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"abstract": "BACKGROUND\nClostridium perfringens is an uncommon pathogen in endophthalmitis, causing rapid destruction of ocular tissues. Clostridium perfringens infection typically occurs after penetrating injury with soil-contaminated foreign bodies.\n\n\nMETHODS\nHere, we describe the case of a 17-year-old male who sustained a penetrating injury with a metallic intraocular foreign body and who rapidly developed severe C. perfringens panophthalmitis with orbital cellulitis. He was managed by systemic and intravitreal antibiotics, resulting in preservation of the globe, but a poor visual outcome.\n\n\nCONCLUSIONS\nClostridial endophthalmitis secondary to penetrating injuries is a fulminant infection, almost always resulting in loss of the globe in the case of advanced infection. When feasible, early vitrectomy and intravitreal antibiotics should be considered in patients with penetrating eye injuries with contaminated foreign bodies.",
"affiliations": "Ophthalmology Department, Amiens-Picardie University Hospital, Amiens, France.;Ophthalmology Department, Amiens-Picardie University Hospital, Amiens, France.;Ophthalmology Department, Amiens-Picardie University Hospital, Amiens, France.;Ophthalmology Department, Beauvais Hospital, Beauvais, France.;Clinical Bacteriology Department, Amiens-Picardie University Hospital, Amiens, France.;Infectious diseases Department, Amiens-Picardie University Hospital, Amiens, France.;Ophthalmology Department, Amiens-Picardie University Hospital, Amiens, France.;Clinical Bacteriology Department, Amiens-Picardie University Hospital, Amiens, France. Hamdad.Farida@chu-amiens.fr.",
"authors": "Guedira|Ghita|G|;Taright|Nabil|N|;Blin|Hélène|H|;Fattoum|Thameur|T|;Leroy|Jordan|J|;El Samad|Youssef|Y|;Milazzo|Solange|S|;Hamdad|Farida|F|",
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"fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 75110.1186/s12886-018-0751-0Case ReportClostridium perfringens panophthalmitis and orbital cellulitis: a case report Guedira Ghita rita_guedira@hotmail.com 1Taright Nabil Taright.Nabil@chu-amiens.fr 1Blin Hélène Blin.Helene@chu-amiens.fr 1Fattoum Thameur t.fattoum@ch-beauvais.fr 2Leroy Jordan leroy.jordan80@gmail.com 3El Samad Youssef elsamad.youssef@chu-amiens.fr 4Milazzo Solange milazzo.solange@chu-amiens.fr 1Hamdad Farida 00 333 22 08 70 78Hamdad.Farida@chu-amiens.fr 351 0000 0004 0593 702Xgrid.134996.0Ophthalmology Department, Amiens-Picardie University Hospital, Amiens, France 2 Ophthalmology Department, Beauvais Hospital, Beauvais, France 3 0000 0004 0593 702Xgrid.134996.0Clinical Bacteriology Department, Amiens-Picardie University Hospital, Amiens, France 4 0000 0004 0593 702Xgrid.134996.0Infectious diseases Department, Amiens-Picardie University Hospital, Amiens, France 5 Centre de Biologie Humaine, CHU Amiens-Picardie, Avenue R. Laennec, 80054 Amiens Cedex1, France 10 4 2018 10 4 2018 2018 18 883 3 2017 23 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nClostridium perfringens is an uncommon pathogen in endophthalmitis, causing rapid destruction of ocular tissues. Clostridium perfringens infection typically occurs after penetrating injury with soil-contaminated foreign bodies.\n\nCase report\nHere, we describe the case of a 17-year-old male who sustained a penetrating injury with a metallic intraocular foreign body and who rapidly developed severe C. perfringens panophthalmitis with orbital cellulitis. He was managed by systemic and intravitreal antibiotics, resulting in preservation of the globe, but a poor visual outcome.\n\nConclusion\nClostridial endophthalmitis secondary to penetrating injuries is a fulminant infection, almost always resulting in loss of the globe in the case of advanced infection. When feasible, early vitrectomy and intravitreal antibiotics should be considered in patients with penetrating eye injuries with contaminated foreign bodies.\n\nKeywords\nC. perfringensPanophthalmitisDiagnosisTreatmentissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPost-traumatic infectious endophthalmitis is an uncommon but severe complication of ocular trauma. The outcome of the infection varies according to the type of injury, the microorganisms involved and the time between injury and treatment [1]. The visual prognosis is also determined by the anatomic site of the intraocular foreign body (IOFB), as the majority of IOFBs are located in the posterior segment of the eye, which is associated with a poorer visual prognosis than those located in the anterior segment [2–4].\n\nClinical signs of endophthalmitis include severe pain, purulent exudate from the site of injury, eyelid edema, chemosis, and hypopyon. The infection can progress, resulting in panophthalmitis and can be complicated by possibly life-threatening orbital cellulitis.\n\nClostridial endophthalmitis secondary to penetrating injuries is a fulminant infection, almost always associated with loss of the eye [5], and antibiotics are unlikely to prevent this process.\n\nCase report\nA 17-year-old male was admitted to the Ophthalmology Department of Amiens-Picardie University Hospital on May 28, 2013. He described a 24-h history of loss of vision and pain after projection of a foreign metallic into the left eye following a perforating eye injury while performing housework. He did not present any notable medical history.\n\nThe patient presented elevated intraocular pressure and palpebral edema associated with pre septal cellulitis. Slit lamp examination revealed extensive chemosis with fibrin in the anterior chamber and hypopyon. The cornea was whitened and the iris and crystalline lens were not visible [Fig. 1].Fig. 1 The conjunctiva is congested with subconjunctival hemorrhage\n\n\n\nVision was impaired to no light perception (NLP). All eye movements were grossly restricted, with mild proptosis and swollen lids. The patient was afebrile, but presented an elevated white blood cell count of 30,200 cells/mm3 and C-Reactive Protein (CRP) of 52.9 mg/L.\n\nOrbital computed tomography (CT) showed an IOFB in the left eye [Fig. 2]. A gas bubble was visualized, associated with periseptal and retroseptal soft tissue edema [Fig. 3a-b].Fig. 2 Orbital computed tomography demonstrates a metallic intraocular foreign body with edema of the left eye\n\nFig. 3 a Orbital computed tomography showing proptosis, posterior dislocation of the lens, thickening of the periorbital soft tissue and the posterior wall of the globe. b Gas bubbles in the left eye\n\n\n\nExamination under general anesthesia and primary repair were performed in the emergency room. Orbital cellulitis was diagnosed. The anterior chamber was full of a gelatinous substance, which precluded vitrectomy. A 3.2 mm clear corneal incision was performed and anterior chamber washout. The IOFB was removed with a magnet.\n\nSamples of discharge from the site of injury, anterior chamber aspirate and vitreous tap were sent to the Clinical Bacteriology Department for examination. Intravitreal antibiotics were then administered (ceftazidime 2.25 mg/0.1 mL and vancomycin 1 mg/0.1 mL) following surgery.\n\nExamination on postoperative day 1 found a slightly hypotonic globe; chemosis with considerable redness, and corneal infiltrate, while the fundus could still not be visualized. A diagnosis of panophthalmitis with lens expulsion was proposed [Fig. 3a].\n\nB-scan ultrasound showed dense vitreous opacities with choroidal thickening [Fig. 3a]. Visual acuity remained NLP.\n\nGram stain of the corneal specimen in the Clinical Bacteriology Department revealed a large number of white blood cells and numerous gram-positive bacilli. On postoperative day 2, all culture samples yielded C. perfringens, which was identified by Matrix-Assisted Laser Desorption-Ionization Time-of-Light Mass Spectrometry with a very good validity score of > 2 (2.2). The isolate was sensitive to a wide range of the antibiotics usually used for anaerobic bacteria.\n\nOn May 31, systemic imipenem 50 mg/kg every 6 h, metronidazole 500 mg 4 times daily and gentamicin 6 mg/ kg were then administered simultaneously. Anticoagulants were added to prevent septic thrombophlebitis. Gentamicin (8 μg) and ceftazidime were injected into the subconjunctival space daily.\n\nFollow-up CT scan revealed orbital cellulitis with no cerebral thrombophlebitis or abscess. Despite treatment, the patient’s vision remained NLP with total hypopyon and no evidence of resolution of the infection was observed at this time. Loss of vision was rapid and complete with a flat electroretinogram of the left eye.\n\nOn June 3, the anterior chamber was washed out under topical anesthesia, but the thick cyclitic membrane could not be completely removed. Intravitreal ceftazidime and vancomycin were also administered simultaneously. Ceftazidime, vancomycin and gentamicin eye drops were administered postoperatively.\n\nOn June 4, inflammation had significantly decreased in response to intensive antibiotic therapy and topical steroids. The white blood cell count and CRP levels had decreased to 9700 cells/mm3 and 6 mg/L, respectively.\n\nThe patient continued to improve and was discharged from hospital on June 11 with oral amoxicillin 2 g, 3 times daily and metronidazole 500 mg, 3 times daily for 10 days. Evisceration was considered due to the loss of vision, underlying infection and inflammation. However, the patient declined this procedure and the infection was completely eradicated. Evisceration was therefore not performed.\n\nAn esthetic overlay prosthesis was performed 4 weeks later due to the phthisis bulbi caused by loss of consistency of the internal structures of the eye, [Fig. 4].Fig. 4 a Phthisis bulbi, (b) Esthetic overlay prosthesis\n\n\n\nDiscussion\nPost-traumatic endophthalmitis can be due to both Gram-positive and Gram-negative micro-organisms. Polymicrobial and fungal infections also have been reported. Gram-positive organisms such as Staphylococcus epidermidis and Bacillus cereus are the organisms most commonly cultured [1]. C. perfringens is an uncommon cause of endophthalmitis and typically occurs after penetrating injury by soil- and plant-contaminated foreign bodies, causing rapid destruction of ocular tissues [6]. However, despite the potential frequency of contamination, intraocular C. perfringens infection is rare.\n\nC. perfringens is a spore-forming anaerobic exotoxin-producing gram-positive bacillus present ubiquitously in the environment. On blood agar, C. perfringens produces a double zone of hemolysis due to the alpha and beta toxins produced by this species. The ocular destruction caused by C. perfringens infection is related to massive necrosis of ocular structures by potent exotoxins. Antibiotics are therefore unlikely to prevent this process once the infection has become established.\n\nTraumatic intraocular inoculation of C. perfringens can result in fulminant endophthalmitis with little hope of a positive outcome.\n\nClinical signs of infection associated with this pathogen include gas bubbles in the anterior chamber, amaurosis, and greenish-brown hypopyon. These signs usually occur rapidly, often within 24 h after injury.\n\nAs described above, C. perfringens panophthalmitis is a devastating malignant eye infection because the bacteria produce a multitude of extracellular tissue-destructive factors. The case reported here presented no signs of systemic dissemination and the toxins were confined to the globe.\n\nAll previously reported cases progressed despite aggressive treatment, often resulting in evisceration or enucleation [5, 7]. In the rare cases in which the eye was preserved, the visual outcome remained poor.\n\nThe case reported here presented the classic clinical signs of clostridial endophthalmitis. Despite aggressive treatment including intravitreal and systemic antibiotics, the patient had a poor visual outcome, but without evisceration. Systemic antibiotics were used in combination with intravitreal antibiotics. The antibiotics most commonly used for post-traumatic endophthalmitis are vancomycin and ceftazidime [1]. Topical antibiotics are almost always used together with intravitreal antibiotics for the treatment of endophthalmitis in an attempt to increase intraocular antibiotic concentrations.\n\nThe efficacy of vitrectomy in C. perfringens endophthalmitis has been previously reported [8]. Vitrectomy can remove a considerable proportion of the infectious inoculum, clear the media by removing vitreous membranes and debris, and eliminate vitreous scaffolding that may cause tractional retinal detachment.\n\nVitrectomy combined with intravitreal antibiotics may be a more effective strategy to sterilize the vitreous cavity compared to intravitreal antibiotics alone [1, 9–11]. When visualization is compromised, endoscopy-guided vitrectomy may be the best treatment option in these difficult cases.\n\nConclusion\nIn conclusion, this case report highlights the fact that, due to the rapidly devastating outcome, penetrating eye injuries with soil-contaminated foreign bodies must be considered to be at high risk for clostridial infection and should be treated promptly by vitrectomy and antibiotics. Otherwise, delayed surgery results in evisceration or poor visual outcomes.\n\nEarly vitrectomy and early removal of foreign material from the eye is important because this removes the growth media and potential source of infection. Vitrectomy also reduces the inoculum of harmful pathogens.\n\nAbbreviations\nCRPC-reactive protein\n\nCTComputed tomography\n\nIOFBIntraocular foreign body\n\nMALDI-TOF MSMatrix-Assisted Laser Desorption-Ionization Time-of-Light Mass Spectrometry\n\nNLPNo light perception\n\nNone\n\nFunding\nThis study did not require any specific grant from any public, commercial or not-for-profit funding agency.\n\nAvailability of data and materials\nAll data are presented in the manuscript and Figures.\n\nAuthors’ contributions\nGG, NT, HB, TF, YES and SM conducted clinical examination of the patient. JL and FH performed bacteriological diagnosis and HF drafted the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\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.\n\nCompeting interests\nThe authors declare that they have no competing interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Bhagat N Nagori S Zarbin M Post-traumatic infectious Endophthalmitis Surv Ophthalmol 2011 56 3 214 251 10.1016/j.survophthal.2010.09.002 21397289 \n2. De Juan E Jr Sternberg P Jr Michels RG Penetrating ocular injuries. Types of injuries and visual results Ophthalmology 1983 90 11 1318 1322 10.1016/S0161-6420(83)34387-6 6664670 \n3. Williams DF Mieler WF Abrams GW Lewis H Results and prognostic factors in penetrating ocular injuries with retained intraocular foreign bodies Ophthalmology 1988 95 7 911 916 10.1016/S0161-6420(88)33069-1 3262852 \n4. Woodcock MG Scott RA Huntbach J Kirkby GR Mass and shape as factors in intraocular foreign body injuries Ophthalmology 2006 113 12 2262 2269 10.1016/j.ophtha.2006.06.002 17157134 \n5. Abu el-Asrar AM Tabbara KF Clostridium perfringens endophthalmitis Doc Ophthalmol 1994 87 2 177 182 10.1007/BF01204795 7835187 \n6. Leavelle RB. Gas gangrene panophthalmitis. AMA Arch Ophthalmol 1955;53(5):634-642.\n7. Hsu HY Lee SF Hartstein ME Harocopos GJ Clostridium perfringens keratitis leading to blinding panophthalmitis Cornea 2008 2 10 1200 1203 10.1097/ICO.0b013e318180e5a1 \n8. Kelly LD Steahly LP Successful prophylaxis of Clostridium perfringens Endophthalmitis Arch Ophthalmol 1991 109 9 1199 10.1001/archopht.1991.01080090023012 1929949 \n9. Conway BP Campochiaro PA Macular infarction after endophthalmitis treated with vitrectomy and intravitreal gentamicin Arch Ophthalmol 1986 104 3 367 371 10.1001/archopht.1986.01050150067028 3485422 \n10. Mieler WF Mittra RA The role and timing of pars plana vitrectomy in penetrating ocular trauma Arch Ophthalmol 1997 115 9 1191 1192 10.1001/archopht.1997.01100160361017 9298064 \n11. Mittra RA Mieler WF Controversies in the management of open-globe injuries involving the posterior segment Surv Ophthalmol 1999 44 3 215 259 10.1016/S0039-6257(99)00104-6 10588440\n\n",
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"issue": "18(1)",
"journal": "BMC ophthalmology",
"keywords": "C. perfringens; Diagnosis; Panophthalmitis; Treatment",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D000293:Adolescent; D003015:Clostridium Infections; D003016:Clostridium perfringens; D005129:Eye Foreign Bodies; D015818:Eye Infections, Bacterial; D015807:Eye Injuries, Penetrating; D006801:Humans; D008297:Male; D054517:Orbital Cellulitis",
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"title": "Clostridium perfringens panophthalmitis and orbital cellulitis: a case report.",
"title_normalized": "clostridium perfringens panophthalmitis and orbital cellulitis a case report"
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"abstract": "Objective We aimed to investigate risk of hepatitis B virus reactivation in systemic lupus erythematosus patients with different hepatitis B virus infection statuses receiving immunosuppressive therapy. Methods We retrospectively analyzed systemic lupus erythematosus patients with positive hepatitis B surface antigen or anti-hepatitis B core IgG antibody who underwent immunosuppressive therapies from January 2001 to December 2012 at a medical center in Taiwan for evidence of hepatitis B virus reactivation. Results During this period, 906 out of 3125 patients who were diagnosed with systemic lupus erythematosus received screening tests for hepatitis B virus. Thirty-eight patients were identified as hepatitis B surface antigen-positive. Fifteen of 38 (39.5%) hepatitis B surface antigen-positive patients developed hepatitis B virus reactivation, and 53.3% of these patients experienced severe hepatitis flare. Three of 157 hepatitis B surface antigen-negative/anti-hepatitis B core IgG antibody-positive patients (1.9%) experienced hepatitis B surface antigen seroreversion after immunosuppressive therapy. Five patients received prophylactic or preemptive antiviral therapy and none of them developed hepatitis B virus flares. A daily dose of prednisolone greater than 5 mg was a risk factor for hepatitis B reactivation by multivariate logistic analysis. Conclusions The risk of hepatitis B virus reactivation is high in lupus patients receiving immunosuppressive therapy. Antiviral prophylaxis or preemption can effectively reduce the incidence of hepatitis B virus reactivation in lupus patients.",
