenvatinib to the patient despite severe side effects, including PRES, because we thought that lenvatinib would prolong her survival. It was recently reported that lenvatinib treatment was effective for locally advanced ATC and led to an improved quality of life as well as prolonged survival in Japanese patients (2, 23). As previously mentioned, most ATC patients die within 6 months of the diagnosis (1-3). The patient in our case lived for 8 months after the postoperative diagnosis of ATC, while receiving lenvatinib treatment. Notably, PRES did not recur in the present case; this is consistent with a previous report, which noted that recurrent PRES attacks are rare (24). Taken together, these data suggest that intermittent lenvatinib treatment can prolong survival in patients with ATC.\n\nIn conclusion, this is the first report about a case of PRES induced by lenvatinib treatment for ATC. All of the clinical and radiological findings of PRES disappeared after one week of treatment interruption, and there was no recurrence of PRES, despite repeated treatment with progressively lower doses of lenvatinib. Intermittent lenvatinib treatment may prolong the survival of patients with inoperable ATC.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Chiacchio S , Lorenzoni A , Boni G , Rubello D , Elisei R , Mariani G \nAnaplastic thyroid cancer: prevalence, diagnosis and treatment . Minerva Endocrinol \n33 : 341 -357 , 2008 .18923370 \n2. Sugitani I , Miyauchi A , Sugino K , Okamoto T , Yoshida A , Suzuki S \nPrognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients . World J Surg \n36 : 1247 -1254 , 2012 .22311136 \n3. Akaishi J , Sugino K , Kitagawa W , et al \nPrognostic factors and treatment outcomes of 100 cases of anaplastic thyroid carcinoma . Thyroid \n21 : 1183 -1189 , 2011 .21936674 \n4. Keizer RJ , Gupta A , MacGillavry MR , et al \nA model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080 . J Pharmacokinet Pharmacodyn \n37 : 347 -363 , 2010 .20652729 \n5. Schlumberger M , Tahara M , Wirth LJ , et al \nLenvatinib versus placebo in radioiodine-refractory thyroid cancer . N Engl J Med \n372 : 621 -630 , 2015 .25671254 \n6. Tahara M , Kiyota N , Yamazaki T , et al \nLenvatinib for Anaplastic Thyroid Cancer . Front Oncol \n7 : 25 , 2017 .28299283 \n7. \nLENVIMA Guidebook; lenvatinib management information for doctors provided by Eisai\n[cited 2015 May 1]. Available from:\nhttp://www.eisai.co.jp\n\n8. Hinchey J , Chaves C , Appignani B , et al \nA reversible posterior leukoencephalopathy syndrome . N Engl J Med \n334 : 494 -500 , 1996 .8559202 \n9. Fugate JE , Rabinstein AA \nPosterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions . Lancet Neurol \n14 : 914 -925 , 2015 .26184985 \n10. Li R , Mitchell P , Dowling R , Yan B \nIs hypertension predictive of clinical recurrence in posterior reversible encephalopathy syndrome? \nJ Clin Neurosci \n20 : 248 -252 , 2013 .23219827 \n11. Glusker P , Recht L , Lane B \nReversible posterior leukoencephalopathy syndrome and bevacizumab . N Engl J Med \n354 : 980 -982 , 2006 .\n12. Ozcan C , Wong SJ , Hari P \nReversible posterior leukoencephalopathy syndrome and bevacizumab . N Engl J Med \n354 : 980 -982 , 2006 .\n13. Dogan E , Aksoy S , Arslan C , Dede DS , Altundag K \nProbable sorafenib-induced reversible encephalopathy in a patient with hepatocellular carcinoma . Med Oncol \n27 : 1436 -1437 , 2010 .20012235 \n14. Padhy BM , Shanmugam SP , Gupta YK , Goyal A \nReversible posterior leucoencephalopathy syndrome in an elderly male on sunitinib therapy . Br J Clin Pharmacol \n71 : 777 -779 , 2011 .21480952 \n15. Palma JA , Gomez-Ibañez A , Martin B , Urrestarazu E , Gil-Bazo I , Pastor MA \nNonconvulsive status epilepticus related to posterior reversible leukoencephalopathy syndrome induced by cetuximab . Neurologist \n17 : 273 -275 , 2011 .21881470 \n16. Chelis L , Souftas V , Amarantidis K , et al \nReversible posterior leukoencephalopathy syndrome induced by pazopanib . BMC Cancer \n12 : 489 , 2012 .23088634 \n17. Myint ZW , Sen JM , Watts NL , et al \nReversible posterior leukoencephalopathy syndrome during regorafenib treatment: a case report and literature review of reversible posterior leukoencephalopathy syndrome associated with multikinase inhibitors . Clin Colorectal Cancer \n13 : 127 -130 , 2014 .24461491 \n18. Kim CA , Price-Hiller J , Chu QS , et al \nAtypical reversible posterior leukoencephalopathy syndrome (RPLS) induced by cediranib in a patient with metastatic rectal cancer . Invest New Drugs \n32 : 1036 -1045 , 2014 .24853074 \n19. Kitamura M , Hayashi T , Suzuki C , et al \nSuccessful recovery from a subclavicular ulcer caused by lenvatinib for thyroid cancer: a case report . World J Surg Oncol \n15 : 24 , 2017 .28088233 \n20. Xie C , Jones VT \nReversible posterior leukoencephalopathy syndrome following combinatorial cisplatin and pemetrexed therapy for lung cancer in a normotensive patient: a case report and literature review . Oncol Lett \n11 : 1512 -1516 , 2016 .26893771 \n21. Stjepanovic N , Capdevila J \nMultikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib . Biologics \n8 : 129 -139 , 2014 .24748771 \n22. Ancker OV , Wehland M , Bauer J , et al \nThe adverse effect of hypertension in the treatment of thyroid cancer with multi-kinase inhibitors . Int J Mol Sci \n18 : E625 , 2017 .28335429 \n23. Fukuhara T , Donishi R , Koyama S , et al \nSignificant amelioration of tracheal stenosis following lenvatinib in a patient who has anaplastic thyroid carcinoma with bronchomediastinal infiltration: a case report . Case Rep Oncol \n10 : 175 -181 , 2017 .28413394 \n24. Roth C , Ferbert A \nPosterior reversible encephalopathy syndrome: long-term follow-up . J Neurol Neurosurg Psychiatry \n81 : 773 -777 , 2010 .19955114\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "anaplastic thyroid carcinoma; lenvatinib; posterior reversible encephalopathy syndrome; tyrosine kinase inhibitor",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D010671:Phenylurea Compounds; D054038:Posterior Leukoencephalopathy Syndrome; D011804:Quinolines; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1015-1019",
"pmc": null,
"pmid": "29225265",
"pubdate": "2018-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20012235;18923370;23088634;28413394;25671254;20652729;22311136;26184985;21480952;24748771;26893771;28335429;16510760;24461491;16514715;21936674;8559202;24853074;28299283;21881470;23219827;19955114;28088233",
"title": "Posterior Reversible Encephalopathy Syndrome after Lenvatinib Therapy in a Patient with Anaplastic Thyroid Carcinoma.",
"title_normalized": "posterior reversible encephalopathy syndrome after lenvatinib therapy in a patient with anaplastic thyroid carcinoma"
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"companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2016-018291",
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"abstract": "We identified a HIV-positive cohort in virologic failure (VF) who re-suppressed without drug switch. We characterized their drug resistance mutations (DRM) and adherence profiles to learn how to better manage HIV drug resistance. A retrospective cohort study utilizing clinical data and stored samples. Patients received ART at three Nigerian treatment centres. Plasma samples stored when they were in VF were genotyped.\n\n\n\nOf 126 patients with samples available, 57 were successfully genotyped. From ART initiation, the proportion of patients with adherence ≥90% increased steadily from 54% at first high viral load (VL) to 67% at confirmed VF, and 81% at time of re-suppressed VL. Sixteen (28%) patients had at least one DRM. Forty-six (81%) patients had full susceptibility to the three drugs in their first-line (1 L) regimen. Thirteen (23%) were resistant to at least one antiretroviral drug but three were resistant to drugs not used in Nigeria. Ten patients had resistance to their 1 L drug(s) and six were fully susceptible to the three drugs in the recommended second-line regimen.\n\n\n\nThis cohort had little drug resistance mutations. We conclude that if adherence is not assured, patients could exhibit virologic failure without having developed mutations associated with drug resistance.",
"affiliations": "Microbiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212, Nigeria. chikaonwuamah@yahoo.com.;Jos University Teaching Hospital, Jos, Plateau State, Nigeria.;Microbiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212, Nigeria.;Jos University Teaching Hospital, Jos, Plateau State, Nigeria.;Harvard T. H. Chan School of Public Health, Boston, MA, USA.;Microbiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212, Nigeria.;APIN Public Health Initiative Nigeria, Ltd./Gte, Abuja, FCT, Nigeria.;Microbiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212, Nigeria.;Harvard T. H. Chan School of Public Health, Boston, MA, USA.;Centers for Disease Control-Nigeria, Abuja, FCT, Nigeria.;Jos University Teaching Hospital, Jos, Plateau State, Nigeria.;APIN Public Health Initiative Nigeria, Ltd./Gte, Abuja, FCT, Nigeria.;Microbiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212, Nigeria.;Centers for Disease Control-Nigeria, Abuja, FCT, Nigeria.;University of Ibadan, Ibadan, Oyo State, Nigeria.;University of Ibadan, Ibadan, Oyo State, Nigeria.;APIN Public Health Initiative Nigeria, Ltd./Gte, Abuja, FCT, Nigeria.;Microbiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212, Nigeria.;Centers for Disease Control and Prevention, Atlanta, GA, USA.;Centers for Disease Control and Prevention, Atlanta, GA, USA.;Harvard T. H. Chan School of Public Health, Boston, MA, USA.;Microbiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212, Nigeria.",
"authors": "Onwuamah|Chika K|CK|0000-0002-5111-1822;Okpokwu|Jonathan|J|;Audu|Rosemary|R|;Imade|Godwin|G|;Meloni|Seema T|ST|;Okwuraiwe|Azuka|A|;Chebu|Philippe|P|;Musa|Adesola Z|AZ|;Chaplin|Beth|B|;Dalhatu|Ibrahim|I|;Agbaji|Oche|O|;Samuels|Jay|J|;Ezechi|Oliver|O|;Ahmed|Mukhtar|M|;Odaibo|Georgina|G|;Olaleye|David O|DO|;Okonkwo|Prosper|P|;Salako|Babatunde Lawal|BL|;Raizes|Elliot|E|;Yang|Chunfu|C|;Kanki|Phyllis J|PJ|;Idigbe|Emmanuel O|EO|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
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"doi": "10.1186/s12866-020-1706-1",
"fulltext": "\n==== Front\nBMC MicrobiolBMC MicrobiolBMC Microbiology1471-2180BioMed Central London 170610.1186/s12866-020-1706-1Research ArticleLow levels of HIV-1 drug resistance mutations in patients who achieved viral re-suppression without regimen switch: a retrospective study http://orcid.org/0000-0002-5111-1822Onwuamah Chika K. chikaonwuamah@yahoo.com 1Okpokwu Jonathan 2Audu Rosemary 1Imade Godwin 2Meloni Seema T. 3Okwuraiwe Azuka 1Chebu Philippe 4Musa Adesola Z. 1Chaplin Beth 3Dalhatu Ibrahim 5Agbaji Oche 2Samuels Jay 4Ezechi Oliver 1Ahmed Mukhtar 5Odaibo Georgina 6Olaleye David O. 6Okonkwo Prosper 4Salako Babatunde Lawal 1Raizes Elliot 7Yang Chunfu 7Kanki Phyllis J. 3Idigbe Emmanuel O. 11 0000 0001 0247 1197grid.416197.cMicrobiology Department, Centre for Human Virology and Genomics, Nigerian Institute of Medical Research, 6 Edmund Crescent, Yaba, Lagos, 101212 Nigeria 2 0000 0004 1783 4052grid.411946.fJos University Teaching Hospital, Jos, Plateau State Nigeria 3 000000041936754Xgrid.38142.3cHarvard T. H. Chan School of Public Health, Boston, MA USA 4 grid.432902.eAPIN Public Health Initiative Nigeria, Ltd./Gte, Abuja, FCT Nigeria 5 Centers for Disease Control-Nigeria, Abuja, FCT Nigeria 6 0000 0004 1794 5983grid.9582.6University of Ibadan, Ibadan, Oyo State Nigeria 7 0000 0001 2163 0069grid.416738.fCenters for Disease Control and Prevention, Atlanta, GA USA 20 1 2020 20 1 2020 2020 20 179 8 2019 14 1 2020 © The Author(s). 2020Open 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\nWe identified a HIV-positive cohort in virologic failure (VF) who re-suppressed without drug switch. We characterized their drug resistance mutations (DRM) and adherence profiles to learn how to better manage HIV drug resistance.\n\nA retrospective cohort study utilizing clinical data and stored samples. Patients received ART at three Nigerian treatment centres. Plasma samples stored when they were in VF were genotyped.\n\nResult\nOf 126 patients with samples available, 57 were successfully genotyped. From ART initiation, the proportion of patients with adherence ≥90% increased steadily from 54% at first high viral load (VL) to 67% at confirmed VF, and 81% at time of re-suppressed VL. Sixteen (28%) patients had at least one DRM. Forty-six (81%) patients had full susceptibility to the three drugs in their first-line (1 L) regimen. Thirteen (23%) were resistant to at least one antiretroviral drug but three were resistant to drugs not used in Nigeria. Ten patients had resistance to their 1 L drug(s) and six were fully susceptible to the three drugs in the recommended second-line regimen.\n\nConclusion\nThis cohort had little drug resistance mutations. We conclude that if adherence is not assured, patients could exhibit virologic failure without having developed mutations associated with drug resistance.\n\nKeywords\nDrug resistance mutationAdherenceRe-suppressionVirologic failureUS Centres for Disease Control and PreventionU2G GH000770Idigbe Emmanuel O. issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nFor treatment of HIV-1 in resource-limited settings, the World Health Organization (WHO) specifies that if viral load (VL) is > 1000 copies per millilitre (cp/mL) after 6 months on treatment, virologic failure (VF) is suspected [1]. In this scenario, adherence support is recommended by the Nigerian national guideline along with treatment of any opportunistic infections followed by reassessment in 3 months for clinical and laboratory parameters. If improvement is noted, the patient is continued on their first-line (1 L) regimen. However, if there is no improvement, a second VL test is performed. Per guidelines, patients with a second VL ≥1000 cp/mL are switched to a second-line (2 L) regimen [1].\n\nThe emergence of HIV drug resistance mutations (DRMs) is influenced by many factors, foremost of which is adherence to antiretroviral therapy (ART) [2, 3]. Adherence to ART can be measured by various methods [4], including MEM system [5], face-to-face interviews [2, 3], self-reported adherence [6], review of pharmacy refill pick-ups, [7] and measuring blood or hair antiretroviral (ARV) levels [8]. It has long been accepted in clinical practice that an intermediate level of adherence at 70–89% is associated with higher risks of VF and detection of DRMs as compared with patients having high (≥90%) or low (< 70%) levels of cumulative adherence [2]. In addition, increased failure rates on second-line regimens have been reported in sub-Saharan Africa, mostly due to non-adherence to treatment [9].\n\nWe discovered a cohort of patients who met the criteria for virologic failure but surprisingly re-suppressed VL without a change of regimen. At present, there is little data regarding DRMs in patients that re-suppress VL following confirmed VF, particularly in the context of adherence patterns. Thus, we conducted this evaluation to examine the range of HIV DRMs, drug resistance and adherence patterns in this cohort. We believe findings will guide management of HIV drug resistance, especially in resource-constrained settings that have limited drug options.\n\nResults\nDemographics\nIn total, 126 patients who met the inclusion criteria for the study and had remnant samples available were tested (Fig. 1). Among the 126 samples tested, 57 (45%) were successfully genotyped and included in the final analysis. There was no significant difference in demographics and viral load between those successfully sequenced and those not sequenced (Table 1). Of the 57 patients, 39 (68%) were female and the median age was 34 years (interquartile range (IQR): 30.0–41.5; Table 2). Thirty-four patients (60%) were on zidovudine (AZT)-based 1 L regimens while 16 (28%) were on tenofovir (TDF)-based 1 L regimens (Table 2). Seven (12%) patients had substitutions in their original 1 L backbone regimen and were classified as “other” 1 L regimens. The major subtypes represented in the cohort were subtype G (44%) and CRF02_AG (40%). Except for sex (p = 0.042), none of the other variables were significantly associated with drug resistance in the bivariate analyses (Table 2).\nFig. 1 Study Consort Diagram. TDF = Tenofovir; AZT = Zidovudine; *Others = Backbone NRTI was switched\n\n\nTable 1 Comparison of Viral load (VL) between samples not sequenced (n = 69) and those successfully genotyped (n = 57)\n\n\tOption\tSample Bleed Year\tTotal\t\n2006\t2007\t2008\t2009\t2010\t\nGenotyping Successful?\tNo\t6\t5\t12\t27\t19\t69\t\nMedian VL\t3250.5\t14,467.0\t4861.0\t6499.3\t6222.9\t\t\nYes\t4\t3\t3\t23\t24\t57\t\nMedian VL\t4356.5\t13,703.0\t33,500.0\t15,044.2\t5418.9\t\t\nSample Retrieval\tNo\t0\t2\t14\t7\t1\t24\t\nTotal\t150\t\n\nTable 2 Characteristics* of the patients successfully genotyped (N = 57)\n\nCategory\tParameters\tCharacteristics\tTotal [N (% or IQR)]\t#P-Values\t\nDemographics\tSex\tFemale\t39 (68)\t0.042\t\nMale\t18 (32)\t\nAge at baseline\tMedian (IQR) years\t34 (30–42)\t0.921\t\nMarital Status\tSingle\t12 (21)\t0.663\t\nMarried\t29 (51)\t\nDivorced/Separated\t4 (7)\t\nWidowed\t12 (21)\t\nEducation\tNone\t6 (11)\t0.770\t\nPrimary\t14 (25)\t\nSecondary\t18 (32)\t\nTertiary\t19 (33)\t\nOccupation\tNot Employed\t15 (26)\t0.338\t\nEmployed\t42 (74)\t\nClinical Parameters\tFirst-line Backbone NRTI\tAZT\t34 (60)\t0.978\t\nTDF\t16 (28)\t\nbOthers\t7 (12)\t\nFirst-line Second NRTI\t3TC\t39 (68)\t0.666\t\nFTC\t18 (32)\t\nFirst-line NNRTI\tNVP\t43 (75)\t0.071\t\nEFV\t14 (25)\t\nTime on First-line ART (Months)\tART Initiation to F1\t21 (12–36)\t0.217\t\nF1 to FC\t5 (4–6)\t0.086\t\nFC to Viral Re-suppression\t5 (3–10)\t0.118\t\nLaboratory Parameters\tBaseline CD4+ cells/μL\t< 200\t38 (67)\t0.780\t\n200–350\t17 (30)\t\n> 350\t2 (4)\t\nMedian (IQR)\t155 (105–235)\t\nBaseline Viral Load (VL), copies/mL\t≤100,000\t36 (63)\t0.774\t\n> 100,000\t18 (32)\t\nUnknown\t3 (5)\t\nMedian (IQR)\t43,587 (13128–176,990)\t\nVL at initial failure (copies/mL)\tMedian (IQR)\t9113 (3680–49,670)\t0.768\t\nVL at confirmatory failure (copies/mL)\tMedian (IQR)\t16,266 (2042–4,002,513)\t0.454\t\nHIV-1 Subtype\tG\t25 (44)\t0.261\n\nGrouped as G, CRF02_AG and Others\n\n\t\nCRF02_AG\t23 (40)\t\nA\t3 (5)\t\nCRF06_cpx\t3 (5)\t\nJ\t1 (2)\t\nC\t1 (2)\t\nRecombinant of A1, G\t1 (2)\t\naDemographic characteristics of those successfully genotyped were not significantly different from those not genotyped; F1 First VL ≥ 1000 cp/mL; FC Second VL ≥ 1000 cp/mL. #P-value is for difference in patient characteristic and drug resistance. IQR Interquartile range. bOthers = Backbone NRTI was switched\n\n\n\nDrug resistance mutations\nAmong the 57 patients with genotype data available, 16 (28%) had at least one HIV-1 DRM (Table 4). Four patients (7%) had DRMs to NRTIs while 14 (25%) had DRMs to non-nucleoside reverse transcriptase inhibitor (NNRTIs). Of the 16 patients with at least one HIV-1 DRM, four (7% of 57) patients had DRMs to both NRTIs and NNRTIs. Two patients (4% of 57) had DRMs to protease inhibitors (PIs): one patient had M46 L (major PI DRM) while the other patient had L23I (minor PI DRM). In addition, 51 (90%) patients had the K20I polymorphism, which is a consensus amino acid in subtypes G and CRF02_AG. Only one patient had a thymidine analogue mutation.\n\nAdherence, HIV drug resistance mutations and viral load\nIn the evaluation of adherence patterns from ART initiation to the first VL ≥ 1000 cp/mL (F1); F1 to the second VL ≥ 1000 cp/mL (FC); FC to VL re-suppression, the proportion of patients with adherence ≥90% increased steadily (Fig. 2). Stratified into < 70%, 70–89% and ≥ 90%, adherence between ART initiation to F1 only was significantly associated with drug resistance (p = 0.037) as six of eight patients with drug resistance to at least one drug had 70–89% adherence. This association was specifically with only NRTI resistance and the M184 V mutation (Table 3). However. individual changes in adherence were not significantly associated with the detection of DRMs nor drug resistance. Median VL was also significantly higher for those with median adherence < 90% but at F1 only (Table 4).\nFig. 2 Pattern of improvement in adherence from ART initiation till viral re-suppression. AI to F1: Period between ART Initiation to the first VL above 1000 cp/mL (F1);.F1 to FC: Period between the first VL above 1000 cp/mL (F1) and confirmatory VL above 1000 cp/mL (FC);.FC to Suppression: Period between the confirmatory VL above 1000 cp/mL (FC) and viral re-suppression\n\n\nTable 3 Drug Resistance Patterns by Median Adherence Prior to F1\n\nAdherence from ART Initiation to F1\tTotal [n (%)]\t≥1 DRM\tResistance to NRTI\tResistance to NNRTI\tResistance to M184 V\t\n< 70%\t4 (7)\t7%\t0%\t8%\t0%\t\n70–89%\t22 (39)\t50%\t100%\t58%\t100%\t\n≥ 90%\t31 (54)\t43%\t0%\t33%\t0%\t\n\tp-value\t0.583\t0.033a\t0.245\t0.033a\t\nART Antiretroviral therapy, F1 First VL ≥ 1000 cp/mL. aStatistically significant\n\n\nTable 4 Median Viral Load (VL) by Median Adherence\n\nViral Load\tAdherence\tP-Value\t\n< 70%\t< 70–89%\t≥ 90%\t\nMedian VL at F1\t94,670\n\nIQR: 15902–271,109\n\n\t19,833\n\nIQR: 5822–103,041\n\n\t4745\n\nIQR: 3565–17,610\n\n\t0.021a\t\nMedian VL at FC\t30,439\n\nIQR: 5466–96,682\n\n\t16,266\n\nIQR: 4471–51,973\n\n\t20,201\n\nIQR: 4107–74,390\n\n\t0.950\t\nF1 First VL ≥ 1000 cp/mL, FC Second VL ≥ 1000 cp/mL, IQR Interquartile range\n\n\n\nPredicted drug susceptibility profiles among this cohort\nDespite confirmed VF and the presence of DRMs in some patients, most of the patients (n = 46; 81%) were fully susceptible to their 1 L regimens, including six patients with detectable DRMs. Of all the 16 patients with DRMs, only thirteen (23% of 57) patients had resistance to any ARVs (Table 5; patients 3, 5–16). Of these thirteen, four patients (7% of 57) retained susceptibility to only one drug in their current 1 L regimen, ranging from intermediate-level resistance (n = 1), low-level resistance (n = 1) to susceptible (n = 2; Table 5; patients 13–16). All patients were susceptible to lopinavir/ritonavir (LPV/r) and atazanavir/ritonavir (ATV/r), the two PIs recommended for 2 L regimens in Nigeria, while only one patient had less than two 2 L drugs to which they were susceptible (GSS = 1.5). Of the 13 patients with resistance to at least one drug, eight had GSS = 3 for the recommended 2 L regimen. Three of the four patients with DRMs to NRTI were on an AZT-based 1 L regimen and the fourth patient was on a TDF-based 1 L regimen (Table 5). Nine out of the 14 patients with DRMs to NNRTI were on NVP-based ART, while the remaining five patients were receiving EFV-based regimens (Table 5). Drug susceptibility patterns for the entire cohort can be seen in Additional file 1.\nTable 5 Drug Susceptibility Profiles of patients with HIV Drug Resistance Mutations Detected\n\nPatient No.\tRegimen\tDrug Resistance Mutation Types\tSusceptibility to 1 L Drugs\tSusceptibility to 2 L Drugs\t2 L GSS\tSubtype\t\nNRTIs\tNNRTIs\tPIs\tABC\tAZT\tFTC\t3TC\tTDF\tEFV\tETR\tNVP\tRPV\tDRV/r\tATV/r\tLPV/r\t\n1\tbOthers/FTC/NVP\tNone\tV90I\tK20I\tS\tS\taS\tS\taS\tS\tS\taS\tS\tS\tS\tS\t3.0\t02_AG\t\n2\tTDF/FTC/NVP\tNone\tV90IV\tK20I\tS\tS\taS\tS\taS\tS\tS\taS\tS\tS\tS\tS\t3.0\t02_AG\t\n3\tAZT/3TC/EFV\tNone\tNone\tM46 L, K20I\tS\taS\tS\taS\tS\taS\tS\tS\tS\tS\tS\tS\t2.75\tG\t\n4\t#Others/3TC/EFV\tNone\tNone\tL10I, L23IL\tS\taS\tS\taS\tS\t*S\tS\tS\tS\tS\tS\tS\t3.0\tA1\t\n5\tAZT/3TC/NVP\tNone\tE138EG\tNone\tS\taS\tS\taS\tS\tS\tS\t*S\tL\tS\tS\tS\t3.0\tC\t\n6\tTDF/FTC/EFV\tNone\tK103Q, E138AE\tK20I\tS\tS\taS\tS\taS\taS\tS\tS\tL\tS\tS\tS\t3.0\tG\t\n7\tAZT/3TC/NVP\tNone\tV90IV, V108IV\tNone\tS\taS\tS\taS\tS\tS\tS\taL\tS\tS\tS\tS\t3.0\tJ\t\n8\tAZT/3TC/NVP\tNone\tV108I\tK20I\tS\taS\tS\taS\tS\tS\tS\taL\tS\tS\tS\tS\t3.0\tG\t\n9\tAZT/3TC/EFV\tNone\tK103 N\tK20I\tS\taS\tS\taS\tS\taH\tS\tH\tS\tS\tS\tS\t3.0\tG\t\n10\tAZT/3TC/EFV\tNone\tV106A, F227 L\tK20I\tS\taS\tS\taS\tS\taH\tS\tH\tS\tS\tS\tS\t3.0\t02_AG\t\n11\tbOthers/FTC/NVP\tNone\tK103KN\tK20I\tS\tS\taS\tS\taS\tH\tS\taH\tS\tS\tS\tS\t3.0\t02_AG\t\n12\tTDF/FTC/NVP\tNone\tV90I, K103 N\tK20I\tS\tS\taS\tS\taS\tH\tS\taH\tS\tS\tS\tS\t3.0\t02_AG\t\n13\tAZT/3TC/NVP\tM184 V\tK103 N, E138A\tK20I\tL\taS\tH\taH\tS\tH\tS\taH\tL\tS\tS\tS\t2.0\tG\t\n14\tAZT/3TC/EFV\tD67DN, K70R, M184 V, K219E\tK103 N, V108I\tK20I\tL\taL\tH\taH\tL\taH\tS\tH\tS\tS\tS\tS\t1.5\t02_AG\t\n15\tTDF/3TC/EFV\tK70E, M184 V\tK103 N, V108I, H221Y\tL10I, K20I\tL\tS\tH\taH\taL\taH\tS\tH\tS\tS\tS\tS\t2.0\t02_AG\t\n16\tAZT/3TC/NVP\tM184 V\tA98AG, K101E, Y181C\tK20I\tL\taS\tH\taH\tS\tL\tL\taH\tH\tS\tS\tS\t2.0\t02_AG\t\nS Susceptible and Potential low-level resistance, L Low-level resistance and Intermediate-level resistance, H High-level resistance. NRTIs Nucleoside Reverse Transcriptase Inhibitors, NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors, PIs Protease Inhibitors; 1 L-First-line; 2 L = Second-line: GSS Genotype Sensitivity Score. aIndicate drugs in patient’s First-line regimen; bOthers = Backbone NRTI was switched\n\n\n\nDiscussion\nIn this study, we determined DRM, drug resistance and adherence profiles of ART patients with confirmed VF who re-suppressed their VL in the absence of a regimen switch. The difference in sex is related to the higher number of females in the treatment cohorts at these centres as they have better treatment-seeking behaviour than men. Sixteen (28%) patients in this cohort had at least one HIV DRM, but only 13 (23%) were resistant to at least one drug. Of the 13 patients with resistance to at least one drug, all were susceptible to the PIs recommended for 2 L regimens in Nigeria.\n\nWe find that most patients failed and re-suppressed without developing DRMs. In addition, those who had DRMs were still able to re-suppress VL. Firstly, it is not surprising that patients without DRMs re-suppressed VL. Secondly, we note that some patients with functional monotherapy were still able to re-suppress VL, reiterating that the presence of DRMs itself does not necessarily predicts VF. However, its noteworthy that all four patients with dual-class DRMs (NRTI and NNRTIs), with only their NRTI backbone being sensitive, had the M184 V mutation. The M184 V mutation reduces viral replication, increases susceptibility to AZT and TDF, and thus slow emergence of VF to these drugs. These effects could be partly responsible for viral re-suppression especially in these four with several DRMs.\n\nImproved adherence appears to have helped them achieve re-suppression, given that adherence before suppression improved for over 80% of participants. We could not perform further statistical analysis due to the small study sample size. Some patients had lower confirmatory VLs than their initial failing VL, which may be due to improved adherence. Although lower confirmatory VL levels (still above 1000 cp/mL) were recorded for half of the patients with confirmed DRMs, a drop in VL levels may not indicate that DRMs are not being developed as mutant viruses may have a fitness cost, resulting in lower viral replication capacity and/or hyper-susceptibility to other ARVs [10].\n\nGiven that this cohort re-suppressed VL after confirmation of VF and in the absence of a drug switch, it is not surprising that they had low levels of DRMs and only 23% had confirmed resistance to at least one drug. Our findings reiterate the utility of VL and DRM monitoring, as reported in other studies, and show these may be best utilised in combination with the adherence profile especially when considering drug switch [11–13]. An evaluation of adherence patterns in patients with confirmed VF may be necessary before deciding to switch/change regimen.\n\nPatients suspected to be failing treatment clinically are required to undergo intensified adherence counselling while the result of repeat VL is awaited [14–16]. Counselling reinforces the importance of adherence, for both the 1 L and the 2 L, in case the patient is eventually switched, as poor adherence is considered to be a major driver of 2 L treatment failures [17]. Several factors influence patients’ adherence to therapy and these factors are consistent across different economic settings [18, 19]. Reported barriers to adherence include HIV-associated stigma, forgetfulness, complicated regimen, and falling asleep, whereas facilitators of adherence include simplified regimen, understanding the need for adherence, having an adherence partner and use of reminder tools [4, 18]. In this cohort with 51% married, if the couples are sero-concordant and have disclosed, they could serve as adherence partners for each other.\n\nThere are limitations in this study. Firstly, the population were selected retrospectively from electronic medical records and may not be representative of the population. Secondly, we are not certain why these patients with confirmed VF were not switched at the various ART centres and if adherence was considered at the time. Given this is a retrospective study, data were not captured on the reasons why each patient was not switched. It is possible patients were not switched due to other issues, such as logistics challenges or delays in data availability for clinical decision-making. Secondly, the small sample size, due to over half of the samples failing genotyping, reduced the power for statistical analysis outcomes. The failure to genotype might be caused by the degradation of RNAs in the stored plasma samples.\n\nConclusions\nDespite the limitations of the study, our results reveal that in the absence of a regimen switch, patients who re-suppressed their VL following confirmed virologic failure had few underlying DRMs and remained largely susceptible to the current 1 L regimens. We surmise that when consistent adherence is not assured, patients could exhibit virologic failure, with two VLs above 1000cp/mL, without developing mutations associated with drug resistance.\n\nMethods\nStudy design and sites\nAs part of a larger evaluation on DRMs in patients experiencing virologic failure (VF) [20], we conducted a retrospective cohort study utilizing stored data and samples from patients who had been receiving ART at three large tertiary treatment centres affiliated with the Harvard/APIN Public Health Initiatives (PHI), the Centers for Disease Control and Prevention-funded United States President’s Emergency Plan for AIDS Relief (PEPFAR) Program in Nigeria: the Nigerian Institute of Medical Research (NIMR), Jos University Teaching Hospital in Jos (JUTH), and University College Hospital in Ibadan (UCH). With PEPFAR funding, all three comprehensive treatment centres have been performing VL routinely since 2004, have capacities for routine − 80 °C sample storage and for sequencing HIV in-country. An electronic medical record system (EMRS) has been utilized to record demographic, medical history, pharmacy pickups, laboratory and clinical data of each patient as well as consent for programmatic and/or for research use of samples/data [21]. At Harvard/PHI PEPFAR sites in Nigeria, clinicians in facilities with electronic medical records use the pharmacy refill data to assess adherence.\n\nStudy population\nAdult ART patients with the following characteristics were included in the study: 1) provided consent for use of data and samples in future research studies; 2) received 1 L ART, either AZT + 3TC + NVP/EFV or TDF + 3TC/FTC + NVP/EFV, between the years of 2004–2009 for at least 6 months; 3) met World Health Organisation VF criteria for 1 L treatment failure (two consecutive VL measurements greater than 1000 cp/mL); and 4) re-suppressed VL to ≤400 cp/mL following confirmation of VF. These patients may not be representative of their various population being selected from electronic medical records for meeting the criteria above. In addition, we report here findings from the second aim of a study, see Additional file 1 for more details on the study population. Findings from aims one cohort have been earlier reported [19]. The cohort in aims one were patients who failed, did not re-supress viral load on 1 L regimen and were subsequently switch to second-line regimen.\n\nLaboratory methods\nData on VLs were accessed from existing clinical databases (EMRS). VL were earlier determined using the Roche Cobas Amplicor Monitor assay, version 1.5 (Roche Diagnostics, Branchburg, NJ, USA) and the Roche Cobas Ampliprep/COBAS TaqMan HIV-1 Test, v2.0 kits (Indianapolis, IN, USA). Stored frozen plasma samples collected from patients who met the inclusion criteria were retrieved for HIV drug resistance testing using ATCC® HIV-1 Drug Resistance Genotyping Kit [22] (American Type Culture Collection, Manassas, VA, USA). We analysed the samples collected at the initial unsuppressed VL time point (first high VL, F1). If the first attempt for genotyping was not successful, a plasma sample collected at the confirmatory VF time point (FC) was used for repeat genotyping. In brief, HIV ribonucleic acid (RNA) was extracted from the plasma samples using the Qiagen Viral RNA Kit (Qiagen Inc., Valencia, CA, USA). Reverse transcriptase-polymerase chain reaction (RT-PCR) and nested PCR were performed using the ATCC® HIV-1 Drug Resistance Genotyping kit module 1. The nested PCR products were purified using ExoSAP-IT enzyme and used for cycle sequencing with the kit module 2. The sequencing was performed with Genetic Analyser 3130xL (Applied Biosystems, Foster City, CA, USA) and AB1 files were used to generate consensus sequences using ReCall 2.25 software (University of British Columbia, Vancouver, BC, Canada). Sequence identity matrices were performed using BioEdit software (Ibis Biosciences, Carlsbad, CA, USA) to check for contamination and the quality-confirmed sequence files were analysed with Stanford HIVDB Calibrated Population Resistance “QA details” to confirm base calls [23].\n\nHIV DRM interpretation and impact on drug regimens\nHIV DRMs and profiles were determined using HIVdb algorithm version 8.2 [24] at the Stanford HIVDB website. To analyse the impact of DRMs on the efficacy of the potential 2 L regimens on those patients carrying drug resistant viruses, the genotype sensitivity score (GSS) was calculated per individual drug and compiled to obtain a GSS for each patient [25]. The GSS for each drug in the regimen were assigned as follows: susceptible = 1.0, potential low-level resistance = 0.75, low-level resistance = 0.5, intermediate resistance = 0.25, and high-level resistance = 0.0. HIV-1 subtyping used the REGA HIV-1 subtyping tool - version 3.0 (University of Pretoria, Pretoria, Gauteng South Africa and the REGA Institute, Katholieke Universiteit Leuven, Leuven, Belgium) on the newly obtained sequences.\n\nStatistical analyses\nPatient characteristics at ART initiation, including estimated adherence and VL measurements were examined using univariate methods. Adherence was estimated as medicine possession ratio (MPR) using pharmacy drug refill data. MPR was computed by dividing the total number of pills provided by the number of days in the period between drug pick-ups and then multiplied by 100. Average adherence was computed for the time from ART initiation to F1, time from F1 to FC, and time from FC to viral re-suppression. Bivariate methods were used to examine the relationship between patient characteristics and drug resistance using Epi Info software. ANOVA or Wilcoxon Two-Sample Test (Kruskal-Wallis test) was used for continuous variables while chi-squared or Fisher’s exact tests was used for categorical variables as appropriate. The deidentified study database is available as Additional file 2.\n\nEthical approval\nEthical approval for this study was obtained from ethics committees of NIMR, JUTH, UCH and the Harvard T. H. Chan School of Public Health. The study was reviewed according to the Centers for Disease Control and Prevention (CDC) human research protection procedures and was approved as research, but CDC was not engaged. At these tertiary facilities, HIV-positive persons at enrolment either deny access or provide written consent for further use of their samples for research purposes. Only patients who consented and gave documented approval for use of their samples for research purposes were included in this study.\n\nSupplementary information\n\nAdditional file 1. Study Population. Gives greater details about the study population and how the participants were selected.\n\n \nAdditional file 2. Study Database. Unlinked database without personal identifiable data.\n\n \n\n\nAbbreviations\n1 LFirst-line\n\n2 LSecond-line\n\n3TCLamivudine\n\nARTAntiretroviral therapy\n\nARVAntiretroviral drugs\n\nATV/rAtazanavir/ritonavir\n\nAZTZidovudine\n\nCDCCenters for disease control and prevention\n\nDRMDrug resistance mutation\n\nEFVEfavirenz\n\nEMRSElectronic medical record system\n\nF1First viral load above 1000 copies/mL\n\nFCAnother viral load above 1000 copies/mL confirming virologic failure\n\nFTCEmtricitabine\n\nGSSGenotype sensitivity score\n\nIQRInterquartile range\n\nJUTHJos University Teaching Hospital, University of Jos\n\nLPV/rLopinavir/ritonavir\n\nMPRMedicine possession ratio\n\nNFVNelfinavir\n\nNIMRNigerian institute of medical research\n\nNNRTINon-nucleoside reverse transcriptase inhibitor\n\nNRTINucleoside reverse transcriptase inhibitor\n\nNVPNevirapine\n\nPCRPolymerase chain reaction\n\nPEPFARUnited States president’s emergency plan for aids relief\n\nPIProtease inhibitor\n\nRPVRilpivirine\n\nTDFTenofovir\n\nUCHUniversity college hospital, university of ibadan\n\nVFVirologic failure\n\nVLViral load\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12866-020-1706-1.\n\nAcknowledgements\nThe authors gratefully acknowledge the patients and the incredible work and dedication of the clinical, data, and laboratory staff at all the Harvard/PHI PEPFAR ART Centres.\n\nAuthors’ contributions\nEO, PJ, PO, DO, OA and ST contributed to conception, design and acquisition of funding. CK, JO, RA, GI, ST, AO, PC, AZ, BCJS, OE, GO, ER and CY made substantial contributions to the acquisition of data. CK, RA, GI, BC, ID, OC, JS, OE, MA, DO, PO, BL, ER, PJ and EO contributed immensely to study administration and supervision. All authors made substantial contributions to the analysis and interpretation of data at several data review meetings. All authors were involved in drafting the manuscript or revising it critically for important intellectual content. All authors read and approved the final manuscript\n\nFunding\nThis study was supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) [under the terms of cooperative agreement U2G GH000770 to Professor Oni Idigbe].\n\nAs the study sponsor, the Centers for Disease Control (CDC) implemented monitoring or auditing of study activities to ensure the scientific integrity of the study and to ensure the rights and protection of study participants. Monitoring and auditing activities was done by CDC staff and/or contracted “external” party by on-site visits, telephone calls and written correspondence. The study was still subject regulatory authorities (national or foreign) as well as the IECs/IRBs.\n\nThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding agencies. The funding agency did not influence the study, results and interpretation in any way.\n\nAvailability of data and materials\nThe sample sequences have been submitted to GenBank with submission number BankIt1960888 and accession numbers MF684375-MF684431.\n\nDatabase supporting the conclusion of this study is included as additional file: Additional File 1: Study Database. Database containing deidentified clinical and laboratory data of participants.\n\nEthics approval and consent to participate\nEthical approval for this study was obtained from the Institutional Review Boards (IRBs) of:\nThe Nigerian Institute of Medical Research, Lagos, Nigeria (NHREC/11/02/2009a)\n\nThe Jos University Teaching Hospital (JUTH), Jos, Plateau State (NHREC/13/03/2010)\n\nThe University of Ibadan/UCH, Ibadan, Oyo State (NHREC/05/01/2008a)\n\nThe Harvard T. H. Chan School of Public Health, Dept. of Immunology & Infectious Diseases, U.S.A.\n\n\n\nConsent to participate was obtained from patients at the point of initiation into care. Patients included gave written permission for the further research use of their samples and data (Harvard T. H. Chan School of Public Health, Dept. of Immunology & Infectious Diseases, U.S.A. Protocol #16506).\n\nThe study was reviewed according to the Centers for Disease Control and Prevention (CDC) human research protection procedures and was approved as research, but CDC was not engaged.\n\nConsent for publication\nNot applicable as individually identifiable data is not used.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Federal Ministry of Health Nigeria. National Guidelines for HIV Prevention, Treatment and Care. In: (NASCP) NAaSsCP, editor. ISBN: 978–978–954-309-0 ed. Abuja, Nigeria: Federal Ministry of Health, Nigeria; 2016.\n2. Sethi AK Celentano DD Gange SJ Moore RD Gallant JE Association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance Clin Infect Dis 2003 37 8 1112 1118 10.1086/378301 14523777 \n3. 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Turner BJ Adherence to antiretroviral therapy by human immunodeficiency virus-infected patients J Infect Dis 2002 185 Suppl 2 S143 S151 10.1086/340197 12001036 \n8. de Truchis P Lê MP Daou M Madougou B Nouhou Y Moussa Saley S High efficacy of first-line ART in a west African cohort, assessed by dried blood spot virological and pharmacological measurements J Antimicrob Chemother 2016 71 11 3222 3227 10.1093/jac/dkw286 27439522 \n9. Edessa D Sisay M Asefa F Second-line HIV treatment failure in sub-Saharan Africa: a systematic review and meta-analysis PLoS One 2019 14 7 e0220159 10.1371/journal.pone.0220159 31356613 \n10. Lucas GM Antiretroviral adherence, drug resistance, viral fitness and HIV disease progression: a tangled web is woven J Antimicrob Chemother 2005 55 4 413 416 10.1093/jac/dki042 15722389 \n11. Hoffmann CJ Maritz J van Zyl GU CD4 count-based failure criteria combined with viral load monitoring may trigger worse switch decisions than viral load monitoring alone Tropical Med Int Health 2016 21 2 219 223 10.1111/tmi.12639 \n12. Muri L Gamell A Ntamatungiro AJ Glass TR Luwanda LB Battegay M Development of HIV drug resistance and therapeutic failure in children and adolescents in rural Tanzania: an emerging public health concern AIDS 2017 31 1 61 70 10.1097/QAD.0000000000001273 27677163 \n13. Abreu Juliana Costa de Vaz Sara Nunes Netto Eduardo Martins Brites Carlos Virological suppression in children and adolescents is not influenced by genotyping, but depends on optimal adherence to antiretroviral therapy The Brazilian Journal of Infectious Diseases 2017 21 3 219 225 10.1016/j.bjid.2017.02.001 28253476 \n14. Oku AO Owoaje ET Ige OK Oyo-Ita A Prevalence and determinants of adherence to HAART amongst PLHIV in a tertiary health facility in south-South Nigeria BMC Infect Dis 2013 13 401 10.1186/1471-2334-13-401 24229404 \n15. McDonald HP Garg AX Haynes RB Interventions to enhance patient adherence to medication prescriptions: scientific review JAMA. 2002 288 22 2868 2879 10.1001/jama.288.22.2868 12472329 \n16. World Health Organization, World Health Organization Department of HIV/AIDS Antiretroviral therapy for HIV infection in adults and adolescents : recommendations for a public health approach 2010 Geneva World Health Organization \n17. Johnston V Cohen K Wiesner L Morris L Ledwaba J Fielding KL Viral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch J Infect Dis 2014 209 5 711 720 10.1093/infdis/jit411 23943851 \n18. 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Zhou Z Wagar N DeVos JR Rottinghaus E Diallo K Nguyen DB Optimization of a low cost and broadly sensitive genotyping assay for HIV-1 drug resistance surveillance and monitoring in resource-limited settings PLoS One 2011 6 11 e28184 10.1371/journal.pone.0028184 22132237 \n23. Gifford RJ Liu TF Rhee SY Kiuchi M Hue S Pillay D The calibrated population resistance tool: standardized genotypic estimation of transmitted HIV-1 drug resistance Bioinformatics. 2009 25 9 1197 1198 10.1093/bioinformatics/btp134 19304876 \n24. Liu TF Shafer RW Web resources for HIV type 1 genotypic-resistance test interpretation Clin Infect Dis 2006 42 11 1608 1618 10.1086/503914 16652319 \n25. Frentz D Boucher CA Assel M De Luca A Fabbiani M Incardona F Comparison of HIV-1 genotypic resistance test interpretation systems in predicting virological outcomes over time PLoS One 2010 5 7 e11505 10.1371/journal.pone.0011505 20634893\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2180",
"issue": "20(1)",
"journal": "BMC microbiology",
"keywords": "Adherence; Drug resistance mutation; Re-suppression; Virologic failure",
"medline_ta": "BMC Microbiol",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D009154:Mutation; D009549:Nigeria; D010349:Patient Compliance; D012189:Retrospective Studies; D019562:Viral Load",
"nlm_unique_id": "100966981",
"other_id": null,
"pages": "17",
"pmc": null,
"pmid": "31959116",
"pubdate": "2020-01-20",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "29255731;24589279;19304876;28253476;22461980;12472329;22132237;26584666;12001036;25301692;17121449;24229404;28588979;31356613;20634893;14523777;26186609;15722389;16652319;23943851;21306643;27677163;27439522",
"title": "Low levels of HIV-1 drug resistance mutations in patients who achieved viral re-suppression without regimen switch: a retrospective study.",
"title_normalized": "low levels of hiv 1 drug resistance mutations in patients who achieved viral re suppression without regimen switch a retrospective study"
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"abstract": "We report on the occurrence of a rare and as yet unforseeable adverse reaction to treatment with celecoxib, a cyclooxygenase-2 (COX-2) selective, non-steroidal, anti-inflammatory drug. A previously healthy adult suffered fatal acute multiple organ failure presumably after diffuse allergic vasculitis with diffuse necrotic purpura. Although no conclusive proof is available, such a reaction could have been triggered by at least one of two mechanisms: an allergic reaction linked to the chemical structure of celecoxib; or an interaction of the drug with synthesis of endothelial eiconasoids leading to an imbalance between vasoactive end products, resulting in widespread rise to local thrombosis.",
"affiliations": null,
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"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib",
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"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D011720:Pyrazoles; D013449:Sulfonamides; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
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"title": "Fatal allergic vasculitis associated with celecoxib.",
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"abstract": "Re-exposure to immunotherapy in metastatic colorectal cancer may be indicated in selected patients that previously benefitted from immunotherapy with tolerable irAEs.",
"affiliations": "Danish Colorectal Cancer Center South Vejle Hospital University Hospital of Southern Denmark Vejle Denmark.;Danish Colorectal Cancer Center South Vejle Hospital University Hospital of Southern Denmark Vejle Denmark.;Danish Colorectal Cancer Center South Vejle Hospital University Hospital of Southern Denmark Vejle Denmark.;Danish Colorectal Cancer Center South Vejle Hospital University Hospital of Southern Denmark Vejle Denmark.;Danish Colorectal Cancer Center South Vejle Hospital University Hospital of Southern Denmark Vejle Denmark.",
"authors": "Hamre|Tonje Riise|TR|;Stougaard|Julie Kristine|JK|;Havelund|Birgitte Mayland|BM|;Jensen|Lars Henrik|LH|https://orcid.org/0000-0002-0020-1537;Hansen|Torben Frøstrup|TF|https://orcid.org/0000-0001-7476-671X",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4349\nCCR34349\nCase Report\nCase Reports\nRe‐exposure to immunotherapy in metastatic colon cancer: A case report\nHAMRE et al.\nHamre Tonje Riise 1\nStougaard Julie Kristine 1\nHavelund Birgitte Mayland 1\nJensen Lars Henrik https://orcid.org/0000-0002-0020-1537\n1 2\nHansen Torben Frøstrup https://orcid.org/0000-0001-7476-671X\n1 2 torben.hansen@rsyd.dk\n\n1 Danish Colorectal Cancer Center South Vejle Hospital University Hospital of Southern Denmark Vejle Denmark\n2 Institute of Regional Health Research University of Southern Denmark Vejle Denmark\n* Correspondence\nTorben Frøstrup Hansen, Danish Colorectal Cancer Center South, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark.\nEmail: torben.hansen@rsyd.dk\n\n24 6 2021\n6 2021\n9 6 10.1002/ccr3.v9.6 e0434921 4 2021\n21 1 2021\n04 5 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nRe‐exposure to immunotherapy in metastatic colorectal cancer may be indicated in selected patients that previously benefitted from immunotherapy with tolerable irAEs.\n\nRe‐exposure to immunotherapy in metastatic colorectal cancer may be indicated in selected patients that previously benefitted from immunotherapy with tolerable irAEs.\n\ncolon cancer\nimmunotherapy\nmicrosatellite instability\nsource-schema-version-number2.0\ncover-dateJune 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.06.2021\nHamre TR , Stougaard JK , Havelund BM , Jensen LH , Hansen TF . Re‐exposure to immunotherapy in metastatic colon cancer: A case report. Clin Case Rep. 2021;9 :e04349. 10.1002/ccr3.4349\n==== Body\n1 INTRODUCTION\n\nPatients with metastatic colorectal cancer characterized by a deficient mismatch repair status are candidates for immunotherapy. Knowledge about reintroduction of immunotherapy, however, is missing. This case reports on the outcome of doublet immunotherapy in a patient previously exposed to monoimmunotherapy, and how these treatments may alter the expected outcome.\n\nColorectal cancer (CRC) is one of the leading causes of cancer‐related deaths worldwide with a 5‐year survival rate of 14% in patients with metastatic CRC (mCRC). 1 A minority of mCRC patients (approximately 5%) have a tumor with DNA mismatch repair deficiency and/or high microsatellite instability (dMMR/MSI‐H). 2 This patient group may respond poorly to conventional chemotherapy and have shorter overall survival compared to patients with mismatch repair proficient (pMMR) tumors. 3\n\nThe mismatch repair (MMR) system corrects spontaneous errors occurring during DNA replication. In dMMR tumors, errors accumulate resulting in microsatellite length mutation, microsatellite instability (MSI), 4 and truncated peptides that are able to activate the immune system. 5 The interest in evaluating the effect of immunotherapy in this particular patient group has therefore been tremendous.\n\nSeveral studies have demonstrated durable response and disease control by single anti‐programmed death PD‐1 checkpoint inhibitors such as pembrolizumab and nivolumab in dMMR metastatic colon cancers, and generally, one third of the patients show objective response. 6 , 7 , 8 Evidence has suggested enhanced efficacy with an objective response rate of 55% when combining nivolumab and ipilimumab (a CTLA‐4 inhibitor) and thereby targeting two sites of the immune‐regulatory system simultaneously, although the immune‐related adverse events (irAEs) are expectedly more frequent in this setting. 9 However, the safety profile of the combination is reported to be manageable with one third of the patients experiencing grade 3‐4 irAEs and only 13% discontinuing treatment. 10\n\nInteresting evidence is emerging from studies having examined the effect of immunotherapy as first‐line treatment in metastatic colon cancer 11 in conjunction with other treatment modalities such as radiation therapy 12 and in the neoadjuvant setting. 13 A recent study demonstrated significantly longer progression‐free survival with pembrolizumab compared to standard chemotherapy (16.5 vs 8.2 months) when applied as first‐line treatment in patients with dMMR/MSI‐H metastatic colon cancer. The rate of serious irAEs was significantly lower in the pembrolizumab group. 11\n\nThe growing evidence on immunotherapeutic treatment of dMMR/MSI‐H colon cancer has increased the number of patients receiving the treatment, and selecting the right patients is of utmost importance. 14 The expected clinical outcome of reintroduction of immunotherapy, however, remains widely unknown. Different therapeutic approaches following progression on immunotherapy are being investigated, and the clinical responsiveness to subsequent treatments may depend on previous exposure to immunotherapy. We present a case of a patient with metastatic colon cancer successfully treated with nivolumab and ipilimumab after previous progression on pembrolizumab. The outcome was quite surprising.\n\n2 CASE PRESENTATION\n\nA 53‐year‐old man was diagnosed with BRAF V600E‐mutated metastatic colon cancer with dMMR and a synchronous renal cell carcinoma in 2016. He was initially treated with standard oncology therapy as previously presented, 15 followed by 15 months of pembrolizumab monotherapy (Figure 1). Upon progression, fluorouracil and irinotecan (FOLFIRI) were reintroduced and bevacizumab added at the sixth cycle. The metastatic sites were the liver and peritoneal cavity. The combination of FOLFIRI and bevacizumab surprisingly resulted in stable disease for 8 months, despite the fact that the disease had previously progressed directly on both FOLFIRI and a bevacizumab containing regimen. At this point, an evaluation CT scan showed increasing carcinomatosis, and clinically, the patient presented with subfebrile temperature, weight loss, and increased abdominal pain.\n\nFIGURE 1 Treatment overview from the initiation of first‐line FOLFOX + bevacizumab in February 2016 to the latest update in September 2020 during the first treatment break. The width of the individual “treatment column” corresponds to the duration on treatment. The red curve illustrates changes in carcinoembryonic antigen in µg/L measured continuously since the introduction of pembrolizumab\n\nSince the patient requested further treatment and had a performance status of 0, second‐line immunotherapy with nivolumab and ipilimumab was initiated in March 2019 based on approval by the National Board of Health. In a 6‐week treatment cycle, the patient received nivolumab 3 mg/kg and low‐dose ipilimumab 1 mg/kg on day one followed by nivolumab 3 mg/kg on days 14 and 28. Table 1 summarizes the clinical events during this treatment. Figure 1 provides an overview of the patient's treatments and their duration. The level of carcinoembryonic antigen (CEA) was measured after initiation of pembrolizumab.\n\nTABLE 1 Clinical overview during re‐exposure to immunotherapy\n\nTimeline\tEvent\tConsequence\t\nMarch 2019\tTreatment initiation of Nivolumab and Ipilimumab\t\t\nMarch 2019\tDropping CEA, decreased pain, declining appetite, abdominal discomfort, weight loss 1.5 kilos\tLow‐dose prednisolone 10 mg daily for 1 wk and 5 mg daily in the subsequent wk\t\nApril 2019\tFurther drop of CEA, increased well‐being, weight gain of 1 kilo, and cessation of abdominal discomfort. No longer taking opioids. Performance status 0.\n\nDry, scaly, and itchy skin.\n\nCT scan showed increased carcinosis\n\n\tPrednisolone decreased to 2.5 mg daily for 1 wk and discontinued after a total of 6 wk.\n\nTreatment with a mild topical steroid and antihistamines initiated.\n\nResults of the first CT scan interpreted as pseudoprogression\n\n\t\nMay 2019\tCEA continuously dropping, performance status 0, slightly increased coughing.\n\nThe second CT scan, after 12 wk, showed stable disease and increased interstitial lung pattern\n\n\tPrednisolone 5 mg daily initiated (discontinued in February 2020)\t\nJuly 2019\tCT scan after 16 wk showed stable disease and slight regression of liver metastases\t\t\nMarch 2020\tTSH dropped to 0.15 and T4 increased to 24. Patient experienced no symptoms of hyperthyroidism\t\t\nApril 2020\tCT scan showed increased bilateral ground‐glass opacities. No clinical pulmonary symptoms.\n\nThyroid count spontaneously normalized\n\n\tIpilimumab discontinued due to radiologic pulmonary changes. Nivolumab monotherapy 3 mg/kg continued every 2 wk\t\nJuly 2020\tThe patient had clinical symptoms of tiredness and exercise‐induced dyspnea, which had increased over the last 2 mo, and developed grade 2‐3 immune‐mediated pneumonitis. No impairment of ADL. Otherwise performance status 0.\n\nCT scan revealed severe progression of ground‐glass opacities but otherwise stable disease\n\n\tThe patient was referred to a pulmonologist and a cardiologist. Cardiologic examination was normal. DLCO was severely reduced to 30% and Nivolumab was paused. Treatment with oral prednisolone 100 mg daily and prophylactic trimethoprim/ sulfamethoxazole was started. Prednisolone was tapered off over 3 mo\t\nSeptember 2020\tCT scan showed stable disease and CEA is stably low. Clinically, shortness of breath worsened after prednisolone 5 mg was discontinued\tPrednisolone 25 mg daily was reintroduced and tapered off over the next 6 wk\t\nJohn Wiley & Sons, Ltd\n\nDuring the first month of treatment the patient presented with decreased pain, a drop in CEA, and reduced consumption of opioids. At the same time, he experienced declining appetite, abdominal discomfort, and a weight loss of 1.5 kg leading to initiation of prednisolone. The second month resulted in physical improvement with weight gain, cessation of abdominal discomfort, and a further drop in CEA. Prednisolone was tapered off over 6 weeks. A CT scan after the first cycle showed progression of abdominal carcinomatosis but was interpreted as immune infiltration. The subsequent CT scan showed stable disease and no longer signs of increasing carcinomatosis. Again, the CEA level dropped. However, due to a slightly increased radiological lung pattern and mild coughing, prednisolone 5 mg daily was initiated. After the third treatment cycle, the CT scan revealed slight regression of liver metastases.\n\nDuring the following 9 months, stable disease was confirmed radiologically and biochemically with a continuous drop of CEA and clinically supported by weight gain and increasing physical activity of the patient. Except for a mild skin rash treated with antihistamines and mild topical steroids, the treatment was tolerated well.\n\nAfter 13 months of treatment, the CT scan showed increased bilateral ground‐glass opacities. The patient was clinically unaffected and the CEA level continued dropping. The radiological changes were interpreted as side effects to long‐term immunotherapy. Consequently, ipilimumab was discontinued and nivolumab continued as monotherapy. Three months later, the radiological ground‐glass opacities significantly worsened, and the patient now presented with tiredness and exercise‐induced dyspnea consistent with irAE grade 2‐3 pneumonitis. Hospitalization was not needed, but the condition required termination of nivolumab and treatment with high‐dose prednisolone of 100 mg daily tapered down over the next 3 months.\n\nTo this date, re‐exposure to immunotherapy has been effective for 18 months and ongoing, with manageable side effects that did not require hospitalization. The patient is currently on a treatment break for the first time after 52 months of continuous treatments. He is clinically unaffected and had stable disease on the most recent CT scans in September and December 2020. CEA remains stable at the lowest level seen in this individual.\n\n3 DISCUSSION\n\nThe number of mCRC patients treated with immunotherapy is increasing due to a growing number of approved indications. Recently, pembrolizumab was approved by the U.S Food and Drug Administration as first‐line treatment for patients with dMMR/MSI‐H mCRC. Meanwhile, multiple studies explore novel therapeutic approaches with immunotherapy, including combinations with radiation therapy, chemotherapy, and targeted therapy and treatment for early‐stage CRC in the neoadjuvant and adjuvant settings.\n\nConsequently, there is an increasingly relevant question of how to proceed after previous progression on immunotherapy. Its reintroduction is rather new in clinical oncology and knowledge on the issue is sparse. A major concern is that re‐exposure to immunotherapy may lead to multiple and severe irAEs due to a previously primed immune system in a fashion similar to allergic reactions. Also, the treatment strategy over the last years has moved from monotherapy to combination therapy with dual blockage of PD‐1 and CTLA‐4, which further enhances the risk of severe toxicity. The choice to reintroduce immunotherapy is therefore complex and should always be carefully balanced between the possible clinical benefit and treatment‐related toxicity in the individual patient.\n\nOur case illustrates a patient with dMMR metastatic colon cancer who achieved long‐term disease stabilization on combination immunotherapy with nivolumab and ipilimumab after previous progression on pembrolizumab. FOLFIRI and bevacizumab were given for 8 months during the immunotherapy pause. The decision to reintroduce immunotherapy was based on previous clinical response and mild irAEs during treatment with pembrolizumab and the lack of other treatment options. The combination was chosen partly since nivolumab and ipilimumab act synergistically to promote antitumor response through complementary mechanisms of action and seem to be superior to nivolumab monotherapy, 9 and partly in order to overcome a possible, acquired PD‐1‐resistance.\n\nTo the best of our knowledge, there is only one other and very recent case report on re‐exposure of immunotherapy in mCRC. Nivolumab and ipilimumab in their case were also well tolerated and had a meaningful benefit comparable to our results. 16 Data on three additional cases with a similar outcome were reported at the Society for Immunotherapy for Cancer (SITC) conference 2020. 17 Based on these data and the present case, we propose that reintroduction of immunotherapy may be indicated in selected patients in which irAEs have previously been manageable and clinical benefit documented.\n\nMore recently, preclinical and clinical evidence has suggested a mutual, enhanced effect of immunotherapy and antiangiogenic treatment. Antiangiogenic treatment reverses tumor‐induced immunosuppression in the tumor microenvironment (TME) and enhances drug delivery due to vessel normalization, thereby improving the efficacy of immunotherapy. 18 Also, immunotherapy can promote vascular normalization through a stimulation of interferon gamma (ifn‐Y) released from the activated T cells. 19 In the present case, the responsiveness to FOLFIRI and bevacizumab may have been altered due to a prolonged immunogenic effect of pembrolizumab after its cessation, resulting in a synergistic effect of pembrolizumab and bevacizumab. Similarly, the subsequent response to nivolumab plus ipilimumab may have been enhanced because of recent treatment with bevacizumab.\n\nThe phase III BEACON study treated 665 BRAF‐mutated mCRC patients who had previously progressed on one or two treatment regimens. They were randomized to receive encorafenib and cetuximab plus/minus binimetinib or standard treatment. The triplet and doublet treatments inhibiting BRAF, EGFR, and/or MEK resulted in significantly longer overall survival and a higher response rate compared to standard treatment. 20 To this date, our patient has been on a treatment break since July 2020. When the disease progresses, the likely next step will therefore be to target the BRAF and EGFR receptors based on data from the BEACON study.\n\n4 CONCLUSION\n\nRe‐exposure to immunotherapy may be indicated in selected patients with metastatic colon cancer and dMMR leading to tolerable irAEs and a meaningful clinical benefit. Reintroducing a treatment targeting the same receptor as previously (PD‐1) seems to provide benefit based on the combination with a treatment targeting another regulatory side (CTLA‐4). The benefit from the chemotherapy given in‐between might be due to long‐term effects of the initial immunotherapy.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nTRH: identified the special learning points and conceived the idea for the case report, was responsible for collection and assembly of data, drafted the manuscript, discussed the results, commented, and approved the final version of the manuscript. JKS: identified the special learning points and conceived the idea for the case report, discussed the results, commented, and approved the final version of the manuscript. BMH: identified the special learning points and conceived the idea for the case report, discussed the results, commented, and approved the final version of the manuscript. LHJ: identified the special learning points and conceived the idea for the case report, discussed the results, commented, and approved the final version of the manuscript. TFH: identified the special learning points and conceived the idea for the case report, was responsible for collection and assembly of data, co‐drafted the manuscript, discussed the results, commented, and approved the final version of the manuscript.\n\nETHICAL APPROVAL\n\nThe patient has provided oral and written consent to this case report.\n\nACKNOWLEDGMENTS\n\nWe are very thankful for the willingness of the patient to share his history, and we thank Karin Larsen for linguistic editing of the manuscript. The study was supported by the Regional Strategic Council for Research in the Region of Southern Denmark, which had no influence on any part of the study.\n\nDATA AVAILABILITY STATEMENT\n\nAll relevant data are presented in the case.\n==== Refs\nREFERENCES\n\n1 Institute UNC . Surveillance, epidemiology, and end results program: cancer stat facts: colon and rectum cancer. https://seer.cancer.gov/statfacts/html/colorect.html\n2 Venderbosch S , Nagtegaal ID , Maughan TS , et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20 :5322‐5330.25139339\n3 Heinemann V , Kraemer N , Buchner H , et al. Somatic DNA mutations, tumor mutational burden (TMB), and MSI status: association with efficacy in patients (pts) with metastatic colorectal cancer (mCRC) of FIRE‐3 (AIO KRK‐0306). ASCO Annual Meeting abstract 3591. J Clin Oncol. 2018;36 (15_suppl ):3591‐3591.30372390\n4 Laporte GA , Leguisamo NM , Kalil AN , Saffi J . Clinical importance of DNA repair in sporadic colorectal cancer. Crit Rev Oncol Hematol. 2018;126 :168‐185.29759559\n5 Viale G , Trapani D , Curigliano G . Mismatch repair deficiency as a predictive biomarker for immunotherapy efficacy. Biomed Res Int. 2017;2017 :4719194. 10.1155/2017/4719194 28770222\n6 Le DT , Uram JN , Wang H , et al. PD‐1 blockade in tumors with mismatch‐repair deficiency. N Engl J Med. 2015;372 :2509‐2520.26028255\n7 Overman MJ , McDermott R , Leach JL , et al. Nivolumab in patients with metastatic DNA mismatch repair‐deficient or microsatellite instability‐high colorectal cancer (CheckMate 142): an open‐label, multicentre, phase 2 study. Lancet Oncol. 2017;18 :1182‐1191.28734759\n8 Le DT , Kim TW , Van Cutsem E , et al. Phase II open‐label study of pembrolizumab in treatment‐refractory, microsatellite instability‐high/mismatch repair‐deficient metastatic colorectal cancer: KEYNOTE‐164. J Clin Oncol. 2020;38 :11‐19.31725351\n9 Overman MJ , Lonardi S , Wong KYM , et al. Durable clinical benefit with nivolumab plus ipilimumab in dna mismatch repair‐deficient/microsatellite instability‐high metastatic colorectal cancer. J Clin Oncol. 2018;36 :773‐779.29355075\n10 Morse MA , Overman MJ , Hartman L , et al. Safety of nivolumab plus low‐dose ipilimumab in previously treated microsatellite instability‐high/mismatch repair‐deficient metastatic colorectal cancer. Oncologist. 2019;24 :1453‐1461.31147488\n11 Andre T , Shiu KK , Kim TW , et al. Pembrolizumab in microsatellite‐instability‐high advanced colorectal cancer. N Engl J Med. 2020;383 :2207‐2218.33264544\n12 Levy A , Massard C , Soria JC , Deutsch E . Concurrent irradiation with the anti‐programmed cell death ligand‐1 immune checkpoint blocker durvalumab: single centre subset analysis from a phase 1/2 trial. Eur J Cancer. 2016;68 :156‐162.27764686\n13 Chalabi M , Fanchi LF , Dijkstra KK , et al. Neoadjuvant immunotherapy leads to pathological responses in MMR‐proficient and MMR‐deficient early‐stage colon cancers. Nat Med. 2020;26 :566‐576.32251400\n14 Basile D , Garattini SK , Bonotto M , et al. Immunotherapy for colorectal cancer: where are we heading? Expert Opin Biol Ther. 2017;17 :709‐721.28375039\n15 Trabjerg ND , Rask C , Jensen LH , Hansen TF . Pseudoprogression during treatment with pembrolizumab followed by rechallenge with chemotherapy in metastatic colorectal cancer: a case report. Clin Case Rep. 2019;7 :1445‐1449.31360509\n16 Das S , Allen A , Berlin J . Immunotherapy after immunotherapy: response rescue in a patient with microsatellite instability‐high colorectal cancer post‐pembrolizumab. Clin Colorectal Cancer. 2020;19 :137‐140.32146081\n17 Kasi P , Chan C . Circulating tumor DNA (ctDNA) serial analysis during progression on PD‐1 blockade and later CTLA4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. J Immunother Cancer. 2020;8 . 10.1136/jitc-2020-SITC2020.0023\n18 Yi M , Jiao D , Qin S , Chu Q , Wu K , Li A . Synergistic effect of immune checkpoint blockade and anti‐angiogenesis in cancer treatment. Mol Cancer. 2019;18 :60. 10.1186/s12943-019-0974-6 30925919\n19 Liu Z , Wang Y , Huang Y , et al. Tumor vasculatures: a new target for cancer immunotherapy. Trends Pharmacol Sci. 2019;40 :613‐623.31331639\n20 Kopetz S , Grothey A , Yaeger R , et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E‐mutated colorectal cancer. N Engl J Med. 2019;381 :1632‐1643.31566309\n\n",
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"title": "Re-exposure to immunotherapy in metastatic colon cancer: A case report.",
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"abstract": "Many studies have documented the increased risk of non-melanoma skin cancers in organ transplant recipients (OTRs). However, the incidence of melanoma is less well defined. To date, there have been no studies on the incidence of melanoma in Canadian OTRs. Herein, we determine the incidence and clinical features of melanoma in a cohort of OTRs in Southern Alberta, Canada.\n\n\n\nWe used the Southern Alberta Transplant database to identify kidney and liver transplant recipients between the years 2000 and 2012. This population was cross-referenced with the Alberta Cancer Registry for a diagnosis of melanoma. The clinical features of all cases were obtained, and the standardized incidence rate was calculated.\n\n\n\nWe identified 993 OTR patients, representing 5955 person-years. Only one patient developed a melanoma post-transplant, and this was a nodular melanoma. The age-standardized incidence rate was 11 per 100 000 (0.6 per 5955), compared to 13.4 per 100 000 in the general Alberta population (incidence rate ratio of 1.29, with 95% confidence interval of 0.17 to 9.82).\n\n\n\nThis is the first Canadian study to investigate the association between organ transplantation and melanoma. Our study did not identify an increased risk of developing a de novo melanoma post-transplant.",
"affiliations": "Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada.;Division of Nephrology, Department of Medicine and Community Health, University of Calgary, Calgary, AB, Canada.;Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada. regine.mydlarski@albertahealthservices.ca.",
"authors": "Tran|Mimi|M|;Sander|Megan|M|;Ravani|Pietro|P|;Mydlarski|P Régine|PR|",
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"keywords": "epidemiology; immunosuppression; melanoma; transplant",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000416:Alberta; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D011183:Postoperative Complications; D018570:Risk Assessment; D012307:Risk Factors; D012878:Skin Neoplasms; D055815:Young Adult",
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"title": "Incidence of melanoma in organ transplant recipients in Alberta, Canada.",
"title_normalized": "incidence of melanoma in organ transplant recipients in alberta canada"
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"abstract": "Bilateral adrenal hemorrhage is a rare but potentially catastrophic complication of chemoprophylaxis. We report a patient who underwent a total knee arthroplasty and subsequently developed bilateral adrenal hemorrhage from enoxaparin. Once the patient was diagnosed with acute adrenal insufficiency, corticosteroids were promptly started, and the patient made a dramatic recovery and did not suffer further complications.",
"affiliations": "Department of Orthopaedics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;HipKnee Arkansas Foundation, Little Rock, AR, USA.;Department of Orthopaedics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; HipKnee Arkansas Foundation, Little Rock, AR, USA.",
"authors": "Park|Kwan Jun|KJ|;Bushmiaer|Marty|M|;Barnes|C Lowry|CL|",
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"doi": "10.1016/j.artd.2015.02.001",