"affiliations": "1 Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.;2 Division of Allergy, Immunology & Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.;2 Division of Allergy, Immunology & Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.;4 Division of Immunology and Rheumatology, China Medical University Hospital, Taichung, Taiwan.;1 Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.;1 Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.;1 Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.",
"authors": "Lin|W T|WT|;Chen|Y M|YM|;Chen|D Y|DY|;Lan|J L|JL|;Chang|C S|CS|;Yeh|H Z|HZ|;Yang|S S|SS|",
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"title": "Increased risk of hepatitis B virus reactivation in systemic lupus erythematosus patients receiving immunosuppressants: a retrospective cohort study.",
"title_normalized": "increased risk of hepatitis b virus reactivation in systemic lupus erythematosus patients receiving immunosuppressants a retrospective cohort study"
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"abstract": "In the era of carbapenem-resistance in Acinobacter baumannii and Enterobacteriaceae, there are limited treatment options for these pathogens. It is essential that clinicians fully assess all available therapeutic alternatives for these multidrug-resistant organisms. We herein describe the approach of the antimicrobial stewardship team at the Detroit Medical Center (DMC) for the evaluation and use of intravenous (IV) minocycline for the treatment of these resistant organisms, given potential advantages of IV minocycline over tigecycline and doxycycline. In vitro analyses at the DMC demonstrated good activity against A. baumannii (78% susceptibility), including 74% of carbapenem-resistant strains, but limited activity against our carbapenem-resistant K.pneumoniae (12% susceptibility.) Based in part on these results, IV minocycline was added to the formulary, primarily for the treatment of carbapenem-resistant A. baumannii. Early experience has been positive: 6/9 (67%) of patients who received IV minocycline had infections due to these organisms cured, including 6/7 (86%) who received doses of 200 mg twice daily.",
"affiliations": "Department of Pharmacy, Sinai-Grace Hospital, Detroit Medical Center Wayne State University School of Medicine, Detroit.;Wayne State University School of Medicine, Detroit.;Department of Pharmacy, Detroit Receiving Hospital, Detroit Medical Center.;Wayne State University School of Medicine, Detroit.;Wayne State University School of Medicine, Detroit Detroit Medical Center University Laboratories.;Wayne State University School of Medicine, Detroit Department of Internal Medicine, Division of Infectious Diseases, Detroit Medical Center, Michigan.",
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"abstract": "Long-term therapy with tyrosine kinase inhibitors (TKI) has resulted in improved outcomes for patients suffering from Bcr-Abl fusion protein-harboring leukemias. As a result, a growing population of patients on TKI therapy present to their primary care providers. In this case, we report on the case of a 62-year-old male who presented with a symptomatic pericardial effusion. After pericardiocentesis, malignancy and infectious etiologies were excluded. The pericardial effusion was attributed to his TKI, with a transition of this medication to a different TKI. A repeat evaluation 1 month following the withdrawal of the offending agent showed no recurrence of his pericardial effusion on echocardiogram. In this report, we will highlight a rare but important side effect of TKI therapy before discussing its purported mechanisms and differing incidence rates. Early recognition of serosal inflammation related to long-term TKI therapy by primary care providers is important in preventing patient morbidity and mortality.",
"affiliations": "Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md., USA.;Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md., USA.;Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Md., USA.",
"authors": "Agrawal|Vineet|V|;Christenson|Eric S|ES|;Showel|Margaret M|MM|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000375484cro-0008-0088Published online: February, 2015Tyrosine Kinase Inhibitor Induced Isolated Pericardial Effusion Agrawal Vineet a*Christenson Eric S. aShowel Margaret M. baDepartment of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md., USAbSidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Md., USA*Vineet Agrawal, MD, PhD, Department of Medicine, The Johns Hopkins University School of Medicine, 601 North Caroline Street, Baltimore, MD 21287 (USA), E-Mail vagrawa4@jhmi.eduJan-Apr 2015 13 2 2015 13 2 2015 8 1 88 93 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Long-term therapy with tyrosine kinase inhibitors (TKI) has resulted in improved outcomes for patients suffering from Bcr-Abl fusion protein-harboring leukemias. As a result, a growing population of patients on TKI therapy present to their primary care providers. In this case, we report on the case of a 62-year-old male who presented with a symptomatic pericardial effusion. After pericardiocentesis, malignancy and infectious etiologies were excluded. The pericardial effusion was attributed to his TKI, with a transition of this medication to a different TKI. A repeat evaluation 1 month following the withdrawal of the offending agent showed no recurrence of his pericardial effusion on echocardiogram. In this report, we will highlight a rare but important side effect of TKI therapy before discussing its purported mechanisms and differing incidence rates. Early recognition of serosal inflammation related to long-term TKI therapy by primary care providers is important in preventing patient morbidity and mortality.\n\nKey Words\nTyrosine kinase inhibitorPericardial effusionLeukemia\n==== Body\nIntroduction\nWith improved outcomes for patients suffering from Bcr-Abl fusion protein-harboring leukemias [1, 2, 3, 4], there is a growing population of patients on long-term therapy with tyrosine kinase inhibitors (TKI) directed at the Bcr-Abl fusion product of the Philadelphia chromosome. While previous TKIs have been associated with pleural effusions, the effect of newer TKIs on the development of serositis is less known. We present a case report of a patient who developed an isolated pericardial effusion after treatment with nilotinib for pre-B cell acute lymphoblastic leukemia (ALL).\n\nClinical Case Report\nA 62-year-old male with a history of pre-B cell ALL presented to our hospital with a 2- to 3-day history of shortness of breath with exertion. He endorsed a decreasing exercise tolerance and increased lower extremity edema over the previous 2 weeks. He denied chest pain, heart palpitations, neck pain, jaw pain, lightheadedness, dizziness, or sick contacts.\n\nHis oncologic history extends back 2 months; at this time he was diagnosed with pre-B cell ALL after a routine lab work showed an abnormal complete blood count with 30,000 white blood cells and 29% blasts. He was initiated on HyperCVAD chemotherapy (consisting of cyclophosphamide, vincristine, doxorubicin, dexamethasone, high-dose methotrexate), which was discontinued prior to the end of the first cycle, secondary to acute kidney injury. Based on cytogenetic studies showing the presence of the Philadelphia chromosome, he was started on nilotinib, a second-generation TKI, as an adjunct to chemotherapy. A bone marrow biopsy 1 week prior to presentation following the first cycle of HyperCVAD and 6 weeks of nilotinib therapy showed a mildly hypercellular bone marrow with trilineage hematopoiesis. Pathology, flow cytometry and chromosome studies showed no evidence of leukemia in the bone marrow or peripheral blood.\n\nUpon initial evaluation, he was found to have a regular pulse of 84, a blood pressure of 132/80, a respiratory rate of 20 and nonlabored breathing at rest. His SaO2 was 100% in room air. His initial exam was significant for clear oropharynx and nares, gray tympanic membranes bilaterally and clear lungs with good air movement. His cardiac exam was notable for muffled S1 and S2 with an S3 at the left lower sternal border and apex, a nondisplaced point of maximum impulse, a jugular venous distension of 17 cm H2O with sustained hepatojugular reflexes, and a pitting edema extending up to the mid-lower-legs bilaterally. He demonstrated the presence of pulsus paradoxus with a decrease in systolic blood pressure by 15 mm Hg with inspiration. There was no friction rub. His EKG was notable for a new finding of low voltage with electrical alternans (fig. 1, fig. 2). A transthoracic echocardiogram showed a 2.2-cm pericardial effusion during systole with a 2.7-cm effusion during diastole with an early diastolic tamponade physiology (fig. 3). His prior echocardiograms had shown a normal right and left ventricular function without any wall motion abnormalities or evidence of effusion.\n\nHe underwent pericardiocentesis with the removal of 450 ml of serosanginous fluid and catheter placement with a subsequent normalization of his EKG (fig. 4). He experienced an additional 100 ml of drainage over the next 24 h and prior to the removal of the catheter. The effusion was bloody with 2,257 white blood cells, 40 polymorphs and 60% mononuclear cells. Cytopathology and flow cytometry revealed no evidence of leukemia. The plasma and pericardial fluid were negative for Epstein-Barr virus, cytomegalovirus, parvovirus B19, enterovirus, and adenovirus via polymerase chain reaction. The pericardial fluid was negative for cryptococcal antigen. Plasma beta-D-glucan, galactomannan, antinuclear antibodies, rapid plasma reagin, histoplasma, and HIV tests were all negative. A nasopharyngeal aspirate respiratory viral panel was negative. Bacterial, fungal, and mycobacterial cultures resulted in no growth from the pericardial fluid.\n\nAs the evaluation of the effusion ruled out likely alternative etiologies, it was attributed to the patient's TKI, nilotinib. This medication was transitioned to bosutinib and he underwent a repeat transthoracic echocardiogram 1 month after discharge, noting the presence of only a trace of pericardial effusion. At that time, his symptoms of dyspnea on exertion had resolved and he showed no evidence of jugular-venous distention, pulsus paradoxus, hepatojugular reflux, or lower extremity edema.\n\nDiscussion\nIn the era of targeted therapy and personalized medicine, the development of therapies aimed at the inhibition of disease-specific pathways has led to a widespread use of TKIs. Therapeutic applications of these medications range from treatment of both solid and leukemic malignancies to modulation of autoimmune conditions such as rheumatoid arthritis [6]. There are currently at least 15 clinically available TKIs on the market today. While these therapies are considered attractive options due to their perceived association with fewer side effects, it is now known that many of these therapies may have unintended consequences either as a result of their intended mechanism of action or off-target effects.\n\nSerositis or serosal inflammation is a rare, but important side effect of the family of TKIs directed at the Bcr-Abl fusion product that has previously been reported in clinical trials. The incidence of effusions ranges from 7 to 35% in dasatinib, the agent most often associated with pleural effusions. Other agents such as imatinib, nilotinib, and bosutinib are associated with an incidence of serosities of less than 1% [7, 8].\n\nThe development of serosal inflammation in response to TKI agents can occur at any time, with previous studies reporting a range from 3 weeks to 2 years from the onset of therapy to the first documented episode of effusion [9]. The risk of serosal inflammation is thought to be dose dependent [5]. While the most common manifestation is a pleural effusion, concurrent pericardial effusions have been noted in up to 29% of cases [10]. Risk factors for the development of TKI-related serosal inflammation include a history of previous cardiac disease, hypertension, hyperlipidemia, autoimmune disease or a previous history of rash in response to TKI therapy [9]. In our case report, the presence of pericardial effusion notably occurred in the absence of a pleural effusion without a history of previous medical problems. To our knowledge, this is the first reported presentation of an isolated pericardial effusion after treatment with TKI.\n\nOur patient presented with an exudative pericardial effusion with negative cultures and cytology, and withdrawal of the TKI resulted in improvement without recurrence after months of surveillance. In cases where fluid has been obtained, TKI-related effusions are reported to be exudative 80% of the time. In each of these cases, fluid cytology and bacterial/mycobacterial cultures yielded no evidence of malignancy or infection [10]. While general management of pericardial effusions is dependent on multiple parameters such as size of effusion, systemic symptoms (dyspnea, fever), and hemodynamic sequelae [11], identification of etiology and pericardiocentesis is imperative in patients with a history of malignancy to rule out both infection and recurrent malignancy. In cases where a negative workup is obtained, withdrawal of the TKI and/or changing to a different TKI within the same class prevents a recurrence of serosal inflammation [5], with steroid therapy providing more expeditious regression of inflammation within 3 days in highly symptomatic patients [10].\n\nThe mechanisms underlying the development of pleural and pericardial effusions have not been fully elucidated, but off-target tyrosine kinase inhibition and effect of TKIs on the function of the immune system have previously been implicated in their pathogenesis. Dasatinib, the Bcr-Abl target agent most often associated with effusions, is known to have multiple off-target effects including PDGFR-β, while imatinib, nilotinib, and bosutinib are all known to be weaker inhibitors of PDGFR-β [5]. Additional studies have also suggested that off-target effects of TKIs on the immune system may be responsible for the development of serosal inflammation [10]. This is supported by the association between serosal inflammation and the history of autoimmune disease, the exudative nature of effusions that are identified, and the historical response of highly symptomatic patients to steroids [10].\n\nIn conclusion, pericardial effusion is an important, possibly life-threatening complication that must be considered in any patient on TKI medication. Although less associated with newer TKI agents, we present the case of an isolated pericardial effusion that occurred after treatment with nilotinib. While thought to be dose dependent, pericardial effusion can occur at any time during therapy. After confirming the absence of malignant or infectious etiologies, withdrawal of the offending TKI is generally the standard treatment. With the increased use of TKIs for multiple applications, and with the increase in patients with a history of leukemia on long-term TKI therapy, it is incumbent upon providers to recognize this potentially life-threatening complication. Additionally, we report for the first time that TKI treatment can result in isolated pericardial effusion, in the absence of other effusions.\n\nDisclosure Statement\nThe authors declare no conflict of interest and have no financial disclosures to report.\n\nFig. 1 Baseline EKG shows a normal sinus rhythm.\n\nFig. 2 Presenting EKG shows the evidence of low-voltage and electrical alternans.\n\nFig. 3 Parasternal long-axis view of pericardial effusion on echocardiogram.\n\nFig. 4 Following pericardiocentesis, EKG shows a normal sinus rhythm.\n==== Refs\nReferences\n1 Huang X Cortes J Kantarjian H Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy Cancer 2012 11 3123 3127 22294282 \n2 Torgeson SR Haddad RY Atallah E Chronic myelogenous leukemia for primary care physicians Dis Mon 2012 58 168 176 22449366 \n3 Roberts KG Li Y Payne-Turner D Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia N Engl J Med 2014 371 1005 1011 25207766 \n4 Xie Y Davies SM Xiang Y Trends in leukemia incidence and survival in the United States (1973-1998) Cancer 2004 97 2229 2235 12712476 \n5 Kelly K Swords R Mahalingam D Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors Target Oncol 2009 4 99 105 19381453 \n6 Levitzki A Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance Annu Rev Pharmacol Toxicol 2013 53 161 185 23043437 \n7 Druker BJ Five-year follow-up of patients receiving imatinib for chronic myelogenous leukemia N Engl J Med 2006 355 2408 2417 17151364 \n8 Kantarjian HM Giles F Gattermann N Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance Blood 2007 110 3540 3546 17715389 \n9 de Lavallade H Punnialingam S Milojkovic D Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis Br J Haematol 2008 141 745 747 18331365 \n10 Quintas-Cardama A Kantarjian H O'Brien S Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure J Clin Oncol 2007 25 3908 17761974 \n11 Imazio M Adler Y Management of pericardial effusion Eur Heart J 2013 34 1186 1197 23125278\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "8(1)",
"journal": "Case reports in oncology",
"keywords": "Leukemia; Pericardial effusion; Tyrosine kinase inhibitor",
"medline_ta": "Case Rep Oncol",
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"nlm_unique_id": "101517601",
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"title": "Tyrosine kinase inhibitor induced isolated pericardial effusion.",