"fulltext": "\n==== Front\nArthroplasty TodayArthroplasty TodayArthroplasty Today2352-3441Elsevier S2352-3441(15)00008-410.1016/j.artd.2015.02.001Case ReportBilateral adrenal hemorrhage in a total knee patient associated with enoxaparin usage Park Kwan Jun MDaBushmiaer Marty APNbBarnes C. Lowry MDlbarnes@arspecialty.comab∗a Department of Orthopaedics, University of Arkansas for Medical Sciences, Little Rock, AR, USAb HipKnee Arkansas Foundation, Little Rock, AR, USA∗ Corresponding author. 1701 Aldersgate Road, Suite 3, Little Rock, AR 72205, USA. Tel.: +1 501 246 4439. lbarnes@arspecialty.com28 8 2015 9 2015 28 8 2015 1 3 65 68 9 12 2014 2 2 2015 15 2 2015 Copyright © 2015 Published by Elsevier Inc. on behalf of American Association of Hip and Knee Surgeons.2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Bilateral adrenal hemorrhage is a rare but potentially catastrophic complication of chemoprophylaxis. We report a patient who underwent a total knee arthroplasty and subsequently developed bilateral adrenal hemorrhage from enoxaparin. Once the patient was diagnosed with acute adrenal insufficiency, corticosteroids were promptly started, and the patient made a dramatic recovery and did not suffer further complications.\n\nKeywords\nBilateral adrenal hemorrhageTotal joint replacementAnticoagulationEnoxaparin\n==== Body\nIntroduction\nDeep venous thrombosis (DVT) is a known complication of total joint replacement surgery and, without appropriate anticoagulation prophylaxis, the prevalence of DVT is reported to be 40–80% in total knee replacements, 50–60% in total hip replacements, and 30–60% after hip fracture [1], [2]. The associated risk of pulmonary embolism is approximately 10% with an overall fatality rate of 5% [1], [2]. Several anticoagulation prophylaxis modalities, including pharmacological and mechanical methods, have been designed to prevent this complication. However, pharmacological agents, such as unfractionated heparin, warfarin, low-molecular-weight-heparin, or rivaroxaban, are not without risks [3]. Development of hematoma, persistent hemorrhage, and wound complications are among the commonly reported pharmacophylaxis-related complications [3], [4].\n\nAcute bilateral adrenal hemorrhage (BAH), although rare, has been reported as a potentially catastrophic complication of anticoagulation therapy [1], [5], [6], [7]. However, this condition also occurs in the settings of post-operative period, septicemia, pregnancy, anti-phospholipid syndrome, heparin-associated thrombocytopenia, trauma, and coagulopathies [1], [5], [6], [7].\n\nBAH presents a diagnostic challenge to treating physicians due to non-specific complaints and symptoms that range from vague abdominal pain, nausea, vomiting, neuropsychiatric symptoms, hypotension or shock, and fever [5], [6], [7].\n\nTo our knowledge, several case reports of BAH from warfarin and unfractionated heparin exist in a subset of orthopedic patients undergoing joint replacement surgeries [1], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. However, this is the first reported case of enoxaparin-induced BAH following arthroplasty. We report a case of BAH secondary to enoxaparin use after unilateral knee replacement surgery.\n\nCase history\nA 65 year-old female with end-stage osteoarthritis of the right knee had progressively worsening joint pain that was refractory to all non-operative measures. The patient's medical comorbidities included well-controlled hypertension, gastroesophageal reflux disease, and remote history of DVT. Once the patient failed non-operative management of her osteoarthritis, the patient was recommended to undergo right total knee arthroplasty. The risks and the benefits of the surgery were explained, and informed consent was obtained. The patient's perioperative and post-operative courses were uncomplicated, and was discharged home on post-operative day (POD) two. The patient was placed on enoxaparin (30 mg B.I.D) for DVT prophylaxis on POD one and was discharged home with the same regimen for an additional ten days.\n\nOn POD eight, the patient was admitted with complaints of vague epigastric pain, lethargy, and febrile episodes. Symptoms included decreased appetite, somnolence, anxiety, and nausea without vomiting. Physical examination was unremarkable, and vital signs included temperature 101.7 F, heart rate 111, respiration 20, blood pressure 123/87, and oxygen saturation 92% at admission. Laboratory values showed significant hyponatremia (126), hypokalemia (2.6), glucose (60), hematocrit (25.3), creatinine (0.8), WBC count (14,900), and platelet count (161,000). The patient was immediately evaluated, and the differential diagnosis included pulmonary embolism, sepsis, metabolic encephalopathy, and adrenal insufficiency.\n\nHowever, the patient's chest CT scan was negative for pulmonary embolism, and the MRI of the brain was negative for acute pathology. The medicine team was concerned for presumed sepsis, and empirical intravenous antibiotics (ceftriaxone, vancomycin, and acyclovir) were promptly started, and various cultures including CSF, urine, and blood were obtained.\n\nThe patient deteriorated rapidly and was transferred to the intensive care unit and received aggressive intravenous volume support with pressors. Subsequent clinical and laboratory findings suggested possible adrenal insufficiency. Basal cortisol levels were obtained before and after cosyntropin (ACTH) stimulation, and both values were 0.3 nmol/L. Abdominal CT revealed bilateral adrenal hemorrhages (Fig. 1). Enoxaparin was immediately discontinued, and the patient was started on high dose hydrocortisone. The patient improved dramatically and subsequently left the intensive care unit within 24–48 h of glucocorticoid administration. Glucocorticoid was tapered, and the patient improved clinically and was discharged without further complications.\n\nThe patient most recently followed up with the senior author at her 1-year visit, and her knee has excellent range of motion, and X-rays demonstrate well-placed components with no evidence of loosening. She has since returned to her previous activity level including bowling.\n\nDiscussion\nMultiple guidelines exist in order to assist physicians with clinical decisions regarding DVT prophylaxis for elective joint replacement surgery patients [3], [11]. While both mechanical and pharmacological methods are effective, chemoprophylaxis remains a popular choice due to its higher compliance rate and ease of use [3], [11]. However, chemoprophylaxis is associated with increased risk of bleeding, wound complications, and heparin-induced thrombocytopenia [3], [4], [6], [11], [17]. BAH is a rare complication of chemoprophylaxis. While spontaneous adrenal hemorrhage has been reported, BAH has been reported in settings of sepsis, trauma, intra-operative/post-operative complications, severe burns, anticoagulant therapy, other coagulopathies [6], [7], [17].\n\nFollowing a detailed literature search for BAH cases in hip and knee arthroplasty patients, a total of 16 cases were identified (Table 1). The mean age was 66.5. Six patients (37.5%) underwent bilateral total knee replacements, and one patient underwent revision total knee arthroplasty. Clinical symptoms and signs are summarized in Table 2. Some patients presented with laboratory abnormalities, such as, hyponatremia (8 patients) and hypokalemia (2). Acute anemia was present in two patients, and thrombocytopenia was present in seven patients. BAH was determined at the time of autopsy in two cases.\n\nIn seven cases, heparin-induced-thrombocytopenia was identified as the cause of BAH after confirmatory HIT antibody tests, however, in three cases (including our case), the HIT antibody test was negative. In our patient, platelet count was 161,000 at initial presentation, and remained between 200,000 and 250,000 during hospitalization. Abdominal CT scans revealed BAH in 12 of 16 patients, and it was the most reliable diagnostic test. In 10 of 16 patients, acute adrenal insufficiency was further confirmed by a cosyntropin stimulation test, and these patients received corticosteroids and made remarkable recovery within 24–48 h.\n\nBAH often presents with non-specific signs and symptoms, and clinical associations are commonly unrecognized, making prospective diagnosis and early treatment exceedingly difficult. Physical examinations are rarely diagnostic, with fever and abdominal pain being two consistent clinical features [5], [18], [19]. Laboratory clues include unexplained drop in hematocrit, leukocytosis, eosinophilia, hyponatremia, hyperkalemia, and hypoglycemia [1], [5], [6], [7], [8], [11], [12], [19], [20], [23]. While the biochemical evidence of adrenal insufficiency including hyponatremia and hyperkalemia with volume contraction can provide diagnostic clues for acute adrenal insufficiency, not all patients presented with such laboratory abnormalities. Only 8 of 16 patients presented with hyponatremia, two patients had hypokalemia only, and no patient had hyperkalemia at the time of presentation.\n\nCT, MRI and U/S are recommended diagnostic BAH imaging modalities [19]. Diagnosis is made on abdominal CT or MRI with common characteristics featuring bilateral rounded adrenal gland enlargement, confirmed by cosyntropin stimulation. The mass seen on CT and MRI of adrenal gland with no enhancement or enhancement only in a pattern of a thin peripheral rim can be used to distinguish hematoma from other pathologies [12], [21].\n\nWhen suspicious for acute adrenal insufficiency, cosyntropin stimulation should be performed to measure the adrenal gland response to a cosyntropin challenge at 30 and 60 min intervals. A normal, appropriate response is approximately a two-fold increase in serum cortisol levels after cosyntropin administration [5], [6], [18]. With steroid administration, the dramatic improvement in the cardiovascular status was usually seen, and all patients who received the corticosteroid therapy made remarkable recovery within 24–48 h of administration [7], [18], [22]. However, the clinical course of this disease does not always follow a favorable one, and, once the shock is too severe, even large doses of steroids may be ineffective [18].\n\nThe loss of adrenal function associated with adrenal atrophy is almost universal in patients who survived acute adrenal insufficiency [22]. While our patient did not require long-term steroid therapy, all 10 patients in the literature who recovered via the corticosteroid replacement therapy were placed on long-term replacement therapy.\n\nRao et al. reported their experience in treating several patients with BAH and developed an algorithm for the diagnosis and treatment of bilateral massive adrenal hemorrhage [18]. In this algorithm, they have categorized the progression of the disease into different levels depending on the severity of cardiopulmonary status [18]. They emphasized the importance of having high clinical suspicion for BAH and recommended early intervention with intravenous corticosteroids.\n\nSummary\nBAH is a rare complication that can occur with DVT prophylaxis such as enoxaparin or coumadin. Total joint patients with chemoprophylaxis, who present with non-specific symptoms including abdominal distress, fever, and anxiety related complaints on post-operative day 4–10, should not be ignored, and a high index of clinical suspicion is required to prevent this catastrophic event. CT scans and hormone assays should be obtained at earliest suspicion of acute adrenal insufficiency, and presumptive steroid treatment should be initiated while awaiting confirmatory tests.\n\nAppendix A Supplementary data\nThe following is/are the supplementary data related to this article:Conflict of Interest Statement 1\n Conflict of Interest Statement 2\n Conflict of Interest Statement 3\n \n\nOne or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to http://dx.doi.org/10.1016/j.artd.2015.02.001.\n\nFigure 1 Axial CT image demonstrating bilateral adrenal gland enlargements and diffuse hemorrhage (arrows).\n\nTable 1 Characteristics of total arthroplasty patients who suffered bilateral adrenal hemorrhages (BAH).\n\nAuthor\tAge\tSex\tProcedure\tPost op days\tDvt prophylaxis\tOutcome\tComplaints\tInitial labs\tImaging\tHIT\tTx\t\nLaban et al. [1]\t83\tF\tB/L TKA\t8\tSQ heparin and warfarin\tDC home\tEpigastric pain, nausea\tNa 126, K 3.4, no anemia\tCT\tUnk\tHydrocortisone\t\nRajamanickam et al. [5]\t52\tM\tB/L TKA\t9\tEnoxaparin\tdc home\tAbdominal pain, nausea, vomiting, constipation, shock, confusion, fever\tNa 134, hct 30, HIT neg\tCT\tNo\tHydorcortisone\t\nBarrou et al. [8]\t80\tM\tTKA\t6\tEnoxaparin\tDC home\tAbdominal pain, anxiety, confusion, fever, hypotension\tNa 129, K 5.5\tCT\tNo\tCorticosteroids\t\nBest et al. [9]\t75\tF\tTHA\t9\tDabigatran\tUnknown\tSob, fever, ab pain\tUnknown\tCT\tUnk\tUnknown\t\nBleasel et al. [10]\t69\tF\tTKA rev\tUnknown\tSQ heparin\tUnknown\tFever, nausea, vomiting, abdominal pain\tUnknown\tNone\tYes\tUnknown\t\nChow et al. [11]\t44\tM\tB/L TKA\t10\tHeparin drip\tDC home\tAbdominal pain, tachycardia, fever\tNa 124, K 4.9, low platelets\tCT\tYes\tMethylprednisolone, hydrocortisone taper\t\nCozzolino et al. [12]\t66\tF\tTKA\t7\tCoumadin\tDC home\tNausea, anorexia, and emesis\tNa 129, K 5.2, Hct 23\tCT\tUnk\tCorticosteroids\t\nDelhumeau et al. [13]\t74\tM\tTHA\t4\tSQ heparin\tUnknown\tAbdominal pain, fever, hypotention, ab tenderness\tUnknown\tCT\tYes\tUnknown\t\nErnest et al. [14]\t68\tF\tTHA\tUnknown\tSQ heparin\tUnknown\tShock\t\t\tYes\t\t\nHardwicke et al. [15]\t63\tF\tB/L TKA\t7\tSQ heparin and warfarin\tDC home\tNausea, vomiting, anorexia, vague feeling of illness, hypotension, dizziness\tNa 127, K 4.6\tCT\tUnk\tDexamthasone\t\nKurtz et al. [16]\t54\tF\tTHA\tUnknown\tSQ dalteparin\tAlive\tFever, abdominal pain, anorexia\tNa 131, NL K, low PLT\tCT\tYes\tCorticosteroids\t\nMongardon et al. [17]\t64\tM\tTHA\t7\tSQ heparin\tAlive\tFever, abdominal pain, shock\tNormal labs\tCT\tYes\tCorticosteroids\t\nSchuchmann et al. [19]\t83\tF\tB/L TKA\t5\tSQ heparin\tDeath\tAnxious, sob, shock, fever\tNa 122, K 4.2, Hct 31.2\tNone\tUnk\tNone\t\nSouied et al. [20]\t63\tF\tTHA\t10\tSQ heparin\tDeath\tHypotension, shock, fever\tNa 138, K 4.5, PLT 380000\tCT\tYes\tCorticosteroids\t\nRies, Guiney et al. [21]\t61\tM\tB/L TKA\t9\tWarfarin\tDeath\tAbdominal pain, nausea, fever, hypotension\tUnknown\tNone\tUnk\tNone\t\nPark et al.*\t65\tF\tTKA\t8\tEnoxaparin\tDC home\tAbdominal pain, nausea, fever, hypotension\tNa 126, K 2.6, Hct 25.3\tCT\tNo\tCorticosteroids\t\n*Our patient described in the case report.\n\nTable 2 Clinical signs and symptoms of the patients from reported BAH cases.\n\nSymptoms\tNumber of patients\t\nNausea\t8/16 (50%)\t\nAbdominal pain\t16/16 (100%)\t\nEmesis\t3/16 (19%)\t\nFebrile\t12/16 (75%)\t\nConfusion/neuropsychiatric symptoms\t5/16 (31%)\t\nHypotension/Shock\t9/16 (56%)\t\nShortness of breath\t2/16 (13%)\n==== Refs\nReferences\n1 LaBan M.M. Whitmore C.E. Taylor R.S. Bilateral adrenal hemorrhage after anticoagulation prophylaxis for bilateral knee arthroplasty Am J Phys Med Rehabil 82 5 2003 418 12704285 \n2 Stringer M.D. Steadman C.A. Hedges A.R. Deep vein thrombosis after elective knee surgery. An incidence study in 312 patients J Bone Joint Surg Br 71 3 1989 492 2785998 \n3 Johanson N.A. Venous thromboembolism guidelines and prophylaxis. Hip and Knee Reconstruction Orthopedic Knowledge Update (OKU) 4 2011 American Association of Orthopaedic Surgeons Rosemont, IL \n4 Colwell C.W. Jr. Froimson M.I. Anseth S.D. A mobile compression device for thrombosis prevention in hip and knee arthroplasty J Bone Joint Surg Am 96 3 2014 177 24500578 \n5 Rajamanickam A. Patel P. Anbazhagan P. Harte B. A life threatening complication of anticoagulation prophylaxis-bilateral adrenal hemorrhage J Hosp Med 4 9 2009 E25 20013867 \n6 Rosenberger L.H. Smith P.W. Sawyer R.G. Bilateral adrenal hemorrhage: the unrecognized cause of hemodynamic collapse associated with heparin-induced thrombocytopenia Crit Care Med 39 4 2011 833 21242799 \n7 Vella A. Nippoldt T.B. Morris J.C. 3rd Adrenal hemorrhage: a 25-year experience at the Mayo Clinic Mayo Clin Proc 76 2 2001 161 11213304 \n8 Barrou Z. Verny C. Cohen-Bittan J. Verny M. Bilateral adrenal necrosis after knee arthroplasty J Am Geriatr Soc 58 11 2010 2248 21054321 \n9 Best M. Palmer K. Jones Q.C. Wathen C.G. Acute adrenal failure following anticoagulation with dabigatran after hip replacement and thrombolysis for massive pulmonary embolism BMJ Case Rep 2013 2013 \n10 Bleasel J.F. Rasko J.E. Rickard K.A. Richards G. Acute adrenal insufficiency secondary to heparin-induced thrombocytopenia-thrombosis syndrome Med J Aust 157 3 1992 192 1635495 \n11 Chow V.W. Abnousi F. Huddleston J.I. Lin L.H. Heparin-induced thrombocytopenia after total knee arthroplasty, with subsequent adrenal hemorrhage J Arthroplasty 27 7 2012 1413 e15 22397862 \n12 Cozzolino D. Peerzada J. Heaney J.A. Adrenal insufficiency from bilateral adrenal hemorrhage after total knee replacement surgery Urology 50 1 1997 125 9218034 \n13 Delhumeau A. Moreau X. Chapotte C. Houi N. Bigorgne J.C. Heparin-associated thrombocytopenia syndrome: an underestimated etiology of adrenal hemorrhage Intensive Care Med 19 8 1993 475 8294632 \n14 Ernest D. Fisher M.M. Heparin-induced thrombocytopaenia complicated by bilateral adrenal haemorrhage Intensive Care Med 17 4 1991 238 1744311 \n15 Hardwicke M.B. Kisly A. Prophylactic subcutaneous heparin therapy as a cause of bilateral adrenal hemorrhage Arch Intern Med 152 4 1992 845 1558445 \n16 Kurtz L.E. Yang S. Bilateral adrenal hemorrhage associated with heparin induced thrombocytopenia Am J Hematol 82 6 2007 493 17266058 \n17 Mongardon N. Bruneel F. Henry-Lagarrigue M. Shock during heparin-induced thrombocytopenia: look for adrenal insufficiency! Intensive Care Med 33 3 2007 547 17186288 \n18 Rao R.H. Vagnucci A.H. Amico J.A. Bilateral massive adrenal hemorrhage: early recognition and treatment Ann Intern Med 110 3 1989 227 2643380 \n19 Schuchmann J.A. Friedman P.A. Bilateral adrenal hemorrhage: an unusual complication after bilateral total knee arthroplasty Am J Phys Med Rehabil 84 11 2005 899 16244529 \n20 Souied F. Pourriat J.L. Le Roux G. Adrenal hemorrhagic necrosis related to heparin-associated thrombocytopenia Crit Care Med 19 2 1991 297 1842892 \n21 Hoeffel C. Legmann P. Luton J.P. Chapuis Y. Fayet-Bonnin P. Spontaneous unilateral adrenal hemorrhage: computerized tomography and magnetic resonance imaging findings in 8 cases J Urol 154 5 1995 1647 7563311 \n22 Kovacs K.A. Lam Y.M. Pater J.L. Bilateral massive adrenal hemorrhage. Assessment of putative risk factors by the case-control method Medicine (Baltimore) 80 1 2001 45 11204502 \n23 Ries M.D. Guiney W. Lynch F. Fatal massive adrenal hemorrhage after bilateral total knee arthroplasty J Arthroplasty 9 5 1994 559 7807117\n\n",
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"journal": "Arthroplasty today",
"keywords": "Anticoagulation; Bilateral adrenal hemorrhage; Enoxaparin; Total joint replacement",
"medline_ta": "Arthroplast Today",
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"pages": "65-68",
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"pubdate": "2015-09",
"publication_types": "D002363:Case Reports",
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"title": "Bilateral adrenal hemorrhage in a total knee patient associated with enoxaparin usage.",
"title_normalized": "bilateral adrenal hemorrhage in a total knee patient associated with enoxaparin usage"
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"abstract": "BACKGROUND\nValproic Acid is a commonly used psychiatric drug primarily used as a mood stabilizer. Mild hyperammonemia is a Valproic Acid common adverse effect. This report presents an example of treated hyperammonemia on Valproic acid therapy managed with L-carnitine administration in BD patients characterized by sudden vulnerability.\nWe report the case of a 29-year-old man suffering from bipolar disorder (BD) and substance use disorder who exhibited sudden altered mental status upon admittance to the inpatient unit. The patient was started on Valproic acid with no improvement.\nThe patient had remarkably high ammonia levels (594 μg/dL) without hepatic insufficiency, likely due to his valproate treatment.\n\n\nMETHODS\nThe patient was administered lactulose, intravenous hydration, and i.v. levocarnitine supplementation 4.5 g/day.\n\n\nRESULTS\nThe administration leads to reduction of ammonia levels to 99 μg/dL within 12 hours upon initiation of carnitine therapy and progressive restore of his mental status within 24 hours.\n\n\nCONCLUSIONS\nResolution of hyperammonemia caused by Valproic acid therapy may be enhanced with the administration of L-carnitine. An interesting aspect of this case was how rapidly the patient responded to the carnitine therapy.",
"affiliations": "Asl Novara, Department of Mental Health - Outpatient Unit Asl Novara, Department of Mental Health - Inpatient Unit- Borgomanero, Novara Department of Neuroscience, University School of Naples \"Federico II\", Naples, Italy.",
"authors": "Cattaneo|Carlo Ignazio|CI|;Ressico|Francesca|F|;Valsesia|Roberta|R|;D'Innella|Pierluigi|P|;Ballabio|Matteo|M|;Fornaro|Michele|M|",
"chemical_list": "D018692:Antimanic Agents; D014635:Valproic Acid; D002331:Carnitine",
"country": "United States",
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"doi": "10.1097/MD.0000000000008117",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28953637MD-D-17-0318510.1097/MD.0000000000008117081175000Research ArticleClinical Case ReportSudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient Essential review of the literature and case reportCattaneo Carlo Ignazio MDa∗Ressico Francesca MDaValsesia Roberta MDbD’Innella Pierluigi MDbBallabio Matteo MAaFornaro Michele MD, PhDcManchia. Mirko a Asl Novara, Department of Mental Health – Outpatient Unitb Asl Novara, Department of Mental Health – Inpatient Unit- Borgomanero, Novarac Department of Neuroscience, University School of Naples “Federico II”, Naples, Italy.∗ Correspondence: Carlo Ignazio Cattaneo, Azienda Sanitaria Locale Novara, Borgomanero 28021, Novara, Italy (e-mail: dr.carloignaziocattaneo@gmail.com).9 2017 29 9 2017 96 39 e811723 5 2017 15 8 2017 1 9 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nValproic Acid is a commonly used psychiatric drug primarily used as a mood stabilizer. Mild hyperammonemia is a Valproic Acid common adverse effect. This report presents an example of treated hyperammonemia on Valproic acid therapy managed with L-carnitine administration in BD patients characterized by sudden vulnerability.\n\nPatient concerns:\nWe report the case of a 29-year-old man suffering from bipolar disorder (BD) and substance use disorder who exhibited sudden altered mental status upon admittance to the inpatient unit. The patient was started on Valproic acid with no improvement.\n\nDiagnoses:\nThe patient had remarkably high ammonia levels (594 μg/dL) without hepatic insufficiency, likely due to his valproate treatment.\n\nInterventions:\nThe patient was administered lactulose, intravenous hydration, and i.v. levocarnitine supplementation 4.5 g/day.\n\nOutcomes:\nThe administration leads to reduction of ammonia levels to 99 μg/dL within 12 hours upon initiation of carnitine therapy and progressive restore of his mental status within 24 hours.\n\nLessons:\nResolution of hyperammonemia caused by Valproic acid therapy may be enhanced with the administration of L-carnitine. An interesting aspect of this case was how rapidly the patient responded to the carnitine therapy.\n\nKeywords\nbipolar disordercarnitinehepatic dysfunctionhyperammonemianeurotoxicityvalproic acidOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nValproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that inhibits degradation, and promotes postsynaptic transmission of gamma-aminobutyric acid (GABA).[1] VPA is widely used for the treatment of epilepsy, migraine, and a variety of psychiatric symptoms, including bipolar disorder (BD), borderline personality disorder (BPD), and alcohol withdrawal (AW). VPA has been used effectively to reduce agitation and aggression in both acute and postacute traumatic brain injury (TBI) patients,[2,3] as well as a variety of other neuropsychiatric syndromes, including dementia and mental retardation (MR).[4]\n\nOverall, VPA is well tolerated with respect to cognitive functioning, yet common, essentially dose-related, adverse effects (AEs) include fatigue, gastrointestinal disturbances, weight gain, tremor, hair loss, thrombocytopenia, teratogenicity. On the contrary, pancreatitis, hepatotoxicity, and hyperammonemia are infrequent AEs.[5]\n\nHyperammonemia can be defined as a serum level of ammonia higher than 50 μmol/L. It can be due to genetic conditions in newborns involving metabolism or liver disease, such as carnitine deficiency, malignancies, or portosystemic shunts. Elevated levels of ammonia can also be secondary to certain medications, such as 5-fluorouracil, salicylate, asparaginase, acetazolamide, diuretics, and VPA. Ammonia levels are increased in 12% to 52% of asymptomatic patients treated with VPA.[6] A recent study examined the frequency of hyperammonemia in a sample of older adults taking VPA compared with those not taking such medication, documenting 2-fold increased risk for hyperammonemia following VPA intake.[7]\n\n2 Case history\nWe report the case of a 29-year-old male with lifetime diagnosis BD, according to DMS-V criteria (APA, 2013), and substance use disorder (SUD) who was forcedly hospitalized due to aggressive behavior. His family history was negative for psychiatric illness, while his personal history was also positive for childhood epilepsy and characterized by several prior involuntary hospitalizations occurred in similar contexts, and a poor compliance to both psychiatric interviews and medications. He was receiving haloperidol decanoate 150 mg q 28 days: the latest injection had been administered 4 days before hospitalization. His current SUD involved both nicotine and substances of abuse; urine toxicology screen performed at the Emergency Department (E.R.) documented the following records: opioids >2000 ng/mL (negative <300); cocaine >5000 ng/mL (negative <300); benzodiazepines 898 ng/mL (negative <200); buprenorphine 13 ng/mL (negative <5). Hemochrome, serum electrolytes, and liver functioning were within normal ranges, as the electrocardiography (ECG) tracking was.\n\nUpon admission, he was alert and oriented to the person, place, and time. He was irritable and aggressive. He was started on VPA 1000 mg/day, lorazepam 7.5 mg/day, flurazepam 30 mg/day per o.s. (oral administration), and clotiapine 120 mg/day i.m. (intramuscular), which was later switched to oral formulation. One week upon admission, plasma valproate level was 73 μg/dL (reference range 27–102).\n\nDespite the pharmacological treatment, he was still disputatious, irritable, suspicious, interpretative; he kept refusing treatment and going against any rehabilitation program.\n\nThus, VPA was slowly increased up to 1800 mg/day, clotiapine and flurazepam were stopped, while he started chlorpromazine 100 mg/day and haloperidol 6 mg/day.\n\nTwenty days later, he showed no improvement in agitation, rather he was still fluctuating between aggressiveness and altered consciousness through lethargy, altogether with an altered walking mobility, characterized by an irregular gait pattern with a widened base of support and a decreased step length. His blood test revealed plasma valproate 124 μg/dL; serum ammonia was strikingly high—594 μg/dL, while his liver function was within normal range: aspartate aminotransferase (AST) 10 U/L, alanine aminotransferase (ALT) 8 U/L, gamma-glutamyl transpeptidase (GGT) 12 U/L, alkaline phosphatase (ALP) 59 U/L, prothrombin time International Normalized Ratio (PT INR) 1.13, Protothrombin Time Ratio (PR) 1.13, albumin 4.6 g/dL. Blood pressure was 110/70 mm Hg and the heart rate was 88 bpm. His temperature was 36.3°C and his respiratory rate was 20 breaths/min.\n\nThe patient was not delivered to the intensive care unit, rather he was treated on-site. VPA and antipsychotics were withdrawn, and he was administered lactulose (20 g orally 3 times a day), intravenous (i.v.) hydration (1500 mL/24 h), and i.v. L-carnitine supplementation 4.5 g/day diluted in 0.9% sodium chloride infusion solution. This latter treatment schedule was then administered for 2 consecutive days.\n\nAmmonia levels reduced to 99 μg/dL about 12 hours following initiation of carnitine therapy; the patient's mental status gradually improved back to baseline over 24 hours. At that time, plasma VPA was back within therapeutic limits (65 μg/dL).\n\nFour days later, he underwent EEG (electroencephalogram), which showed short sequences of slow-wave theta activity across the temporal cortex, bilaterally, yet the baseline EEG tracing was evaluated as normal. Abdominal ultrasonography showed a slightly enlarged liver, yet homogeneous in structure and free from focal lesions; gallbladder and bile ducts were also normal.\n\nTwelve days after being diagnosed with hyperammoniemia, he was alert, calm, cooperative, euthymic; impulsiveness had recovered, motricity was normal. He was then discharged in good clinical conditions (Fig. 1).\n\nFigure 1 Valproate-induced hyperammonemia development and treatment: timeline of a case report.\n\n3 Discussion\nVPA can cause hyperammonemia in the setting of both high and therapeutic drug levels without evidence of hepatic dysfunction. Prompt measurement of serum ammonia should be considered when there is a decreased level of consciousness in patients receiving VPA irrespective of the diagnosis and even after a long-term exposure.\n\nHyperammonemia can be asymptomatic or may progress to focal neurological deficit, seizure, marked sedation, coma, due to encephalopathy. Clinically significant AEs occur in approximately 10% of the patients showing valproate-related hyperammonemia, with ammonia levels about 2-fold increased beyond normal ranges (35–65 μmol/L). Yet, conclusive relationship between the daily doses of VPA and the onset and severity of VHE (valproate-induced hyperammonemic encephalopathy) has not been established.[8] A direct relationship between the development of VHE and serum VPA levels seems excluded, even though data available in literature are not concordant.\n\nVPA is known to be associated with decreased carnitine levels and occasionally true deficiency, which is an unusual problem in the healthy, well-nourished adult population. VPA depletes carnitine storages through different mechanisms, usually in long-term or high-dose treatment [9,10]: the effects of VPA on urea metabolism occur primarily in the liver mitochondria, via the inhibition of the enzyme required for the first step in the urea cycle, CPS1.[11] This may lead to a dose-independent increase in the concentration of its substrate, ammonia, in the blood.[12] Carnitine results also necessary in the mitochondria for the transport and the subsequent oxidation of fatty acids.[13] VPA inhibits carnitine transport, causing the increase in renal carnitine excretion.[14] Indeed, a carnitine deficiency leads to the reduction of fatty acids metabolism and the successive increase of protein utilization. VPA also accelerates ammonia production by the kidney [13]\n\nL-carnitine is an aminoacid derivative and important nutrient involved in fat metabolism. Up to 75% of L-carnitine is provided by diet, particularly red meat and dairy products. It is also biosynthesized endogenously from dietary amino acids (methionin, lysine), especially in the liver and in the kidneys.[15] Carnitine is responsible for 2 metabolic functions. It eases the fatty acyl-group transport into mitochondria and it also preserves the ratio of acyl-CoA to free CoA in the mitochondria. [16]\n\nCarnitine supplementation has been suggested in the treatment of a variety of health conditions such as cardiomyopathies, diabetic neuropathy, tuberculosis, dementia, renal failure, and anemia, and has been added to newborns’ foods and milk, even though data are preliminary.[17]\n\nAs VPA-induced hyperammonemia and VHE could be mediated at least in part by carnitine deficiency, it has been hypothesized that L-carnitine supplementation may prevent, correct, or attenuate these AEs.[16]\n\nVPA-induced hyperammonemia is an AE that may be prevented, corrected, or attenuated by L-carnitine supplementation because of VHE mediation, at least partly, by carnitine deficiency. [16]\n\nBohan et al [18] analyzed the association of L-carnitine treatment with hepatic survival in 92 patients with severe, symptomatic, VPA-induced hepatotoxicity, reporting that prompt intervention with i.v. rather than enteral L-carnitine was associated with the greatest hepatic survival. Because of the low (15%) bioavailability of enteral L-carnitine, the better survival with i.v. treatment may be related to higher blood levels.\n\nSome Authors [19,20] also suggest that carnitine might be considered as a novel therapeutic option in the management of depression and associated mood disorders, as well as attention-deficit hyperactivity disorder. Fernandes [21] reviewed the emerging evidence on the role of carnitine in mood disorders, yet results are not univocal: some studies examined depression scores in further detail after 12 weeks of carnitine treatment, whereas others found no statistically significant negative correlation between patients’ depression scores and total levels of serum carnitine. Carnitine supplementation has also been advocated in chronic VPA treatment, but data are limited [21].\n\nIn addition, patients who are treated with multiple anticonvulsants—such as VPA combined with PHT (phenobarbital), PB (phenytoin), or CBZ (carbamazepine)—are at a higher risk of developing hyperammonemia [22]. Yamamoto et al [23] evaluated a total of 2944 epileptic pediatric patients to identify risk factors for hyperammonemia: the authors observed that the mean ammonia level of the patients on VPA along with AEDs was significantly higher than that of those on VPA monotherapy, especially when VPA was combined to PHT or PB, rather than CBZ. The patient described herein was not suffering from epilepsy, thus was not taking any other AED, which would have increased his risk of developing hyperammonemia (and contributed to hindered interpretation of the results due to confounding bias). His VPA serum levels were normal, but as we previously observed, data in literature are not concordant with respect to a direct relationship between the development of VHE and serum VPA levels. Moreover, he had previously been treated with VPA, without developing hyperammonemia, which reasonably allows us to exclude a genetically inherited urea cycle disorder, even though genetic testing was not performed.\n\nIn conclusion, resolution or prevention of hyperammonemia may be enhanced with the administration of L-carnitine, yet further investigation is required. An interesting aspect of this case was how rapidly the patient responded to the carnitine therapy.\n\nAbbreviations: AED = antiepiletic drug, AEs = adverse effects, AW = alcohol withdrawal, BD = bipolar disorder, BPD = borderline personality disorder, CBZ = carbamazepine, ECG = electrocardiography, EEG = electroencephalogram, i.m = intramuscular, i.v = intravenous, MR = mental retardation, o.s = oral administration, PB = phenytoin, PHT = phenobarbital, SUD = substance use disorder, TBI = traumatic brain injury, VHE = valproate-induced hyperammonemic encephalopathy, VPA = valproic acid.\n\nInformed consent was obtained from the patient for publication of this case report.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Davis LL Ryan W Adinoff B \nComprehensive review of the psychiatric uses of valproate . J Clin Psychopharmacol \n2000 ;20 (1 Suppl 1) :1S –7S .10646685 \n[2] Chatham Showalter PE Kimmel DN \nAgitated symptom response to divalproex following acute brain injury . J Neuropsychiatry Clin Neurosci \n2000 ;12 :395 –7 .10956575 \n[3] Wroblewski BA Joseph AB Kupfer J \nEffectiveness of valproic acid on destructive and aggressive behaviours in patients with acquired brain injury . Brain Inj \n1997 ;11 :37 –47 .9012550 \n[4] Lindenmayer JP Kotsaftis A \nUse of sodium valproate in violent and aggressive behaviors: a critical review . J Clin Psychiatry \n2000 ;61 :123 –8 .10732659 \n[5] Nanau RM Neuman MG \nAdverse drug reactions induced by valproic acid . Clin Biochem \n2013 ;46 :1323 –38 .23792104 \n[6] Murphy JV Marquardt K \nAsymptomatic hyperammonemia in patients receiving valproic acid . Arch Neurol \n1982 ;39 :591 –2 .6810855 \n[7] Adler LW Regenold WT \nValproate-related hyperammonemia in older adult psychiatric inpatients . Prim Care Companion CNS Disord \n2015 ;17 : E-collection 2015 .\n[8] Verrotti A Trotta D Morgese G \nValproate-induced hyperammonemic encephalopathy . Metab Brain Dis \n2002 ;17 :367 –73 .12602513 \n[9] Ishikura H Matsuo N Matsubara M \nValproic acid overdose and L-carnitine therapy . J Anal Toxicol \n1996 ;20 :55 –8 .8837953 \n[10] Raskind JY El-Chaar GM \nThe role of carnitine supplementation during valproic acid therapy . Ann Pharmacother \n2000 ;34 :630 –8 .10852092 \n[11] Ghodke-Puranik Y Thorn CF Lamba JK \nValproic acid pathway: pharmacokinetics and pharmacodynamics . Pharmacogenet Genomics \n2013 ;23 :236 –41 .23407051 \n[12] Wadzinski J Franks R Roane D \nValproate-associated hyperammonemic encephalopathy . J Am Board Fam Med \n2007 ;20 :499 –502 .17823470 \n[13] Bezinover D Postula M Donahue K \nPerioperative exacerbation of valproic acid-associated hyperammonemia: a clinical and genetic analysis . Anesth Analg \n2011 ;113 :858 –61 .21821508 \n[14] Camina MF Rozas I Castro-Gago M \nAlteration of renal carnitine metabolism by anticonvulsant treatment . Neurology \n1991 ;41 :1444 –8 .1891096 \n[15] Borum PR Bennett SG \nCarnitine as an essential nutrient . J Am Coll Nutr \n1986 ;5 :177 –82 .3088084 \n[16] Lheureux PE Penaloza A Zahir S \nScience review: carnitine in the treatment of valproic acid-induced toxicity: what is the evidence? \nCrit Care \n2005 ;9 :431 –40 .16277730 \n[17] Evangeliou A Vlassopoulos D \nCarnitine metabolism and deficit: when supplementation is necessary? \nCurr Pharm Biotechnol \n2003 ;4 :211 –9 .12769764 \n[18] Bohan TP Helton E McDonald I \nEffect of L-carnitine treatment for valproate-induced hepatotoxicity . Neurology \n2001 ;56 :1405 –9 .11376200 \n[19] Tobe EH \nMitochondrial dysfunction, oxidative stress, and major depressive disorder . Neuropsychiatr Dis Treat \n2013 ;9 :567 –73 .23650447 \n[20] Anglin RE Mazurek MF Tarnopolsky MA \nThe mitochondrial genome and psychiatric illness . Am J Med Genet B Neuropsychiatr Genet \n2012 ;159B :749 –59 .22887963 \n[21] Fernandes R \nAcetyl-L-carnitine for depression and mood disorders . J IHP . 2014 :73 –79 .\n[22] Mock CM Schwetschenau KH \nLevocarnitine for valproic-acid-induced hyperammonemic encephalopathy . Am J Health Syst Pharm \n2012 ;69 :35 –9 .22180549 \n[23] Yamamoto Y Takahashi Y Imai K \nRisk factors for hyperammonemia in pediatric patients with epilepsy . Epilepsia \n2013 ;54 :983 –9 .23409971\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "96(39)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D001714:Bipolar Disorder; D002331:Carnitine; D006801:Humans; D022124:Hyperammonemia; D008297:Male; D019966:Substance-Related Disorders; D016896:Treatment Outcome; D014635:Valproic Acid",
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"pages": "e8117",
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"pmid": "28953637",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17823470;1891096;6810855;10646685;3088084;12769764;9012550;22180549;12602513;23407051;23650447;22887963;23409971;10956575;10852092;16277730;21821508;23792104;10732659;8837953;11376200;26445683",
"title": "Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: Essential review of the literature and case report.",
"title_normalized": "sudden valproate induced hyperammonemia managed with l carnitine in a medically healthy bipolar patient essential review of the literature and case report"
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"abstract": "Methotrexate (MTX) is an antimetabolite that was initially developed as a chemotherapeutic agent to treat malignancies but later used extensively to treat rheumatological conditions. MTX-induced toxicity is dose- and duration-dependent. Myelosuppression is a rare but fatal complication of MTX that can occur even with low doses used for inflammatory conditions. Multiple factors such as age, renal impairment, and nutritional status increase the risk of developing MTX toxicity. Frequent monitoring of symptoms and lab values are the hallmarks of prompt diagnosis and prevention of complications. Clinicians should have a high degree of suspicion to diagnose pancytopenia secondary to MTX especially in patients with multiple confounding comorbidities. We present the case of a 79-year-old male who presented with mucositis and pancytopenia diagnosed to be secondary to weekly MTX for giant cell arteritis leading to anemia and septic shock causing death.",
"affiliations": "Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.;Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.;Internal Medicine, Drexel University College of Medicine, Philadelphia, USA.;Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.;Internal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA.",
"authors": "Kanderi|Tejaswi|T|;Chan Gomez|Janet|J|;Puthenpura|Max M|MM|;Yarlagadda|Keerthi|K|;Gangireddy|Mounika|M|",
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"doi": "10.7759/cureus.8492",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8492\nMedical Education\nOncology\nHematology\nPancytopenia as a Complication of Low-Dose Methotrexate in a Septuagenarian: A Rare Presentation\nMuacevic Alexander Adler John R Kanderi Tejaswi 1 Chan Gomez Janet 1 Puthenpura Max M 2 Yarlagadda Keerthi 1 Gangireddy Mounika 1 \n1 \nInternal Medicine, University of Pittsburgh Medical Center (UPMC) Pinnacle, Harrisburg, USA \n\n2 \nInternal Medicine, Drexel University College of Medicine, Philadelphia, USA \n\nTejaswi Kanderi tejaswi.kanderi@outlook.com\n7 6 2020 \n6 2020 \n12 6 e849221 5 2020 7 6 2020 Copyright © 2020, Kanderi et al.2020Kanderi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/33197-pancytopenia-as-a-complication-of-low-dose-methotrexate-in-a-septuagenarian-a-rare-presentationMethotrexate (MTX) is an antimetabolite that was initially developed as a chemotherapeutic agent to treat malignancies but later used extensively to treat rheumatological conditions. MTX-induced toxicity is dose- and duration-dependent. Myelosuppression is a rare but fatal complication of MTX that can occur even with low doses used for inflammatory conditions. Multiple factors such as age, renal impairment, and nutritional status increase the risk of developing MTX toxicity. Frequent monitoring of symptoms and lab values are the hallmarks of prompt diagnosis and prevention of complications. Clinicians should have a high degree of suspicion to diagnose pancytopenia secondary to MTX especially in patients with multiple confounding comorbidities. We present the case of a 79-year-old male who presented with mucositis and pancytopenia diagnosed to be secondary to weekly MTX for giant cell arteritis leading to anemia and septic shock causing death.\n\npancytopeniamethotrexateleucovorinimpaired renal functionThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nMethotrexate (MTX) is an antimetabolite that was initially developed as a chemotherapeutic agent in the management of malignancy. It was only later that MTX at low doses gained popularity as a disease-modifying agent for autoimmune diseases. Giant cell arteritis (GCA) is a prolific autoimmune disorder defined as a systemic inflammatory disease of the medium and large arterial vessels, with high prevalence in the elderly population [1]. Active GCA has a high risk of permanent vision loss if left untreated [2]. Histological confirmation with temporal artery biopsy is the gold standard for diagnosis; however, sensitivity is low given the skip pattern of inflammation [1]. Glucocorticoids are the mainstay of treatment, but in cases of anticipated glucocorticoid side effects where patients have a protracted treatment course or exacerbating comorbid conditions such as diabetes mellitus, glucocorticoid-sparing agents are used as an adjunct therapy or instead of traditional steroid treatment [2,3]. MTX is a widely used alternative therapy due to its ability to dampen systemic auto-inflammatory response [3,4]. However, like most therapeutics, MTX has its side-effect profile, with one of the most drastic and complicated adverse outcomes being medication-induced pancytopenia. Careful monitoring and clinical discretion should be used in following patients with MTX-induced pancytopenia until a resolution, as the condition carries a mortality of around17-44% [5].\n\nHere we discuss the case of a 79-year-old male who presented with pancytopenia attributed to MTX toxicity after excluding other possible etiologies.\n\nCase presentation\nA 79-year-old Caucasian male with a medical history of anemia of chronic disease, chronic kidney disease (stage 3), iron deficiency anemia, insulin-dependent type 2 diabetes mellitus, hypertension, coronary artery disease, paroxysmal atrial fibrillation (Afib), GCA, IgG kappa MGUS (monoclonal gammopathy of undetermined significance), and internal hemorrhoids presented to the ED with complaints of generalized weakness and mouth sores for the past two weeks. Vitals on presentation include a temperature of 37.5 °C (99.5 °F), pulse rate of 79, respiratory rate of 19 breaths per minute, blood pressure of 176/66, and saturation level of 100% on room air. The physical examination was significant for large circular oral ulcers, with surrounding erythema bilaterally in the mouth and throat, and the rest of the physical examination including the neuroexamination was unremarkable. The patient has a 30 pack-year smoking history and drinks alcohol occasionally. \n\nLabs included hemoglobin of 7.9 g/dL (baseline: 10 g/dL), white blood cell count of 0.50 K/uL (baseline 9-10 K/uL), and platelets of 12 K/uL (baseline: 300-400 K/uL). White blood cell count with differential revealed neutrophils of 14% (reference: 50-70%) and absolute neutrophil count (ANC) of 70 cells/uL (reference: 1,800-7,400) with +2 anisocytosis, microcytosis, +2 poikilocytosis, +1 schistocytosis along with dhole bodies, atypical lymphocytes, and toxic granulation.\n\nLabs were also significant for red cell distribution width (18% [reference: 12- 15%]), creatinine (2.57 mg/dL [baseline: 1.8-2.0 mg/dL]), glomerular filtration rate (23 mL/minute [baseline: 40-60 mL/minute]), aspartate transaminase (14 U/L [reference <40 U/L]), alanine transaminase (37 U/L [reference: <60 U/L]), alkaline phosphatase (117 U/L [reference: <100 U/L]), ferritin (>5,000 ng/mL [reference: <300 ng/mL]), iron (57 mcg/dL [reference: 60-150 mcg/dL]), iron saturation (17% [reference: 20-50%]), iron-binding capacity (150 mcg/dL [reference: 250-450 mcg/dL]), and sedimentation rate (110 mm/hour [reference: 0-20 mm/hour]); mean corpuscular volume and folic acid were normal. Peripheral smear showed rare megaloblasts with no blasts besides anemia, leucopenia, and thrombocytopenia.\n\nOf note, his dabigatran (anticoagulation for Afib) was held for the past month due to recurrent episodes of epistaxis. The patient has been on PROCRIT® for anemia of chronic disease and has had intravenous iron in the past for iron deficiency anemia.\n\nThe patient was transfused one unit of platelets and was started on neutropenic precautions and broad-spectrum antibiotics with cefepime and vancomycin. He underwent esophagogastroduodenoscopy and colonoscopy, which revealed mild gastritis and internal hemorrhoids, respectively, with no active bleeding. Blood cultures grew methicillin-resistant coagulase-negative staphylococci (MRCNS) sensitive to vancomycin and pan-sensitive Escherichia coli. Careful medication reconciliation revealed that the patient was started on oral MTX 15 mg once every week, folic acid 1 mg daily, and prednisone 2 mg once daily less than six months ago for his GCA. Onset and worsening of pancytopenia and mucosal ulcers correlated to the period of starting the medications. The impaired renal function might have also contributed to MTX toxicity as the drug is excreted primarily by kidneys. MTX levels on admission were not available. The hematology team was consulted for assistance in the treatment of MTX-induced pancytopenia, resulting in discontinuation of MTX and starting intravenous leucovorin 10 mg/m2 every six hours for four doses along with folic acid on the day of admission. Throughout the hospital course, the patient also received blood and platelet transfusions with a hemoglobin goal of 7.5 to 8 g/dL and a platelet goal of 20 K/uL if no bleeding. Pancytopenia significantly improved over the next week with a white blood cell count of 5.7 k/uL, ANC of 730 cells/uL, hemoglobin of 9.7 g/dL, and platelets of 104 K/uL. Please refer to Figures 1-3 for trends in hemoglobin, white blood cell count, and platelets, respectively.\n\nFigure 1 Trend in hemoglobin\nDay 1 is the day of admission. Values marked in black represent the values that prompted blood transfusion.\n\nFigure 2 Trend in white blood cell count\nDay 1 is the day of admission.\n\nFigure 3 Trend in platelets\nDay 1 is the day of admission. Values marked in black represent the values that prompted platelet transfusion.\n\nOral mucositis gradually worsened to a point where the patient could tolerate any oral intake, leading to percutaneous endoscopic gastrostomy tube placement and discharge to long-term acute care (LTACH) facility given the overall deconditioning.\n\nWe did not see a need for bone marrow biopsy as the decrease in cell counts correlated with the start of MTX, and cell counts improved with discontinuation of MTX and treatment with folinic acid within one week. Interestingly, the patient underwent a bone marrow biopsy in 2009 and was diagnosed with MGUS with no evidence of lymphoproliferative process or clonal expansion of plasma cells; since then he was being followed by hematology and had normal paraproteins a year before the presentation.\n\nHe completed the antibiotic course as recommended by the infectious disease team. His course at LTACH was complicated by a v-fib arrest, return of spontaneous circulation (ROSC) was achieved, and the patient was transferred to the intensive care unit, where his clinical status further worsened despite being on multiple vasopressors, leading the family to change him to the DNR (do-not-resuscitate) status; shortly thereafter the patient succumbed to cardiac arrest (PEA [pulseless electrical activity] arrest).\n\nDiscussion\nMTX is a folate antagonist that inhibits dihydrofolate reductase (DHFR), preventing the conversion of dihydrofolate to tetrahydrofolate and thus blocking the synthesis of purines and pyrimidines and, therefore, inhibiting DNA, RNA, and protein synthesis. However, coming to its effect against autoimmune diseases, multiple mechanisms such as inhibition of T-cell activation, selective downregulation of B cells, and inhibition of methyltransferase activity are thought to play a role in addition to inhibiting DHFR [6,7].\n\nMTX-induced pancytopenia is dose- and duration-dependent and is seen in approximately 1.4% of the reported side effects, with a female preponderance (62.51%), with around 59% in patients above 60 years of age [8,9]. The effects of pancytopenia include anemia, leukopenia, and thrombocytopenia. This results in systemic manifestations including fatigue due to low hemoglobin, infections secondary to leukopenia and/or neutropenia, bleeding, and ecchymosis from decreased platelet count. Monitoring patients for clinical signs and symptoms of pancytopenia is crucial in timing for tapering or discontinuing treatment and administering rescue therapy such as leucovorin (folinic acid), which has demonstrated some efficacy in expediting recovery [10].\n\nMTX toxicity is reported to start with stomatitis and progress to pancytopenia, which can occur at any time of the treatment [11]. Myelosuppression/ pancytopenia as a complication of MTX is well known, but low doses causing the same is not well documented, which needs strong emphasis as the drug has gained wide acceptance among rheumatologists due to its efficacy and relatively safe therapeutic window in a wide variety of inflammatory rheumatologic conditions including GCA [12,13]. Case reports and meta-analysis report a decrease in the risk of relapse and limiting the duration of steroids by using 10-15 mg/week of MTX as adjunctive therapy in patients with GCA [14,15].\n\nPossible risk factors include age and age-related decline in renal function owing to increased levels of MTX. Hypoalbuminemia also increases the risk of toxicity due to increased levels of free MTX than albumin-bound MTX [16]. Studies also reported nutritional status, polypharmacy, use of other antifolate drugs, and prescribing errors as other risk factors [11]. Poor nutritional status has been reported to be a risk factor due to prolonged half-life and a significant decrease in clearance in undernourished patients [16,17]. Mucositis and ulceration, in turn, lead to poor nutritional intake and worsening of renal function, and also serve as sites of serious infection. In our patient age, a poor nutritional status due to mucositis and acute-on-chronic decrement of renal function may have also contributed to the toxicity.\n\nThe American College of Rheumatology recommends complete blood count (CBC), serum creatinine, and transaminase tests to be performed at baseline before initiating MTX therapy, with monitoring every 2-4 weeks for the first three months, 8-12 weeks for the next three months, and once every 12 weeks thereafter [18]. Recovery time from pancytopenia varies depending on other comorbidities and concomitant infection; however, studies reported median recovery time around four to six days [11].\n\nMTX-induced pancytopenia is commonly reported with the treatment of rheumatoid arthritis (RA) than with GCA. RA by itself can cause anemia, neutropenia, and thrombocytopenia (in case of Felty syndrome with splenomegaly), whereas GCA can cause anemia, although other hematological manifestations are rarely reported, drawing a possibility of disease process augmenting pancytopenia in addition to MTX in RA.\n\nFolic acid supplementation may reduce MTX toxicity. Studies also report that folic acid can prevent MTX-induced hyperhomocysteinemia, thus ensuring cardioprotection [19]. However, MTX toxicity has been reported even with supplementation of folic acid, just like in our patient. Leucovorin is thought to prevent stomatitis and also can aid in quick recovery from toxic effects. Studies also report the use of G-CSF (granulocyte colony-stimulating factor and steroids for MTX-induced myelosuppression in patients with RA, but there is a need for further studies to confirm similar findings in GCA [20].\n\nFrequent lab monitoring and careful increments of dose, if needed, are the cornerstone in preventing and prompt diagnosis of MTX toxicity. We also think that MTX-induced pancytopenia is underreported and overlooked especially in patients with multiple comorbidities with the possibility of misattributing pancytopenia to other conditions.\n\nConclusions\nCaution should be taken before prescribing MTX to the elderly, especially those with impaired renal function. In addition to periodic monitoring with CBC, patients and their families should be educated about the possible toxic effects and symptoms such as stomatitis, fatigue, and fever, as long-term use of MTX for inflammatory conditions is becoming prevalent. Clinicians should have a high degree of suspicion to diagnose MTX-induced pancytopenia for the appropriate management, thereby avoiding fatal outcomes.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Giant cell arteritis: early diagnosis is key Eye Brain Baig IF Pascoe AR Kini A Lee AG 1 12 11 2019 30697092 \n2 [Treatment of giant cell arteritis and polymyalgia rheumatica] Z Rheumatol Horvath L Hellmich B 175 185 79 2020 32078029 \n3 Polymyalgia rheumatica and giant cell arteritis: a systematic review JAMA Buttgereit F Dejaco C Matteson EL Dasgupta B 2442 2458 315 2016 27299619 \n4 Systematic literature review informing the 2018 update of the EULAR recommendation for the management of large vessel vasculitis: focus on giant cell arteritis RMD Open Monti S Agueda AF Luqmani RA 1003 5 2019 \n5 Single low-dose methotrexate-induced fatal pancytopenia: case report and review of the literature Biomed J Sci Tech Res Uz B 2763 15 2019 \n6 Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis Rheumatology (Oxford) Wessels JA Huizinga TW Guchelaar HJ 249 255 47 2008 18045808 \n7 Increased peripheral blood B-cells expressing the CD5 molecules in association to autoantibodies in patients with lupus erythematosus and evidence to selectively down-modulate them Biomed Pharmacother Böhm I 338 343 58 2004 15194170 \n8 How should we manage low-dose methotrexate-induced pancytopenia in patients with rheumatoid arthritis? Clin Rheumatol Cansu DÜ Teke HÜ Bodakçi E Korkmaz C 3419 3425 37 2018 30056523 \n9 Will you have pancytopenia with methotrexate? 6 2020 2020 https://www.ehealthme.com/ds/methotrexate/pancytopenia/ \n10 Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis Semin Arthritis Rheum MacKinnon SK Starkebaum G Willkens RF 119 126 15 1985 https://www.ncbi.nlm.nih.gov/pubmed/3877983 3877983 \n11 Methotrexate-induced pancytopenia: a case series of 46 patients Int J Rheum Dis Ajmani S Preet Singh Y Prasad S 846 851 20 2017 28261918 \n12 Low-dose methotrexate-induced pancytopenia Clin Rheumatol Singh YP Aggarwal A Misra R Agarwal V 84 87 26 2007 16636937 \n13 A case of low dose methotrexate toxicity causing pancytopenia Chest Grist W Elamir Y 100 155 2019 \n14 Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis Arthritis Rheum Mahr AD Jover JA Spiera RF 2789 2797 56 2007 17665429 \n15 Methotrexate treatment in large vessel vasculitis and polymyalgia rheumatica Clin Exp Rheumatol Spies CM Burmester GR Buttgereit F 172 177 28 2010 https://www.clinexprheumatol.org/abstract.asp?a=4323 \n16 Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years Rheumatology Lim AYN Gaffney K Scott DGI 1051 1055 44 2005 15901903 \n17 Pharmacokinetics of methotrexate in adult Indian patients and its relationship to nutritional status Cancer Treat Rep Rajeswari R Shetty PA Gothoskar BP Akolkar PN Gokhale SV 727 732 68 1984 https://www.ncbi.nlm.nih.gov/pubmed/6722831 6722831 \n18 American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease‐modifying antirheumatic drugs in rheumatoid arthritis Arthritis Rheum Saag KG Teng GG Patkar NM 762 784 59 2008 18512708 \n19 Severe pancytopenia induced by low-dose methotrexate therapy for rheumatoid arthritis Blood Patsiornik Y Chandra AB Volozhanina E Barua T Huang Y 4224 114 2009 \n20 Benefit of simultaneous rhG-CSF and methylprednisolone 'pulse' therapy for methotrexate-induced bone marrow failure in rheumatoid arthritis Int J Hematol Kondo H Date Y 159 163 65 1997 https://pubmed.ncbi.nlm.nih.gov/9071820/ 9071820\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(6)",
"journal": "Cureus",
"keywords": "impaired renal function; leucovorin; methotrexate; pancytopenia",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e8492",
"pmc": null,
"pmid": "32656010",
"pubdate": "2020-06-07",
"publication_types": "D002363:Case Reports",
"references": "32078029;18045808;30056523;28261918;15901903;30697092;18512708;27299619;15194170;3877983;17665429;6722831;16636937;31673411;21044455;9071820",
"title": "Pancytopenia as a Complication of Low-Dose Methotrexate in a Septuagenarian: A Rare Presentation.",
"title_normalized": "pancytopenia as a complication of low dose methotrexate in a septuagenarian a rare presentation"
} | [
{
"companynumb": "US-MEDEXUS PHARMA, INC.-2020MED00216",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional":... |
{
"abstract": "Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.",
"affiliations": "1Rocky Mountain Poison and Drug Center, Denver Health, Denver, CO; 2Department of Emergency Medicine, University of Colorado, Aurora, CO; 3School of Nursing, Vanderbilt University, Nashville TN; 4Cincinnati Drug and Poison Information Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 5Division of Medical Toxicology, UCSD Medical Center, San Diego, CA; 6Pediatric Emergency Department and the Toxicology Unit, Assaf Harofeh Medical Center, Zerifin, Israel; and 7Department of Medicine, School of Medicine, University of Connecticut, Farmington, CT.",
"authors": "Heard|Kennon|K|;Bui|Alison|A|;Mlynarchek|Sara L|SL|;Green|Jody L|JL|;Bond|G Randall|GR|;Clark|Richard F|RF|;Kozer|Eran|E|;Koff|Raymond S|RS|;Dart|Richard C|RC|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e3182459c53",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "21(3)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000082:Acetaminophen; D000367:Age Factors; D018712:Analgesics, Non-Narcotic; D056486:Chemical and Drug Induced Liver Injury; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D014481:United States",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "174-83",
"pmc": null,
"pmid": "22407198",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "11319578;19101060;14632590;18086077;18004067;19651573;21192756;21098156;20564754;20170750;21242792",
"title": "Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.",
"title_normalized": "toxicity from repeated doses of acetaminophen in children assessment of causality and dose in reported cases"
} | [
{
"companynumb": "PHHY2015US071678",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
"d... |
{
"abstract": "Type-1 cryoglobulinemic vasculitis (CV) and mixed CV differ in their pathophysiology, clinical expression and treatment response. We report one patient with type-1 cryoglobulinemic vasculitis and skin ulcers that had remained active despite treatment with a variety of immunomodulating drugs including rituximab. The patient had a past medical history of non-Hodgkin lymphoma 10 years after CV onset for which she went into complete remission. The patient developed subsequent hematological anomalies in the serum and in the bone marrow without a definite diagnosis of myeloma. The patient finally went into clinical remission of her cryoglobulinemic vasculitis after treatment with bortezomib and dexamethasone. But she did not achieve an immunological remission and still had positive cryoglobulinemia and serum kappa-type free light chains. This suggests that bortezomib, a proteasome inhibitor that inhibits angiogenesis and production of paraproteins, is a promising treatment in type-1 cryoglobulinemic vasculitis.",
"affiliations": "Bone and Joint Research Group, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway. emilio.besada@unn.no",
"authors": "Besada|Emilio|E|;Vik|Anders|A|;Koldingsnes|Wenche|W|;Nossent|Johannes C|JC|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069283:Rituximab; D000069286:Bortezomib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-013-1323-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "97(6)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D003449:Cryoglobulinemia; D005260:Female; D006801:Humans; D011719:Pyrazines; D000069283:Rituximab; D017211:Treatment Failure; D016896:Treatment Outcome; D014657:Vasculitis",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "800-3",
"pmc": null,
"pmid": "23616220",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "22474249;22645181;21560117;22147444;4216269;22193964;18756542;22385269;22301823;20346005;22080846;22147661",
"title": "Successful treatment with bortezomib in type-1 cryoglobulinemic vasculitis patient after rituximab failure: a case report and literature review.",
"title_normalized": "successful treatment with bortezomib in type 1 cryoglobulinemic vasculitis patient after rituximab failure a case report and literature review"
} | [
{
"companynumb": "NO-CONCORDIA PHARMACEUTICALS INC.-GSH201705-002862",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
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"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"druga... |
{
"abstract": "Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.",
"affiliations": "Hematology Department, Institut Paoli-Calmettes, Marseille, France.;Hematology Department, Institut Paoli-Calmettes, Marseille, France.;Hematology Department, Centre Hospitalo Universitaire De Lille, Lille, France.;Hematology Department, Assistance Publique-Hôpitaux De Paris (APHP), Hopital Saint Louis, Paris and Paris 7 University, France.;Hematology Department, Centre Hospitalo Universitaire De Nice, Nice, France.;Hematology Department, King's College, London, United Kingdom.;Hematology Department, Insitut Gustave Roussy, Villejuif, France.;Biostatistics Department, Institut paoli-Calmettes, Marseille, France.;Hematology Department, Assistance Publique-Hôpitaux De Paris (APHP), Hopital Saint Louis, Paris and Paris 7 University, France.;Hematology Department, Hopital Avicenne (APHP) and Paris 13 University, Bobigny, France.;Hematology Department, Centre Hospitalo Universitaire De Toulouse, Toulouse, France.;Hematology Department, Centre Hospitalo Universitaire De Nantes, Nantes, France.;Hematology Department, Hopital Cochin (APHP) and Paris 5 University, Paris, France.;Hematology Department, King's College, London, United Kingdom.;Hematology Department, Assistance Publique-Hôpitaux De Paris (APHP), Hopital Saint Louis, Paris and Paris 7 University, France.;Hematology Department, Institut Paoli-Calmettes, Marseille, France.",
"authors": "Wanquet|Anne|A|;Prebet|Thomas|T|;Berthon|Céline|C|;Sebert|Marie|M|;Roux|Clémence|C|;Kulasekararaj|Austin|A|;Micol|Jean-Baptiste|JB|;Esterni|Benjamin|B|;Itzykson|Raphael|R|;Thepot|Sylvain|S|;Recher|Christian|C|;Delaunay|Jacques|J|;Dreyfus|François|F|;Mufti|Ghulam|G|;Fenaux|Pierre|P|;Vey|Norbert|N|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.24099",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "90(10)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064591:Allografts; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D001752:Blast Crisis; D002869:Chromosome Aberrations; D002893:Chromosomes, Human, Pair 3; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D015996:Survival Rate",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "859-63",
"pmc": null,
"pmid": "26113240",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities.",
"title_normalized": "azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities"
} | [
{
"companynumb": "FR-CELGENE-FRA-2015072059",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "We report the cases of two patients with secondary hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors, who were diagnosed using the recently developed HScore. The first patient presented with fever, cytopenia, and elevated liver enzyme levels at 46 days post-pembrolizumab administration. The HScore was 175. The second patient developed an immune-related adverse event at 30 days after the final pembrolizumab dose. The HScore was 185. Hemophagocytic lymphohistiocytosis was confirmed in both patients, and corticotherapy improved their condition. It is challenging to diagnose hemophagocytic lymphohistiocytosis, particularly after development at a late stage. Our patients developed hemophagocytic lymphohistiocytosis late after immune checkpoint inhibitor administration. However, the HScore enabled us to diagnose both cases precisely and in a timely manner.",
"affiliations": "Department of Respiratory, Showa General Hospital, Kodaira-city, Japan.;Department of Respiratory, Showa General Hospital, Kodaira-city, Japan.;Department of Respiratory, Showa General Hospital, Kodaira-city, Japan.;Department of Respiratory, Showa General Hospital, Kodaira-city, Japan.",
"authors": "Kurozumi|Atsumasa|A|0000-0002-3877-1770;Takahashi|Hidenori|H|;Watanabe|Takayasu|T|;Iwasaki|Yoshinobu|Y|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.13954",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n33783978\n10.1111/1759-7714.13954\nTCA13954\nCase Report\nCase Reports\nTwo cases of lung cancer with hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors\nKurozumi et al.\nKurozumi Atsumasa https://orcid.org/0000-0002-3877-1770\n1 atsumasakurozumi@gmail.com\n\nTakahashi Hidenori 1\nWatanabe Takayasu 1\nIwasaki Yoshinobu 1\n1 Department of Respiratory Showa General Hospital Kodaira‐city Japan\n* Correspondence\nAtsumasa Kurozumi, Department of Respiratory, Showa General Hospital, Kodaira‐city, Tokyo, Japan.\nEmail: atsumasakurozumi@gmail.com\n\n30 3 2021\n5 2021\n12 10 10.1111/tca.v12.10 16251628\n14 3 2021\n11 2 2021\n14 3 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nWe report the cases of two patients with secondary hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors, who were diagnosed using the recently developed HScore. The first patient presented with fever, cytopenia, and elevated liver enzyme levels at 46 days post‐pembrolizumab administration. The HScore was 175. The second patient developed an immune‐related adverse event at 30 days after the final pembrolizumab dose. The HScore was 185. Hemophagocytic lymphohistiocytosis was confirmed in both patients, and corticotherapy improved their condition. It is challenging to diagnose hemophagocytic lymphohistiocytosis, particularly after development at a late stage. Our patients developed hemophagocytic lymphohistiocytosis late after immune checkpoint inhibitor administration. However, the HScore enabled us to diagnose both cases precisely and in a timely manner.\n\nTwo cases of lung cancer developed HLH caused by immune checkpoint inhibitors. Both cases were diagnosed promptly using the HScore, which shows the effectiveness of the score for the diagnosis of secondary HLH by immune checkpoint inhibitors.\n\nHemophagocytic lymphohistiocytosis; Hscore\nhyperferritinemia\nimmune checkpoint inhibitor\nlung adenocarcinoma\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:09.05.2021\nKurozumi A , Takahashi H , Watanabe T , Iwasaki Y . Two cases of lung cancer with hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors. Thorac Cancer. 2021;12 :1625–1628. 10.1111/1759-7714.13954\n==== Body\nINTRODUCTION\n\nRecently, immune checkpoint inhibitors (ICIs) have been used to treat lung cancers. ICIs induce immune responses to cancer cells but may cause immune‐related adverse events (AEs) such as secondary hemophagocytic lymphohistiocytosis (HLH). HLH is a lethal syndrome caused by excessive inflammation, which presents as multiple organ damage. HLH is often characterized by extremely high ferritin levels, cytopenia, and elevated liver enzyme levels; however, there are many overlapping mechanisms with other systemic inflammatory syndromes, including cytokine release syndrome, sepsis, and multiple organ dysfunction syndrome. These conditions sometimes complicate the differential diagnosis of HLH. This is why there are no well‐established criteria for secondary HLH, which is often empirically diagnosed by experts. Recently, HLH has been diagnosed using the HScore, a parameter used to calculate HLH probability. Regarding HLH treatment, corticosteroids should be administered as soon as possible. The HLH‐2004 protocol suggests the effectiveness of dexamethasone and etoposide for more severe HLH patients. 1 Treatment can be intensified by adding other immunosuppressive agents.\n\nHere, we report two HLH cases that met the HScore cutoff value and improved with corticotherapy.\n\nCASE REPORT\n\nCase 1\n\nA 75‐year‐old man was diagnosed with stage IV lung adenocarcinoma. He was administered carboplatin + pemetrexed as the first‐line chemotherapy and developed grade 4 AEs after two cycles; his chemotherapy was interrupted. He was admitted to our department, and pembrolizumab was initiated as the second‐line therapy.\n\nHe developed a fever, and his liver enzyme levels were elevated at 10 days after the first dose of pembrolizumab (200 mg). Corticotherapy was initiated to treat suspected immune‐related AEs, and his symptoms gradually improved. On day 46, after the first dose, he developed fever, cytopenia, coagulation abnormality, and elevated liver enzyme levels. We suspected HLH, and laboratory tests revealed a ferritin level of 11 273 ng/mL. Bone marrow aspiration showed hemophagocytic macrophages; his HScore was 175. No infections were detected. We initiated corticotherapy, and his blood test findings improved (Figure 1(a)).\n\nFIGURE 1 (a) Clinical course after administration of pembrolizumab in the first patient. AST, aspartate aminotransferase; BT, body temperature; HLH, hemophagocytic lymphohistiocytosis; LDH, lactate dehydrogenase; mPSL, methylprednisolone; Plt, platelet; PSL, prednisolone. (b) Clinical course after administration of the last pembrolizumab dose in the second patient. AST, aspartate aminotransferase; Hb, hemoglobin; HLH, hemophagocytic lymphohistiocytosis; LDH, lactate dehydrogenase; mPSL, methylprednisolone; PSL, prednisolone\n\nCase 2\n\nA 60‐year‐old woman was diagnosed with stage IIIB lung adenocarcinoma. She was treated with concurrent chemoradiotherapy, and durvalumab was administered as consolidation therapy. We found brain metastasis in the cranial magnetic resonance imaging scan after 16 cycles of durvalumab. She underwent whole‐brain irradiation and chemotherapy. Six days after the second cycle of pemetrexed + pembrolizumab (200 mg), she developed acute appendicitis and underwent appendectomy. On day 30, after the last dose of pembrolizumab, she developed cytopenia, coagulation abnormalities, and elevated liver enzyme levels. We suspected HLH because of the elevated ferritin levels (64 726 ng/mL). Her HScore was 185, confirming HLH. After ensuring that the patient had no infections, we initiated corticotherapy, which significantly improved her laboratory findings (Figure 1(b)).