"title_normalized": "tyrosine kinase inhibitor induced isolated pericardial effusion"
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"companynumb": "US-JNJFOC-20150606628",
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"abstract": "SARS-CoV-2 infection may predispose patients to thrombotic disease. Patients with COVID-19 pneumonia who are receiving non-vitamin K antagonists or direct oral anticoagulants for chronic disease are usually switched to heparin treatment during hospitalization. However, information about the most appropriate antithrombotic therapy after the acute infection phase is lacking.\nWe report the case of a patient with chronic atrial fibrillation who was recently hospitalized for severe COVID-19 pneumonia. Four weeks after discharge he experienced an episode of an acute pulmonary embolism while on rivaroxaban therapy with adequate drug plasma levels, and in the absence of strong predisposing risk factors.\nThis case highlights the risk of thrombotic complications after COVID-19 infection, raises some concern about their underlying mechanisms, and supports the use of effective anti-thrombotic therapy.\nCOVID-19 infection is associated with frequent thrombotic events.A pro-coagulative status could be triggered by the persistent inflammatory phase of the infection despite anticoagulation.Adequate antithrombotic therapy is necessary for the prevention of acute and later thrombotic complications and needs close monitoring.",
"affiliations": "Division of Cardiology, Ospedale di Cremona, Italy.;Division of Cardiology, Ospedale di Cremona, Italy.;Division of Cardiology, Ospedale di Cremona, Italy.;Haemostasis and Thrombosis Center, Ospedale di Cremona, Italy.;Division of Cardiology, Ospedale di Cremona, Italy.",
"authors": "Di Tano|Giuseppe|G|;Moschini|Luigi|L|;Loffi|Marco|M|;Testa|Sophie|S|;Danzi|Gian Battista|GB|",
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"doi": "10.12890/2020_001790",
"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594 SMC Media Srl \n\n10.12890/2020_001790\n1790-1-14423-1-10-20200617\nArticles\nLate Pulmonary Embolism after COVID-19 Pneumonia despite Adequate Rivaroxaban Treatment\nDi Tano Giuseppe 1 Moschini Luigi 1 Loffi Marco 1 Testa Sophie 2 Danzi Gian Battista 1 \n1 Division of Cardiology, Ospedale di Cremona, Italy\n\n2 Haemostasis and Thrombosis Center, Ospedale di Cremona, Italy\n2020 \n18 6 2020 \n7 7 00179009 6 2020 13 6 2020 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseIntroduction\nSARS-CoV-2 infection may predispose patients to thrombotic disease. Patients with COVID-19 pneumonia who are receiving non-vitamin K antagonists or direct oral anticoagulants for chronic disease are usually switched to heparin treatment during hospitalization. However, information about the most appropriate antithrombotic therapy after the acute infection phase is lacking.\n\nCase Description\nWe report the case of a patient with chronic atrial fibrillation who was recently hospitalized for severe COVID-19 pneumonia. Four weeks after discharge he experienced an episode of an acute pulmonary embolism while on rivaroxaban therapy with adequate drug plasma levels, and in the absence of strong predisposing risk factors.\n\nConclusion\nThis case highlights the risk of thrombotic complications after COVID-19 infection, raises some concern about their underlying mechanisms, and supports the use of effective anti-thrombotic therapy.\n\nLEARNING POINTS\nCOVID-19 infection is associated with frequent thrombotic events.\n\nA pro-coagulative status could be triggered by the persistent inflammatory phase of the infection despite anticoagulation.\n\nAdequate antithrombotic therapy is necessary for the prevention of acute and later thrombotic complications and needs close monitoring.\n\nViral diseasespneumoniathrombosispulmonary embolismrivaroxaban\n==== Body\nINTRODUCTION\nEmerging evidence suggests that the coagulation function is significantly deranged during SARS-CoV-2 (COVID-19) infection and may predispose to arterial and venous thrombotic complications due to excessive inflammation, platelet activation, endothelial dysfunction and stasis [1]. During the acute infection phase, patients chronically managed with antithrombotic agents (non-vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs)) are usually switched to alternative parenteral antithrombotic medications such as low molecular weight heparin (LMWH) [2, 3]. However, information about the most appropriate antithrombotic therapy after the acute infection period is lacking.\n\nWe report the case of a patient with chronic atrial fibrillation (AF) who was recently hospitalized for severe COVID-19 pneumonia. Four weeks after discharge he experienced an episode of acute pulmonary embolism (APE) while on rivaroxaban therapy at the appropriate dosage and with adequate drug plasma levels.\n\nCASE DESCRIPTION\nA 79-year-old man was hospitalized for severe bilateral COVID-19 pneumonia after 10 days of fever and dyspnoea. He had a history of hypertension and of long-standing AF for which he was on rivaroxaban therapy (20 mg per day). During hospitalization, DOAC was switched to LMWH at a therapeutic regimen (enoxaparin 100 IU/kg bid) and administered with hydroxychloroquine, lopinavir/ritonavir, empiric antimicrobial treatment and supplemental oxygen to maintain SpO2 in the 93–96% range. Coagulation parameters were in the normal range. The patient’s clinical condition improved and the hospital course was uneventful. He was discharged after 19 days with the indication to resume rivaroxaban treatment together with the anti-hypertensive drug losartan (100 mg per day).\n\nTwo weeks later he suddenly complained of severe respiratory distress with cough and chest pain. In the emergency department, the electrocardiogram confirmed the presence of AF with a ventricular rate of 110 bpm. Laboratory tests revealed a normal complete blood count with increased values of hs-troponin I (230.2 ng/l, normal value <34.2), D-dimer (3.99 μg/ml, normal value <5.00), C-reactive protein (47 mg/l, normal value <5.00), fibrinogen (376 mg/dl, normal value <200), lactate dehydrogenase (325 U/l, normal value <248) and ferritin (353 ng/ml, normal value 21–246). Transthoracic echocardiography showed normal size and function of the right ventricle with a mild increase in pulmonary pressures (40 mmHg). Computed tomography pulmonary angiography showed APE involving the lateral and posterior basal segmental branches of the right pulmonary artery and the posterior basal segmental branch of the left pulmonary artery (Fig. 1A,B). The ground-glass opacities documented on computed tomography scanning during the first hospitalization had evolved into areas of consolidation and of interlobular and intralobular septal thickening (Fig. 1C,D). The patient stated that he was taking the drugs regularly. The rivaroxaban plasma level was promptly measured (20 hours after last administration the day before hospitalization) and was 68 ng/ml (normal value in the absence of the drug is <25 ng/ml) with an elevated PT INR of 2.16 and aPTT of 1.45 (normal value <1.2). Based on these findings, the patient was switched to LMWH at a full dose regimen (100 IU/kg bid). Lower limb compression ultrasonography was negative for venous thromboembolism (DVT). The clinical course was uneventful and the patient was discharged home 9 days later on therapeutic doses of LMWH.\n\nDISCUSSION\nThrombotic events in patients who are on anticoagulation therapy are uncommon. In the PREFER Registry, among patients receiving chronic anticoagulation for AF, the DVT recurrence rate was 3.9% with an overall incidence of PE of 1.3% [4]. Furthermore, only one recurrent episode of DVT (1.7 events per 100 patient-years) was documented in the more recent Dresden NOAC Registry [5]. The main reason for a breakthrough event is underlying disease and sub-therapeutic drug level.\n\nDuring COVID-19, patients on oral anticoagulation therapy are exposed to the risk of an unstable therapeutic level due to concomitant therapies. For this reason, in order to prevent bleeding complications, oral anticoagulants are replaced with heparins during hospitalization[3].\n\nInformation about the most appropriate antithrombotic therapy after the acute infection phase is lacking. However, recent suggestions recommend DOACs should be preferred over VKAs because of their better safety with fixed dosing without the need for laboratory monitoring and to limit patient contact with healthcare services, all characteristics of particular relevance for outpatient management in this pandemic [2, 4].\n\nOur case raises some concerns about the appropriateness of DOAC treatment in the subacute phase of COVID-19 infection for patients who need oral anticoagulation treatment. Despite correct adherence to rivaroxaban therapy with the expected plasma levels, the patient developed an acute pulmonary thrombotic event after the interstitial pneumonia had apparently, but not completely, resolved. Indeed 2 weeks after discharge, inflammatory markers such as C-reactive protein, lactate dehydrogenase, fibrinogen and ferritin were still high.\n\nWe suppose that the segmental APE event in our patient, without evidence of DVT, may be closely related to the pro-coagulative status triggered by the persistent inflammatory phase of the SARS-CoV-2 infection [1]. Autopsy specimens from COVID-19 patients showed that pulmonary arteries at the hilum were free of thromboemboli, whereas small-vessel thrombus formation was seen in the periphery of the lung parenchyma in the majority of cases, supporting the concept of a hypercoagulative status, and a high frequency of pulmonary micro-thrombosis [6, 7]. SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with the presence of viral bodies) and of the host inflammatory response [7]. These observations could explain the inefficacy of a direct inhibitor of activated factor Xa such as rivaroxaban, which is active only on the coagulation cascade, while the anti-inflammatory and immunomodulatory properties of heparin, which can stabilize the endothelium, could be more helpful for this specific situation as reported [8].\n\nIn conclusion, our case highlights the risk of later thrombotic complications after COVID-19 infection despite appropriate oral anticoagulant therapy and raises some concern about the underlying mechanism. In patients on chronic oral anticoagulant therapy, discharged after hospitalization for acute COVID-19, close monitoring is recommended, and LMWH replacement should be considered only until evidence of complete remission of disease.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 (A) CT pulmonary angiography (axial view) showing filling defects involving the lateral and posterior basal segmental branches of the right pulmonary artery (open circles) and the posterior basal segmental branch of the left pulmonary artery (open circle). (B) CT pulmonary angiography (sagittal view) depicting a filling defect localized on the inferior lobar branch of the left pulmonary artery (open circle). (C) Chest CT scan (axial view) during the first hospitalization showing extensive areas of ground-glass opacities involving both lung parenchymas. (D) Control chest CT scan during rehospitalization showing areas of consolidations and interlobular and intralobular septal thickening\n==== Refs\nREFERENCES\n1 Bikdeli B Madhavan MV Jimenez D Chuich T Dreyfus I Driggin E COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up J Am Coll Cardiol 2020 75 23 2950 2973 32311448 \n2 Thachil J Tang N Gando S Falanga A Cattaneo M Levi M ISTH interim guidance on recognition and management of coagulopathy in COVID-19 J Thromb Haemost 2020 18 5 1023 1026 32338827 \n3 Testa S Paoletti O Giorgi-Pierfranceschi M Pan A Switch from oral anticoagulants to parenteral heparin in SARS-CoV-2 hospitalized patients Intern Emerg Med 2020 4 15 1 3 10.1007/s11739-020-02331-1 [Epub ahead of print] 31834587 \n4 Cohen AT Gitt AK Bauersachs R Fronk EM Laeis P Mismetti P The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry Thromb Haemost 2017 117 7 1326 1337 28405675 \n5 Beyer-Westendorf J Förster K Pannach S Ebertz F Gelbricht V Thieme C Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC Registry Blood 2014 124 955 962 24859362 \n6 Fox SE Akmatbekov A Harbert JL Li G Brown JQ Vander Heide RS Pulmonary and cardiac pathology in COVID-19: the first autopsy series from New Orleans medRxiv Preprint 2020 10.1101/2020.04.06.20050575 \n7 Varga Z Flammer AJ Steiger P Haberecker M Andermatt R Zinkernagel AS Endothelial cell infection and endotheliitis in COVID-19 Lancet 2020 395 10234 1417 1418 32325026 \n8 Thachil J The versatile heparin in COVID-19 J Thromb Haemost 2020 18 1020 1022 32239799\n\n",
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"issue": "7(7)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Viral diseases; pneumonia; pulmonary embolism; rivaroxaban; thrombosis",
"medline_ta": "Eur J Case Rep Intern Med",
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"title": "Late Pulmonary Embolism after COVID-19 Pneumonia despite Adequate Rivaroxaban Treatment.",
"title_normalized": "late pulmonary embolism after covid 19 pneumonia despite adequate rivaroxaban treatment"
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"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-264144",
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"abstract": "The impact on heterozygous familial hypercholesterolemia (HeFH) health led by high-intensity lipid-lowering therapy (HILLT) is unknown, and the question remains if there is still an unacceptably high residual risk to justify treatment with new lipid-lowering drugs.\n\n\n\nThis observational, retrospective, multicenter, national study in Spain, whose information was obtained from a national dyslipemia registry, was designed to establish the current prevalence of cardiovascular disease (CVD) in HeFH and to define the impact of HILLT on CVD in this population. Odds were estimated using several logistic regression models with progressive adjustment.\n\n\n\n1958 HeFH, mean age 49.3 ± 14.3 years, were included in the analysis. At inclusion in the registry, 295 patients (15.1%) had suffered CVD and 164 (55.6%) had suffered the first event before the onset lipid-lowering treatment. Exposition to treatment associated more than ten times lower odds for CVD than in subjects naïve to treatment (OR 0.085, 95% CI 0.063-0.114, p < 0.001). A first CVD event after a mean treatment period of 9.1 ± 7.2 years occurred in 131 out of 1615 (8.1%) HeFH subjects, and 115 (87.8%) of them were on HILLT.\n\n\n\nCurrent prevalence of CVD among HeFH is one third of that reported before the statins era. Early initiation and prolonged lipid-lowering treatment was associated with a reduction in CVD. New cases of CVD, in spite of HILLT, appeared mostly among patients accumulating risk factors and probably they may be considered for further lipid-lowering drugs.",
"affiliations": "Lipid Unit. Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain.;Lipid Unit. Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain.;Lipid Unit. Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain.;Lipid Unit. Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain.;Lipid and Vascular Risk Unit, Department of Endocrinology and Nutrition, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.;Unitat de Medicina Vascular i Metabolism, Hospital Universitari Sant Joan, Institut d'Investigación Sanitaria Pere Virgili (IISPV), CIBERDEM, Reus, Tarragona, Spain.;Lipid Unit, Endocrinology Department, Hospital Universitario Insular de Gran Canaria, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de, Gran Canaria, Spain.;Lipid Unit, Endocrinology and Nutrition Service, Institut d'Investigacions Biomèdiques August Pi Sunyer, Hospital Clínic, CIBEROBN, Barcelona, Spain.;Lipid Unit, Hospital Universitario Donostia, San Sebastián, Spain.;Lipid Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, CIBEROBN, Universidad de Córdoba, Spain.;Lipid Unit, Hospital San Rafael, A Coruña, Spain.;Lipid Unit. Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain; Universidad de Zaragoza, Zaragoza, Spain. Electronic address: civeira@unizar.es.",
"authors": "Perez-Calahorra|Sofía|S|;Laclaustra|Martín|M|;Marco-Benedí|Victoria|V|;Lamiquiz-Moneo|Itziar|I|;Pedro-Botet|Juan|J|;Plana|Núria|N|;Sanchez-Hernandez|Rosa M|RM|;Amor|Antonio J|AJ|;Almagro|Fátima|F|;Fuentes|Francisco|F|;Suarez-Tembra|Manuel|M|;Civeira|Fernando|F|;|||",
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"keywords": "Cardiovascular disease; Familial hypercholesterolemia; Lipid-lowering; Statins",
"medline_ta": "Atherosclerosis",
"mesh_terms": "D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II; D000960:Hypolipidemic Agents; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "Effect of lipid-lowering treatment in cardiovascular disease prevalence in familial hypercholesterolemia.",
"title_normalized": "effect of lipid lowering treatment in cardiovascular disease prevalence in familial hypercholesterolemia"
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... |
{
"abstract": "Aripiprazole is a partial dopamine agonist with only minor neurological and psychiatric adverse effects, making it a potential first-line drug for the treatment of psychiatric disorders. However, the evidence of its use in children and adolescents is rather sparse. The aim of this case study is to discuss adverse drug reaction (ADR) reports concerning aripiprazole-associated neurological and psychiatric events in children and adolescents. The ADR report database at Danish Medicines Agency was searched for all ADRs involving children and adolescents (<18 years) reported by the search term [aripiprazole] AND all spontaneous reports since the introduction of aripiprazole in 2003 until December 31, 2015. Nineteen case reports were included in the study and included both patients with psychotic disorders (PS group) and nonpsychotic disorders (non-PS group). The PS group consisted of 5 patients with schizophrenia and psychoses, not otherwise specified; and the non-PS group consisted of fourteen cases including autism spectrum disorders, attention deficit and hyperactivity disorder, obsessive-compulsive disorder, and Tourette syndrome. The main reported adverse effects in the non-PS group were chronic insomnia, Parkinsonism, behavioral changes psychoses, and weight gain, whereas the adverse effects in the PS group was predominantly anxiety, convulsions, and neuroleptic malignant syndrome. Although aripiprazole is considered safe and well tolerated in children and adolescents, severe adverse events as neuroleptic malignant syndrome, extreme insomnia, and suicidal behavior has been reported to health authorities. Clinicians should pay attention to these possible hazards when prescribing aripiprazole to this vulnerable group of patients.",