\n\nDISCUSSION\n\nThe HLH‐2004 diagnosis criteria have been widely used for HLH, requiring five out of the eight criteria to be met for diagnosis (Table 1). However, there are several problems in diagnosing secondary HLH. 2 First, the criteria were originally established for primary HLH and not validated for secondary HLH, which has been empirically diagnosed by experts. Second, the eight criteria are not weighted. Therefore, HLH may still be diagnosed by some experts despite five criteria not being met. 3 Third, it is difficult to measure some criteria routinely, such as natural killer cell activity or soluble interleukin‐2 receptor levels. Recently, hyperferritinemia has been considered a strong indicator of HLH. 3 Fardet et al. developed the HScore, which uses weighted criteria, to calculate HLH probability. 2 The HScore cutoff value for HLH is 169 (sensitivity, 93%; specificity, 86%) 2 , 3 (Table 2). There has been no trial to determine whether the HLH‐2004 diagnosis criteria or HScore is superior. However, the high sensitivity and specificity of the HScore suggest its effectiveness at diagnosing HLH.\n\nTABLE 1 HLH‐2004 diagnosis criteria\n\nFever ≥38.5°C\t\nSplenomegaly\t\nCytopenia with at least two of the following (Hb <10 g/dL, Plt <100 000/μL, Neu <1000/μL)\t\nTG >265 mg/dL and/or fibrinogen <150 mg/dL\t\nFerritin >500 ng/mL\t\nsIL‐2R >age‐adjusted laboratory‐specific norms\t\nHemophagocytosis in bone marrow, spleen, lymph node, or liver\t\nLow or absent NK cell activity\t\nNote: Five of the eight criteria are needed to fulfill HLH diagnosis.\n\nAbbreviations: Hb, hemoglobin; Neu, neutrophils; NK, natural killer; Plt, platelets; sIL‐2R, soluble interleukin‐2 receptor; TG, triglycerides.\n\nTABLE 2 HScore\n\nKnown underlying immunosuppression\tNo (0), Yes (18)\t\nTemperature (°C)\t<38.4 (0), 38.4–39.4 (33), >39.4 (49)\t\nOrganomegaly\tNo (0), hepatomegaly or splenomegaly (23),\n\nhepatomegaly and splenomegaly (38)\n\n\t\nNumber of cytopenias\t1 lineage (0), 2 lineages (24), 3 lineages (34)\t\nFerritin (ng/mL)\t<2000 (0), 2000–6000 (35), >6000 (50)\t\nTriglyceride (mg/dL)\t<132.7 (0), 132.7–354 (44), >354 (64)\t\nFibrinogen (g/L)\t>2.5 (0), ≤2.5 (30)\t\nAST (U/L)\t<30 (0), ≥30 (19)\t\nHemophagocytosis features on bone marrow aspirate\tNo (0), Yes (35)\t\nNote: Cytopenia is defined as hemoglobin ≤9.2 mg/dL, white blood cell ≤5000/mm3, and platelets ≤110 000/mm3.\n\nAbbreviation: AST, aspartate aminotransferase.\n\nOnly 45 HLH cases have been reported to be caused by pembrolizumab, according to VigiBase, as of January 2021 (http://www.vigiaccess.org/). We reviewed 11 cases of ICI‐induced HLH, including our cases (Table 3). 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 The median interval from the last dose to HLH diagnosis was 24 days; therefore, the two patients discussed in our report were diagnosed in the late phase. Based on the time interval, cases in which HLH was diagnosed after a long interval showed a lower HScore than those diagnosed after a short interval (Figure 2). In almost all late‐HLH cases over 24 days, ICI treatment was interrupted to treat other immune‐related AEs using steroids, which may have alleviated the condition and HScore.\n\nTABLE 3 Characteristics, HScore, and clinical courses of patients with ICI‐related hemophagocytic lymphohistiocytosis\n\nStudy\tAge/sex\tDay from last ICI\tSteroid administration before HLH\tHScore\tKnown underlying immunosuppression\tBT\tOrganomegaly (liver/spleen)\tNumber of cytopenias\tFerritin\tTG\tFibrinogen\tAST\tBone marrow aspirate\tTreatments\tClinical courses\t\nMalissen et al. 4\t42/M\t5\tNo\t212\tYes\t–\t–\t–\t–\t–\t–\t–\t–\tCorticotherapy\tImproved\t\nMalissen et al. 4\t81/M\t5\tNo\t231\tYes\t–\t–\t–\t–\t–\t–\t–\t–\tCorticotherapy\tDied\t\nMichot et al. 5\t52/F\t56\tYes\t196\tYes\tN/A\tN/A/N/A\t3\t>6000\t>300\tN/A\tN/A\tYes\tDexamethasone and etoposide\tDied\t\nKalmuk et al. 6\t61/M\t4\tNo\t289\tNo\t> 39.4\tYes/Yes\t2\t57 934\t285\t1.34\t289\tYes\tDexamethasone and etoposide\tImproved\t\nHonjo et al. 7\t52/F\t14\tNo\t223\tYes\t38.6\tN/A/N/A\t2\t3877\t357\t1.85\t1556\tN/A\tCorticotherapy and MMF\tImproved\t\nThummalapalli et al. 8\t74/M\t25\tYes\t205\tYes\tN/A\tYes/Yes\t1\t33 738\t843\tN/A\tN/A\tYes\t–\tDied\t\nSatzger et al. 9\t26/F\t22\tYes\t197\tYes\t>38.4\tN/A/Yes\t2\t22 871\tN/A\t0.65\t1100\tN/A\tCorticotherapy and MMF\tImproved\t\nOkawa et al. 10\t78/M\t24\tYes\t178\tYes\t>38.4\tYes/N/A\t1\t35 400\tN/A\tN/A\t98\tYes\tCorticotherapy\tImproved\t\nAkagi et al. 11\t74/M\t27\tYes\t193\tYes\t38.9\tYes/Yes\t1\t28 976\t88\t4.94\t84\tYes\tDexamethasone and etoposide\tImproved\t\nOur first case\t78/M\t46\tYes\t175\tYes\t<38.4\tYes/N/A\t1\t11 273\tN/A\t0.643\t126\tYes\tCorticotherapy\tImproved\t\nOur second case\t60/F\t30\tNo\t185\tYes\t<38.4\tNo/No\t2\t64 726\t139\t2.07\t300\tN/A\tCorticotherapy\tImproved\t\nNote: N/A is counted as a negative finding.\n\nAbbreviations: AST, aspartate aminotransferase; BT, body temperature; ICI, immune checkpoint inhibitor; MMF, mycophenolate mofetil; N/A, not available; TG, triglyceride.\n\nFIGURE 2 Relationship between HScore and days from administration of the last dose of immune checkpoint inhibitors. Late presentation of hemophagocytic lymphohistiocytosis (HLH) leads to a lower HScore (R2 = 0.4409)\n\nThe mortality rate associated with HLH is 23%, which is one of the highest rates among immune‐related AEs 12 ; the prognosis can be improved by early intervention in the case of Epstein–Barr virus (EBV)‐associated HLH. 13 Late presentation cases of HLH are difficult to diagnose. However, our two cases were diagnosed promptly using the HScore over 24 days. We introduce a procedure for diagnosing secondary HLH caused by ICIs. HLH is suspected by the occurrence of cytopenia and marked inflammatory responses. If a patient had hyperferritinemia, we calculated the HScore to estimate HLH probability. This procedure will make it easier for any clinician to diagnose HLH, ensuring timely treatment.\n\nTable 3 shows that cases with high HScore (>190) were improved not only by steroids but also by other immunosuppressive agents, suggesting that the treatment option may depend on HScore.\n\nOnly a few HLH cases have been reported. Additional cases are required to evaluate effectiveness of the HScore for patients with ICIs.\n\nCONFLICT OF INTEREST\n\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n\n1 Henter JI , Horne A , Aricó M , Egeler RM , Filipovich AH , Imashuku S , et al. HLH‐2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48 :124–31.16937360\n2 Fardet L , Galicier L , Lambotte O , Marzac C , Aumont C , Chahwan D , et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66 :2613–20.24782338\n3 Rosee LP . Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133 :2465–77.30992265\n4 Malissen N , Lacotte J , Du‐Thanh A , Gaudy‐Marqueste C , Guillot B , Grob JJ . Macrophage activation syndrome: a new complication of checkpoint inhibitors. Eur J Cancer. 2017;77 :88–9.28365531\n5 Michot JM , Pruvost R , Mateus C , Champiat S , Voisin AL , Marabelle A , et al. Fever reaction and haemophagocytic syndrome induced by immune checkpoint inhibitors. Ann Oncol. 2018;29 :518–20.29088318\n6 Kalmuk J , Puchalla J , Feng G , Giri A , Kaczmar J . Pembrolizumab‐induced hemophagocytic lymphohistiocytosis: an immunotherapeutic challenge. Cancers Head Neck. 2020;5 :3.32025343\n7 Honjo O , Kubo T , Sugaya F , Nishizaka T , Kato K , Hirohashi Y , et al. Severe cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report. J Immunother Cancer. 2019;7 :97.30944043\n8 Thummalapalli R , Heumann T , Stein J , Khan S , Priemer DS , Duffield AS , et al. Hemophagocytic lymphohistiocytosis secondary to PD‐1 and IDO inhibition in a patient with refractory glioblastoma. Case Rep Oncol. 2020;13 :508–14.32518546\n9 Satzger I , Ivanyi P , Länger F , Kreipe HH , Schaper‐Gerhardt K , Beutel G , et al. Treatment‐related hemophagocytic lymphohistiocytosis secondary to checkpoint inhibition with nivolumab plus ipilimumab. Eur J Cancer. 2018;93 :150–3.29472154\n10 Okawa S , Kayatani H , Fujiwara K , Ozeki T , Takada K , Iwamoto Y , et al. Pembrolizumab‐induced autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis in non‐small cell lung cancer. Intern Med. 2019;58 :699–702.30828042\n11 Akagi Y , Awano N , Inomata M , Kuse N , Tone M , Yoshimura H , et al. Hemophagocytic lymphohistiocytosis in a patient with rheumatoid arthritis on pembrolizumab for lung adenocarcinoma. Intern Med. 2020;59 :1075–80.32009093\n12 Zhuang J , Du J , Guo X , et al. Clinical diagnosis and treatment recommendations for immune checkpoint inhibitor‐related hematological adverse events. Thorac Cancer. 2020;11 :799–804.32017466\n13 Imashuku S , Kuriyama K , Sakai R , Nakao Y , Masuda SI , Yasuda N , et al. Treatment of Epstein‐Barr virus‐associated hemophagocytic lymphohistiocytosis (EBV‐HLH) in young adults: a report from the HLH study center. Med Pediatr Oncol. 2003;41 :103–9.12825212\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "12(10)",
"journal": "Thoracic cancer",
"keywords": "Hemophagocytic lymphohistiocytosis; Hscore; hyperferritinemia; immune checkpoint inhibitor; lung adenocarcinoma",
"medline_ta": "Thorac Cancer",
"mesh_terms": null,
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "1625-1628",
"pmc": null,
"pmid": "33783978",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "32017466;33783978;29088318;32025343;30828042;24782338;29472154;12825212;28365531;30944043;32518546;16937360;30992265;32009093",
"title": "Two cases of lung cancer with hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors.",
"title_normalized": "two cases of lung cancer with hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors"
} | [
{
"companynumb": "JP-009507513-2010JPN002270J",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Relapsed/refractory Primary Central Nervous System Lymphoma (R/R PCNSL) has a poor prognosis with no established preferred treatment. We report the efficacy and toxicity of a combination chemotherapy regimen: methotrexate, carmustine, etoposide, and prednisone with or without rituximab (RMBVP). This retrospective study included thirty patients who received a median of two 28-day cycles (0.5-5). The median age was 66 years (23-81); median KPS was 70 (30-90); 14 (46.7%) were women. Patients received a median of 2 prior lines of therapy and all received prior methotrexate. Of 29 evaluable patients, the overall response rate was 73.3% (n = 22). Median progression-free survival (PFS) was 15.6 months. Patients who recurred or progressed <12 months since last chemotherapy had a shorter median PFS (7.6 vs 37.6 months). Toxicity was moderate with 20% rates of severe myelosuppression. RMBVP is a tolerable treatment option for R/R PCNSL, with favorable response rates in those with recurrent disease.",
"affiliations": "Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Flatiron Health, New York, NY, USA.;Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"authors": "Reiss|Samantha N|SN|0000-0002-4926-9508;Yerram|Prakirthi|P|;Modelevsky|Lisa|L|;Grommes|Christian|C|0000-0002-7485-0441",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2021.1998481",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": null,
"journal": "Leukemia & lymphoma",
"keywords": "Lymphoma and Hodgkin disease; chemotherapeutic approaches; pharmacotherapeutics",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": null,
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "34758711",
"pubdate": "2021-11-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rituximab, Methotrexate, Carmustine, Etoposide, and Prednisone (RMBVP) for the treatment of relapsed/refractory primary central nervous system lymphoma: a retrospective single-center study.",
"title_normalized": "rituximab methotrexate carmustine etoposide and prednisone rmbvp for the treatment of relapsed refractory primary central nervous system lymphoma a retrospective single center study"
} | [
{
"companynumb": "US-ROCHE-2962237",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nLimited data exist regarding the safety and efficacy of bevacizumab in pediatric patients under the age of 4 years. Here, we report a large cohort of pediatric patients under 4 years of age treated with bevacizumab.\n\n\nMETHODS\nThe primary objective was to document adverse events with a possible relationship to bevacizumab. Patients (n = 16) were identified through retrospective chart review and harbored a variety of conditions (44% central nervous system (CNS) tumors, 31% vascular anomalies, 13% neuroblastoma, 12% other).\n\n\nRESULTS\nThe median age was 34.3 months (range 4.9-47.3), including five patients <2 years of age. Patients received bevacizumab for a median duration of 6.2 months, alone or with chemotherapy, and a median dose of 9.25 mg/kg (range 7.0-11.8). Partial responses were seen in 19% of patients, and clinical improvements were seen in 69%. Adverse events known to be associated with bevacizumab occurred in 37%. Outcomes observed in this population resemble those reported for bevacizumab in older pediatric patients. The overall pattern and frequency of adverse events observed was similar to those seen in reports of older pediatric patients with a variety of conditions. The highest level of efficacy observed was seen among patients with vascular malformations or with low-grade CNS tumors.\n\n\nCONCLUSIONS\nOur results suggest that the use of bevacizumab is safe for the youngest children.",
"affiliations": "Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu de Barcelona, Passeig de Sant Joan de Déu num 2, Esplugues del Llobregat, 08950, Barcelona, Spain.;Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu de Barcelona, Passeig de Sant Joan de Déu num 2, Esplugues del Llobregat, 08950, Barcelona, Spain.;Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu de Barcelona, Passeig de Sant Joan de Déu num 2, Esplugues del Llobregat, 08950, Barcelona, Spain.;Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu de Barcelona, Passeig de Sant Joan de Déu num 2, Esplugues del Llobregat, 08950, Barcelona, Spain. jmora@hsjdbcn.org.",
"authors": "Millan|N C|NC|;Poveda|M J|MJ|;Cruz|O|O|;Mora|J|J|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
"country": "Italy",
"delete": false,
"doi": "10.1007/s12094-015-1389-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1699-048X",
"issue": "18(5)",
"journal": "Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico",
"keywords": "Antiangiogenesis; Bevacizumab; Infant and toddlers; Infant tumors",
"medline_ta": "Clin Transl Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D012449:Safety; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "101247119",
"other_id": null,
"pages": "464-8",
"pmc": null,
"pmid": "26318053",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22042784;22229118;22110225;22035272;23143218;24309509;22843947;22934706;23296323;25758812;22735882;24311632;24115645;25257751;21744483;10021335;24232489",
"title": "Safety of bevacizumab in patients younger than 4 years of age.",
"title_normalized": "safety of bevacizumab in patients younger than 4 years of age"
} | [
{
"companynumb": "ES-ROCHE-1631434",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Calcific uremic arteriolopathy (CUA; calciphylaxis), is reported in approximately 4% of patients receiving hemodialysis, and is characterized by skin lesions that may include firm plaques or subcutaneous nodules. The syndrome has been associated with the use of calcium-containing phosphate binders, high serum phosphorus levels, and elevated calcium x phosphorus (Ca x P) product. This report describes a 73-year-old white male with chronic renal failure due to diabetes mellitus and hypertension, who had been on home hemodialysis for 3 years. He developed CUA after an acute elevation in serum phosphorus (8.1 mg/dl) and Ca x P product (84.2), with painful skin lesions that rapidly progressed to become circumferentially located around the entire lower left extremity. The patient declined amputation, opting for a treatment approach that included aggressive management of phosphorus and calcium, more frequent dialysis, and rigorous wound care. All calcium-containing phosphate binders were discontinued. The patient was switched from calcitriol to paricalcitol, a less calcemic form ofvitamin D replacement therapy, from which he was slowly weaned. Dialysis dose and frequency was also increased to 4 hours, 6 times weekly. The patient was given sevelamer hydrochloride (Renagel)--a calcium-free phosphate binder--with meals at an initial dose of 6.4 g/day. After 5 months, the dose was increased to 8 g/day, with additional dietary counseling to restrict phosphorus intake. At this point, serum phosphorus decreased to 4.9 mg/dl and calcium levels had fallen to 8.5 mg/dl, compared to 9.5 - 10.4 mg/dl prior to diagnosis of CUA with an overall decline in the Ca x P product. Significant healing of the lesions was noted at 8 months following diagnosis, with near-total healing by 12 months. Our studies support that lowering of elevated serum phosphorus, calcium, and Ca x P product, together with aggressive wound care may contribute to the successful outcome of patients with CUA.",
"affiliations": "Department of Veterans Affairs, Medicine Service, Indianapolis, Indiana 46202, USA.",
"authors": "Russell|R|R|;Brookshire|M A|MA|;Zekonis|M|M|;Moe|S M|SM|",
"chemical_list": "D004852:Epoxy Compounds; D004872:Ergocalciferols; D011073:Polyamines; D011095:Polyethylenes; D010758:Phosphorus; C084656:paricalcitol; D000069603:Sevelamer; D002118:Calcium",
"country": "Germany",
"delete": false,
"doi": "10.5414/cnp58238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "58(3)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000368:Aged; D002115:Calciphylaxis; D002118:Calcium; D003646:Debridement; D004852:Epoxy Compounds; D004872:Ergocalciferols; D006801:Humans; D007676:Kidney Failure, Chronic; D007871:Leg Ulcer; D008297:Male; D010758:Phosphorus; D011073:Polyamines; D011095:Polyethylenes; D006435:Renal Dialysis; D000069603:Sevelamer; D014945:Wound Healing",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "238-43",
"pmc": null,
"pmid": "12356195",
"pubdate": "2002-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Distal calcific uremic arteriolopathy in a hemodialysis patient responds to lowering of Ca x P product and aggressive wound care.",
"title_normalized": "distal calcific uremic arteriolopathy in a hemodialysis patient responds to lowering of ca x p product and aggressive wound care"
} | [
{
"companynumb": "US-AMGEN-USASP2020157387",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
},
"drugadditional": null,
... |
{
"abstract": "Chronic myeloid leukemia (CML) is characterized by increased and unregulated proliferation of granulocytic lineage in the bone marrow and presence of these immature myeloid cells in the peripheral blood with presence of Philadelphia (Ph) chromosome. Tyrosine kinase inhibitors are the most important drugs in the CML therapy and provide long disease-free survival. Due to the increased survival of CML patients with continual administration of these drugs, the chance of development of secondary malignancies may increase. The most common secondary malignancies are prostate, colorectal and lung cancer, non-Hodgkin lymphoma, malignant melanoma, non-melanoma skin tumors and breast cancer. Herein, we are describing a rare case of Hodgkin lymphoma in a patient of CML after ten year of primary disease presentation. Hodgkin lymphoma in a known case of CML is very rare and further studies are also needed to know the pathogenic relationship between the two entities and to assess the risk of secondary Hodgkin lymphoma in CML patients treated with tyrosine kinase inhibitors. CML itself is a risk factor for development of solid cancers and hematologic malignancies. In addition, patients on chemotherapy are immune-compromised and may be at greater risk of neoplasm driven by infectious agents such as Epstein-Barr virus.",
"affiliations": "Department of Pathology & Laboratory Medicine, Medanta the Medicity, GURGAON, INDIA.",
"authors": "Gajendra|Smeeta|S|;Sharma|Archana|A|;Sharma|Rashi|R|;Gupta|Sunil Kumar|SK|;Sood|Nitin|N|;Sachdev|Ritesh|R|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases",
"country": "Turkey",
"delete": false,
"doi": "10.5146/tjpath.2016.01368",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-5615",
"issue": "35(1)",
"journal": "Turk patoloji dergisi",
"keywords": null,
"medline_ta": "Turk Patoloji Derg",
"mesh_terms": "D018385:Centrosome; D002869:Chromosome Aberrations; D004305:Dose-Response Relationship, Drug; D006689:Hodgkin Disease; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D013997:Time Factors",
"nlm_unique_id": "9440471",
"other_id": null,
"pages": "74-78",
"pmc": null,
"pmid": "28272671",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hodgkin Lymphoma in a Case of Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors.",
"title_normalized": "hodgkin lymphoma in a case of chronic myeloid leukemia treated with tyrosine kinase inhibitors"
} | [
{
"companynumb": "IN-MYLANLABS-2019M1012811",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nTo describe a reversible hypersensitivity reaction characterized by pericardial effusion and acute mixed liver injury in a woman treated with minocycline.\n\n\nMETHODS\nA 39-year-old white woman developed dyspnea and chest pain with pericardial effusion on echocardiography approximately 20 days after starting minocycline treatment. Additional manifestations consisted of eosinophilia and liver injury. No lung, skin, or joint involvement was noted; antinuclear antibody testing was negative.\n\n\nCONCLUSIONS\nMinocycline has been associated with rare but severe hypersensitivity reactions and autoimmune disorders, generally involving the lungs, skin, or joints. We observed a patient with an unusual minocycline-induced reaction with pericardial effusion and acute mixed liver injury. The number of spontaneously reported cases in national and international databases indicates that minocycline-induced pericardial effusion is very rare as a main clinical manifestation.\n\n\nCONCLUSIONS\nClinicians should be aware of the possibility of pericardial effusion without lung, skin, or joint involvement as an adverse effect of minocycline.",
"affiliations": "Department of Geriatrics, University Hospitals of Geneva, Switzerland.",
"authors": "Christe|C|C|;Ricou|F|F|;Stoller|R|R|;Vogt|N|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.19386",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "34(7-8)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000152:Acne Vulgaris; D000208:Acute Disease; D000328:Adult; D000900:Anti-Bacterial Agents; D056486:Chemical and Drug Induced Liver Injury; D004452:Echocardiography; D005260:Female; D006801:Humans; D008911:Minocycline; D010490:Pericardial Effusion",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "875-7",
"pmc": null,
"pmid": "10928400",
"pubdate": "2000",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced pericardial effusion.",
"title_normalized": "minocycline induced pericardial effusion"
} | [
{
"companynumb": "CH-BAUSCH-BL-2021-010257",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "We describe the case of a young man with repeated hospital presentations for a variety of symptoms related to excessive bodybuilding and associated behaviours. He presented to our department (radiology) with right arm pain and loss of function. Ultrasound showed complete triceps rupture, rare in young patients and multiple cystic areas within the muscles of the arm. MRI revealed these to be multiple proteinaceous lesions within the muscle bellies and the possibility of self-innoculation was raised by the reporting radiologist. The patient subsequently admitted to injecting coconut oil to improve muscle contour lost secondary to injury. A review of his hospital presentations was then made and revealed further concerning practices performed by the patient to enhance his muscular appearance.",
"affiliations": "London North West Healthcare NHS Trust, London, UK.;London North West Healthcare NHS Trust, Ealing Hospital, London, UK.;London North West Healthcare NHS Trust, London, UK.",
"authors": "Hameed|Maira|M|http://orcid.org/0000-0002-6290-5695;Sahu|Ajay|A|;Johnson|Maria B|MB|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin; D010938:Plant Oils; D045165:Testosterone Congeners; D014284:Triiodothyronine; D000074263:Coconut Oil",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217208",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001132:Arm; D001828:Body Image; D002481:Cellulitis; D000074263:Coconut Oil; D003617:Dangerous Behavior; D037001:Directive Counseling; D006801:Humans; D007004:Hypoglycemic Agents; D007273:Injections, Intramuscular; D007328:Insulin; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal; D009133:Muscular Atrophy; D010938:Plant Oils; D045165:Testosterone Congeners; D014284:Triiodothyronine; D014891:Weight Lifting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27908914",
"pubdate": "2016-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19901801;10642691;19326015;22592548;11768903;16113147;23620489;20089216",
"title": "Muscle mania: the quest for the perfect body.",
"title_normalized": "muscle mania the quest for the perfect body"
} | [
{
"companynumb": "GB-MYLANLABS-2017M1042209",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nDexamethasone intravitreal implant is an approved preparation in the treatment of macular edema. The most common adverse reactions are increased intraocular pressure and cataract but the inadvertent injection of the dexamethasone implant into the capsular bag is an extremely rare event.\n\n\nMETHODS\nWe present a case of a 78-year-old man treated for persistence of cystoid macular edema (CME) with Ozurdex intravitreal implant in which the procedure was complicated by the injection of the dexamethasone implant into the lens body and discuss the management.\n\n\nRESULTS\nThe patient underwent phacoemulsification of the lens, replacement of the Ozurdex, and implant of a 3-piece lens in the posterior chamber.\n\n\nCONCLUSIONS\nThe injection of an intravitreal dexamethasone implant (Ozurdex) into the lens body is an extremely rare complication that can be effectively and successfully managed with the surgical extraction of the implant from the lens body and implant of a 3-piece intraocular lens in the sulcus.",
"affiliations": "West of England Eye Unit, RD&EH, Exeter - United Kingdom.",
"authors": "Berarducci|Antonio|A|;Sian|Inderpaul S|IS|;Ling|Roland|R|",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.5301/ejo.5000436",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "24(4)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000368:Aged; D020878:Device Removal; D003907:Dexamethasone; D004343:Drug Implants; D005938:Glucocorticoids; D006801:Humans; D007429:Intraocular Pressure; D019654:Lens Implantation, Intraocular; D007908:Lens, Crystalline; D008269:Macular Edema; D008297:Male; D018918:Phacoemulsification",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "620-2",
"pmc": null,
"pmid": "24519508",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Inadvertent dexamethasone implant injection into the lens body management.",
"title_normalized": "inadvertent dexamethasone implant injection into the lens body management"
} | [
{
"companynumb": "PHHY2014GB087615",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "A 62-year-old woman with hypertension, type 2 diabetes mellitus, hyperlipemia and coronary heart disease started taking clopidogrel, with no addition of any other new drugs. However, with the addition of the drug, the patient was diagnosed as having acquired pure red cell aplasia (PRCA), and no any other inducing factors were detected from the patient. Furthermore, with the withdrawal of clopidogrel from the treatment, the patient recovered from the PRCA and did not recur. Therefore, we report PRCA as a rare side effect of clopidogrel for the first time.",
"affiliations": "Department of Pharmacy, Sichuan Provincial People's Hospital, Chengdu, China.",
"authors": "Li|Gang|G|;Li|Zhao-quan|ZQ|;Yang|Qi-yu|QY|;Yang|Jia-dan|JD|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-013-1031-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "38(2)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": null,
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000077144:Clopidogrel; D003327:Coronary Disease; D048909:Diabetes Complications; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D006949:Hyperlipidemias; D006973:Hypertension; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012010:Red-Cell Aplasia, Pure; D013988:Ticlopidine",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "215-7",
"pmc": null,
"pmid": "24297264",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15621125;15824129;21532231;16850864;21713046;14703701;18252131;20871773;10852999;10841130;18367863;18272634;11146710",
"title": "Acquired pure red cell aplasia due to treatment with clopidogrel: first case report.",
"title_normalized": "acquired pure red cell aplasia due to treatment with clopidogrel first case report"
} | [
{
"companynumb": "CN-MYLAN-2014M1001409",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PERINDOPRIL"
},
"drugadditional": null,
... |
{
"abstract": "It is rare for children to receive more than one course of support with extracorporeal membrane oxygenation, and in those who do undergo multiple episodes, the interval is usually days to weeks between events. Little data exists on re-cannulation years after an initial extracorporeal membrane oxygenation run, and late repeat cannulation can pose unique challenges. We report the case of a 10-year-old male patient with right jugular vein occlusion due to a previous course of extracorporeal membrane oxygenation as a neonate, who was successfully supported via central cannulation. This case demonstrates the importance of adequate imaging of target vasculature prior to attempting re-cannulation of a previously used vessel. Establishing a thoughtful strategy for late repeat cannulation is essential to achieve safe access in unusual and challenging situations.",
"affiliations": "Division of Pediatric Surgery, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.;Division of Pediatric Critical Care Medicine, Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.;Division of Pediatric Surgery, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.;Section of Pediatric Cardiovascular Surgery, Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.;Section of Pediatric Cardiovascular Surgery, Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.;Division of Pediatric Critical Care Medicine, Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.;Division of Pediatric Surgery, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.",
"authors": "Carr|Benjamin D|BD|0000-0002-3563-8974;Kohne|Joseph|J|0000-0001-9978-2759;Ralls|Matthew W|MW|;Sassalos|Peter|P|;Ohye|Richard G|RG|;Odetola|Folafoluwa O|FO|;Gadepalli|Samir K|SK|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0267659120925351",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0267-6591",
"issue": "36(2)",
"journal": "Perfusion",
"keywords": "multiple run extracorporeal membrane oxygenation; pediatric extracorporeal membrane oxygenation; re-cannulation; repeat cannulation; venogram",
"medline_ta": "Perfusion",
"mesh_terms": "D002404:Catheterization; D002648:Child; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D007231:Infant, Newborn; D007601:Jugular Veins; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "8700166",
"other_id": null,
"pages": "204-206",
"pmc": null,
"pmid": "32460608",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Venogram before long-interval repeat cannulation for pediatric extracorporeal membrane oxygenation.",
"title_normalized": "venogram before long interval repeat cannulation for pediatric extracorporeal membrane oxygenation"
} | [
{
"companynumb": "US-MYLANLABS-2021M1091232",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SILDENAFIL"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nThere is a lack of experience with fully covered self-expandable metal stents (SEMSs) for benign esophageal disorders in children.\n\n\nMETHODS\nEleven children (six boys, five girls) with a median age of 30.5 months (range, 1 month-11 years) who underwent treatment with SEMSs for a benign esophageal condition between February 2006 and January 2014 were recruited to this retrospective study. Etiologies included esophageal atresia with postoperative stricture (n=4), recurrent fistula (n=1), and/or anastomotic leak (n=1), as well as iatrogenic perforation of the esophagus following endoscopy (n=4) or laparoscopic fundoplication (n=1). As part of an interdisciplinary cooperation patients were jointly managed from the Department of Pediatric Surgery and Central Interdisciplinary Endoscopy at our institution.\n\n\nRESULTS\nMedian duration of individual stent placement was 29 days (range, 17-91 days). In 4 cases up to four different SEMSs were placed successively over time. There were no complications noted at stent insertion or removal. At follow-up, 6 patients (55%) were successfully treated without further intervention. Two children each (18%) underwent one single dilatation after stent removal and remained well afterward. Three patients (27%) did not improve following stenting and required definite surgery. Minor stent-related complications were noted in 5 cases (45%), including gastroesophageal reflux (n=2), silent stent migration (n=2), and pneumonia (n=1).\n\n\nCONCLUSIONS\nSEMSs for benign esophageal disorders in children can be used safely and effectively in selected cases, including esophageal anastomotic strictures, esophageal leaks following primary surgery, or perforations postdilatation. An SEMS can be applied either as an emergency procedure or as an adjuvant treatment further to endoscopy or previous surgery. Establishment of a standardized approach in the pediatric population is mandatory.",
"affiliations": "1 Department of Pediatric Surgery, Medical Faculty Mannheim, Heidelberg University , University Medical Center Mannheim, Mannheim, Germany .",
"authors": "Lange|Bettina|B|;Kubiak|Rainer|R|;Wessel|Lucas M|LM|;Kähler|Georg|G|",
"chemical_list": "D008670:Metals",
"country": "United States",
"delete": false,
"doi": "10.1089/lap.2014.0203",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-6429",
"issue": "25(4)",
"journal": "Journal of laparoendoscopic & advanced surgical techniques. Part A",
"keywords": null,
"medline_ta": "J Laparoendosc Adv Surg Tech A",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D004935:Esophageal Diseases; D004945:Esophagoscopy; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008670:Metals; D012189:Retrospective Studies; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "9706293",
"other_id": null,
"pages": "335-41",
"pmc": null,
"pmid": "25768949",
"pubdate": "2015-04",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Use of fully covered self-expandable metal stents for benign esophageal disorders in children.",
"title_normalized": "use of fully covered self expandable metal stents for benign esophageal disorders in children"
} | [
{
"companynumb": "DE-JNJFOC-20150503821",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugadditi... |
{
"abstract": "The prognosis for relapsing AML patients is disappointing and the preferred salvage chemotherapy is unclear. Among other regimens, cladribine, cytarabine, and idarubicin (CLA-Ida) is used.\n\n\n\nWe analyzed relapsing AML patients receiving CLA-Ida chemotherapy between July 2012 and April 2015 at three academic centers in Switzerland.\n\n\n\nThirty-four patients underwent at least one cycle of CLA-Ida chemotherapy, with 6 patients having two cycles. Treatment-related mortality was 5.9% (2/34 patients). Eighteen patients (52.9%) achieved a complete remission (CR2), and 16 (47.1%) received subsequent allogeneic transplantation, with 8 (23.5%) of these patients remaining in complete remission after a median follow-up of 6 months. In contrast, all 16 patients not achieving CR2 died within 12 months after relapse due to progressive disease.\n\n\n\nOur data suggest a promising rate of complete remission following CLA-Ida salvage treatment in relapsing AML patients enabling a substantial proportion of such patients to proceed to allogeneic transplantation.",