"affiliations": "From the *Department of Clinical Medicine, Aalborg University; †Department of Psychiatry, Aalborg University Hospital, Aalborg; ‡Danish Medicines Agency, Copenhagen; §Centre for Child and Adolescent Mental Health, Mental Health Services; ∥Mental Health Centre Copenhagen, Department O, Capital Region of Denmark; and ¶Faculty of Health Sciences of Copenhagen University, University of Copenhagen, Copenhagen, Denmark.",
"authors": "Jakobsen|Klaus Damgaard|KD|;Bruhn|Christina Hedegaard|CH|;Pagsberg|Anne-Katrine|AK|;Fink-Jensen|Anders|A|;Nielsen|Jimmi|J|",
"chemical_list": "D014150:Antipsychotic Agents; D000068180:Aripiprazole",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0000000000000548",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "36(5)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001289:Attention Deficit Disorder with Hyperactivity; D000067877:Autism Spectrum Disorder; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D003718:Denmark; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders; D009771:Obsessive-Compulsive Disorder; D011618:Psychotic Disorders; D012559:Schizophrenia; D005879:Tourette Syndrome",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "496-9",
"pmc": null,
"pmid": "27504593",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neurological, Metabolic, and Psychiatric Adverse Events in Children and Adolescents Treated With Aripiprazole.",
"title_normalized": "neurological metabolic and psychiatric adverse events in children and adolescents treated with aripiprazole"
} | [
{
"companynumb": "DK-TEVA-711392ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "A 67-year critically ill patient suffered from a hypertensive crisis (200 mm Hg) because of a norepinephrine overdose. The overdose occurred when the clinician exchanged an almost-empty syringe and the syringe pump repeatedly reported an error. We hypothesized that an object between the plunger and the syringe driver may have caused the exertion of too much force on the syringe. Testing this hypothesis in vitro showed significant peak dosing errors (up to +572%) but moderate overdose (0.07 mL, +225%) if a clamp was used on the intravenous infusion line and a large overdose (0.8 mL, +2700%) if no clamp was used. Clamping and awareness are advised.",
"affiliations": "From the *Department of Medical Technology and Clinical Physics; †Department of Anaesthesiology, Intensive Care and Emergency Medicine; ‡Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands; and §Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.",
"authors": "Snijder|Roland A|RA|;Knape|Johannes T A|JT|;Egberts|Toine C G|TC|;Timmerman|Annemoon M D E|AM|",
"chemical_list": "D009638:Norepinephrine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000458",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "8(7)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000368:Aged; D016638:Critical Illness; D062787:Drug Overdose; D006801:Humans; D006973:Hypertension; D007262:Infusions, Intravenous; D008297:Male; D019300:Medical Errors; D009638:Norepinephrine; D013594:Syringes",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "178-181",
"pmc": null,
"pmid": "27898549",
"pubdate": "2017-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypertensive Crisis During Norepinephrine Syringe Exchange: A Case Report.",
"title_normalized": "hypertensive crisis during norepinephrine syringe exchange a case report"
} | [
{
"companynumb": "NL-PFIZER INC-2017201371",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nEpilepsy with myoclonic absences (EMA) is a rare childhood-onset syndrome characterized by absences of responsiveness accompanied by bilateral rhythmic clonic-like myoclonic jerks. Herein, we describe the case of a child with EMA, resistant to multiple commonly used antiepileptic drugs, in whom low-dose phenobarbital unexpectedly achieved complete remission of epilepsy.\n\n\nMETHODS\nA 10-year-old boy was referred to our hospital because of pharmaco-resistant frequent myoclonic absence seizures (MASs) and occasional generalized tonic-clonic seizures (GTCSs) that had commenced at the age of 7 years. Antiepileptic drugs including valproate sodium (VPA), levetiracetam, ethosuximide (ESM), clobazam, zonisamide, topiramate, clonazepam and lamotrigine were tested without significant effects. At the age of 8 years, phenobarbital was added to the VPA and ESM and increased to 1.2 mg/kg/day (blood concentration 8.6 µg/mL), which suppressed MASs completely within 1 month, and epileptic discharges on electroencephalography (EEG) within 5 months. To date, the boy has been seizure-free with normal EEG for 2 years.\n\n\nCONCLUSIONS\nPhenobarbital is a potential therapeutic option for pharmaco-resistant EMA.",
"affiliations": "Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, Japan. Electronic address: ito.susumu@twmu.ac.jp.;Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, Japan.;Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, Japan.;Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, Japan.;Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, Japan.",
"authors": "Ito|Susumu|S|;Nagumo|Kaoruko|K|;Nishikawa|Aiko|A|;Oguni|Hirokazu|H|;Nagata|Satoru|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2020.12.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "43(5)",
"journal": "Brain & development",
"keywords": "Case report; Epilepsy with myoclonic absences; Myoclonic absence seizures; Phenobarbital; Treatment; Video-electroencephalography",
"medline_ta": "Brain Dev",
"mesh_terms": null,
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "666-668",
"pmc": null,
"pmid": "33461850",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Low-dose phenobarbital for epilepsy with myoclonic absences: A case report.",
"title_normalized": "low dose phenobarbital for epilepsy with myoclonic absences a case report"
} | [
{
"companynumb": "JP-LUNDBECK-DKLU3029875",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia (MLL) gene rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.",
"affiliations": "Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.;Duke University Medical Center, Durham, NC.;Mayo Clinic Scottsdale Arizona, Scottsdale, AZ.;Sarah Cannon Research Institute, Nashville, TN.;Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.;Erasmus University Medical Center, Rotterdam, The Netherlands.;Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL.;Epizyme, Inc., Cambridge, MA.;Epizyme, Inc., Cambridge, MA.;Epizyme, Inc., Cambridge, MA.;Epizyme, Inc., Cambridge, MA.;Epizyme, Inc., Cambridge, MA.;Epizyme, Inc., Cambridge, MA.;Epizyme, Inc., Cambridge, MA.;Dana-Farber Cancer Institute, Boston, MA; and.;Dana-Farber Cancer Institute, Boston, MA; and.;Celgene, San Francisco, CA.;Epizyme, Inc., Cambridge, MA.;Erasmus University Medical Center, Rotterdam, The Netherlands.;Memorial Sloan Kettering Cancer Center, New York, NY.",
"authors": "Stein|Eytan M|EM|;Garcia-Manero|Guillermo|G|;Rizzieri|David A|DA|;Tibes|Raoul|R|;Berdeja|Jesus G|JG|;Savona|Michael R|MR|;Jongen-Lavrenic|Mojca|M|;Altman|Jessica K|JK|;Thomson|Blythe|B|;Blakemore|Stephen J|SJ|;Daigle|Scott R|SR|;Waters|Nigel J|NJ|;Suttle|A Benjamin|AB|;Clawson|Alicia|A|;Pollock|Roy|R|;Krivtsov|Andrei|A|;Armstrong|Scott A|SA|;DiMartino|Jorge|J|;Hedrick|Eric|E|;Löwenberg|Bob|B|;Tallman|Martin S|MS|",
"chemical_list": "D000970:Antineoplastic Agents; D001562:Benzimidazoles; C583893:EPZ-5676; D006657:Histones; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2017-12-818948",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "131(24)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008745:Methylation; D008780:Methyltransferases; D008875:Middle Aged; D055815:Young Adult",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2661-2669",
"pmc": null,
"pmid": "29724899",
"pubdate": "2018-06-14",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11840284;16862118;23801631;12097318;23361907;26118503;24993360;12453418;10781681;12453419;12941810;25596271;17855633;23138183;11314021;12805060;21741596;15851025;26385168;24415392;21521783;12393746;22017583;27335278;18668134;17957188;27258906;21123966;21741597;21159644;18977325;10521349;15542854;25635757;9748598",
"title": "The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.",
"title_normalized": "the dot1l inhibitor pinometostat reduces h3k79 methylation and has modest clinical activity in adult acute leukemia"
} | [
{
"companynumb": "US-CELGENEUS-USA-20180703110",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "An 85-year-old woman presented at the emergency ward. She had had shortness of breath for several days and no bowel movements for 3 days. On the day ofhospitalisation she experienced sudden abdominal pain and collapsed as she went to the toilet. She was being treated for multiple conditions, including type-2 diabetes. She appeared to have lactic acidosis. At first, the symptoms were not attributed to metformin because she was receiving a low dose and serum-creatinine concentrations were within the normal range (98 micromol/l). Bowel ischaemia was suspected and surgery was performed but no defects were found. She was subsequently treated for metformin-related lactic acidosis but died shortly thereafter due in part to postoperative complications. Lactic acidosis is a rare side effect of metformin. In this patient, the retrospectively calculated glomerular filtration rate (GFR) was extremely low (23 ml/min). The serum-creatinine concentration was normal because the patient's body weight was low (40 kg). Impaired renal function is a risk factor for metformin-related lactic acidosis. Renal function can appear to be normal when measured by serum-creatinine concentration in older patients with reduced muscle mass, but calculation of GFR often reveals impairment. Metformin is contraindicated in patients with poor renal function. The increasing use of metformin in older patients for the treatment of diabetes mellitus warrants renewed attention to this severe side effect.",
"affiliations": "Universitair Medisch Centrum Utrecht, afd. Geriatrie, B05.256, Postbus 85-500, 3508 GA Utrecht.",
"authors": "van der Linden|C M J|CM|;Knol|W|W|;van Marum|R J|RJ|;Jansen|P A F|PA|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin; D003404:Creatinine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "151(17)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000140:Acidosis, Lactic; D000369:Aged, 80 and over; D000075202:Contraindications; D003404:Creatinine; D003924:Diabetes Mellitus, Type 2; D017809:Fatal Outcome; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007004:Hypoglycemic Agents; D007422:Intestines; D007511:Ischemia; D007674:Kidney Diseases; D008687:Metformin",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "977-80",
"pmc": null,
"pmid": "17520852",
"pubdate": "2007-04-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016420:Comment",
"references": null,
"title": "Metformin-related lactic acidosis in an 85-year-old woman.",
"title_normalized": "metformin related lactic acidosis in an 85 year old woman"
} | [
{
"companynumb": "NL-AUROBINDO-07-AUR-00034",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Optimal treatment of extremity soft tissue sarcomas (ESTS) is controversial. The aim of this study was to evaluate neoadjuvant chemotherapy (ChT) plus concomitant hypofractionated RT (hypo-RT) in local and distant disease relapse. Here we report safety, feasibility and early outcomes.\n\n\n\nThis was a prospective, single arm study with a goal accrual of 70 patients. Between 2015 and 2018, 18 patients with histologically confirmed nonmetastatic ESTS were assigned to receive doxorubicin and ifosfamide for three neoadjuvant cycles, concomitant with hypo-RT (25 Gy in 5 fractions) followed by surgery. The primary endpoint was disease-free survival (DFS). Secondary outcomes were pathologic response, wound complications (WC), and morbidity rates.\n\n\n\nMedian follow-up was 29 months. At last follow-up, 13/18 patients were alive without evidence of local or systemic disease (DFS 72%), 1 had died due to metastatic disease, and 3 were alive with distant metastasis. One patient presented with local relapse within the irradiated field. Mean DFS time was 48.6 months (95% CI: 37.3-59.9). Six patients (33%) had no residual viable tumor detected in pathologic specimens (3 of these myxoid liposarcomas). There was a significant difference in WC among patients with acute RT skin toxicity. Six patients (33%) developed major WC. No grade 3 or 4 ChT adverse events were reported.\n\n\n\nDespite the limited sample size, these early outcomes demonstrate that this treatment regimen is feasible and well tolerated with high rates of limb preservation, local control, and pathologic complete response, supporting further investigation in a multi-institutional setting.\n\n\n\nClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654.",
"affiliations": "Department of Radiation Oncology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: leticia.silva@accamargo.org.br.;Department of Clinical Oncology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: celso.mello@accamargo.org.br.;Division of Surgery, Department of Sarcoma, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: samuel.aguiar@accamargo.org.br.;Department of Anatomic Pathology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: felipe.costa@accamargo.org.br.;Division of Surgery, Department of Sarcoma, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: paulo.stevanato@accamargo.org.br.;Division of Surgery, Department of Sarcoma, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: tiago.bezerra@accamargo.org.br.;Division of Surgery, Department of Orthopedics, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: suely.nakagawa@accamargo.org.br.;Department of Anatomic Pathology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: nascimento.antonio@accamargo.org.br.;Department of Anatomic Pathology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: isabela.werneck@rededor.com.br.;Division of Surgery, Department of Sarcoma, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: ranyell.spencer@gmail.com.;Department of Clinical Oncology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: ulisses.nicolau@accamargo.org.br.;Department of Clinical Oncology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: nirvana.formiga@accamargo.org.br.;Department of Statistics, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: janaina.germano@accamargo.org.br.;Division of Surgery, Department of Sarcoma, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: bruna.catin@accamargo.org.br.;Department of Radiation Oncology, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: acapellizzon@accamargo.org.br.;Division of Surgery, Department of Sarcoma, A C Camargo Cancer Center, São Paulo, Brazil. Electronic address: ademar.lopes@accamargo.org.br.",
"authors": "Gobo Silva|Maria Leticia|ML|;Lopes de Mello|Celso Abdon|CA|;Aguiar Junior|Samuel|S|;D'Almeida Costa|Felipe|F|;Stevanato Filho|Paulo Roberto|PR|;Santoro Bezerra|Tiago|T|;Nakagawa|Suely Akiko|SA|;Nascimento|Antonio Geraldo|AG|;Werneck da Cunha|Isabela|I|;Spencer Sobreira Batista|Ranyell Matheus|RM|;Nicolau Daher|Ulisses Ribaldo|UR|;Da Cruz Formiga|Maria Nirvana|MN|;Germano|Janaina Naiara|JN|;Catin Kupper|Bruna Elisa|BE|;De Assis Pellizzon|Antonio Cassio|AC|;Lopes|Ademar|A|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.radonc.2021.03.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-8140",
"issue": "159()",
"journal": "Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology",
"keywords": "Combined modality treatment; Extremity soft tissue sarcoma; Hypofractionated radiotherapy; Neoadjuvant chemotherapy and radiotherapy; Pathologic response; Wound complications",
"medline_ta": "Radiother Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D005121:Extremities; D005240:Feasibility Studies; D006801:Humans; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D012509:Sarcoma; D016896:Treatment Outcome",
"nlm_unique_id": "8407192",
"other_id": null,
"pages": "161-167",
"pmc": null,
"pmid": "33798613",
"pubdate": "2021-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Neoadjuvant hypofractionated radiotherapy and chemotherapy for extremity soft tissue sarcomas: Safety, feasibility, and early oncologic outcomes of a phase 2 trial.",
"title_normalized": "neoadjuvant hypofractionated radiotherapy and chemotherapy for extremity soft tissue sarcomas safety feasibility and early oncologic outcomes of a phase 2 trial"
} | [
{
"companynumb": "BR-AMGEN-BRASP2021065161",
"fulfillexpeditecriteria": "2",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Bortezomib is a landmark drug in the therapeutic history of multiple myeloma as the first-generation proteasome inhibitor. It is widely used clinically, and its common adverse reaction is peripheral nerve lesion. We observed a severe syndrome of inappropriate antidiuresis (SIAD) in a female patient with multiple myeloma treated with bortezomib. This paper reviews the treatment process and relevant research progress regarding SIAD through a case report so as to improve the clinicians' ability to recognize and diagnose this rare complication.