"affiliations": "a Department of Medical Oncology , University Hospital Berne and University of Berne , Berne , Switzerland.;b Department of Hematology , University Hospital , Basel , Switzerland.;c Division of Hematology , University Hospital Zurich and University of Zurich , Zurich , Switzerland.;d Department of Clinical Research , University of Berne , Berne , Switzerland.;b Department of Hematology , University Hospital , Basel , Switzerland.;c Division of Hematology , University Hospital Zurich and University of Zurich , Zurich , Switzerland.;a Department of Medical Oncology , University Hospital Berne and University of Berne , Berne , Switzerland.",
"authors": "Fridle|Chantal|C|;Medinger|Michael|M|;Wilk|Matthias C|MC|;Seipel|Katja|K|;Passweg|Jakob|J|;Manz|Markus G|MG|;Pabst|Thomas|T|",
"chemical_list": "D003561:Cytarabine; D017338:Cladribine; D015255:Idarubicin",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2016.1235274",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "58(5)",
"journal": "Leukemia & lymphoma",
"keywords": "AML; CLA-Ida; complete remission; overall survival; relapse",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017338:Cladribine; D003561:Cytarabine; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015255:Idarubicin; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1068-1075",
"pmc": null,
"pmid": "27735213",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cladribine, cytarabine and idarubicin (CLA-Ida) salvage chemotherapy in relapsed acute myeloid leukemia (AML).",
"title_normalized": "cladribine cytarabine and idarubicin cla ida salvage chemotherapy in relapsed acute myeloid leukemia aml"
} | [
{
"companynumb": "CH-FRESENIUS KABI-FK201703275",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLADRIBINE"
},
"drugadditional": null,
... |
{
"abstract": "Vancomycin is a glycopeptide antibiotic which is the drug of choice against methicillin-resistant Staphylococcus aureus. It has a narrow therapeutic index, and thus therapeutic drug monitoring (TDM), and clinical pharmacokinetic assessment are necessary in order to prevent adverse drug reactions such as nephrotoxicity. In this study, we aimed to develop a simple and validated HPLC method for vancomycin assay in order to establish a TDM center for patients admitted to the ICU of Nemazee Hospital in southern Iran.\nIn this study, a brief review of different parameters and variables which could affect the sensitivity, selectivity of the validated HPLC method for vancomycin determination were considered. According to the previous studies a simple, fast, and the relatively low-cost method was established for vancomycin determination in plasma samples.\nThe developed HPLC assay indicated a calibration curve with R-square of > 0.999, acceptable selectivity, the accuracy of 90-105%, CV% of less than 15%, the limit of quantification of 1 μg/mL, and limit of detection of 300 ng/mL. Vancomycin trough level, the area under the curve, renal clearance, the volume of distribution, and elimination constant were measured in patients using this validated method.\nValidated method for assay of vancomycin plasma levels was used to quantify vancomycin levels of four patients who were admitted to the ICU of Nemazee Hospital. According to the results, two of these patients showed lower levels than recommended therapeutic purposes while one of them showed a toxic level. According to the results, the TDM assessment of vancomycin is strongly recommended for patients who are hospitalized in ICU.",
"affiliations": "Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.;Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.;Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.;Department of Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.;Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.;Department of Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.",
"authors": "Ghasemiyeh|Parisa|P|;Vazin|Afsaneh|A|;Zand|Farid|F|;Azadi|Amir|A|;Karimzadeh|Iman|I|;Mohammadi-Samani|Soliman|S|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.4103/1735-5362.301337",
"fulltext": "\n==== Front\nRes Pharm Sci\nRes Pharm Sci\nRPS\nResearch in Pharmaceutical Sciences\n1735-5362\n1735-9414\nWolters Kluwer - Medknow India\n\nRPS-15-529\n10.4103/1735-5362.301337\nOriginal Article\nA simple and validated HPLC method for vancomycin assay in plasma samples: the necessity of TDM center development in Southern Iran\nGhasemiyeh Parisa 12\nVazin Afsaneh 1\nZand Farid 3\nAzadi Amir 2\nKarimzadeh Iman 1\nMohammadi-Samani Soliman 24*\n1 Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran\n2 Department of Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran\n3 Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, I.R. Iran\n4 Center for Nanotechnology in Drug delivery, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran\n* Corresponding author: S. Mohammadi-Samani Tel: +98-7132426070, Fax: +98-7132424126 Email: smsamani@sums.ac.ir\n12 2020\n27 11 2020\n15 6 529540\n16 11 2019\n08 6 2020\n08 11 2020\nCopyright: © 2020 Research in Pharmaceutical Sciences\n2020\nThis is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nBackground and purpose:\n\nVancomycin is a glycopeptide antibiotic which is the drug of choice against methicillin-resistant Staphylococcus aureus. It has a narrow therapeutic index, and thus therapeutic drug monitoring (TDM), and clinical pharmacokinetic assessment are necessary in order to prevent adverse drug reactions such as nephrotoxicity. In this study, we aimed to develop a simple and validated HPLC method for vancomycin assay in order to establish a TDM center for patients admitted to the ICU of Nemazee Hospital in southern Iran.\n\nExperimental approach:\n\nIn this study, a brief review of different parameters and variables which could affect the sensitivity, selectivity of the validated HPLC method for vancomycin determination were considered. According to the previous studies a simple, fast, and the relatively low-cost method was established for vancomycin determination in plasma samples.\n\nFindings/Results:\n\nThe developed HPLC assay indicated a calibration curve with R-square of > 0.999, acceptable selectivity, the accuracy of 90-105%, CV% of less than 15%, the limit of quantification of 1 μg/mL, and limit of detection of 300 ng/mL. Vancomycin trough level, the area under the curve, renal clearance, the volume of distribution, and elimination constant were measured in patients using this validated method.\n\nConclusion and implications:\n\nValidated method for assay of vancomycin plasma levels was used to quantify vancomycin levels of four patients who were admitted to the ICU of Nemazee Hospital. According to the results, two of these patients showed lower levels than recommended therapeutic purposes while one of them showed a toxic level. According to the results, the TDM assessment of vancomycin is strongly recommended for patients who are hospitalized in ICU.\n\nAcute kidney injury\nAUC\nHPLC\nICU\nTDM\nVancomycin\n==== Body\nINTRODUCTION\n\nVancomycin is a large glycopeptide antibiotic with a molecular weight of 1450 Da. The mechanism of action is binding to the D- Ala-D-Ala dipeptide of peptidoglycan and blocking the biosynthesis of the cell wall (1). Vancomycin is the antibiotic of choice for targeted and empirical therapy of many Gram-positive microorganisms especially methicillin- resistant Staphylococcus aureus. It could be used in many infectious diseases such as septicemia, osteomyelitis, endocarditis, pneumonitis, meningitis, etc. (23). Vancomycin has very low oral absorption. Therefore, the most common route of administration is slow intravenous infusion.\n\nThe main elimination pathway of this drug is renal and approximately 85% of the drug could be detected unchanged in urine after 24 h of a single dose administration (4). Vancomycin has a very narrow therapeutic index which is responsible for any adverse drug reactions related to vancomycin administration. The most important adverse effect is vancomycin- associated nephrotoxicity. A serum trough level of 15-20 μg/mL is recommended for vancomycin in various complicated infectious diseases (2) and in this regard, therapeutic drug monitoring (TDM) of vancomycin was suggested by several authors. The monitoring of peak and trough levels of vancomycin after steady state has been proposed in previous studies. Nevertheless according to recent studies monitoring the daily area under the curve (24 h-AUC) was suggested as a more useful pharmacokinetic parameter (5). Although in the majority of patients trough level of 15 to 20 μg/mL results in AUC/minimum inhibitory concentration (MIC) ratio of ≥ 400, but in many cases, this target value could be achieved with a trough level of less than 15 μg/mL. So, recent studies are focused on AUC/MIC ratio calculation for vancomycin TDM in order to maintain a trough level lower than 15 μg/mL to avoid vancomycin-associated nephrotoxicity which is more common with a trough level of higher than 15 μg/mL (6). Another study reported that 24 h-AUC and peak level (Cmax) are more relevant to vancomycin-associated nephron-toxicity in comparison with the trough level. Although 24 h-AUC of 400-600 μg.h/mL could provide enough efficacy, the exact 24 h-AUC range accompanied by vancomycin-associated nephrotoxicity has not been established yet but a limit of 700 μg.h/mL was rationalized in order to avoid nephrotoxicity (7). In this study a modified and validated high-performance liquid chromatography (HPLC) method was developed in order to assess serum trough, intermediate, and peak levels of vancomycin to calculate 24h-AUC of vancomycin for TDM purposes. Although immunoassay methods because of the simplicity and fast evaluation process have been used frequently in many previous studies these methods due to the lack of enough precision and sensitivity and also due to the cross-reaction with vancomycin metabolites has its own limitations. In spite of the fact that HPLC is the most selective and sensitive method for vancomycin analysis in serum samples especially at lower concentrations (89), but analysis of vancomycin in biological matrices using HPLC method has been encountered many challenges that should be overcome.\n\nMany methods have precipitated plasma proteins prior to the extraction of drugs from plasma by an organic solvent. Protein precipitation has been accomplished by using perchloric acid followed by extraction with ethyl acetate (810). Organic solvents such as isopropyl alcohol, acetonitrile (11), and methanol (12) have also been used for plasma protein precipitation.\n\nDue to the effects of unexpected variables on the extraction process during the various steps of drug extraction and reducing the variations in different samples between each run, recruitment of an efficient IS in plasma samples is necessary. By the inclusion of IS, the ratio of drug to IS would be used in calculations and so the variation in extraction would be diminished to the minimum levels. The selected IS should have similar λmax to vancomycin in order to obtain the possibility of simultaneous analysis. Zidovudine (9), caffeine (11), cefuroxime (13), erythromycin (14), para amino benzoic acid (15), phenacetin, and norvancomycin (16) are the examples of IS which have been considered for vancomycin assay in plasma samples.\n\nThe other parameter which could highly affect the precision and efficiency of the HPLC method for vancomycin assay is the instrument condition such as the type of HPLC column, column temperature, column length, and internal diameter, lambda max (λmax) and wavelength, mobile phase, flow rate, etc. (891217). In this study, we worked on different variables to optimize the influencing parameters to propose a simple, low-cost, and validated HPLC method for the determination of vancomycin in blood samples. Different variables including mobile phase, flow rate, wavelength, and pH were tested to achieve the optimum conditions which could precisely detect vancomycin peak among endogenous plasma peaks, IS, and other drugs in poly-pharmacy patients.\n\nMATERIALS AND METHODS\n\nMaterials\n\nHPLC grade acetonitrile was from Merck (Germany) and purchased from a domestic supplier. Ortho-phosphoric acid, sodium hydroxide, and perchloric acid 70% were from Merck, Germany. Pure powder of acetaminophen and vancomycin were purchased from Dena Pharmaceutical Company, Tabriz, Iran. Meropenem, ampicillin sulbactam, piperacillin tazobactam, ceftriaxone, and levofloxacin vials and amikacin ampule were prepared from the market.\n\nStandard sample preparation\n\nStandard stock samples were prepared in water. At first, a stock solution of 1 mg/mL was prepared and then samples with concentrations of 120, 60, 40, 20, 8, and 4 μg/mL were prepared and used to prepare plasma samples with vancomycin at 30, 15, 10, 5, 2, and 1 μg/mL. IS (acetaminophen) stock solution of 100 μg/mL was prepared by dissolving 10 mg IS in purified water, then working IS concentration was daily prepared from the stock solution at 25 μg/mL.\n\nDrug extraction from plasma\n\nIn this regard, 0.25 mL of vancomycin standard solutions and 0.25 mL of IS solution was mixed with 0.5 mL of plasma (obtained from blood transfusion center, Shiraz, Iran.). Then 50 μL of perchloric acid 70% was added to precipitate plasma proteins. The mixture was shaken for 1 min and after that centrifuged at 12000 rpm for 15 min. The supernatant was analyzed by HPLC.\n\nHPLC condition\n\nSamples were analyzed by HPLC Azura (Knauer, Germany). The column was C18 (250 mm length × 4.6 mm I.D.; 5 μm pore size; Knauer, Germany). The flow rate was 0.72 mL/min and λmax was adjusted on 225 nm. The mobile phase was phosphate buffer (30 mM, pH of 2.2) and acetonitrile (86:14 %v/v). The column temperature was set at 25 °C.\n\nHPLC validation (18)\n\nLinearity\n\nIn order to evaluate the linearity of the calibration curve with this HPLC method, samples with different concentrations (ranges between 1 to 30 μg/mL) of vancomycin and equal concentrations of IS (acetaminophen 25 μg/mL) were analyzed by HPLC. Then vancomycin concentration was plotted versus the ratio of vancomycin peak area to the acetaminophen peak area. Linearity was reported in terms of R square and adjusted R square. A regression test was done and significance F value and P-value of X-variable (slope) were calculated.\n\nSelectivity\n\nIn order to evaluate the selectivity of this HPLC method for vancomycin detection, different samples with different concentrations of vancomycin and equal concentration of IS were injected and retention times of vancomycin and acetaminophen were reported.\n\nSensitivity\n\nThe sensitivity of this HPLC method for detection of vancomycin was assessed in terms of limit of quantification (LOQ) and limit of detection (LOD), while LOQ is based on precision and accuracy at the lowest calibration point and LOD is based on signal to noise ratio of ≥3. LOD refers to the smallest concentration or amount of analyte that could be detected and LOQ refers to the smallest concentration or amount of analyte that could be quantitatively analyzed with acceptable reliability and precision (19).\n\nRange\n\nThis method has been validated in order to assess the vancomycin trough level for TDM purposes. Also, it could be used to assess peak level and intermediate level of vancomycin in order to calculate the area under the curve (AUC). For these purposes, a calibration curve with a vancomycin concentration range of 1 to 30 μg/mL was considered.\n\nPrecision\n\nIn order to evaluate the precision of this method, samples with a concentration range of 1 to 30 μg/mL were assessed in triplicate in one day to calculate within-day precision, and then samples were analyzed in three different days to assess between days precision (everyday samples were prepared freshly). Within and between-day precision have been reported by the coefficient of variations (%CV). The lower the %CV values, the higher the precision of the method.\n\nAccuracy\n\nIn order to evaluate the accuracy of this method, each sample was assessed in triplicate in one day to calculate within day accuracy, and then these samples were analyzed in three days to assess between days' accuracy. Within and between day accuracy have been reported by percent according to the following equation:\n\nSystem suitability tests\n\nNumber of theoretical plates\n\nThe number of theoretical plate (N) was calculated by the following equation:\n\nwhile TR is retention time and Wh/2 is the peak width at half of the peak height.\n\nTailing factor or peak symmetry\n\nPeak symmetry (PS) was calculated by the following equation:\n\nwhere, W is peak width at 0.05 of the peak height and f is front half peak width at 0.05 of the peak height.\n\nRetention factor\n\nRetention factor (K′) was calculated by the following equation:\n\nwhere, TR is drug retention time and Ta is solvent retention time.\n\nPotential interaction of vancomycin with other common drugs administered in ICU\n\nIn order to evaluate the potential chromatographic interaction of vancomycin and IS peaks with other common antibiotics which are administered simultaneously in ICU, seven drugs containing meropenem, ceftriaxone, ampicillin sulbactam, piperacillin tazobactam, levofloxacin, colistin, and amikacin were selected. In this regards, 50 μL of each of these drugs, 50 μL of vancomycin, and 50 μL of IS (acetaminophen) were mixed and added to 500 μL of plasma (obtained from blood transfusion center, Shiraz, Iran) in order to obtain therapeutic plasma concentrations. Then drug extraction was performed according to the aforementioned procedure. The supernatant of this drug cocktail was analyzed with the developed HPLC method and results were compared with a blank plasma (without any drug) and a plasma sample containing vancomycin and IS. Also, the results were compared with a plasma sample which was spiked with these seven drugs without vancomycin and IS in order to clarify all possible chromatographic interactions.\n\nPatient blood sample analysis\n\nAfter the HPLC validation process, four patients, who received vancomycin, were selected randomly from ICU of Nemazee Hospital, Shiraz, Iran (Ethics code No. 97-01-36-19208) in order to assess the performance of the developed HPLC method. A blood sample (30 min before the next dose; trough level) was collected from the first patient (a 25-year old woman, known case of CVA) who was admitted to ICU of Nemazee hospital. Her medical antibiotic regimen was colistin 3000000 IU Q8h, meropenem 2 g Q8 h, and vancomycin 1 g Q12 h through IV route of administration since 5 days before blood sampling. The blood sample was freshly centrifuged at 2500 rpm for 15 min in order to separate plasma from whole blood. Then 0.5 mL of plasma sample was mixed with 0.5 mL of acetaminophen solution (IS; concentration of 25 μg/mL). Then 50 μL of perchloric acid was added to precipitate plasma proteins. The sample was mixed for 1 min and then centrifuged at 12000 rpm for 10 min. Finally, one-half of the supernatant was directly analyzed with the developed HPLC method and the remaining supernatant was mixed with an equal volume of vancomycin solution (concentration of 50 μg/mL) in order to confirm the vancomycin peak area by spiked peak. When needed, samples were diluted prior to analysis in order to maintain the concentration range within the calibration curve concentration ranges.\n\nThe second patient (a 71-year old man, known case of status epilepticus) who was admitted to ICU of Nemazee hospital and received vancomycin for 10 days. Blood samples were collected at 1 h (peak level; just after the end of 1 h-infusion), 4 h (intermediate level), and 12 h (trough level, before the next dose administration). Patients' serum creatinine was checked at baseline and every day as routine lab data. His antibiotic regimen was vancomycin 1 g Q12 h, meropenem 1g Q8 h, ciprofloxacin 400 mg Q12 h, and ampicillin sulbactam 9 g Q8 h through IV route of administration. According to these three blood samples 12 h- and 24 h-AUC of vancomycin were calculated by the trapezoidal method. Other pharmacokinetic parameters such as clearance and elimination rate constant were also calculated from AUC according to the following equations:\n\nwhile CLs is the systemic clearance (in L/h) which is approximately equal to renal clearance for vancomycin, X0 is the administered dose (in mg), and AUC is 12 h- AUC (in mg.h/L).\n\nwhere, Ke is renal excretion constant (h-1) which is approximately equal to elimination constant (k) for vancomycin due to the approximately complete renal excretion of this drug, CLr is renal clearance (in L/h), and Vd is the volume of distribution which was varied between 0.5-0.9 L/kg according to the previous literature. So, because of high inter-individual variability in vancomycin pharmacokinetics, in this study, Vd was calculated using equation 7 (20):\n\nwhere, Vd is the volume of distribution (L), the dose is the amount of administered drug in each interval (mg), peak level, and trough level are vancomycin concentrations (mg/L) 1 h after and just before the next dose administration, respectively.\n\nSince vancomycin half-life (t½) in patients with normal renal function is about 6 h, so Ke in normal population has been assumed 0.116 h-1 according to Equation 8 (if a one- compartment open model is assumed).\n\nThe third patient (a 45-year old man, known case of epilepsy) was admitted to the ICU of Nemazee Hospital and received vancomycin 3 days before blood sampling. His antibiotic regimen was vancomycin 500 mg Q24 h, azithromycin 500 mg QOD, ceftriaxone 2 g Q12 h. His baseline serum creatinine (before vancomycin administration) was 5.1 mg/dL and vancomycin dose adjustment was suggested for him according to glomerular filtration rate (GFR) value (500 mg Q24 h). Blood samples were collected at 1, 4, and 12 h after vancomycin infusion in order to assess peak, intermediate, and trough levels, respectively. AUC, Vd, Ke, and CLr were also assessed for this patient.\n\nThe fourth patient (a 45-year old man, known case of epilepsy) who was admitted to the ICU of Nemazee Hospital received vancomycin from 2 weeks before blood sampling. His antibiotic regimen was vancomycin 1 g Q12 h and ceftriaxone 1 g Q12 h. Blood samples were collected at 1, 4, and 12 h after vancomycin infusion, and pharmacokinetic parameters were calculated and assessed.\n\nRESULTS\n\nHPLC validation\n\nCalibration curve and linearity\n\nIn this study, the HPLC method has been validated and modified in order to analyze plasma samples of patients who received vancomycin in the hospital. Six concentrations of standard solutions were injected into HPLC (n = 5) and results were plotted as vancomycin concentration versus area under the peak ratio of vancomycin to IS and passed the acceptance validation criteria of calibration curve from USP guidelines which is ±15% of nominal concentrations (18). In this plot, as depicted in Fig. 1, R square was 0.9996 and linear equation was y = 0.0148 X + 0.0139. The retention time of vancomycin and acetaminophen were 5.5 and 8 min, respectively. Also, a regression test was done on these data. F-values and P-values were lower than 0.05.\n\nFig. 1 Vancomycin calibration curve in biological samples.\n\nSelectivity\n\nSamples with different concentrations were analyzed. In all samples, vancomycin retention time was 5.5 min and IS (acetaminophen) retention time was 8 min and no interaction with plasma endogenous peaks (Fig. 2) were observed.\n\nFig. 2 Representative chromatograms of (A) blank plasma, (B) vancomycin (30 μg/mL) and IS (acetaminophen; 25 μg/mL), and (C) vancomycin (15 μg/mL) and IS (acetaminophen; 25 μg/mL). IS, internal standard.\n\nSensitivity\n\nLOD was 0.3 μg /mL and LOQ was 1 μg/mL. The analyte response at LOQ was ≥ 5- times the analyte response of the blank plasma (zero calibrator) (20).\n\nRange\n\nVancomycin standard solution in different concentrations ranging between 1 and 30 μg/mL were injected into the chromatograph. According to the results, a linear correlation between the vancomycin concentrations and peak area ratios were established in this range.\n\nPrecision\n\nBetween day and within-day precision results are shown in Table 1. All samples had %CV lower than 15% that was in accordance with USP guidelines (18) which suggested the precision of ± 15 %CV.\n\nTable 1 Within- and between-day precision and accuracy of vancomycin HPLC assay (n = 3).\n\nConcentrations (μg/mL)\tPrecision\tAccuracy\t\n\t\nWithin day (%)\tBetween day (%)\tWithin day (%)\tBetween day (%)\t\n1\t1.137\t4.678\t89.867\t96.924\t\n2\t4.325\t7.978\t95.470\t101.63\t\n5\t2.122\t12.11\t98.474\t96.074\t\n10\t4.508\t12.71\t101.31\t99.391\t\n15\t1.767\t13.35\t103.67\t102.26\t\n30\t0.919\t13.01\t98.750\t99.498\t\n\nAccuracy\n\nBetween day and within-day accuracy results are shown in Table 1. All samples had accuracy ranging between 90 and 103%, which was compatible with USP validation guidelines (acceptable accuracy range of 85-115%) (18).\n\nSystem suitability test\n\nN, PS, and K′ were calculated for both vancomycin and IS, and results are shown in Table 2. N is the criterion of the column efficiency, whereas PS revealed the symmetry of the peak, and K′ shows the suitability of the method to differentiate between drug peak and solvent peak. N values should not be below 2000, acceptable PS range is 0.8-1.8, and K′ values should be at least 0.5 to pass method validation criteria.\n\nTable 2 System suitability test results (n=3)\n\nMedications\tNumber of theoretical plates\tPeak symmetry\tRetention factor\t\nVancomycin\t1009.665\t1.250\t0.657\t\nAcetaminophen\t4098.714\t0.860\t1.331\t\n\nPotential interaction of vancomycin with other common drugs administered in ICU\n\nChromatograms (Fig. 3) of blank plasma, a plasma sample spiked with vancomycin and IS, a plasma sample spiked with drug cocktail containing vancomycin, IS, and other seven aforementioned concomitant drugs, and a plasma sample spiked with those seven drugs without vancomycin and IS, all in therapeutic plasma concentrations, revealed that there is no interaction between vancomycin and/or IS peaks with other common drugs administered simultaneously in this developed HPLC method for vancomycin assay in plasma samples.\n\nFig. 3 Representative chromatograms of (A) blank plasma, (B) vancomycin and IS (acetaminophen), (C) drug cocktail (vancomycin, IS, and other seven drugs containing meropenem, ceftriaxone, ampicillin sulbactam, piperacillin tazobactam, levofloxacin, colistin, and amikacin), and (D) seven drugs without vancomycin and IS. IS, internal standard.\n\nPatient blood sample analysis results\n\nIn order to confirm the suitability of the validated HPLC method plasma sample of the patients and spiked plasma samples with vancomycin was analyzed for a poly-pharmacy patient and chromatograms are depicted in Fig. 4. Results revealed that this method has acceptable precision and selectivity to distinguish vancomycin peak among other drugs and endogenous plasma peaks. The use of a spiked peak chromatogram confirmed the exact location of the vancomycin peak. Trough plasma level was 8.79 μg/mL which was below the recommended trough level of vancomycin (15-20 μg/mL).\n\nFig. 4 Representative chromatograms of first patient (A) trough level and (B) spiked trough level. IS, internal standard.\n\nResults of the second patient revealed that his vancomycin trough level was 69.365 μg/mL, intermediate (4 h) was 76.6 μg/mL, and the peak level was 122.3 μg/mL. 12 h-AUC was calculated 972.5 μg.h/mL according to Fig. 5, 24 h-AUC was 1945 μg.h/mL. Vancomycin CLr was calculated 1.03 l/h, Vd was 18.89 L and Ke was 0.055 h-1. Baseline serum creatinine for this patient was 1.2 mg/dL and serum creatinine at the day of blood sampling was 2.4 mg/dL but it was reached 3.6 mg/dL the day after the blood sampling. Finally, serum creatinine in this patient was reached 6.8 mg/dL within 10 days after blood sampling time and the patient was expired.\n\nFig. 5 12 h-AUC which has been calculated through the trapezoidal method; AUC = A1 + A2 + A3. AUC, the area under the curve.\n\nResults of the third patient revealed that vancomycin peak level was 24.05 μg/mL and the trough level was 0 μg/mL. 24 h-AUC was 24.3 μg.h/mL which revealed that this patient was receiving an under-dose drug and confirm that vancomycin dose adjustment solely based on GFR is not adequate and TDM is necessary.\n\nResults of the fourth patient revealed that vancomycin peak level was 31.69 μg/mL, the intermediate level was 20.51 μg/mL, and the trough level was 13.45 μg/mL. 12 h-AUC was 245.13 μg.h/mL and 24 h-AUC was 490.26 μg.h/mL. In this patient Vd was 54.82 L, Clr was 4.08 L/h and Ke was 0.074 h-1.\n\nDISCUSSION\n\nIn the present study, we proposed a modified and optimized extraction process which is simple and economically beneficial for plasma samples collected from critically ill patients who received vancomycin at Nemazee Hospital, Shiraz, Iran. The most important challenge in the selection of a suitable extraction method is the necessity of avoidance of peak interactions and peak overlaps of simultaneously administered drugs, internal standard (IS), and endogenous plasma peaks. In this study, a validated HPLC method has been developed to minimize these kinds of interactions. Among different IS which have been studied for vancomycin assay, acetaminophen was selected. Acetaminophen has good absorptivity and similar λmax to vancomycin. Acetaminophen showed different retention time from the vancomycin and endogenous peaks of plasma samples and acceptable absorptivity at the same λmax selected for vancomycin analysis. Calibration curve and linearity results showed the acceptance validation criteria of the calibration curve according to USP guidelines which are ±15% of nominal concentrations (1821). R square of 0.9996 and adjusted R square of 0.9995 revealed that there is an acceptable linear relationship between vancomycin concentration and area of the vancomycine peak over that of IS ratios. Regression test results showed significance F values lower than 0.05 which confirmed the significant linear relationship. X-variable (slope) P-value was lower than 0.05 which also confirmed that the curve slope had a significant difference with zero. This method showed acceptable selectivity in the determination of vancomycin levels in plasma samples in accordance with the USP bioanalytical method validation guideline (18) which has been suggested that blank plasma should be free of interference at the retention times of the analyte and IS. The analyte response at LOQ was ≥ 5-times the analyte response of the blank plasma (zero calibrator) (18). Sensitivity results revealed that this validated method has acceptable sensitivity to analyze vancomycin trough, intermediate, and peak plasma levels. All samples had %CV lower than 15% that was in accordance with USP guidelines which suggested the precision of ± 15 %CV. Accuracy results were compatible with USP validation guidelines (acceptable accuracy range of 85-115%) (18). Therefore, according to the results, this method has acceptable accuracy and precision for vancomycin assay in plasma samples.\n\nAccording to the results, in this developed HPLC method for vancomycin assay in plasma samples, there was no interference between vancomycin and/or IS peaks with other common drugs that might be administered simultaneously in ICU patients. This method showed sufficient selectivity and sensitivity for vancomycin level assay in plasma samples of critically ill patients.\n\nResults of the first patient's samples revealed the trough level was 8.79 μg/mL which is below the recommended trough level of vancomycin (15-20 μg/mL). In this patient, after trough level measurement, vancomycin dosage was enhanced to 1 g every 8 h in order to adjust the optimum trough level to 15 to 20 μg/mL and the patient's blood culture changed to negative after 7 days of antibiotic therapy with optimized dosage. Low vancomycin trough levels are common especially in young patients with normal renal function when vancomycin is administered with the usual dose of 1 g every 12 h (22). So, the loading and maintenance dose of vancomycin should be individualized based on patients' renal function, weight, and measured plasma levels (23). The results of this analysis confirmed the importance of TDM in patients who are receiving vancomycin.\n\nResults of the second patient's samples revealed that 1.2 mg/dL increase in serum creatinine level within 24 h was a sign of acute kidney injury (AKI) in this patient due to the very high trough level of vancomycin (69 μg/mL) while dose adjustment between 15 and 20 μg/mL is necessary. Also, 24 h-AUC of 1945 μg.h/mL confirmed vancomycin- associated (24) nephrotoxicity which is far from a target goal of 400-600 μg.h/mL. Another pharmacokinetic parameter that revealed vancomycin-associated nephrotoxicity was Ke, in this patient Ke value of 0.055 h-1 was significantly lower than the vancomycin Ke value in the normal population which is 0.116 h-1. Reduction in Ke value is another criterion of the occurrence of nephrotoxicity. Finally, serum creatinine in this patient was raised to 6.8 mg/dL within 10 days and the patient was expired which might be the consequence of irreversible AKI related to vancomycin nephrotoxicity. The results of this patient also revealed the necessity of TDM to avoid vancomycin-associated nephrotoxicity. According to these results consideration of optimum sampling time, which is at least 48 h after initiation of vancomycin therapy, is highly recommended in order to an early decision about dose modification and prevention of these kinds of irreversible vancomycin-induced AKIs which was seen in the second patient.\n\nAccording to the results of the third patient who was in under-dose regimen, vancomycin- dose adjustment is necessary, and only based on GFR decision making is not sufficient (5) and TDM is essential to provide essential pharmacokinetic parameters. In this patient vancomycin, the dosage was modified to 1 g every 12 h and then blood culture became negative within 10 days of antibiotic therapy with modified dosage.\n\nResults of the fourth patient emphasized the priority of AUC calculation over trough level assessment because in this patient 24 h-AUC was in acceptable range (400-600 μg.h/mL) but trough level was lower than 15 μg/mL which is the recommended clinical target level. In this patient, because of suitable vancomycin 24 h-AUC level, antibiotic therapy was continued with the previous dosage of 1 g every 12 h for 7 days until removal of clinical and laboratory presentations of infection. The results of these patients' blood sample analysis emphasized the importance of TDM of vancomycin during drug administration to avoid severe adverse drug reactions related to overdose or failure to therapy-related to under-dose drug administration in critically ill patients. The most important advantage of the HPLC method in comparison with immunoassay methods is its higher sensitivity and selectivity especially in lower concentrations, and also avoidance of cross-reactions with vancomycin metabolites which could prevent false-positive results during drug assay. Critically ill patients who are admitted to ICU are highly prone to sepsis and the occurrence of AKI, so TDM of vancomycin, as a nephrotoxic drug, is highly essential in these patients in order to prevent further complications. After pharmacists' intervention in dose adjustment by pharmacokinetic analysis, patients could gain the optimum trough level and AUC values, and clinical and laboratory presentations of infections were resolved within 10 days of antibiotic therapy with optimized dosage. According to the results of this study, vancomycin TDM is strongly recommended for patients admitted to the ICU of Nemazee Hospital, a referral center in southern Iran, which has not been performed so far.\n\nCONCLUSION\n\nAccording to the previous studies a simple, fast, and relatively low-cost method has been established and proposed for vancomycin assay. This validated HPLC method for the assay of vancomycin plasma levels was utilized to measure vancomycin levels in four patients and pharmacokinetic parameters were calculated individually. According to the results of this study, pharmacist-guided TDM for vancomycin is strongly recommended in this center. Individualized dose adjustment of vancomycin in critically ill patients is essential in order to avoid unwanted adverse reactions especially vancomycin-induced AKI and also to achieve optimum clinical efficacy. It seems that the total costs of vancomycin TDM center establishment would be lower than the costs of nephrotoxicity associated with vancomycin overdose and its further complications. Also, applying TDM in critically ill patients would be accompanied with a shorter duration of hospitalization that can result in lower total costs for both patients and health care systems.\n\nCONFLICT OF INTEREST STATEMENT\n\nThe authors declared no conflict of interest in this study.\n\nAUTHORS' CONTRIBUTION\n\nP. Ghasemiyeh Carried out the experiment, analyzed the data, writing original draft preparation, reviewing and editing. A. Vazin supervised and carried out the methodology, writing, reviewing, and editing the manuscript. F. Zand, A. methodology, writing, reviewing, and editing the manuscript. S. Mohammadi-Samani supervised, conceptualized, methodology, writing, reviewing. and editing the manuscript.\n\nACKNOWLEDGEMENTS\n\nThis study was a part of the Ph.D. thesis of Dr. Parisa Ghasemiyeh. 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optimization for the therapeutic drug monitoring of vancomycin J Anal Bioanal Sep Tech 2017 2 2 89 95 DOI: 10.15436/2476-1869.17.1733\n14 Abu-Shandi KH Determination of vancomycin in human plasma using high-performance liquid chromatography with fluorescence detection Anal Bioanal Chem 2009 395 2 527 532 DOI: 10.1007/s00216-009-2948-9 19655128\n15 Cao Y Yu J Chen Y Zhang J Wu X Zhang Y Development and validation of a new ultra- performance liquid chromatographic method for vancomycin assay in serum and its application to therapeutic drug monitoring Ther Drug Monit 2014 36 2 175 181 DOI: 10.1097/FTD.0b013e3182a458bc 24216537\n16 Muppidi K Pumerantz AS Betageri G Wang J Development and validation of a rapid high- performance liquid chromatography method with UV detection for the determination of vancomycin in mouse plasma J Chromat Separation Techniq 2013 4 1 1 5 DOI: 10.4172/2157-7064.1000165\n17 Plock N Buerger C Kloft C Successful management of discovered pH dependence in vancomycin recovery studies: novel HPLC method for microdialysis and plasma samples Biomed Chromatogr 2005 19 3 237 244 DOI: 10.1002/bmc.446 15558685\n18 Health UDo Services H Bioanalytical method validation, guidance for industry 2001 Accessed January 02, 2019 Available from: http://wwwfdagov/cder/guidance/4252fnl htm\n19 Uhrovčík J Strategy for determination of LOD and LOQ values-some basic aspects Talanta 2014 119 178 180 DOI: 10.1016/j.talanta.2013.10.061 24401401\n20 Tsang M A Practice of anesthesia for infants and children Can J Anesth 2018 65 12 1392 1393 DOI: 10.1007/s12630-018-1201-4\n21 Rezazadeh M Emami J A simple and sensitive HPLC method for analysis of imipramine in human plasma with UV detection and liquid-liquid extraction: Application in bioequivalence studies Res Pharm Sci 2016 11 2 168 176 27168757\n22 Šíma M Hartinger J Grus T Slanař O Initial dosing of intermittent vancomycin in adults: estimation of dosing interval in relation to dose and renal function Eur J Hosp Pharm 2019 DOI: 101136/ejhpharm-2019-002013\n23 Šíma M Hartinger J Netíková IŠ Slanar O Creatinine clearance estimations for vancomycin maintenance dose adjustments Am J Ther 2018 25 5 e602 e604 DOI: 10.1097/MJT.0000000000000616 28650911\n24 Soltani R Khorvash F Meidani M Badri S Alaei S Taheri S Vitamin E in the prevention of vancomycin- induced nephrotoxicity Res Pharm Sci 2020 15 2 137 143 DOI: 10.4103/1735-5362.283813 32582353\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1735-5362",