.",
"affiliations": null,
"authors": "Peng|Bo|B|;Chen|Hu|H|;Lou|Xiao|X|",
"chemical_list": "D000970:Antineoplastic Agents; D000069286:Bortezomib",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203109",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "55(12)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000069286:Bortezomib; D005260:Female; D006801:Humans; D007177:Inappropriate ADH Syndrome; D009101:Multiple Myeloma",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "910-914",
"pmc": null,
"pmid": "29092733",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Bortezomib-induced syndrome of inappropriate antidiuresis in a patient with multiple myeloma: A case report and literature review
.",
"title_normalized": "bortezomib induced syndrome of inappropriate antidiuresis in a patient with multiple myeloma a case report and literature review"
} | [
{
"companynumb": "CN-TAKEDA-2018MPI000257",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Introduction. Patients with urothelial carcinoma of the bladder often present with metastases to regional lymph nodes, with lymphadenopathy on physical examination or radiographic imaging. Case Presentation. We present the case of a 73-year-old Caucasian man with presumed metastatic urothelial carcinoma of the bladder to regional pelvic and retroperitoneal lymph nodes. He underwent systemic chemotherapy for treatment of urothelial carcinoma and was discovered on restaging to have findings suggestive of disease progression but ultimately was found to have a concurrent secondary malignancy. Conclusion. Our case suggests that in patients with urothelial carcinoma, the concurrent presentation of regional lymphadenopathy may not be metastatic urothelial carcinoma and may warrant further investigation.",
"affiliations": "Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Department of Internal Medicine, University of Central Florida, Orlando, FL, USA.;Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.;Department of Radiation Oncology, University of Florida, Gainesville, FL, USA.;Department of Urology, University of Florida, Gainesville, FL, USA.;Department of Pathology, University of Florida, Gainesville, FL, USA.;Department of Radiology, University of Florida, Gainesville, FL, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA.",
"authors": "Ali|Azka|A|0000-0001-7476-6664;Skelton|William P|WP|;Akhavan|Neeka N|NN|;Nguyen|Thu-Cuc|TC|;Taylor|Zachary A|ZA|;Townsend|Tabitha|T|;Pathak|Prajwol|P|0000-0002-4057-8822;Hasija|Nalini|N|;Li|Li|L|;Indrisek|Jacqueline|J|;Watson|Scott|S|;Nixon|Isis|I|;Dang|Nam H|NH|;Zlotecki|Robert|R|;Crispen|Paul|P|0000-0002-3699-6183;Allan|Robert|R|;Abbitt|Patricia|P|;Dang|Long H|LH|0000-0002-6139-6294",
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"doi": "10.1155/2016/8125898",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2016/8125898Case ReportLow Grade Lymphoma Mimicking Metastatic Urothelial Carcinoma: When Do We Need Further Histologic Staging? http://orcid.org/0000-0001-7476-6664Ali Azka \n1\nSkelton IV William P. \n1\nAkhavan Neeka N. \n1\nNguyen Thu-Cuc \n2\nTaylor Zachary A. \n1\nTownsend Tabitha \n3\nhttp://orcid.org/0000-0002-4057-8822Pathak Prajwol \n3\nHasija Nalini \n3\nLi Li \n3\nIndrisek Jacqueline \n3\nWatson Scott \n3\nNixon Isis \n3\nDang Nam H. \n3\nZlotecki Robert \n4\nhttp://orcid.org/0000-0002-3699-6183Crispen Paul \n5\nAllan Robert \n6\nAbbitt Patricia \n7\nhttp://orcid.org/0000-0002-6139-6294Dang Long H. \n3\n\n*\n1Department of Internal Medicine, University of Florida, Gainesville, FL, USA2Department of Internal Medicine, University of Central Florida, Orlando, FL, USA3Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA4Department of Radiation Oncology, University of Florida, Gainesville, FL, USA5Department of Urology, University of Florida, Gainesville, FL, USA6Department of Pathology, University of Florida, Gainesville, FL, USA7Department of Radiology, University of Florida, Gainesville, FL, USA*Long H. Dang: long.dang@medicine.ufl.eduAcademic Editor: Su Ming Tan\n\n2016 22 11 2016 2016 812589830 7 2016 17 10 2016 31 10 2016 Copyright © 2016 Azka Ali 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.\nIntroduction. Patients with urothelial carcinoma of the bladder often present with metastases to regional lymph nodes, with lymphadenopathy on physical examination or radiographic imaging. Case Presentation. We present the case of a 73-year-old Caucasian man with presumed metastatic urothelial carcinoma of the bladder to regional pelvic and retroperitoneal lymph nodes. He underwent systemic chemotherapy for treatment of urothelial carcinoma and was discovered on restaging to have findings suggestive of disease progression but ultimately was found to have a concurrent secondary malignancy. Conclusion. Our case suggests that in patients with urothelial carcinoma, the concurrent presentation of regional lymphadenopathy may not be metastatic urothelial carcinoma and may warrant further investigation.\n==== Body\n1. Introduction\nEach year, 74,000 people are diagnosed with urothelial carcinoma of the bladder in the United States [1]. Of this group, one-third will have muscle-invasive disease on presentation, and half of those patients will have lymph node involvement or distant metastases [2]. Urothelial bladder carcinoma originates in the bladder mucosa, subsequently spreading to the lamina propria, muscularis propria, perivesical fat, nearby pelvic structures, and ultimately to the lymph nodes marking progression of the disease [3]. Untreated, muscle-invasive bladder cancer has a two-year mortality approaching 85% [4]. The most significant factors in determining survival in bladder cancer are primary tumor stage and lymph node metastasis; metastases are staged as N1, N2, or N3 according to the TNM system based on the number and size of metastatic nodes [5].\n\nThe gold standard therapy for high grade muscle-invasive urothelial carcinomas is neoadjuvant chemotherapy followed by radical cystectomy with urinary diversion [4]. Prior to the 1990s, radical cystectomy alone was the standard therapy. Multiple randomized controlled trials in the 1990s and 2000s led us to determine a substantial advantage of neoadjuvant chemotherapy in improving bladder cancer related mortality [6]. The current neoadjuvant chemotherapy standard is combined with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or GC (gemcitabine and cisplatin) [6]. Another acceptable curative treatment option is TURBT followed by definitive chemoradiation [7].\n\nA second primary cancer (SPC) is defined by the National Cancer Institute, as a new primary malignancy that occurs in a patient with a prior history of cancer [8]. There is very little information in the literature, regarding second primary cancers in the setting of known urothelial carcinoma of the bladder. This case describes a patient with the diagnosis of urothelial carcinoma with lymph node spread, who on subsequent biopsy of lymph nodes was found to have a second primary B cell lymphoma.\n\n2. Case Presentation\nThe patient presented here is a 73-year-old Caucasian man with presumed metastatic urothelial carcinoma of the bladder. He had a history of congestive heart failure, hypertension, obstructive sleep apnea, and morbid obesity (BMI 50). His past surgical history included appendectomy, bilateral hip replacement, and pacemaker placement. Urothelial carcinoma was initially discovered by computed tomography (CT) scan of the abdomen and pelvis, which was performed as a workup of persistent abdominal pain, anorexia, and weight loss. The CT scan showed large posterior-lateral dome bladder thickening that measured 4.6 cm × 2.5 cm, 3 mm lung nodule, bilateral exophytic hypodensities of the kidneys, and pelvic and retroperitoneal lymphadenopathy (Figures 1(a) and 1(b)).\n\nCystoscopy revealed a large bladder mass. The patient underwent transurethral resection of bladder with complete excision of mass, which involved one-third of the bladder and weighed 23 grams. Pathology confirmed high grade invasive urothelial carcinoma of the bladder with indeterminate lymphovascular invasion and was staged as T2N3M1 (Figures 1(c) and 1(d)). Due to the extent of lymph node involvement which likely represented metastatic urothelial cancer, the patient was not deemed an appropriate surgical candidate. He was started on GC combination chemotherapy with the goal of curative surgery or, if lymph nodes persisted, would continue to definitive chemoradiation. The treatment course was complicated with an episode of urinary retention and urinary tract infection. He developed thrombocytopenia with platelet count drop from 185,000 to 63,000, and subsequently, day 15 of cycle 1 chemotherapy was held. Initially, GC frequency was reduced from three weekly doses every 28 days to every other week dosing, and then gemcitabine was dose-reduced by 20%. After 3 months of chemotherapy, follow-up CT scan showed further progression of lymphadenopathy with prominent lymph nodes in axilla (one on the left measuring 17 mm and one on the right measuring 13 mm), mediastinal and hilar nodes 9–11 mm in short axis, retroperitoneal nodes (prominent node measuring 25 × 13 mm above the aortic bifurcation on the right), and interval growth in external iliac and pelvic nodes (Figures 2(a)–2(d)).\n\nHe underwent core biopsy of left axillary and right iliac nodes, which revealed low grade B cell lymphoma. Histologic sections of the axillary node showed a monotonous population of small lymphocytes with mature nuclear chromatin and distinct rims of cytoplasm (Figures 3(a) and 3(b)). Flow cytometric studies from this specimen showed a dim surface kappa clonal, relatively bright CD19/CD20+ B cell population with coexpression of CD5 and CD23 without expression of CD10 or significant CD38 (Figure 4). Additional immunohistochemistry showed expression of MUM1 without expression of BCL6, Cyclin D1, or SOX11. The differential diagnosis of this low grade B cell lymphoma included marginal zone lymphoma and lymphoplasmacytic lymphoma and less likely small lymphocytic lymphoma. The biopsy of the inguinal lymph node showed similar morphologic and immunophenotypic findings (not shown here). Neither contained evidence of metastatic urothelial carcinoma. Repeat bladder wash revealed normal bladder cells. There was no indication for treatment of low grade B cell lymphoma. Radiation oncology and medical oncology chose to continue with definitive concurrent cisplatin and radiation therapy for curative intent for his urothelial carcinoma of the bladder, which was restaged as T2N0M0.\n\n3. Discussion\nIn this case, the patient was diagnosed with urothelial carcinoma, initially shown on CT scan of abdomen and pelvis, which showed thickening of the posterior-lateral dome of the bladder measuring 4.6 cm × 2.5 cm, as well as significant pelvic and retroperitoneal lymphadenopathy. After pathology confirmed invasive high grade papillary urothelial (transitional cell) carcinoma with muscularis propria involvement, this cancer was staged as T2N3M1.\n\nRepeat imaging was conducted after appropriate treatment of 3 months of GC combination chemotherapy, which showed the presence of multiple lymph nodes, included in the left axilla, right axilla, retroperitoneum, external iliac, and pelvis. At that time, the differential diagnosis included persistent and progressive metastatic involvement with urothelial carcinoma, a lymphoproliferative disorder, or a secondary carcinoma of unknown primary. There was a high suspicion that the persistent lymphadenopathy was not due to metastatic involvement of the urothelial carcinoma, due to the atypical spread to axillary nodes. To distinguish the aforementioned etiologies, core needle biopsies of the left axillary lymph node and right iliac lymph node were performed, which both showed low grade B cell lymphoma. No metastatic carcinoma was detected in the biopsy of either lymph node, suggesting that the lymphadenopathy was due to a second primary malignancy rather than metastatic spread of the urothelial carcinoma. Therefore, based on the fact that low grade B cell lymphoma was biopsy proven in the lymph nodes, the cancer was appropriately restaged as T2N0M0. The patient is now treated for curative intent for his urothelial carcinoma with concurrent chemoradiation.\n\nA second primary malignancy is defined as a cancer that has “arisen independently and not as a result of resurgence, nor as a result of metastasis of the original primary cancer [9].” Oftentimes, many second primary malignancies arise after treatment with radiation or chemotherapy. Radiation exposure is most commonly associated with the development of leukemia, thyroid, or female breast cancer [10], although it has also been associated with development of lung, stomach, esophagus, colon, bladder, ovarian, brain/CNS, and liver cancer [10].\n\nChemotherapies, including alkylating agents [11], cisplatin [12], and topoisomerase II inhibitors [13], can also increase the risk of the development of second primary cancers. These are most often associated with the development of leukemia and myelodysplastic syndromes.\n\nThere are sparse reports of second primary malignancies in the setting of urothelial carcinoma of the bladder. These include reports of urothelial carcinoma developing synchronously with esophageal squamous cell carcinoma [14], urothelial carcinoma presenting with malignant Brenner tumor [15], and prostatic and urothelial carcinoma metastases detected in the same lymph node [16].\n\nIn addition to the synchronously detected second primary cancers, there are also reports of invasive bladder cancer developing after inverted papilloma [17, 18]. Transitional cell carcinoma has also been reported after treatment of lymphoma with cyclophosphamide [19]. There is also evidence of lower tract urothelial carcinoma developing in patients with prior upper tract urothelial carcinoma [20]. Urothelial carcinoma has also been reported prior to the development of thyroid cancer, with some evidence that this may be a rare sporadic neoplastic syndrome [21]. There has also been a report of urothelial carcinoma with a second cancer where it was found that the second cancer (in this case, breast cancer) was in fact metastatic spread of the urothelial carcinoma [22].\n\nTherefore, with respect to our case, it is one of the rare cases of a second primary cancer associated with urothelial carcinoma. Our case is the first presentation of concurrent urothelial carcinoma and lymphoma, confounding clinical staging and treatment decision. On initial assessment, the lymphadenopathy was attributed to metastatic spread of the urothelial carcinoma, which is the most common clinical presentation. The second primary B cell lymphoma was only detected after the atypical progression of lymphadenopathy. Although the lymphadenopathy visible on the initial CT scan was almost assuredly a second primary B cell lymphoma, it is impossible to definitively state as there was no lymph node biopsy performed at the time of diagnosis. It is extremely unlikely that the lymphoma developed as a result of cisplatin chemotherapy due to the short duration of only three months of therapy prior to discovery of second primary B cell lymphoma.\n\n4. Conclusion\nOur study is the first to show that urothelial carcinoma and lymphoma may present at the same time, which may complicate clinical staging and treatment decisions. For urothelial carcinoma, in cases of persistent or progressive lymphadenopathy despite appropriate systemic treatment, it is important to consider the possibility of a second primary malignancy and adjust treatment upon further histologic staging.\n\nDisclosure\nAzka Ali, William P. Skelton IV, and Neeka N. Akhavan are co-first authors.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 (a) Bladder mass, before chemotherapy. (b) Pelvic lymphadenopathy, before chemotherapy. (c) 100x: biopsy of bladder, before chemotherapy, and surface papillary component of the tumor. (d) 200x: biopsy of bladder, before chemotherapy; shown here are invasive malignant cells.\n\nFigure 2 (a) Bladder mass, after chemotherapy. (b) Pelvic lymphadenopathy, after chemotherapy. (c) Retroperitoneal lymph node above aortic bifurcation, after chemotherapy. (d) Axillary lymph nodes, after chemotherapy.\n\nFigure 3 (a) 200x: left axillary monotonous population of small lymphocytes with mature nuclear chromatin and distinct rims of cytoplasm. (b) 400x: left axillary monotonous population of small lymphocytes with mature nuclear chromatin and distinct rims of cytoplasm.\n\nFigure 4 Flow cytometry of core needle biopsy: surface kappa clonal and CD19/CD20+ B cell population along with coexpression of CD5 and CD23 (tumor = red population; background polyclonal B cells = blue).\n==== Refs\n1 Siegel R. L. Miller K. D. Jemal A. Cancer statistics, 2016 CA: A Cancer Journal for Clinicians 2016 66 1 7 30 10.3322/caac.21332 2-s2.0-84954400636 26742998 \n2 Tonyali S. Yazici S. Does solitary- and organ-confined metastasectomy really improve survival in advanced urologic malignancies? International Urology and Nephrology 2016 48 5 671 680 10.1007/s11255-016-1226-y 2-s2.0-84957539618 26843415 \n3 Stein J. P. Lieskovsky G. Cote R. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients Journal of Clinical Oncology 2001 19 3 666 675 2-s2.0-0035254218 11157016 \n4 Cahn D. B. Ristau B. T. Ghiraldi E. M. Bladder preservation therapy: a review of the literature and future directions Urology 2016 96 54 61 10.1016/j.urology.2016.05.041 27257135 \n5 Liedberg F. Månsson W. Lymph node metastasis in bladder cancer European Urology 2006 49 1 13 21 10.1016/j.eururo.2005.08.007 2-s2.0-29044437466 16203077 16203077 \n6 Winquist E. Kirchner T. S. Segal R. Chin J. Lukka H. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis Journal of Urology 2004 171 2 561 569 10.1097/01.ju.0000090967.08622.33 2-s2.0-0347759903 14713760 \n7 Ibrahim S. M. Abd El-Hafeez Z. M. Mohamed E. M. Elsharawy I. A. Kamal K. M. Transurethral Resection of Bladder Tumor (TUR-BT) then concomitant radiation and cisplatin followed by adjuvant gemcitabine and cisplatin in muscle invasive Transitional Cell Carcinoma (TCC) of the urinary bladder Journal of the Egyptian National Cancer Institute 2007 19 1 77 86 18839038 \n8 Chakraborty S. Tarantolo S. R. Batra S. K. Hauke R. J. Incidence and prognostic significance of second primary cancers in renal cell carcinoma American Journal of Clinical Oncology 2013 36 2 132 142 10.1097/coc.0b013e3182438ddf 2-s2.0-84876109573 22441339 \n9 Feller L. Lemmer J. New ‘second primary’ cancers SADJ: Journal of the South African Dental Association 2012 67 4 175 178 2-s2.0-84871867168 23198353 \n10 Travis L. B. The epidemiology of second primary cancers Cancer Epidemiology Biomarkers and Prevention 2006 15 11 2020 2026 10.1158/1055-9965.EPI-06-0414 2-s2.0-33845323515 17057028 17057028 \n11 Radford J. Longo D. L. Second cancers after treatment for Hodgkin's lymphoma—continuing cause for concern The New England Journal of Medicine 2015 373 26 2572 2573 10.1056/nejme1511947 2-s2.0-84951940885 26699173 \n12 Dertinger S. D. Avlasevich S. L. Torous D. K. Persistence of cisplatin-induced mutagenicity in hematopoietic stem cells: implications for secondary cancer risk following chemotherapy Toxicological Sciences 2014 140 2 307 314 10.1093/toxsci/kfu078 24798381 \n13 Pendleton M. Lindsey R. H. Felix C. A. Grimwade D. Osheroff N. Topoisomerase II and leukemia Annals of the New York Academy of Sciences 2014 1310 1 98 110 10.1111/nyas.12358 2-s2.0-84896305694 24495080 24495080 \n14 Vilcea I. D. Vasile I. Tomescu P. Synchronous squamous esophageal carcinoma and urothelial renal cancer Chirurgia 2010 107 6 843 847 2-s2.0-84874070882 \n15 Bouda J. Hes O. An unusual case of malignant Brenner tumor in association with low-grade urothelial carcinoma of the urinary bladder. A case report European Journal of Gynaecological Oncology 1999 20 4 318 320 2-s2.0-0033492518 10475132 10475132 \n16 Pacella E. Ricci F. Colecchia M. Boccardo F. Lopez-Beltran A. Spina B. Prostatic and urothelial metastasis in the same lymph node: a case report Analytical and Quantitative Cytology and Histology 2015 37 2 139 143 2-s2.0-84928798389 \n17 Koizumi K. Shiga J. Yokota H. A case of inverted papilloma of the renal pelvis, associated with metachronous urothelial carcinoma of the urinary bladder Acta Urologica Japonica 2013 59 2 121 124 2-s2.0-84875696477 23552756 \n18 de Knijff D. W. Theunissen P. H. Delaere K. P. Inverted papilloma of the ureter with subsequent invasive bladder cancer Acta Urologica Belgica 1997 65 4 45 46 2-s2.0-0031309355 \n19 Shiga Y. Suzuki K. Tsutsumi M. Ishikawa S. Transitional cell carcinoma of the renal pelvis in a patient with cyclophosphamide therapy for malignant lymphoma: a case report and literature review Acta Urologica Japonica 2002 48 5 301 305 2-s2.0-0036301368 12094715 \n20 Kates M. Badalato G. M. Gupta M. McKiernan J. M. Secondary bladder cancer after upper tract urothelial carcinoma in the US population BJU International 2012 110 9 1325 1329 10.1111/j.1464-410X.2012.11108.x 2-s2.0-84867740280 22564365 22564365 \n21 Albores-Saavedra J. Dorantes-Heredia R. Chablé-Montero F. Córdova-Ramón J. C. Henson D. E. Association of urothelial carcinoma of the renal pelvis with papillary and medullary thyroid carcinomas. A new sporadic neoplastic syndrome? Annals of Diagnostic Pathology 2014 18 5 286 290 10.1016/j.anndiagpath.2014.08.003 2-s2.0-84908205666 25175810 25175810 \n22 Dumont C. Gauthier H. Vérine J. Concomitant bifocal urothelial carcinoma and breast tumor: second primary cancer or metastatic spread to the breast? Case Reports in Oncological Medicine 2014 2014 3 917581 10.1155/2014/917581\n\n",
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"title": "Low Grade Lymphoma Mimicking Metastatic Urothelial Carcinoma: When Do We Need Further Histologic Staging?",
"title_normalized": "low grade lymphoma mimicking metastatic urothelial carcinoma when do we need further histologic staging"
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"abstract": "We report an accidental intra-arterial injection of phenytoin in a 43-year-old woman undergoing ventriculoperitoneal shunt for hydrocephalus. To flush the arterial line with heparin, mistakenly phenytoin was injected which caused cutaneous gangrene along the radial side of the forearm and an absence of pulsation in the radial artery. After flushing the artery with normal saline and lidocaine, the patient was transferred to the Intensive Care Unit. There the patient was put on intravenous heparin that resolved the problem leading to complete recovery of the patient. The case is being reported to emphasize the importance of close surveillance in injecting drugs through the arterial line access.",
"affiliations": "Department of Anesthesiology and Critical Care, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran 14197-33141, Iran.;Department of Anesthesiology and Critical Care, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran 14197-33141, Iran.",
"authors": "Khan|Z H|ZH|;Faghihnassiri|S|S|",
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"doi": "10.4103/1658-354X.174916",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Medknow Publications & Media Pvt Ltd India SJA-10-34210.4103/1658-354X.174916Case ReportAn accidental intra-arterial injection of phenytoin in a 43-year-old woman Khan ZH Faghihnassiri S Department of Anesthesiology and Critical Care, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran 14197-33141, IranAddress for correspondence: Prof. Zahid Hussain Khan, Department of Anesthesiology and Critical Care, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran 14197-33141, Iran. E-mail: khanzh51@yahoo.comJul-Sep 2016 10 3 342 344 Copyright: © Saudi Journal of Anaesthesia2016This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms.We report an accidental intra-arterial injection of phenytoin in a 43-year-old woman undergoing ventriculoperitoneal shunt for hydrocephalus. To flush the arterial line with heparin, mistakenly phenytoin was injected which caused cutaneous gangrene along the radial side of the forearm and an absence of pulsation in the radial artery. After flushing the artery with normal saline and lidocaine, the patient was transferred to the Intensive Care Unit. There the patient was put on intravenous heparin that resolved the problem leading to complete recovery of the patient. The case is being reported to emphasize the importance of close surveillance in injecting drugs through the arterial line access.\n\nAccidentalinjectionintra-arterialphenytoin\n==== Body\nIntroduction\nCraniotomies, especially supratentorial ones are associated with a high-risk of subsequent seizure. About 20-50% of the patients have at least one seizure postoperatively,[12] which mandated a prophylactic dose of phenytoin in this particular case. Mistakenly phenytoin was injected into the radial artery to flush the arterial line, on the erroneous assumption that it was heparin. Intra-arterial injection of phenytoin has been reported in the literature, leading to gangrene, and amputation of the digits.[3]\n\nCase Report\nA 43-year-old woman with raised intracranial pressure was scheduled to undergo ventriculoperitoneal shunt under general anesthesia. After induction of anesthesia, a 16G cannula was inserted into the radial artery and fixed for invasive blood pressure monitoring. The anesthesia staff inadvertently injected 4 ml of phenytoin sodium solution (200 mg) instead of heparin to flush the arterial line access during surgery. After injection, the erratum was immediately recognized, and the arterial line was flushed with 20 ml of normal saline and 0.5% lidocaine. The arterial line was maintained until the patient recovered after general anesthesia and later on unplugged. Fifteen minutes after injection of phenytoin, a red discoloration of the thenar eminence, thumb, index finger, and radial side of the forearm appeared [Figure 1] along with the absence of a pulse at the radial artery. However, the pulse oximetry continued to give correct readings. Suspecting an evolving gangrene of the forearm, we started a therapeutic dose of intravenous heparin (80 unit/kg bolus and then 18 unit/kg/h as an infusion to reach an intended INR of 2-3).[4]\n\nFigure 1 A red discoloration of the thenar eminence, thumb, index finger, and radial side of the forearm\n\nA color Doppler scan of the left forearm was done on day 2 of surgery, revealing thrombosis of the radial artery with a compensatory increase in flow in the ulnar division. Suspecting compartment syndrome,[5] we tried to warm up the affected region with hot towels and placing the hand in an elevated position so as to improve drainage of the affected forearm that was showing signs of increased girth measured with a tape. Nonsteroidal anti-inflammatory drugs were also given as the patient complained of excruciating pain, in the entire forearm.\n\nThe discoloration did further increase in extent but from 5th day onward, the color of the affected region showed a marked improvement [Figure 2]. We also started low molecular weight heparin (LMWH) (enoxaparin) despite the fact that the patient was receiving heparin until the 7th day (1 mg/kg subcutaneously every 12 h). A color Doppler scan was done before discharge that showed resolution of the thrombus along with an improved perfusion in the thenar aspect of the forearm. On day 14, the LMWH was stopped.\n\nFigure 2 A marked improvement of the affected region\n\nAn opinion was taken from the vascular surgeon who suggested no further active intervention. After 3 weeks follow-up, the woman showed good recovery and all the complaints were resolved.\n\nDiscussion\nPhenytoin is an anti-epileptic used for seizure control both during an emergency and intraoperatively.[12] Being very alkaline, extravasation of phenytoin can lead to severe phlebitis and thrombosis. It may also lead to fatal cardiac arrhythmias. Sintenie et al.[3] have described a case similar to that of ours which led to digital gangrene and amputation. Phenytoin extravasation may lead to purple glove syndrome.[6] In hand, the presence of deep palmar arch being fed dually by the radial and ulnar arteries serve as a protective factor, and thrombosis of any one of the arteries and a reduction of flow in one, is compensated by the other one which limits damage, as occurred in our case. In this case, a continuity of flow in the ulnar artery and for that matter in the deep palmar arch provided adequate protection in terms of enough collateral flow which established blood flow and thus saved the patient to encounter an irreversible vascular damage.\n\nA maximum provision in terms of both supportive and therapeutic treatment is a need during an accidental intra-arterial drug injection. Drugs such as hyaluronidase[7] and nitroglycrine[8] have been successfully used after phenytoin extravasation.\n\nPercutaneous catheter-directed thrombolytic infusion has been shown to be effective in the treatment of patients with severe ischemic hand symptoms secondary to thrombosis following radial artery cannulation.[9]\n\nIn our case, heparin followed by LMWH was given to reduce the damage. The thrombosis showed a substantial reduction in size on the 5th day and by the day 14, it had resolved completely. On follow-up 3 weeks later, the patient showed full cosmetic and functional recovery.\n\nConclusion\nWe would like to emphasize that the danger of an injection into the artery always lurks, and all precautions should be made that this territory remains forbidden for injections except those that are needed, such as heparin. An Allen test should routinely be performed before cannulating the radial artery to provide us a clue that the ulnar artery is fully patent. Patency of the ulnar artery in this particular case was the pivotal point in saving the patient from an onslaught of full-blown gangrene and amputation of the affected digits. However, in case of accidental drug injection, prompt measures should be taken, and a surgical consultation sought in case a compartment syndrome is suspected or is in the offing.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 North JB Penhall RK Hanieh A Frewin DB Taylor WB Phenytoin and postoperative epilepsy. A double-blind study J Neurosurg 1983 58 672 7 6339686 \n2 Shaw MD Foy PM Epilepsy after craniotomy and the place of prophylactic anticonvulsant drugs: Discussion paper J R Soc Med 1991 84 221 3 2027149 \n3 Sintenie JB Tuinebreijer WE Kreis RW Breederveld RS Digital gangrene after accidental intra-arterial injection of phenytoin (epanutin) Eur J Surg 1992 158 315 6 1354499 \n4 Zankl AR Andrassy M Volz C Ivandic B Krumsdorf U Katus HA Radial artery thrombosis following transradial coronary angiography: Incidence and rationale for treatment of symptomatic patients with low-molecular-weight heparins Clin Res Cardiol 2010 99 841 7 20625752 \n5 Hasija N Hazarika AJ Sokhal N Kumar S Tissue necrosis of hand caused by phenytoin extravasation: An unusual occurrence Saudi J Anesth 2014 8 309 10 \n6 Senthilkumaran S Balamurgan N Suresh P Thirumalaikolundusubramanian P Purple glove syndrome: A looming threat J Neurosci Rural Pract 2010 1 121 2 21808521 \n7 Sokol DK Dahlmann A Dunn DW Hyaluronidase treatment for intravenous phenytoin extravasation J Child Neurol 1998 13 246 7 9620019 \n8 Edwards JJ Bosek V Extravasation injury of the upper extremity by intravenous phenytoin Anesth Analg 2002 94 672 3 11867395 \n9 Geschwind JF Dagli MS Lambert DL Kobeiter H Thrombolytic therapy in the setting of arterial line-induced ischemia J Endovasc Ther 2003 10 590 4 12932173\n\n",
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"keywords": "Accidental; injection; intra-arterial; phenytoin",
"medline_ta": "Saudi J Anaesth",
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"title": "An accidental intra-arterial injection of phenytoin in a 43-year-old woman.",
"title_normalized": "an accidental intra arterial injection of phenytoin in a 43 year old woman"
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"abstract": "BACKGROUND\nNivolumab (Nivo) is an immune checkpoint inhibitor that has been used to treat advanced melanoma, nonsmall cell lung carcinoma, and renal cell carcinoma since 2015. Nivo is associated with several side effects, including hepatitis, pneumonitis, acute renal failure, endocrine disorder, and other immune-related adverse events. Here, we describe the case of a 65-year-old man with squamous cell lung carcinoma who developed myasthenia gravis (MG) after a third Nivo infusion.\nA 65-year-old man with advanced squamous cell lung carcinoma developed ptosis, diplopia, drop head, and general weakness 5 days after a third Nivo infusion.\nWe diagnosed him with Nivo-related MG and myositis based on clinical symptoms, elevation of muscle enzymes, negativity for autoantibodies and exclusion of other diagnoses. Steroid treatment with methylprednisolone 1 mg/kg/d and pyridostigmine 60 mg twice a day was administered beginning at admission; however, the patient's condition progressively worsened, despite treatment. Respiratory failure developed 2 weeks after admission, and his family declined the use of a mechanical ventilator. The patient died on day 27 after the third Nivo infusion.\n\n\nCONCLUSIONS\nNivo-related MG should be highly suspected in patients who develop ptosis, diplopia, and general weakness. The corresponding treatments include discontinuation of Nivo and steroid treatment with plasmapheresis. The disease course may be rapid and fatal. This report stresses the importance of awareness of this rare and lethal adverse effect while using nivolomab immunotherapy.",
"affiliations": "Division of Rheumatology/Immunology/Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center Department of Neurology, Tri-Service General Hospital, National Defense Medical Center Division of Pulmonary Medicine, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.",