"issue": "15(6)",
"journal": "Research in pharmaceutical sciences",
"keywords": "AUC; Acute kidney injury; HPLC; ICU; TDM; Vancomycin",
"medline_ta": "Res Pharm Sci",
"mesh_terms": null,
"nlm_unique_id": "101516968",
"other_id": null,
"pages": "529-540",
"pmc": null,
"pmid": "33828596",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "24250438;21736328;11236095;24401401;24216537;30936936;19655128;29069326;28650911;27168757;26933623;22851425;29084753;15558685;16323118;22577613;32582353;30662865;28923869",
"title": "A simple and validated HPLC method for vancomycin assay in plasma samples: the necessity of TDM center development in Southern Iran.",
"title_normalized": "a simple and validated hplc method for vancomycin assay in plasma samples the necessity of tdm center development in southern iran"
} | [
{
"companynumb": "IR-AXELLIA-003779",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nThe Anti-CD20 monoclonal antibody Rituximab suppresses B-lymphocytes and may induce hypogammaglobulinemia in treated patients. The incidence and clinical significance of rituximab induced hypogammaglobulinemia in lymphoma patients is underestimated.\n\n\nMETHODS\nWe retrospectively analyzed the rates of hypogammaglobulinemia, infection and infection-related mortality in 136 lymphoma patients who were treated with a combination of chemotherapy and rituximab.\n\n\nRESULTS\nRituximab given in more than 8 doses (OR 6.05, 95% CI: 1.24-29.5), relative hypogammaglobulinemia at time of lymphoma diagnosis (OR 4.2, 95% CI: 1.26-14.1) and the combination of fludarabine with rituximab (OR 3.4, 95% CI: 1.24-9.47) were factors significantly associated with prolonged (more than 6 months) hypogammaglobulinemia. The combination of fludarabine and rituximab (OR 6.4, 95% CI: 1.49-27.0) and secondarily prolonged hypogammaglobulinemia (OR 4.5, 95% CI: 1.19-18.5) were found to be predictive factors for severe infections and infection-related mortality.\n\n\nCONCLUSIONS\nThese data suggest the importance of following serum immunoglobulin levels before and after combination immuno-chemotherapy, particularly in patients with recurrent infections or relapsed/refractory disease.",
"affiliations": "Hematology Institute, Kaplan Medical Center, 76100 Rehovot, Israel. kalmanph@clalit.org.il.",
"authors": "Filanovsky|Kalman|K|;Miller|Edward B|EB|;Sigler|Erica|E|;Berrebi|Alain|A|;Shvidel|Lev|L|",
"chemical_list": "D000069283:Rituximab",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574892811666160129110614",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8928",
"issue": "11(2)",
"journal": "Recent patents on anti-cancer drug discovery",
"keywords": null,
"medline_ta": "Recent Pat Anticancer Drug Discov",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007239:Infections; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab; D055815:Young Adult",
"nlm_unique_id": "101266081",
"other_id": null,
"pages": "228-35",
"pmc": null,
"pmid": "26825174",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Incidence of Profound Hypogammaglobulinemia and Infection Rate in Lymphoma Patients Following the Combination of Chemotherapy and Rituximab.",
"title_normalized": "incidence of profound hypogammaglobulinemia and infection rate in lymphoma patients following the combination of chemotherapy and rituximab"
} | [
{
"companynumb": "IL-FRESENIUS KABI-FK201605061",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in \"100% natural\" or \"herbal\" supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated \"Chinese herbal\" supplement \"Tiger King\" for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was \"possible\" and \"probable\" respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient's clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of \"Tiger king\" in particular, and other counterfeit medications or herbal supplements of unknown origin.",
"affiliations": "Enforcement and Inspection Division, Israeli Ministry of Health, Eliav 9, Jerusalem 9546208, Israel. alina.poperno@mail.huji.ac.il.",
"authors": "Nissan|Ran|R|;Poperno|Alina|A|;Stein|Gideon Y|GY|;Shapira|Barak|B|;Fuchs|Shmuel|S|;Berkovitz|Ronny|R|;Hess|Zipora|Z|;Arieli|Mickey|M|",
"chemical_list": "D004365:Drugs, Chinese Herbal; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886311207040257",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "11(2)",
"journal": "Current drug safety",
"keywords": null,
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000368:Aged; D056486:Chemical and Drug Induced Liver Injury; D004365:Drugs, Chinese Herbal; D006801:Humans; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "184-8",
"pmc": null,
"pmid": "26560492",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Hepatotoxicity Induced by Adulterated \"Tiger King\", a Chinese Herbal Medicine Containing Sildenafil.",
"title_normalized": "a case of hepatotoxicity induced by adulterated tiger king a chinese herbal medicine containing sildenafil"
} | [
{
"companynumb": "IL-PFIZER INC-2016276992",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SILDENAFIL CITRATE"
},
"drugadditional": "3",
... |
{
"abstract": "An association between maternal diabetes, its medication and childhood cancer has not been previously explored in a registry-based setting. With a case-control design, we aimed to explore whether maternal diabetes is associated with an increased risk of childhood cancer in the offspring. Combining data from population-based registries, we analyzed a total of 2,029 cases, that is, persons with childhood cancer diagnosed under the age of 20 years between years 1996-2014 and a total of 10,103 matched population controls. The mothers of the cases/controls and their diagnoses of diabetes (DM) before/during pregnancy as well as their insulin/metformin prescriptions during pregnancy were identified. Conditional logistic regression modeling was used to analyze the risk of childhood cancer. The OR for childhood cancer among those exposed to any maternal diabetes was 1.32 (95% CI 1.14-1.54) compared to the offspring of the nondiabetic mothers. The effect of maternal diabetes on the risk of childhood cancer remained elevated even after adjusting for maternal age, parity and smoking. Our data suggest that maternal diabetes medication may reduce the risk for childhood cancer (adjusted OR 0.83, 95% CI 0.36-1.94), especially in gestational diabetes (adjusted OR 0.26, 95% CI 0.05-1.25), compared to the diabetic mothers without medication. The risk of childhood leukemia was significantly higher among children exposed to any maternal diabetes (OR 1.36, CI 1.04-1.77) compared to the unexposed. Maternal diabetes appears to be associated with an increased risk of childhood cancer in the offspring. The possible risk-reducing effect of an exposure to diabetes medication on offspring cancer risk warrants further investigation.",
"affiliations": "Pediatric Research Center, University of Helsinki, Helsinki, Finland.;Pediatric Research Center, University of Helsinki, Helsinki, Finland.;Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.;Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.;Information Services Department, Unit of Statistics and Registers, National Institute for Health and Welfare, Helsinki, Finland.;Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.",
"authors": "Seppälä|Laura K|LK|0000-0003-3028-9127;Vettenranta|Kim|K|;Pitkäniemi|Janne|J|;Hirvonen|Elli|E|;Leinonen|Maarit K|MK|;Madanat-Harjuoja|Laura-Maria|LM|",
"chemical_list": "D007328:Insulin; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.32757",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "147(3)",
"journal": "International journal of cancer",
"keywords": "\nin utero exposure; childhood cancer; insulin; maternal diabetes; medication; metformin",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003920:Diabetes Mellitus; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007328:Insulin; D016015:Logistic Models; D008297:Male; D008423:Maternal Age; D008687:Metformin; D009369:Neoplasms; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012042:Registries; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "662-668",
"pmc": null,
"pmid": "31658368",
"pubdate": "2020-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Maternal diabetes and risk of childhood cancer in the offspring.",
"title_normalized": "maternal diabetes and risk of childhood cancer in the offspring"
} | [
{
"companynumb": "FI-ALKEM LABORATORIES LIMITED-FI-ALKEM-2019-09886",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nInfliximab therapy is an effective approach to treating Crohn's disease. Development of antinuclear antibodies has been described in patients treated, but the size of the problem and the relationship with autoimmunity have not been investigated. We investigated the occurrence of antinuclear antibodies in 125 consecutive Crohn's disease patients and studied the relationship with symptoms of autoimmunity.\n\n\nMETHODS\nAutoantibodies and clinical data were investigated before and 1, 2, and 3 months after infliximab infusion. If antinuclear antibodies were > or =1:80, further study of double-stranded DNA, single-stranded DNA, histones, and ENA was performed.\n\n\nRESULTS\nCumulative antinuclear antibody incidence at 24 months was 71 of 125 (56.8%). Almost half of these patients developed antinuclear antibodies after the first infusion, and >75% became antinuclear antibody positive after fewer than 3 infusions. So far, only 15 of 71 patients have become seronegative, after a median of 12 months. Of 43 antinuclear antibody-positive patients who were further subtyped, 14 of 43 (32.6%) had double-stranded DNA, 17 (39.5%) had single-stranded DNA, 9 (20.9%) had antihistone, and 0% were ENA positive. Two patients (both antihistone and double-stranded DNA positive) developed drug-induced lupus without major organ damage, and 1 developed autoimmune hemolytic anemia. Antinuclear antibodies were associated with the female sex (odds ratio, 3.166; 95% confidence interval, 1.167-8.585; P = 0.024) and with papulosquamous or butterfly rash (odds ratio, 10.016; 95% confidence interval, 1.708-58.725; P = 0.011).\n\n\nCONCLUSIONS\nThe cumulative incidence of antinuclear antibodies was 56.8% after 24 months in this cohort of infliximab-treated Crohn's disease patients. Antinuclear antibodies persisted up to 1 year after the last infusion, and only a few patients became seronegative. Two patients developed drug-induced lupus erythematosus. Antinuclear antibodies were associated with the female sex and skin manifestations.",
"affiliations": "Gastroenterology Department, University Hospital Gasthiuisberg, Leuven, Belgium.",
"authors": "Vermeire|Severine|S|;Noman|Maja|M|;Van Assche|Gert|G|;Baert|Filip|F|;Van Steen|Kristel|K|;Esters|Nele|N|;Joossens|Sofie|S|;Bossuyt|Xavier|X|;Rutgeerts|Paul|P|",
"chemical_list": "D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1016/s0016-5085(03)00701-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "125(1)",
"journal": "Gastroenterology",
"keywords": null,
"medline_ta": "Gastroenterology",
"mesh_terms": "D000328:Adult; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D004247:DNA; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008297:Male; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "32-9",
"pmc": null,
"pmid": "12851868",
"pubdate": "2003-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study.",
"title_normalized": "autoimmunity associated with anti tumor necrosis factor alpha treatment in crohn s disease a prospective cohort study"
} | [
{
"companynumb": "BE-JNJFOC-20030800463",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Although some prospective studies provided the evidence of corticosteroids for critically ill patients with COVID-19, the optimal dosage or timing of corticosteroids is still unknown. This is a case series of four patients on methyl-prednisolone pulses for the late phase of Coronavirus disease 2019 (COVID-19) with respiratory failure in our hospital. All patients needed invasive mechanical ventilation and had bimodal worseness of their respiratory status with consolidation and volume loss after intubation. All cases could successfully discontinue oxygen therapy without any severe adverse events after this pulse therapy in the late phase of COVID-19. This therapy is believed to be effective on some optimal patients. Hence, further studies to explore this efficacy and safety were needed.",
"affiliations": "Division of Respiratory Diseases, Department of Internal Medicine, Atsugi City Hospital, Kanagawa, 243-8588, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Atsugi City Hospital, Kanagawa, 243-8588, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Atsugi City Hospital, Kanagawa, 243-8588, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Atsugi City Hospital, Kanagawa, 243-8588, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.",
"authors": "Tamura|Kentaro|K|;Nishioka|Saiko|S|;Tamura|Nobumasa|N|;Saito|Zenya|Z|;Kuwano|Kazuyoshi|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101318",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(20)30532-3\n10.1016/j.rmcr.2020.101318\n101318\nCase Report\nSuccessful treatment with methyl-prednisolone pulses for the late phase of COVID-19 with respiratory failure: A single-center case series\nTamura Kentaro kentaro.tamura.512@gmail.com\nab∗\nNishioka Saiko saiko.nishioka@gmail.com\nab\nTamura Nobumasa n.tamura.2204@jikei.ac.jp\nab\nSaito Zenya zyst@jikei.ac.jp\nab\nKuwano Kazuyoshi kkuwano@jikei.ac.jp\nb\na Division of Respiratory Diseases, Department of Internal Medicine, Atsugi City Hospital, Kanagawa, 243-8588, Japan\nb Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan\n∗ Corresponding author. Division of Respiratory Diseases, Department of Internal Medicine, Atsugi City Hospital, 1-16-36 Mizuhiki, Atsugi, Kanagawa, Japan. Tel: +81 46 221 1570; fax: +81 46 294 3335. kentaro.tamura.512@gmail.com\n09 12 2020\n2020\n09 12 2020\n31 10131829 10 2020\n4 12 2020\n7 12 2020\n© 2020 The Authors\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAlthough some prospective studies provided the evidence of corticosteroids for critically ill patients with COVID-19, the optimal dosage or timing of corticosteroids is still unknown. This is a case series of four patients on methyl-prednisolone pulses for the late phase of Coronavirus disease 2019 (COVID-19) with respiratory failure in our hospital. All patients needed invasive mechanical ventilation and had bimodal worseness of their respiratory status with consolidation and volume loss after intubation. All cases could successfully discontinue oxygen therapy without any severe adverse events after this pulse therapy in the late phase of COVID-19. This therapy is believed to be effective on some optimal patients. Hence, further studies to explore this efficacy and safety were needed.\n\nKeywords\n\nCOVID-19\nLate phase\nSteroid\nSteroid pulse therapy\n==== Body\n1 Introduction\n\nCoronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has been spreading worldwide since the first outbreak in Wuhan, China, in December 2019.\n\nSome reports suggested that the steroid therapy might suppress a cytokine storm by COVID-19 [1]. The RECOVERY trial firstly provided the evidence of the efficacy of dexamethasone for patients with COVID-19 who received oxygen therapy [2]. The prospective meta-analysis of clinical trials including the RECOVERY trial also showed that systemic corticosteroids were effective on critically ill patients with COVID-19 [3]. However the optimal dosage or timing of corticosteroids is still unknown. One prospective study proved that methyl-prednisolone pulses (MP) administered within the second week after the onset of symptoms improved outcome of patients with COVID-19 who have inflammatory activity [4]. We would like to share our experience in using MP in the late phase of severe COVID-19 with respiratory failure. This study was approved by the ethics committee of this hospital (approval number: R2-07).\n\n2 Case series\n\n2.1 Day 1 was defined as the first onset of the symptoms\n\n2.1.1 Case 1\n\nThis is the case of a 61-year-old man with hypertension and who is an ex-smoker, who presented with fever, upper respiratory tract symptoms, and myalgia. He was diagnosed with COVID-19 on day 11. Lopinavir/ritonavir, ciclesonide, azithromycin and ampicillin/sulbactam were initiated after diagnosis. He needed invasive mechanical ventilation (IMV) due to a rapid progressive respiratory failure on day 13. The ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) was 136, which was classified as moderate acute respiratory distress syndrome (ARDS) at that time. Low-dose steroid (hydrocortisone 250mg/day), intravenous immunoglobulin, and sivelestat were started after intubation. The respiratory status improved temporarily, but P/F and consolidation with traction bronchiectasis and volume loss worsened. MP (methyl-prednisolone 1000mg for three days) was started from day 19. After this therapy, P/F, LDH, and computed tomography (CT) findings were improved (Fig. 1, Fig. 2).Fig. 1 Clinical course of P/F (the ratio of arterial oxygen partial pressure to fractional inspired oxygen) and LDH (IU/l). Black triangle: the day of intubation. Black square: the day of extubation. Day 1 was set as the initiation of steroid pulse therapy.\n\nFig. 1\n\nFig. 2 Computed tomography of the chest during the clinical course in case 1. It showed bilateral peripheral ground glass opacities on day 11 (on admission). These opacities progressed consolidation with traction bronchiectasis and volume loss on day 19 (the day steroid pulse therapy was started). Patient almost recovered from these findings on day 61.\n\nFig. 2\n\nPrednisolone (PSL) 40mg (0.5mg/kg/day) was started after the pulse therapy, and the dose was gradually tapered. He was successful extubated on day 23, negative conversion of the reverse transcription polymerase chain reaction test (RT-PCR) was confirmed on day 43, and finally he was discharged without oxygen demand on day 48. PSL was finished on day 49.\n\n2.1.2 Case 2\n\nThis is the case of a 43-year-old woman with bronchial asthma who presented with fever, cough, malaise, arthralgia, and dysgeusia. She was diagnosed with COVID-19 on day 6. Lopinavir/ritonavir was initiated when she had pneumonia with oxygen demand on day 8. Hydroxychloroquine, azithromycin, and ampicillin/sulbactam were added on day 9 since her respiratory status worsened. She needed IMV due to a rapid progressive respiratory failure on day 10. P/F was 149, which was classified as moderate ARDS at that time. Ciclesonide, low-dose steroid (hydrocortisone 250mg/day), intravenous immunoglobulin, and sivelestat were started after intubation. The respiratory status improved temporarily, but P/F and consolidation with traction bronchiectasis and volume loss worsened. Initially, prone position therapy was started from day 14, and MP (methyl-prednisolone 1000mg for three days) was initiated from day 15. After this therapy, P/F, LDH, and CT findings were improved (Fig. 1). After the pulse therapy, PSL 30mg (0.5mg/kg/day) was started, and the dose was gradually tapered. She was successfully extubated on day 21, negative conversion of RT-PCR was confirmed on day 27, and finally she was discharged without oxygen demand on day 31. PSL was finished on day 38.\n\n2.1.3 Case 3\n\nThis is the case of a 68-year-old man with hypertension who presented with fever, diarrhea, and dry cough. He was diagnosed with COVID-19 on day 11. Although lopinavir/ritonavir was initiated after diagnosis, he manifested respiratory failure from day 12. Hydroxychloroquine has been added for his treatment on day 16, ampicillin/sulbactam on day 18, ciclesonide on day 19, and azithromycin and low-dose steroid (hydrocortisone 250mg/day) on day 22. He needed IMV due to a progressive respiratory failure on day 23. P/F was 170, which was classified as moderate ARDS at that time. Intravenous immunoglobulin, sivelestat, and prone position therapy were started after intubation. The respiratory status improved temporarily, but P/F and consolidation with traction bronchiectasis and volume loss worsened. MP (methyl-prednisolone 1000mg for three days) was initiated from day 29. After this therapy, P/F, LDH, and CT findings were improved (Fig. 1). PSL was not administered after the pulse therapy. He was successfully extubated on day 30, negative conversion of RT-PCR was confirmed on day 51, and finally he was transferred to a rehabilitation hospital due to disuse syndrome without oxygen demand on day 59.\n\n2.1.4 Case 4\n\nThis is the case of a 77-year-old man with hypertension, emphysema, and old tuberculosis, who is an ex-smoker and who presented with fever and sore throat. Levofloxacin and ciclesonide were administered on day 8 for bilateral pneumonia with respiratory failure. He was diagnosed with COVID-19 on day 10. He needed IMV due to a rapid progressive respiratory failure on day 11. P/F was 170, which was classified as moderate ARDS at that time. Although favipiravir has been initiated, low-dose steroid (hydrocortisone 250mg/day), intravenous immunoglobulin, sivelestat, and prone position therapy were administered after intubation. The respiratory status improved temporarily, but P/F and consolidation with traction bronchiectasis and volume loss worsened. MP (methyl-prednisolone 1000mg for three days) was initiated from day 14. After this therapy, P/F, LDH, and CT findings were improved (Fig. 1). PSL 30mg (0.5mg/kg/day) was started after the pulse therapy, and the dose was gradually tapered. He was successfully extubated on day 30, negative conversion of RT-PCR was confirmed on day 24, and finally he was discharged without oxygen demand on day 30. PSL was finished on day 33.\n\n2.2 Summary of the results for four cases\n\nMP with respiratory failure due to COVID-19 was administered to four patients (three males, one female). The median day of MP administration was day 17 (14–29), the late phase of COVID-19. The median age was 64.5 years (43–77). The comorbidities were hypertension in three cases, history of smoking in two cases, and bronchial asthma, emphysema, and old pulmonary tuberculosis in one case. The median time to diagnosis, respiratory failure, or intubation was 10.5 days (6–11), 9.5 days (8–12), or 12 days (10–23), respectively. The median findings of body temperature, lymphocyte, LDH, and C-reactive protein on intubation were 38.5° Celsius (36.8–38.6), 393.5/μl (219–1227), 442.5IU/l (364–599), and 15.7mg/dl (12.8–35.8), respectively. Lopinavir/ritonavir, hydroxychloroquine, favipiravir, and ciclesonide which were expected to have an antiviral effect were administered on day 10.5 (8–19) (median, range). Intravenous immunoglobulin and antibiotics were administered in all cases. Prone position therapy was performed in three cases. Low-dose corticosteroids were administered in all cases around the timing of intubation. MP improved P/F, LDH, and CT findings in all cases in spite of bimodal worseness after intubation (Figs. 1 and 2). The median duration of systemic corticosteroid, intubation, ICU stay, and negative conversion of RT-PCR was 26 days (13–37), 9.5 days (8–12), 11 days (9–17), and 35 days (24–51), respectively. All cases succeeded in withdrawing from oxygen therapy, but one patient was transferred to a rehabilitation hospital due to disuse symptom. No other adverse events were observed.\n\n3 Discussion\n\nAll cases showed that P/F and consolidation with traction bronchiectasis and volume loss worsened after the temporary improvement on intubation. MP in the late phase of COVID-19 improved pneumonia and P/F without oxygen demand. They were discharged to go home except one patient.\n\nThe Radiological Society of North America suggested that typical CT findings for COVID-19 revealed peripheral and bilateral or multifocal ground grass opacities of rounded morphology with or without consolidation or crazy-paving appearance [5]. This society also reported that consolidation, reserve halo sign, and other findings of organizing pneumonia (OP) were found in the late phase of COVID-19 [5]. A retrospective study in China showed that CT findings including consolidation, linear opacities, crazy-paving pattern, and bronchial wall thickening were associated with disease severity [6]. In general, the treatment for secondary OP is similar to that for cryptogenic OP. The British Thoracic Society guidelines proposed that corticosteroids were the current standard treatment for cryptogenic OP, although the initial dose of corticosteroids was unknown [7]. This society also suggested a steroid pulse therapy for some cases with fulminant cryptogenic OP. Although no histopathological examination was presented to diagnose OP in our cases, CT findings in the late phase of COVID-19 were characteristic of OP. The prospective meta-analysis of clinical trials including the RECOVERY trial and some retrospective studies showed that systemic corticosteroids were effective on critically ill patients with COVID-19 although these studies didn't refer to OP [2,3,8,9]. One prospective study proved that MP administered within the second week after the onset of symptoms improved outcome of patients with COVID-19 [4]. As a result, MP might be effective in patients with the late phase of COVID-19.\n\nA routine use of systemic corticosteroids for COVID-19 wasn't firstly recommended because a previous report showed that systemic corticosteroids delayed viral shedding and that they were harmful due to adverse events for severe acute respiratory syndrome, Middle East respiratory syndrome, and especially increased mortality for influenza [10]. It was reported that the time to negative conversion of RT-PCR was 20 days in mild to severe cases [11,12]. This study had it longer than that of the previous study. It was suggested that systemic corticosteroids might delay viral shedding. Since RT-PCR tests were not performed on continuous days, the time to negative conversion of RT-PCR might be shorter in some cases. One patient was transferred to a rehabilitation hospital due to disuse syndrome. Disuse syndrome might be associated with systemic corticosteroids and bed rest for a long time. However, it was significant that all patients could survive without oxygen therapy. Therefore, a MP therapy might be beneficial because viral load might be low in the late phase of COVID-19. However, corticosteroids should be used in a short-term to diminish this toxicity.\n\nThis study has several limitations. Firstly, this was a single-center case series with small sample. We couldn't set a control group because of small sample. Further investigations are needed in the future. Secondly, no histopathological examination was presented to diagnose OP. Identifying the etiology was based primarily on images and laboratory findings since invasive procedures such as bronchoscopy to reduce viral exposure were not performed.\n\nIn conclusion, MP is effective for patients with respiratory failure in the late phase of COVID-19. Although the use of systemic corticosteroids is of concern due to the delay of viral shedding or toxicity, they can be used safely by selecting optimal cases, timing, and dose. It is necessary to establish its evidence for further case accumulation and research.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.\n\nDeclaration of competing interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\n1 Wu C. Chen X. Cai Y. Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus Disease 2019 pneumonia in Wuhan, China JAMA. Intern. Med. 180 2020 934 943 10.1001/jamainternmed.2020.0994 32167524\n2 Horby P. Lim W.S. Emberson J.R. Dexamethasone in hospitalized patients with covid-19 - preliminary report N. Engl. J. Med 2020 Jul 17 10.1056/NEJMoa2021436 [Preprint]\n3 Sterne J.A.C. Murthy S. Diaz J.V. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis J. Am. Med. Assoc. 324 2020 1330 1341 10.1001/jama.2020.17023\n4 Ruiz-Irastorza G. Pijoan J.I. Bereciartua E. Second week methyl-prednisolone pulses improve prognosis in patients with severe coronavirus disease 2019 pneumonia: an observational comparative study using routine care data PloS One 15 2020 e0239401 10.1371/journal.pone.0239401\n5 Scott S. Kay F.U. Suhny A. Radiological society of North America expert consensus statement on reporting chest CT findings related to COVID-19. Endorsed by the society of thoracic radiology, the American college of radiology, and RSNA J. Thorac. Imag. 35 2020 219 227 10.1097/RTI.0000000000000524\n6 Li K. Wu J. Wu F. Guo D. Chen L. Fang Z. Li C. The clinical and chest CT features associated with severe and critical COVID-19 pneumonia Invest. Radiol. 55 2020 327 331 10.1097/RLI.0000000000000672 32118615\n7 Bradley B. Branley H.M. Egan J.J. Interstitial lung disease guideline: the British thoracic society in collaboration with the thoracic society of Australia and New Zealand and the Irish thoracic society Thorax 63 2008 v1 v58 18757459\n8 Wu C. Chen X. Cai Y. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China JAMA. Intern. Med. 180 2020 934 943 10.1001/jamainternmed.2020.0994 32167524\n9 Chopra A. Chieng H.C. Austin A. Corticosteroid administration is associated with improved outcome in patients with severe acute respiratory syndrome coronavirus 2-related acute respiratory distress syndrome Crit. Care. Explor. 2 2020 e0143 10.1097/CCE.0000000000000143\n10 Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Lancet 395 2020 473 475 10.1016/S0140-6736(20)30317-2 32043983\n11 Zhou F. Yu T. Du R. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Lancet 395 2020 1054 1062 10.1016/S0140-6736(20)30566-3 32171076\n12 Xiao A.T. Tong Y.X. Gao C. Zhu L. Zhang Y.J. Zhang S. Dynamic profile of RT-PCR findings from 301 COVID-19 patients in Wuhan, China: a descriptive study J. Clin. Virol. 127 2020 104346 10.1016/j.jcv.2020.104346 32361324\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "31()",
"journal": "Respiratory medicine case reports",
"keywords": "COVID-19; Late phase; Steroid; Steroid pulse therapy",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101318",
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"pmid": "33318924",
"pubdate": "2020",
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"title": "Successful treatment with methyl-prednisolone pulses for the late phase of COVID-19 with respiratory failure: A single-center case series.",
"title_normalized": "successful treatment with methyl prednisolone pulses for the late phase of covid 19 with respiratory failure a single center case series"
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"abstract": "Progressive multifocal leukoencephalopathy (PML) is a rare rapidly progressive demyelinating disease of the central nervous system caused by reactivation of latent John Cunningham (JC) polyomavirus (JCV) infection. We describe an unusual case of PML in a 54-year-old patient with follicular non-Hodgkin lymphoma who received rituximab plus cyclophosphamide, hydroxydaunorubicin, oncovicin and prednisolone (R-CHOP) therapy. She started to notice gradual progressive neurological symptoms about two months after completion of rituximab treatment and was therefore admitted to hospital. On admission, brain CT and MRI showed widespread lesions consistent with a demyelinating process involving the subcortical and deep white matter of the cerebral and cerebellar hemispheres. CT and MRI findings were suggestive of PML, and JC virus DNA was detected by polymerase chain reaction assay of the cerebrospinal fluid and serum. The patient was treated supportively but reported a progressive worsening of the clinical and radiological findings. Our report emphasizes the role of CT and MRI findings in the diagnosis of PML and suggests that PML should be considered in patients with progressive neurological disorders involving the entire nervous system and mainly the white matter, especially in the presence of previous immunomodulatory treatment or immunosuppression.",
"affiliations": "Division of Radiology, Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy - alessiacat@tiscali.it.;Division of Radiology, Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.;Division of Radiology, Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.;Division of Radiology, Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.;Division of Neurology, Department of Life, Health and Environmental Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.;Division of Neuroradiology, Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.;Division of Neuroradiology, Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.;Division of Neurology, Department of Life, Health and Environmental Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.;Division of Neuroradiology, Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital of L'Aquila; L'Aquila, Italy.",
"authors": "Felli|Valentina|V|;Di Sibio|Alessandra|A|;Anselmi|Monica|M|;Gennarelli|Antonio|A|;Sucapane|Patrizia|P|;Splendiani|Alessandra|A|;Catalucci|Alessia|A|;Marini|Carmine|C|;Gallucci|Massimo|M|",
"chemical_list": "D000970:Antineoplastic Agents; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
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"fulltext": null,