"authors": "Chen|Yu-Hsiu|YH|;Liu|Feng-Cheng|FC|;Hsu|Chang-Hung|CH|;Chian|Chih-Feng|CF|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28682883MD-D-17-0064610.1097/MD.0000000000007350073505700Research ArticleClinical Case ReportNivolumab-induced myasthenia gravis in a patient with squamous cell lung carcinoma Case reportChen Yu-Hsiu MDaLiu Feng-Cheng MD, PhDaHsu Chang-Hung MDbChian Chih-Feng MDc∗Sinnberg. Tobias a Division of Rheumatology/Immunology/Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Centerb Department of Neurology, Tri-Service General Hospital, National Defense Medical Centerc Division of Pulmonary Medicine, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.∗ Correspondence: Chih-Feng Chian, Division of Pulmonary Medicine, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec 2, Cheng-Gong Rd, Neihu 114, Taipei, Taiwan (e-mail: sonice3982@gmail.com)7 2017 07 7 2017 96 27 e73501 2 2017 25 5 2017 4 6 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 License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nNivolumab (Nivo) is an immune checkpoint inhibitor that has been used to treat advanced melanoma, nonsmall cell lung carcinoma, and renal cell carcinoma since 2015. Nivo is associated with several side effects, including hepatitis, pneumonitis, acute renal failure, endocrine disorder, and other immune-related adverse events. Here, we describe the case of a 65-year-old man with squamous cell lung carcinoma who developed myasthenia gravis (MG) after a third Nivo infusion.\n\nPatient concerns:\nA 65-year-old man with advanced squamous cell lung carcinoma developed ptosis, diplopia, drop head, and general weakness 5 days after a third Nivo infusion.\n\nDiagnoses, interventions, and outcomes:\nWe diagnosed him with Nivo-related MG and myositis based on clinical symptoms, elevation of muscle enzymes, negativity for autoantibodies and exclusion of other diagnoses. Steroid treatment with methylprednisolone 1 mg/kg/d and pyridostigmine 60 mg twice a day was administered beginning at admission; however, the patient's condition progressively worsened, despite treatment. Respiratory failure developed 2 weeks after admission, and his family declined the use of a mechanical ventilator. The patient died on day 27 after the third Nivo infusion.\n\nLessons:\nNivo-related MG should be highly suspected in patients who develop ptosis, diplopia, and general weakness. The corresponding treatments include discontinuation of Nivo and steroid treatment with plasmapheresis. The disease course may be rapid and fatal. This report stresses the importance of awareness of this rare and lethal adverse effect while using nivolomab immunotherapy.\n\nKeywords\ncase reportmyasthenia gravisnivolumabsquamous lung carcinomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nNivolumab (Nivo) is a human IgG4 immune checkpoint inhibitor antibody that binds to programed death-1 (PD-1) receptor. PD-1 is an inhibitory immunoreceptor predominately expressed on the surface of activated T cells and plays an important role in immune tolerance and tumor escape from the immune system.[1] Use of Nivo has been shown to suppress the inhibitory activity of T cells, leading to an increased host immune response to the tumor. Nivo has been used to treat various advanced cancers, including melanoma, nonsmall cell lung carcinoma (NSCLC), and renal cell carcinoma.[1] The known side effects of Nivo include hepatitis, pneumonitis, acute renal failure, endocrine disorder, and other immune-related adverse events (irAEs).[2] The current treatment of adverse effects may dependent on the organ system and grade if the condition is severe; it may be appropriate to withdraw Nivo.[1] In case of severe irAEs, immunosuppressive drugs are sometimes needed.\n\nHere we described the case of a 65-year-old man with advanced squamous cell lung carcinoma who developed myasthenia gravis (MG) after Nivo treatment.\n\n2 Case report\nA 65-year-old man presented to our hospital with progressive ptosis, diplopia, and general weakness for 1 week. He was a heavy smoker (2–3 packs/d for 50 years) with chronic obstructive pulmonary disease and had been diagnosed with poorly differentiated squamous cell carcinoma of the left-upper lobe of the lung (size about 6 cm), with encasement of the thoracic aorta, left hilar structures, and subcarinal mediastinal lymphadenopathy (cT4N2M0, stage IIIB) 12 months prior. Concurrent chemoradiotherapy was performed after diagnosis; however, the disease progression and a series of chemotherapy regimens with cisplatin and paclitaxel, cisplatin and gemzar, and vinorelbine had been used within the previous 1 year. Despite these therapies, the disease continued to progress. Thus, the patient underwent immune therapy with Nivo 3 mg/kg every 2 weeks beginning 2 months prior. The final Nivo treatment was 12 days before admission. The patient reported weakness of four extremities 5 days after Nivo infusion. Upon physical examination, the patient had difficulty opening his eyes and had limited eye movement with a notable drop head. The muscle power in the four extremities was found to be grade 4. The laboratory data showed elevated levels of creatine kinase (2216 U/L), aspartate aminotransferase (153 U/L), alanine aminotransferase (110 U/L), lactate dehydrogenase (484 U/L), and troponin-I (2.62 ng/mL). Magnetic resonance imaging of the brain revealed no obvious stroke or brain metastases. Abdominal ultrasonography showed normal liver size and gallbladder polyps of about 0.9 cm. Transthoracic echocardiography showed normal left ventricular systolic function and no impairment of wall motion. These data suggested the presence of myositis and neuromuascular junction disorder. Autoimmune antibodies related to myositis, including antinuclear, anti-Jo1, and anti-Mi-2 antibodies, were negative. Nerve conduction velocity tests indicated polyneuropathy involving the median, ulnar, peroneal, tibial, and sural nerves. Electromyography showed no significant decrease in compound muscle action potential on low-frequency stimulation to the left face. High-frequency repetitive stimulation tests of the trapezius showed no incremental changes in compound muscle action potential. Acetylcholine receptor antibody (AChR ab) was not detected, and botulism serology and stool culture were normal. Peripheral blood lymphocyte analysis showed 21.74% CD4 T cells, 31.24% CD8 T cells, and elevation of the CD8/CD4 ratio (1.4; normal range 0.5–1). AChR ab-related MG, lambert Eton myasthenia syndrome, and botulism intoxication were ruled out. Nivo-related MG was strongly suspected, and the patient was given methylprednisolone 1 mg/kg/d since admission and pyridostigmine 60 mg oral twice/d 2 days after admission. However, he failed to respond to the intervention. He developed drooling with dysphagia and difficulty moving 14 days after admission. We planned to performed plasma exchange for him and discussed the possibility of respiratory failure and the use of a mechanical ventilator with his family. Conscious disturbance was found the next morning, and venous blood gas analysis showed a pH of 7.229, partial pressure of carbon dioxide of 119.2 mm Hg, and HCO3 of 48.7 mm Hg. His families refused the use of a mechanical ventilator. The patient died due to Nivo-related MG and myositis with hypercapnia respiratory failure on day 27 after the third infusion of Nivo.\n\nThe patient was diagnosed with Nivo-related MG and myositis based on the symptoms and timing of drug exposure and the exclusion of any other causes of myasthenic syndrome and myositis.\n\n3 Discussion\nNivo has been used to treat NSCLC since 2015.[3] Adverse events consistent with immune-related causes have been observed, and grade 3 or 4 drug-related adverse events occur in 14% to 17% of patients.[1,2] The known adverse events are fatigue, pneumonitis, and diarrhea.[2] However, neurological, respiratory, musculoskeletal, and cardiac adverse events have also been reported following anti-PD1 treatment, including Nivo.[4–7]\n\nIn this study, we reported a patient diagnosed with Nivo-related MG. Based on the findings from our patient and a review of the literature (Table 1) on Nivo-related MG, we identified 7 cases.[5,8–12] Two of these 7 cases showed stabilization of MG following administration of regular medication before Nivo administration and presented with acute exacerbation after Nivo was given. Two of the 7 cases showed negative anti-AChR-Ab. Three of the 7 patients died despite medical treatment, including steroids, immunoglobulin (IVIG), and pyridostgmin. In these 3 cases, 2 patients died due to respiratory failure without the use of a mechanical ventilator, and the other patient died due to complete heart block, sepsis, and duodenal ulcer bleeding. All 7 cases developed MG or acute exacerbation after the first 3 infusions of Nivo.\n\nTable 1 Summary of seven cases of Nivo-related MG.\n\nMG can be divided according to the distinct clinical feature and antibody specificity. Our patient may belong to the seronegative subgroups. However, antimuscle-specific receptor tyrosine kinase, antilow-density lipoprotein receptor-related protein 4, and pathogenic antibodies against other postsynaptic membrane antigens (interacting with acetylcholine receptors) were not measured in this patient. The diagnosis should be reassessed, and antibody tests should be repeated after 6 to 12 months.[13] Electromyography has 75% to 80% sensitivity of diagnosing MG. Further, electromyography in acute severe generalized disease may not be detected in less than 4 weeks.[14] Our patient developed MG only for 1 week, thus the electromyography might show negative result. A similar case of MG who had negative anti-AChR-Ab and electromyography after Nivo therapy has been reported.[11]\n\nKimura et al[5] reported an 80-year-old man with a history of MG who received Nivo for metastatic melanoma. In their study, the patient exhibited Nivo-related myocarditis, myositis, and myasthenic crisis with a rapid increase in anti-AChR antibody within 2 weeks after the first dose. In addition, after Nivo infusion, the CD8/CD4 T lymphocyte ratio increased, as demonstrated by skeletal muscle biopsy. The patient's peripheral blood mononuclear cell analysis after Nivo infusion showed decreases expression of FOXP3, CD3, and CD4 genes and increased expression of the CD8 gene compared with those before Nivo infusion. Similarly, in our case, elevation of the CD8/CD4 T-cell ratio was also noted. Blocking of the PD-1 receptor by Nivo may enhance the antitumor activity of T cells, causing elevation of the CD8/CD4 ratio and decreasing the numbers of regulatory T cells (Tregs).[15] However, the PD1 pathway and Tregs are also important for self-tolerance and autoimmunity.[16] Blockade of this pathway is thought to cause severe irAEs owing to T-cell activation, and cautious monitoring during the administration of immunotherapy with anti-PD1 agents is crucial.\n\nThe treatments for Nivo-related MG include stopping Nivo immediately, pulsing steroids, plasmapheresis, and IVIG treatments. Supportive treatment with a ventilator is necessary when respiratory failure develops. Since Nivo is often used to treat patients with advanced NSCLC, our case report presents a rare but lethal complication of myathenia gravis induced by Nivo and provides information regarding a potential treatment strategy. One limitation of this case report was that the patient did not receive further plasma exchange and IVIG; thus, we cannot know whether the patient would have responded to immune absorption treatment. The recommended dosage of Nivo is once every 2 weeks for NSCLC treatment; however, there are no biological marker available indicating irAEs. Further investigations of the potential adverse effects of Nivo are strongly recommended.\n\n4 Conclusion\nNivo-related MG should be highly suspected in patients with symptoms including ptosis, diplopia, and general weakness. The corresponding treatments include discontinuation of Nivo and pulse steroid treatment with plasmapheresis. The disease course is fast and fatal. This report stresses the importance of the awareness of this rare and lethal adverse effect while using the anti-PD1 drug nivolomab as immunotherapy.\n\nAbbreviations: AChR ab = acetylcholine receptor antibody, irAE = immune-related adverse event, IVIG = immunoglobulin, MG = myasthenia gravis, Nivo = nivolumab, NSCLC = nonsmall cell lung carcinoma, PD-1 = programed death-1, Treg = regulatory T cell.\n\nEthical approval was not necessary. Patient's anonymity can be maintained in written text and without the use of photographs.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Topalian SL Hodi FS Brahmer JR \nSafety, activity, and immune correlates of anti-PD-1 antibody in cancer . N Engl J Med \n2012 ;366 :2443 –54 .22658127 \n[2] Rizvi NA Mazières J Planchard D \nActivity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial . Lancet Oncol \n2015 ;16 :257 –65 .25704439 \n[3] Brahmer J Reckamp KL Baas P \nNivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer . N Engl J Med \n2015 ;373 :123 –35 .26028407 \n[4] Min L Hodi FS \nAnti-PD1 following ipilimumab for mucosal melanoma: durable tumor response associated with severe hypothyroidism and rhabdomyolysis . Cancer Immunol Res \n2014 ;2 :15 –8 .24778161 \n[5] Kimura T Fukushima S Miyashita A \nMyasthenic crisis and polymyositis induced by one dose of nivolumab . Cancer Sci \n2016 ;107 :1055 –8 .27420474 \n[6] Bilen MA Subudhi SK Gao J \nAcute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody . J Immunother Cancer \n2016 ;4 :1 .\n[7] Yoshioka M Kambe N Yamamoto Y \nCase of respiratory discomfort due to myositis after administration of nivolumab . J Dermatol \n2015 ;42 :1008 –9 .26104017 \n[8] Loochtan AI Nickolich MS Hobson-Webb LD \nMyasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer . Muscle Nerve \n2015 ;52 :307 –8 .25759003 \n[9] Shirai T Sano T Kamijo F \nAcetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma . Jpn J Clin Oncol \n2016 ;46 :86 –8 .26491202 \n[10] Maeda O Yokota K Atsuta N \nNivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis . Nagoya J Med Sci \n2016 ;78 :119 –22 .27019533 \n[11] Polat P Donofrio PD \nMyasthenia gravis induced by nivolumab therapy in a patient with non-small-cell lung cancer . Muscle Nerve \n2016 ;54 :507 –1507 .\n[12] Sciacca G Nicoletti A Rampello L \nBenign form of myasthenia gravis after nivolumab treatment . Muscle Nerve \n2016 ;54 :507 –9 .\n[13] Gilhus NE \nMyasthenia gravis . N Engl J Med \n2016 ;375 :2570 –81 .28029925 \n[14] Liik M Punga AR \nRepetitive nerve stimulation often fails to detect abnormal decrement in acute severe generalized myasthenia gravis . Clin Neurophysiol \n2016 ;127 :3480 –4 .27744133 \n[15] Nishikawa H Sakaguchi S \nRegulatory T cells in cancer immunotherapy . Curr Opin Immunol \n2014 ;27 :1 –7 .24413387 \n[16] Francisco LM Sage PT Sharpe AH \nThe PD-1 pathway in tolerance and autoimmunity . Immunol Rev \n2010 ;236 :219 –42 .20636820\n\n",
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"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009157:Myasthenia Gravis; D000077594:Nivolumab",
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"title": "Nivolumab-induced myasthenia gravis in a patient with squamous cell lung carcinoma: Case report.",
"title_normalized": "nivolumab induced myasthenia gravis in a patient with squamous cell lung carcinoma case report"
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"abstract": "To determine a recommended dose for a biweekly combination neoadjuvant chemotherapy including gemcitabine, nab-paclitaxel, and S-1 (GAS) for patients with locally advanced pancreatic ductal adenocarcinoma (LAPC).\n\n\n\nPatients with borderline resectable or unresectable LAPC without distant metastasis were eligible for this study. The planned dosages of gemcitabine (mg/m2, day 1), nab-paclitaxel (mg/m2, day 1), and S-1 (mg/day, days 1-7) were 800/100/60-100 at level 1, and 1000/125/60-100 at level 2. The treatment cycle was repeated every 2 weeks, and patients were assessed for resectability and response to the treatment after 6 cycles. This study was registered with UMIN Clinical Trial Registry (UMIN000016630).\n\n\n\nWe enrolled 16 patients with LAPC in this study. At dose level 1, one of 8 patients experienced dose-limiting toxicity (DLT). One of the next 8 patients also experienced DLT at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen. Pancreatectomy with curative intent could be performed in 13 of the 16 patients. R0 resection was performed in 12 of 13 patients.\n\n\n\nIn conclusion, recommended doses for a biweekly GAS chemotherapy regimen were determined as nab-paclitaxel: 125 mg/m2, gemcitabine: 1000 mg/m2 on day 1, S-1: <1.25 m2, 60 mg; 1.25-1.5 m2, 80 mg; >1.5 m2, 100 mg twice a day on days 1-7. GAS chemotherapy showed good preliminary efficacy with mild toxicity in this study, and warrants a further phase 2 trial to investigate the efficacy of the GAS regimen for LAPC.",
"affiliations": "Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. k-naru-surg@hiroshima-u.ac.jp.;Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Surgery, Kure Medical Center and Chugoku Cancer Center, Kure, Japan.;Department of Surgery, Hiroshima Memorial Hospital, Hiroshima, Japan.;Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.",
"authors": "Kondo|Naru|N|;Murakami|Yoshiaki|Y|;Uemura|Kenichiro|K|;Sudo|Takeshi|T|;Hashimoto|Yasushi|Y|;Nakagawa|Naoya|N|;Takahashi|Shinya|S|;Ohge|Hiroki|H|;Sueda|Taijiro|T|",
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"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D021441:Carcinoma, Pancreatic Ductal; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010094:Oxonic Acid; D017239:Paclitaxel; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D005641:Tegafur",
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"title": "A phase 1 study of gemcitabine/nab-paclitaxel/S-1 (GAS) combination neoadjuvant chemotherapy for patients with locally advanced pancreatic adenocarcinoma.",
"title_normalized": "a phase 1 study of gemcitabine nab paclitaxel s 1 gas combination neoadjuvant chemotherapy for patients with locally advanced pancreatic adenocarcinoma"
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"abstract": "Background: T-cell prolymphocytic leukemia (T-PLL) is a rare lymphoid malignancy with dismal prognosis. Most patients have increased lymphocyte count (>1,00,000/dL) and widespread disease at presentation. Despite high response rate seen with alemtuzumab, the disease relapse is inevitable. Materials andMethods This was a retrospective observational study done at a tertiary cancer center in South India. All patients diagnosed with T-PLL from August 2010 to July 2015 were studied for the clinical characteristics, pathological findings and treatment outcomes. Results Seven patients were diagnosed as T-PLL over a period of 5 years. The median age at diagnosis was 51 years. In the present series, 6 patients (86%) had splenomegaly and 3 had hepatomegaly (43%). Generalized lymphadenopathy was seen in 4 (57%) patients at presentation. Skin lesions were seen in 5 (71%) patients, whereas pleural effusion was seen in only one patient (14%). All had elevated total leukocyte count, with more than 1, 00,000/dL in 4 patients. The median survival was 5 months with different chemotherapy (CT) regimens (5 patients treated with CT and 2 received best supportive care). Conclusion: T-PLL is a rare disease with no definite treatment guidelines. At present, the best outcomes are achieved if treatment with alemtuzumab is followed by stem cell transplant, but the disease invariably relapses. Countries where affordability remains a big challenge, the best approach needs to be defined beyond the monoclonal antibodies and transplant.",