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"issn_linking": "1971-4009",
"issue": "27(6)",
"journal": "The neuroradiology journal",
"keywords": "JC virus; follicular non-Hodgkin lymphoma; progressive multifocal leukoencephalopathy; rituximab",
"medline_ta": "Neuroradiol J",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001921:Brain; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008228:Lymphoma, Non-Hodgkin; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D014057:Tomography, X-Ray Computed; D014750:Vincristine",
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "657-64",
"pmc": null,
"pmid": "25489887",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9109865;21691572;10718540;20073129;23568998;24163670;23882904;19264918;11357954;7714213;23355583;22082208;22422012;21041380;17613758;18855101;12824781;24141508",
"title": "Progressive Multifocal Leukoencephalopathy Following Treatment with Rituximab in an HIV-Negative Patient with Non-Hodgkin Lymphoma. A Case Report and Literature Review.",
"title_normalized": "progressive multifocal leukoencephalopathy following treatment with rituximab in an hiv negative patient with non hodgkin lymphoma a case report and literature review"
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"activesubstancename": "DOXORUBICIN"
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"abstract": "A 54-year-old man presented with two episodes of dysarthria and left facial droop. Both episodes resolved by the time of examination. MRI of the brain revealed a right frontotemporal, heterogeneously enhancing mass with surrounding vasogenic oedema, suggestive of a high-grade primary brain neoplasm. The patient was administered preoperative 5-aminolevulinic acid hydrochloride (Gliolan), and fluorescence-guided resection of the lesion was undertaken. Cryptococcus gattii infection was diagnosed from the specimen and the patient was given appropriate antifungal treatment. This is the first reported case of Gliolan-mediated fluorescence in a fungal abscess and highlights one of the potential pitfalls in fluorescence-guided surgery.",
"affiliations": "Department of Neurosurgery, John Hunter Hospital, New Lambton, New South Wales, Australia waldo.g.solis@outlook.com.;Department of Neurosurgery, John Hunter Hospital, New Lambton, New South Wales, Australia.",
"authors": "Solis|Waldo Gerard|WG|;Hansen|Mitchell|M|",
"chemical_list": "D000935:Antifungal Agents; D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219469",
"fulltext": null,
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"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Drug therapy related to surgery; Infectious diseases; Neurosurgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000622:Aminolevulinic Acid; D000935:Antifungal Agents; D001921:Brain; D003453:Cryptococcosis; D056285:Cryptococcus gattii; D003937:Diagnosis, Differential; D004401:Dysarthria; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017319:Photosensitizing Agents; D025321:Surgery, Computer-Assisted",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28400397",
"pubdate": "2017-04-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18888792;19248665;21687966;2199524;22313493;22402878;22978537;23810126;24986537;25278580;26508406;27403402",
"title": "Fluorescence in a cryptococcoma following administration of 5-aminolevulinic acid hydrochloride (Gliolan).",
"title_normalized": "fluorescence in a cryptococcoma following administration of 5 aminolevulinic acid hydrochloride gliolan"
} | [
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"companynumb": "AU-MYLANLABS-2017M1032678",
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"activesubstancename": "AMPHOTERICIN B"
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"abstract": "BACKGROUND With the increasing prevalence of substance use in pregnancy, the rates of neonatal abstinence syndrome (NAS) are dramatically increasing. There is little information on the use of multiple substances in adults, even less so of polysubstance abuse during pregnancy and the consequences for the fetus as well as the mother. CASE REPORT A newborn male born at 35 weeks presented post-delivery with hips bilaterally dislocated and hyperflexed. The patient's legs fully extended and their shoulders were bilaterally mid-flexed with arms fully extended. This neonate was also reported to have bilateral hearing and vision loss as well as NAS symptoms of high-pitched crying and respiratory distress. During pregnancy the mother in this case study admitted to using buprenorphine, benzodiazepines, gabapentin, and heroin. The consequences of using this combination has not been well studied in pregnancy. CONCLUSIONS The presented case had severe complications, likely due to maternal polysubstance use and poor prenatal care in pregnancy. Clonidine was used to control the NAS symptoms, ranitidine was used to treat the gastroesophageal reflux, and glycopyrronium bromide was used for the neonate's excessive secretions. After delivery, the patient was placed on a nasal noninvasive cannula for respiratory distress and was transferred to a different hospital for treatment of the more serious comorbid conditions.",
"affiliations": "Department of Family and Community Health, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA.;Hoops Family Children's Hospital at Cabell Huntington Hospital, Huntington, WV, USA.;Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Pediatrics, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA.;Department of Family and Community Health, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, USA.",
"authors": "Maddox|Taylor R|TR|;Haas|Jessica|J|;Andrews|Lacey|L|;Miller|Bobby|B|;Davies|Todd H|TH|",
"chemical_list": "D001569:Benzodiazepines; D002047:Buprenorphine; D000077206:Gabapentin; D003932:Heroin",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.918091",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3174738810.12659/AJCR.918091918091ArticlesAbnormal Presentation of Hypoxic Ischemic Encephalopathy Attributed to Polysubstance Exposure Maddox Taylor R. ABCDEF1Haas Jessica BCD2Andrews Lacey ABCDE3Miller Bobby DF4Davies Todd H. ADEFG1\n1 Department of Family and Community Health, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, U.S.A.\n2 Hoops Family Children’s Hospital at Cabell Huntington Hospital, Huntington, WV, U.S.A.\n3 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, U.S.A.\n4 Department of Pediatrics, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, U.S.A.Authors’ 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: Todd H. Davies, e-mail: daviest@marshall.edu2019 20 11 2019 20 1715 1718 13 6 2019 30 7 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: Male, newborn\n\nFinal Diagnosis: Hypoxic ischemic encephalopathy\n\nSymptoms: Arthrogryposis • bitemporal wasting • graf type IIa dysplasia • NAS symptoms\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Pediatrics and Neonatology\n\nObjective:\nCongenital defects/diseases\n\nBackground:\nWith the increasing prevalence of substance use in pregnancy, the rates of neonatal abstinence syndrome (NAS) are dramatically increasing. There is little information on the use of multiple substances in adults, even less so of polysubstance abuse during pregnancy and the consequences for the fetus as well as the mother.\n\nCase Report:\nA newborn male born at 35 weeks presented post-delivery with hips bilaterally dislocated and hyperflexed. The patient’s legs fully extended and their shoulders were bilaterally mid-flexed with arms fully extended. This neonate was also reported to have bilateral hearing and vision loss as well as NAS symptoms of high-pitched crying and respiratory distress. During pregnancy the mother in this case study admitted to using buprenorphine, benzodiazepines, gabapentin, and heroin. The consequences of using this combination has not been well studied in pregnancy.\n\nConclusions:\nThe presented case had severe complications, likely due to maternal polysubstance use and poor prenatal care in pregnancy. Clonidine was used to control the NAS symptoms, ranitidine was used to treat the gastroesophageal reflux, and glycopyrronium bromide was used for the neonate’s excessive secretions. After delivery, the patient was placed on a nasal noninvasive cannula for respiratory distress and was transferred to a different hospital for treatment of the more serious comorbid conditions.\n\nMeSH Keywords:\nHypoxia, BrainMaternal-Fetal ExchangeNeonatal Abstinence Syndrome\n==== Body\nBackground\nMany children in the catchment area of our institution have been born with neonatal abstinence syndrome (NAS) or other complications due to their exposure in utero to illicit substances, particularly opioids. The following case is that of a neonate who presented with significant in utero exposure to multiple neuroactive substances that are known to be teratogenic [1]. Hypoxic ischemic encephalopathy (HIE) has been demonstrated in adults after prolonged non-medical use of neuroactive substances [2], but this has not yet been reported as a consequence of prenatal exposure to the same substances. It is difficult to determine whether any one of the problems described in this case were due to exposure to one drug or a combination of drugs, poor prenatal care, or an unexplored genetic abnormality. Any of these scenarios could result in a severe hypoxic event that could potentially lead to HIE. Gabapentin exposure has been linked to low birth weight, preterm birth, neonatal jaundice, bradycardia, respiratory distress, and diarrhea [3]. The use of buprenorphine is the current standard of care for medication-assisted treatment in pregnancy; however, a fetus exposed to buprenorphine will have the typical presentation of NAS hypersensitivity: low-grade fevers, tremors, and poor sleep [4]. Neonates who had prolonged exposure to benzodiazepines in utero can have hypotonia, poor suck reflexes, impaired metabolic functions, and slower development for the first year of life [5]. This is one of the more severe cases that has presented to our institution with NAS symptoms and other complications potentially due to drug exposure in utero.\n\nCase Report\nThe mother was a 27-year-old non-Hispanic white female who had little or no prenatal care along with significant substance abuse during pregnancy. She denied alcohol consumption but admitted to the use of buprenorphine, benzodiazepines, gabapentin, and heroin. Urine drug screens revealed buprenorphine, benzodiazepines, gabapentin, heroin, and other opioids. Maternal labs revealed an A positive blood type that was positive for hepatitis C and negative for HIV and syphilis. The mother had no significant medical history, no personal history of hypertension, thyroid disorders, or diabetes mellitus, and no known family history of any members with a similar condition. The mother reported smoking ½ pack per day throughout her pregnancy. There was no significant obstetrical history other than she has had a preterm premature rupture of membranes (PPROM) during a previous pregnancy. The mother was referred to our institution for an abnormal fetal ultrasound, due to a suspicion for cystic structure of the brain.\n\nA male infant was born by cesarean at 35 weeks’ gestation to a 27-year-old gravida 3, para 2 white female. The neonate was small for gestational age, the birth weight was 1920 grams, birth length was 45 cm, head circumference was 31 cm, and the 1- and 5-minute Apgar scores were 7 and 9, respectively. After delivery, the vital signs, including temperature, heart rate, and respiratory rate, were all initially normal. After delivery, the neonate developed respiratory distress and was placed on a nasal cannula. Physical exam revealed bilaterally dislocated and hyperflexed hips with fully extended legs and bilaterally mid-flexed shoulders with fully extended arms. The patient was diagnosed with arthrogryposis (Figure 1C), a congenital condition in which the joints become permanently fixed in either the flexed or extended position [6]. The patient was referred for ophthalmic and hearing screening for concerns of blindness and deafness, and exams showed blindness bilaterally and significant-to-severe bilateral hearing loss. All lab values were within normal ranges. The creatine phosphokinase was within normal range, with a negative microarray. Whole exome and whole genome tests were performed and both tests were negative. It was noted that the placenta had a large umbilical cord.\n\nThe neonate was transferred to a larger regional hospital to receive treatment and evaluation of neuromuscular nerve abnormalities. The patient was diagnosed with profound hypotonia, a decrease in muscle mass including bitemporal wasting. Also, bilateral ptosis, the ability to move his face appropriately, was lacking, and the formal diagnosis was severe HIE. HIE is a condition resulting from diminished cerebral blood flow and oxygen in the brain; this can cause poor suck reflexes, weak or poor muscle tone, and seizures [7].\n\nRadiologic findings showed that this cystic structure was a dilated third ventricle (Figure 1A), and it was also found that the fetus had an abnormality in the ventrolateral thalamus and globus pallidus (Figure 1B). Further physical exam findings included low-set ears, high palate, micrognathia, 2 noted anal tags, and bilateral genu recurvatum, which is an abnormality of the knee joint in which the legs are hyperextend [8]. It was also observed that the patient had an abnormal high-pitched cry, abnormal facial movements, and seizures, which can be associated with NAS.\n\nThis neonate was monitored for NAS due to the extensive exposure to substances in utero. The patient exhibited the hallmark NAS high-pitched cry as well as a poor suck reflex, no gag reflex, no root reflex, a weak grasp, and having excessive secretions. After several days, the patient developed some respiratory distress and was placed on a nasal cannula and later switched to a continuous positive airway pressure (CPAP) device. The neonate was fed donor milk, eventually developing a feeding intolerance and persistence vomiting. A nasogastric tube was placed to manage this.\n\nThe neonate was started on albuterol, ipratropium bromide, and dornase alfa nebulizers on day of life (DOL) 11 for respiratory distress. Vancomyosin 26.5 mg was used to treat the developing sepsis on DOL 11. Ampicillin began on DOL 1 to combat infection, and phenobarbital was administered on DOL 11 and 12 for seizures. A one-time dose of methadone was given on DOL 11 for withdrawal symptoms. The patient received an echo-cardiogram for a heart murmur, which was negative. An upper gastrointestinal tract radiography revealed gastroesophageal reflux. Magnetic resonance imaging (MRI) revealed several abnormalities, including immaturity of the left acetabulum consistent with a Graf type IIa dysplasia (Figure 1D). An electromyography (EMG) showed hypotonia, decreased muscle mass, and diminished conduction and amplitudes in the left tibial and peroneal motor nerves. A renal ultrasound revealed mild hydronephrosis. A peripheral inserted central catheter (PICC) line was placed for better IV access. The patient was placed on clonidine starting DOL 12 for neonatal abstinence syndrome treatment to lessen the withdrawal symptoms, as well as ranitidine for reflux and glycopyrronium bromide for the secretions. Once the neonate’s conditions stabilized, the mother and neonate were transferred to a different hospital for a surgical consult for treatment of the more serious conditions. The stay at the different hospital revealed no abnormalities in the exome or genome.\n\nDiscussion\nThe case described shows the dangers of a child being exposed to substances in utero, as well as the lack of prenatal care, preventing the diagnosis of this infant’s comorbid conditions. Poor prenatal care reduces the likelihood of detecting any problems the fetus may have, and can cause problems shortly after birth and in managing any chronic maternal condition [9]. In this case, the mother had no significant medical history other than illicit substance use and addiction. The diminished prenatal care along with the multiple substance use led to this patient begin born with many problems. Use of prescribed and the illegal substances can have an effect in utero and cause serious consequences after birth. The lack of information about reported polysubstance abuse cases makes it difficult to discern which symptoms were caused by which drug he was exposed to or whether it was due to the combination of them all.\n\nSome of the known risk factors for HIE are maternal uterine rupture, placenta previa or abrupto placenta, cord prolapse, maternal hypotension, shoulder dystonia, and breech presentation [7]. Any of these events can cause a decrease in cerebral blood flow and decrease of oxygen getting to the brain, which can lead to HIE. The development of HIE may be attributed to the mother’s heroin use, as heroin commonly causes hypotension [10]. Genu recurvatum has long been linked to the exposure to teratogenic agents in pregnancy, malposition during delivery, infection, oligohydramnios, and a traumatic event in utero [11]. As mentioned earlier, the mother in this study admitted to limited prenatal care, substance abuse, smoking during pregnancy, and hepatitis C infection. The obstetrical history was unremarkable with the exception of PPROM, and her medical history was unremarkable as she has no history of hypertension, hypotension, diabetes, or thyroid deficiencies. The neonate’s hearing and vision loss can be attributed to the nerve abnormalities; however, the cause of the abnormality could not be determined. Because she does not fit any of the known risk factors for her son developing HIE and genu recurvatum, these conditions may be attributed to the intrauterine exposure to cigarettes and multiple substances and the maternal complications from substance abuse. The patient’s NAS symptoms may have been overshadowed by his other conditions; however, they were addressed with clonidine and his reflux was treated with ranitidine. It was noted that the patient had poor suck and poor grasp reflex. The poor suck reflex could be due to exposure to benzodiazepines, as that is a common complication of maternal use in pregnancy. The low birth weight, respiratory distress, and preterm delivery could be attributed to the gabapentin exposure. Due to the lack of literature on intrauterine heroin exposure, there is no way to differentiate which symptoms could be attributed to exposure to this drug or the interactions of it and the other substances. Any one of these substances could complicate the pharmacologic reaction of another one, and this compounding of substances can have worse or new effects on the fetus than any one substance would have. However, due to the lack of research on these substances being used concurrently, the level of effect is not known.\n\nConclusions\nHIE has not been previously associated with in utero substance exposure. However, with the increase in polysubstance exposure and the hypoxic effects often associated with higher-dosage substance use, this may be an early indication of hypoxia-related symptomology in exposed neonates. This case is a stark reminder that more research into polysubstance exposure is needed to address this new, troubling chapter in NAS.\n\nConflict of interest\n\nNone.\n\nAbbreviations:\nNASneonatal abstinence syndrome;\n\nHIEhypoxic ischemic encephalopathy\n\nFigure 1. (A) Sagittal ultrasound of head, with the red arrow showing the dilated third ventricle. (B) CT scan without contrast of head, with the red arrow showing enlarged bilateral ventricles. (C) X-ray image of the hyperflexed right lower extremity, consistent with arthrogryposis. (D) X-ray image of the hyperflexed lower left extremity. The red arrow indicates the left acetabular immaturity, showing this patient’s Graf type IIa dysplasia.\n==== Refs\nReferences:\n1. Forray A Substance use during pregnancy F1000Res 2016 13 5 \n2. Virmani A Ali SF Binienda ZK Neuroprotective strategies in drug abuse-evoked encephalopathy Ann NY Acad Sci 2010 1199 52 68 20633109 \n3. Fujii H Goel A Bernard N Pregnancy outcomes following gabapentin use: Results of a prospective comparative cohort study Neurology 2013 80 17 1565 70 23553472 \n4. Jones HE Fischer G Heil SH Maternal Opioid Treatment: Human Experimental Research (MOTHER) – approach, issues and lessons learned Addiction 2012 107 Suppl. 1 28 35 23106924 \n5. McElhatton PR The effects of benzodiazepine use during pregnancy and lactation Reprod Toxicol 1994 8 6 461 75 7881198 \n6. Møller-Madsen B Arthrogryposis multiplex congenital – an update J Child Orthop 2015 9 6 425 26 26482521 \n7. Allen KA Brandon DH Hypoxic ischemic encephalopathy: Pathophysiology and experimental treatments Newborn Infant Nurs Rev 2011 11 3 125 33 21927583 \n8. Loudon JK Goist HL Loudon KL Genu recurvatum syndrome J Orthop Sports Phys Ther 1998 27 5 361 67 9580896 \n9. National Institute of Child Health and Human Development What is prenatal care and why is it important? Available from: https://www.nichd.nih.gov/health/topics/pregnancy/conditioninfo/prenatal-care \n10. Paranthaman SK Khan F Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage Chest 1976 69 1 117 19 1244268 \n11. Charif P Reichelderfer TE Genu recurvatum congenitum in the newborn: Its incidence, course, treatment, prognosis Clin Pediatr (Phila) 1965 4 10 587 94 5889980\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": "D001569:Benzodiazepines; D002047:Buprenorphine; D005260:Female; D000077206:Gabapentin; D003932:Heroin; D006801:Humans; D020925:Hypoxia-Ischemia, Brain; D007231:Infant, Newborn; D008297:Male; D009357:Neonatal Abstinence Syndrome; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "1715-1718",
"pmc": null,
"pmid": "31747388",
"pubdate": "2019-11-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9580896;20633109;26482521;21927583;1244268;5889980;23106924;27239283;7881198;23553472",
"title": "Abnormal Presentation of Hypoxic Ischemic Encephalopathy Attributed to Polysubstance Exposure.",
"title_normalized": "abnormal presentation of hypoxic ischemic encephalopathy attributed to polysubstance exposure"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-50060",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"dr... |
{
"abstract": "Microsporidia are opportunistic pathogens that usually cause a limited disease in the gastrointestinal tract. Occasionally, they can cause disseminated disease. In solid organ transplant recipients, disseminated disease has been reported only rarely. We describe a 68-year-old woman who presented with fever, cough, and acute kidney injury 6 months after kidney transplantation. Dissemination was confirmed by identification of microsporidial spores in urine and bronchoalveolar lavage fluid. Polymerase chain reaction analysis identified the species as Encephalitozoon cuniculi.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Nagpal|A|A|;Pritt|B S|BS|;Lorenz|E C|EC|;Amer|H|H|;Nasr|S H|SH|;Cornell|L D|LD|;Iqbal|S|S|;Wilhelm|M P|MP|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12119",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "15(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Encephalitozoon; FUO; immunocompromised host; kidney transplant; microsporidiosis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D001992:Bronchoalveolar Lavage Fluid; D009670:Encephalitozoon cuniculi; D016890:Encephalitozoonosis; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007668:Kidney; D016030:Kidney Transplantation; D009894:Opportunistic Infections; D013172:Spores, Fungal; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "526-32",
"pmc": null,
"pmid": "23947513",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Disseminated microsporidiosis in a renal transplant recipient: case report and review of the literature.",
"title_normalized": "disseminated microsporidiosis in a renal transplant recipient case report and review of the literature"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0055005",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIvabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8-10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4).\n\n\nMETHODS\nIn an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied.\n\n\nRESULTS\nThe mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and > 5 and < 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients.\n\n\nCONCLUSIONS\nThis is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine.",
"affiliations": "Grupo de investigación en Cardiología. Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). Spain.. mhermida@udc.es.",
"authors": "Núñez|Lucía|L|;Crespo-Leiro|María G|MG|;Marrón-Liñares|Grecia M|GM|;Suarez-Fuentetaja|Natalia|N|;Barge-Caballero|Eduardo|E|;Paniagua-Martín|María Jesús|MJ|;Marzoa-Rivas|Raquel|R|;Grille-Cancela|Zulaika|Z|;Muñiz-García|Javier|J|;Vazquez-Rodriguez|Jose Manuel|JM|;Hermida-Prieto|Manuel|M|",
"chemical_list": "D001552:Benzazepines; D002317:Cardiovascular Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D000077550:Ivabradine; D012313:RNA; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human",
"country": "Poland",
"delete": false,
"doi": "10.5603/CJ.a2016.0050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1898-018X",
"issue": "23(5)",
"journal": "Cardiology journal",
"keywords": "CYP3A4; HCN4; heart failure; ivabradine; pharmacogenetic",
"medline_ta": "Cardiol J",
"mesh_terms": "D000328:Adult; D000368:Aged; D001552:Benzazepines; D002317:Cardiovascular Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D051544:Cytochrome P-450 CYP3A; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006333:Heart Failure; D006339:Heart Rate; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000077550:Ivabradine; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels; D012313:RNA",
"nlm_unique_id": "101392712",
"other_id": null,
"pages": "573-582",
"pmc": null,
"pmid": "27439367",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: A preliminary report.",
"title_normalized": "analysis of variants in the hcn4 gene and in three single nucleotide polymorphisms of the cyp3a4 gene for association with ivabradine reduction in heart rate a preliminary report"
} | [
{
"companynumb": "ES-AMGEN-ESPSP2016106910",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPalmo-plantar pustular psoriasis (PPPP) and palmo-plantar pustulosis (PPP) are chronic skin diseases with significant impact on quality of life.\n\n\nOBJECTIVE\nThe purpose of this study was to study the efficacy of ustekinumab in PPPP and PPP and gain more knowledge on the pathophysiology and the role of the interleukin-23 (IL-23) signalling pathway in these diseases.\n\n\nMETHODS\nThirty-three patients with either PPPP (20) or PPP (13) and seven volunteers with normal palmo-plantar skin were recruited. Patients with PPP or PPPP were randomised (1 : 1) to receive either an anti IL-12/IL-23 antibody (ustekinumab 45 mg) or placebo at day 0 and week 4 with subsequent placebo cross-over to ustekinumab at week 16. The primary endpoint was the proportion of patients randomized to ustekinumab achieving a 50% improvement in the Palmo-Plantar Pustular Area and Severity Index (PPPASI-50) as compared to placebo. Skin biopsies of the palms and soles of normal subjects and patients with PPP or PPPP were performed and analysed by RT-PCR and immunohistochemistry.\n\n\nRESULTS\nThere was no statistically significant difference in the proportion of patients randomised to ustekinumab as compared to those randomised to placebo achieving PPPASI-50 at week 16 for patients with PPPP (10%, 20%; P = 1.000) or PPP (20%, 37.5%; P = 1.000) respectively. Compared to normal subjects an 89-fold increase in IL-17A expression was found in palms/soles of patients with PPPP (P = 0.006) and a 190-fold increase for patients with PPP (P = 0.051). There were no statistically significant changes in cytokine expression at week 16 in the palms and soles of patients with PPP or PPPP.\n\n\nCONCLUSIONS\nTaken together these results suggest that ustekinumab at a dose of 45 mg has limited efficacy in PPPP and PPP. IL-17A may have a more important role than IL-23 in patients with PPPP and PPP. Conclusions are limited by the small sample size of this study.",
"affiliations": "Innovaderm Research Inc., Montreal, QC, Canada.",
"authors": "Bissonnette|R|R|;Nigen|S|S|;Langley|R G|RG|;Lynde|C W|CW|;Tan|J|J|;Fuentes-Duculan|J|J|;Krueger|J G|JG|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D000069549:Ustekinumab",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.12272",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "28(10)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D018592:Cross-Over Studies; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17; D053759:Interleukin-23; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011565:Psoriasis; D011788:Quality of Life; D012333:RNA, Messenger; D060888:Real-Time Polymerase Chain Reaction; D000069549:Ustekinumab",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "1298-305",
"pmc": null,
"pmid": "24112799",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial.",
"title_normalized": "increased expression of il 17a and limited involvement of il 23 in patients with palmo plantar pp pustular psoriasis or pp pustulosis results from a randomised controlled trial"
} | [
{
"companynumb": "CA-JNJFOC-20141108654",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDural venous sinus stenting (VSS) is an effective treatment for idiopathic intracranial hypertension (IIH) in adult patients. There are no published series to date evaluating safety and efficacy of VSS in pediatric patients.\n\n\nOBJECTIVE\nTo report on procedural device selection and technique as well as safety and efficacy of VSS for pediatric patients with medically refractory IIH due to underlying venous sinus stenosis.\n\n\nMETHODS\nA multi-institutional retrospective case series identified patients with medically refractory IIH aged less than 18 years who underwent VSS.\n\n\nRESULTS\n14 patients were identified at four participating centers. Patient ages ranged from 10 to 17 years, and 10 patients (71.4%) were female. Mean body mass index was 25.7 kg/m2 (range 15.8-34.6 kg/m2). Stenting was performed under general endotracheal anesthesia in all except two patients. The average trans-stenotic gradient during diagnostic venography was 10.6 mm Hg. Patients had stents placed in the superior sagittal sinus, transverse sinus, sigmoid sinus, occipital sinus, and a combination. Average follow-up was 1.7 years after stenting. Six patients out of 10 (60%) had reduced medication dosing, 12 of 14 patients (85.7%) had improvements in headaches, two patients (100%) with pre-stent tinnitus had resolution of symptoms, and four (80%) of five patients with papilledema had improvement on follow-up ophthalmological examinations. Two patients (14.3%) developed postprocedural groin hematomas, one patient (7.1%) developed a groin pseudoaneurysm, and one patient (7.1%) had postprocedural groin bleeding. No other procedural complications occurred. Four patients (28.6%) required further surgical treatment (cerebrospinal shunting and/or stenting) after their first stenting procedure.\n\n\nCONCLUSIONS\nThis series suggests that VSS is feasible in a pediatric population with IIH and has a low complication rate and good clinical outcomes.",
"affiliations": "Department of Neurosurgery, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.;Department of Neurosurgery, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.;Department of Neurosurgery, University of Virginia Medical Center, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia Medical Center, Charlottesville, Virginia, USA.;Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA.;Penn State Health Neurosurgery, Hershey, Pennsylvania, USA.;Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA.;Department of Neurological Surgery, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.;Department of Neurosurgery, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.;Cabarrus Eye Center, Concord, North Carolina, USA.;Department of Neurological Surgery, Radiology and Mechanical Engineering, University of Washington, Seattle, Washington, USA.;Department of Neurosurgery, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA kfargen@wakehealth.edu.",
"authors": "Lee|Katriel E|KE|http://orcid.org/0000-0001-8367-4470;Zehri|Aqib|A|;Soldozy|Sauson|S|;Syed|Hasan|H|;Catapano|Joshua S|JS|;Maurer|Robert|R|;Albuquerque|Felipe C|FC|;Liu|Kenneth C|KC|;Wolfe|Stacey Q|SQ|;Brown|Sandra|S|;Levitt|Michael R|MR|http://orcid.org/0000-0003-3612-3347;Fargen|Kyle M|KM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/neurintsurg-2020-016183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-8478",
"issue": "13(5)",
"journal": "Journal of neurointerventional surgery",
"keywords": "catheter; intracranial pressure; pediatrics; stent; vein",
"medline_ta": "J Neurointerv Surg",
"mesh_terms": "D000293:Adolescent; D002648:Child; D003392:Cranial Sinuses; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D019635:Neurosurgical Procedures; D011559:Pseudotumor Cerebri; D012189:Retrospective Studies; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "101517079",
"other_id": null,
"pages": "465-470",
"pmc": null,
"pmid": "32732257",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Dural venous sinus stenting for treatment of pediatric idiopathic intracranial hypertension.",
"title_normalized": "dural venous sinus stenting for treatment of pediatric idiopathic intracranial hypertension"
} | [
{
"companynumb": "US-BAYER-2021-156807",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Pregnancy has always been a concern in epidemics all over the world. While coronavirus (COVID-19) disease ravages the world, it is a big curiosity how pregnant women will be affected by this disease. There are a few published case series and commentary of COVID-19 occurring during pregnancy. In this study, we discussed how to manage this disease in pregnant women. A 38-week pregnant, 37-year-old woman whose father passed away from COVID-19 admitted to the hospital with dyspnea, nonproductive cough, and fever. She had positive radiological features for COVID-19, and her rapid antibody test was positive. Lopinavir-ritonavir combination and azithromycin treatments were given, and the patient's symptoms regressed with treatment. The patient was taken to cesarean by providing isolation conditions, and she had a healthy baby with an uncomplicated delivery. There are no certain data about whether COVID-19 infection is worse in pregnant patients or not. On the basis of the limited data in the literature, we cannot see intrauterine transmission from infected mother to baby. However, we know that there would be serious pulmonary complications for the infected mother. Fortunately, the severe acute respiratory syndrome coronavirus 2 infection did not progress more severely in pregnant women than in the normal population compared with the previous severe acute respiratory syndrome outbreak.",
"affiliations": "Department of Chest Diseases, Recep Tayyip Erdoğan University School of Medicine, Rize, Turkey.;Department of Chest Diseases, Recep Tayyip Erdoğan University School of Medicine, Rize, Turkey.;Department of Obstetrics and Gynecology, Recep Tayyip Erdoğan University School of Medicine, Rize, Turkey.;Department of Infectious Diseases and Clinical Microbiology, Recep Tayyip Erdoğan University School of Medicine, Rize, Turkey.",
"authors": "Özçelik|Neslihan|N|http://orcid.org/0000-0002-4672-6179;Özdemir|Serda|S|http://orcid.org/0000-0001-7560-8457;Gürlek|Beril|B|http://orcid.org/0000-0002-4050-3193;Yıldız|İlknur Esen|İE|http://orcid.org/0000-0003-2987-0483",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/TurkThoracJ.2020.20135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2148-7197",
"issue": "21(5)",
"journal": "Turkish thoracic journal",
"keywords": null,
"medline_ta": "Turk Thorac J",
"mesh_terms": null,
"nlm_unique_id": "101648545",
"other_id": null,
"pages": "354-356",
"pmc": null,
"pmid": "33031729",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": "32238084;15295381;30390683;32222119;32151335;32237670;32141062;32180426;32007143",
"title": "COVID-19 Pregnant Patient Management with a Case of COVID-19 Patient with An Uncomplicated Delivery.",
"title_normalized": "covid 19 pregnant patient management with a case of covid 19 patient with an uncomplicated delivery"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-269134",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
... |
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