"affiliations": "Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.;Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India.",
"authors": "Babu Mc|Suresh|S|;Anand|Abhishek|A|;Lakshmaiah|Kuntegowdanahalli C|KC|;Babu K|Govind|G|;Lokanatha|Dasappa|D|;Jacob|Linu Abraham|LA|;Madhumathi|D S|DS|;Lokesh|Kadabur N|KN|;Rudresha|A H|AH|;Rajeev|L K|LK|;Patidar|Rajesh|R|",
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"fulltext": "\n==== Front\nInt J Hematol Oncol Stem Cell ResInt J Hematol Oncol Stem Cell ResIJHOSCRInternational Journal of Hematology-Oncology and Stem Cell Research2008-30092008-2207Tehran University of Medical Sciences, Hematology-Oncology and Stem Cell Transplantation Research Center Tehran, Iran IJHOSCR-12-132Original ArticleT-Cell Prolymphocytic Leukemia: An Experience from a Tertiary Cancer Centre in South India Babu MC Suresh Anand Abhishek Lakshmaiah Kuntegowdanahalli C. Babu K Govind Lokanatha Dasappa Jacob Linu Abraham Madhumathi DS Lokesh Kadabur N Rudresha AH Rajeev LK Patidar Rajesh Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, IndiaCorresponding Author: Abhishek Anand, Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India\nTel:+918105502481\n.Email: drabhishek2508@gmail.com1 4 2018 12 2 132 135 6 6 2017 27 7 2017 \nCopyright : © International Journal of Hematology-Oncology and Stem Cell Research & Tehran University of Medical Sciences\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground: T-cell prolymphocytic leukemia (T-PLL) is a rare lymphoid malignancy with dismal prognosis. Most patients have increased lymphocyte count (>1,00,000/dL) and widespread disease at presentation. Despite high response rate seen with alemtuzumab, the disease relapse is inevitable. \n\n\nMaterials and \nMethods\n: This was a retrospective observational study done at a tertiary cancer center in South India. All patients diagnosed with T-PLL from August 2010 to July 2015 were studied for the clinical characteristics, pathological findings and treatment outcomes. \n\n\nResults\n: Seven patients were diagnosed as T-PLL over a period of 5 years. The median age at diagnosis was 51 years. In the present series, 6 patients (86%) had splenomegaly and 3 had hepatomegaly (43%). Generalized lymphadenopathy was seen in 4 (57%) patients at presentation. Skin lesions were seen in 5 (71%) patients, whereas pleural effusion was seen in only one patient (14%). All had elevated total leukocyte count, with more than 1, 00,000/dL in 4 patients. The median survival was 5 months with different chemotherapy (CT) regimens (5 patients treated with CT and 2 received best supportive care). \n\n\nConclusion: T-PLL is a rare disease with no definite treatment guidelines. At present, the best outcomes are achieved if treatment with alemtuzumab is followed by stem cell transplant, but the disease invariably relapses. Countries where affordability remains a big challenge, the best approach needs to be defined beyond the monoclonal antibodies and transplant. \n\nKey Words\nT-cellsProlymphocytic leukemiaAlemtuzumab\n==== Body\nIntroduction\n T-cell prolymphocytic leukemia (T-PLL) is a rare lymphoid malignancy which presents at an advanced age and carries a dismal prognosis. The disease is characterized by the proliferation of small- to medium-sized prolymphocytes arising from mature post-thymic T cell 1,2. The disease entity was first described in 19731 and was named variably as diffuse small cleaved cell leukemia, small lymphocytic lymphoma (Working Formulation3) and chronic lymphocytic leukemia–T cell type (Kiel classification)4. T-PLL was recognized as a distinct entity in 1994 and was clearly separated from other large granular lymphocytic disorders by REAL classification 5. Skin infiltration and serous effusions are the common presenting features of T-PLL2,6. Most patients have increased lymphocyte count (>1,00,000/dL) and widespread disease at the time of diagnosis7. Compared to B cell prolymphocytic leukemia, anemia and thrombocytopenia are less commonly seen6. The prognosis of T-PLL still remains poor with short survival and no curative therapy. The best response has been seen with anti-CD 52 monoclonal antibody alemtuzumab. Despite high response rate, the disease relapse is inevitable8,9. Herein, we studied the clinicopathological profile and treatment outcome in 7 patients with T-PLL treated at a tertiary cancer center in South India.\n\nMATERIALS AND METHODS\n This was a retrospective observational study done at a tertiary cancer center in South India. The medical records of all patients diagnosed with T-PLL from August 2010 to July 2015 were reviewed to study the clinicopathological profile and treatment outcome. Patient’s clinical characteristics, pathological findings and treatment outcomes were analyzed. The diagnosis of T-PLL was based on the peripheral blood and bone marrow specimen, including immunophenotyping study. \n\nResults\n\nPatients' characteristics\n\n\nWe found 7 patients of T-PLL over a period of 5 years. The median age at diagnosis of T-PLL was 51 years. Out of 7 patients, 4 were male and 3 female. Two male patients were smoker. Two patients with hypertension were on regular medication. None of the patients gave a history of prior radiation, exposure to chemicals or other malignancies. The history of familial or genetic disorders was negative in all patients. \n\n\nClinical presentation\n\n\nAll patients presented with the complaint of easy fatigability with a median duration of 1 month before consultation. The median ECOG performance status was 2. Five out of 7 patients also presented with skin lesions which were in the form of maculopapular rash in 3 and erythematous nodule in 2 patients. Six out of 7 patients had splenomegaly, whereas 3 patients had hepatomegaly. Lymphadenopathy was present in 4 patients at the time of diagnosis. One patient had pleural effusion which was diagnosed during the routine workup. \n\n\nPathological findings\n\n\nElevated total leukocyte count (> 1,00,000/dL) was seen in 4 patients. Anemia and thrombocytopenia were reported in 2 and 3 patients, respectively. Lactate dehydrogenase (LDH) level was raised in all patients. The mean LDH level was 545. Hyperuricemia was seen in 3 patients at the time of initial evaluation although frank tumor lysis syndrome was not seen in any of them.\n\nPeripheral blood smear showed the presence of atypical lymphoid cells in all patients. Bone marrow aspirate examination was done in all patients. The pathological findings were suggestive of lymphoproliferative disorder with lymphocyte ranging from 80 to 95%. Immunophenotyping (IPT) study confirmed the diagnosis of T-PLL with positive CD5, CD2, CD7 and negative TdT, CD1a. Cytogenetic studies failed to yield metaphases in 4 patients, while complex karyotype was seen in the 3 remaining patients (>3 cytogenetic abnormalities).\n\n\nTreatment \n\n\nOut of 7 patients, 2 did not opt for any treatment and received best supportive care. One patient received FCM- (fludarabine+cyclophosphamide+mitoxantrone) based treatment, 2 patients were treated with CHOP (cyclophosphamide+doxorubicin+vincristine+prednisolone), and another two were given chlorambucil plus prednisolone (Table. 1). Due to financial constraints, none of our patients received alemtuzumab. Complete response was seen in the patient who received FCM and transient partial response was seen in one patient treated with CHOP. The median survival was 5 months. The patient receiving FCM- based regimen is still alive and is under regular follow-up. Treatment outcomes are shown in Table 1. \n\nTable 1 Treatment outcome\n\n\nS.No\n\t\nAge\n\t\nTreatment \n\n\nreceived\n\t\nPR\n\t\nCR\n\t\nComplication \n\n\nof treatment\n\t\nSurvival \n\n\n(months)\n\t\n1\t45\tFMC\t-\t+\t\t12(alive)\t\n2\t51\tNA\t-\t-\t\t2\t\n3\t42\tChl+P\t-\t-\t\t8\t\n4\t59\tCHOP\t+\t-\t\t7\t\n5\t55\tNA\t-\t-\t\t5\t\n6\t47\tCHOP\t-\t-\tFN\t3\t\n7\t61\tChl+P\t-\t-\t\t4\t\nChl+P – Chlorambucil + Prednisolone, CHOP – Cyclophosphamide +Doxorubicin + Vincristine + Prednisolone, CR – Complete Response, FCM – Fludarabine+Mitoxantrone + Cyclophosphamide, FN – Febrile Neutropenia, PR – Partial Response\n\nDiscussion\n T-PLL is a rare hematological malignancy and represents less than 2% of mature lymphocytic leukemias 1,7,10. It has been considered a disease of elderly men with an average age of 65 years 11. In our series, the median age at presentation was 51 years, which is comparatively less than other published studies. The male to female ratio was 1.3:1 in our study. Most of the patients presented with splenomegaly (82-92%), hepatomegaly and generalized lymphadenopathy 10. Skin lesions were present in 27%, whereas pleural effusion was seen in 14% of patients at presentation 7. In the present series, 6 patients (86%) had splenomegaly, 3 had hepatomegaly (43%) and generalized lymphadenopathy was seen in 4 (57%) patients. Skin lesions were seen in 5 (71%) patients, whereas pleural effusion was found in only one patient (14%). The incidence of the skin lesion in our series was much higher than previously described in different studies.\n\nAnemia and thrombocytopenia are seen in half of the patients with T-PLL. In the present study, anemia and thrombocytopenia were present in 2 (28.6%) and 3(43%) patients, respectively. Peripheral blood examination usually shows marked lymphocytosis with lymphocyte counts frequently more than 1 lakh 1. In our study, total leukocyte count of more than one lakh was seen in 4 (57%) patients. More than 90% of the circulating cells are prolymphocytes. The prolymphocytes are typically medium sized with condensed chromatin, single prominent nucleolus and intensely basophilic nongranular cytoplasm with cytoplasmic protrusions or blebs. The nuclei may be round, oval or irregular in shape 12,13.\n\nThere is diffuse infiltration of bone marrow by prolymphocytes. In our series, examination of bone marrow revealed the presence of lymphoproliferative disease with more than 80% lymphocytes in all patients. Diagnosis of T-PLL is made by flow cytometry which can be done either on peripheral blood or bone marrow sample. The monoclonal lymphocyte population is positive for T- cell markers, including CD2, CD3, CD5 and a strong CD7. There is a variable expression of CD4 and CD8. T-cell prolymphocytes are mature post-thymic peripheral T- cell and do not express TdT and cortical thymic marker CD1a. CD52 is expressed at high density, which can be used for targeted therapy with alemtuzumab 11,14. CD26 and TCL-1 protein expression are the most specific markers for T-PLL and the overexpression of TCL-1 oncogene can be useful in detecting residual T-PLL after therapy15. In our series, all patients were positive for CD2, CD5, CD7 and negative for TdT and CD1a. CD4+CD8- was seen in 4 (57%); CD4+CD8+ in 2(29%) and CD4-CD+ in 1(14%) patient. \n\nT-PLL are often resistant to therapy and have an aggressive course. With conventional regimens, the response rate is around 30% and the overall survival remains poor with a median survival of 7 months 7. Alemtuzumab is now the first-line treatment of T-PLL which is effective and well tolerated. The overall response rate ranges from 51-95% with a median survival of 15 – 19 months in those who achieve complete response16-18. The use of consolidation treatment after stem cell transplantation increases long-term relapse-free survival 19,20. The purine- analog fludarabine has been tried in combination with cyclophosphamide and mitoxantrone (FMC) with an ORR rate of 68% 21.\n\nIn the study done by Farhad Ravandi et al. 22, none of the 8 patients showed CR with fludarabine-based treatment. In contrast, the present study showed that only one patient treated with FMC achieved CR. This may suggest a role of fludarabine-based chemotherapy in patients with T-PLL. It might achieve a better outcome if many patients could afford the standard therapy including alemtuzumab and consolidation with stem cell transplantation.\n\nCONCLUSION\n T-PLL is a rare disease with no definite treatment guidelines. Although alemtuzumab and stem cell transplantation have been the standard treatment at present, cost remains a major challenge. Moreover, purine analogs like fludarabine-based regimens may show a good promise in the management of T-PLL. Larger studies are needed for optimizing the treatment protocols for this rare malignancy.\n==== Refs\nReferences\n1 Catovsky D Galetto J Okos A Prolymphocytic leukaemia of B and T cell type Lancet 1973 2 7823 232 4 4124423 \n2 Catovsky D Ralfkiaer E Muller-Hermelink HK Jaffe ES Harris NL Stein H Vardiman JW T-cell prolymphocytic leukaemia World Health Organization Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues 2001 Lyon IARC Press 195 196 \n3 National cancer institute sponsored study of classifications of Non-Hodgkin’s Lymphomas: summary and description of a working formulation for clinical usage The NonHodgkin’s Lymphoma pathologic classification project Cancer 1982 49 10 2112 35 6896167 \n4 Stansfeld A Diebold J Kapanci Y Updated kiel classification for lymphomas Lancet 1988 1 8580 292 3 \n5 Harris NL Jaffe ES Stein H A revised EuropeanAmerican classification of lymphoid neoplasms: a proposal from the international lymphoma study group Blood 1994 84 5 1361 92 8068936 \n6 Matutes E Brito-Babapulle V Yullie MR Cheson BD Prolymphocytic leukemia of B- and T-cell types Chronic Lymphoid Leukemias 2001 New York, Basel Marcel Dekker, Inc 525 541 \n7 Matutes E Brito-Babapulle V Swansbury J Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia Blood 1991 78 12 3269 74 1742486 \n8 Dearden CE Matutes E Cazin B High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H Blood 2001 98 6 1721 6 11535503 \n9 Keating MJ Cazin B Coutré S Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed J Clin Oncol 2002 20 1 205 13 11773171 \n10 Robak T Robak P Current treatment options in prolymphocytic leukemia Med Sci Monit 2007 13 4 RA69 80 17392661 \n11 Dearden CE T-cell prolymphocytic leukemia Med Oncol 2006 23 1 17 22 16645226 \n12 Catovsky D Ralfkiaer E Muller-Hermelink HK Jaffe ES Harris NL Stein H Vardiman JW T-cell prolymphocytic leukemia. Pathology and genetics of tumours of haemopoietic and lymphoid tissues World Health Organisation Classifcation of Tumours 2008 Lyon, France IARC Press 270 271 \n13 Dearden CE T-cell prolymphocytic leukemia Med Oncol 2006 23 1 17 22 16645226 \n14 Matutes E T-cell prolymphocytic leukemia Cancer Control 1998 5 1 19 24 \n15 Herling M Khoury JD Washington LT A systematic approach to diagnosis of mature T-cell leukemias reveals heterogeneity among WHO categories Blood 2004 104 2 328 35 15044256 \n16 Dearden CE Matutes E Cazin B High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H Blood 2001 98 6 1721 6 11535503 \n17 Pawson R Dyer MJ Barge R Treatment of T-cell prolymphocytic leukemia with human CD52 antibody J Clin Oncol 1997 15 7 2667 72 9215839 \n18 Keating MJ Cazin B Coutre S Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed J Clin Oncol 2002 20 1 205 13 11773171 \n19 Collins RH Pineiro LA Agura ED Treatment of T prolymphocytic leukemia with allogeneic bone marrow transplantation Bone Marrow Transplant 1998 21 6 627 8 9580345 \n20 Curtin NJ Schwarer AP Nonmyeloablative peripheral blood stem cell transplant for T-cell prolymphocytic leukaemia complicated by fulminant haemolysis and acute renal failure at engraftment secondary to minor ABO incompatibility Clin Lab Haematol 2005 27 3 206 8 15938729 \n21 Hopfinger G Busch R Eichorst B Sequential therapy of fludarabine, mitoxantrone and cyclophosphamide (FMC) induction followed by alemtuzumab consolidation is effective and safe in patients with T-cell prolymphocytic leukemia (T-PLL): results from a multicentre phase II trial of the German CLL study group (GCLLSG) [abstract] Ann Oncol 2011 22 Suppl 4 Abstract 123 \n22 Ravandi F O'Brien S Jones D T-Cell Prolymphocytic Leukemia: A Single-Institution Experience Clin Lymphoma Myeloma 2005 6 3 234 9 16354329\n\n",
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"keywords": "Alemtuzumab; Prolymphocytic leukemia; T-cells",
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"title": "T-Cell Prolymphocytic Leukemia: An Experience from a Tertiary Cancer Centre in South India.",
"title_normalized": "t cell prolymphocytic leukemia an experience from a tertiary cancer centre in south india"
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"abstract": "BACKGROUND\nAlthough it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.\n\n\nMETHODS\nA 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.\n\n\nCONCLUSIONS\nWe successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.",
"affiliations": "Department of Urology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042, Japan.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan. taketokawai@yahoo.co.jp.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;Department of Urology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042, Japan.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;Department of Rheumatology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042, Japan.;Department of Rheumatology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042, Japan.;Department of Rheumatology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042, Japan.;Department of Pathology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042, Japan.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.;Department of Urology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042, Japan.;Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.",
"authors": "Minagawa|Hideyuki|H|;Kawai|Taketo|T|;Matsumoto|Akihiko|A|;Makino|Katsuhiro|K|;Sato|Yusuke|Y|;Nagasaka|Kenji|K|;Tokura|Masami|M|;Tanaka|Nao|N|;Ito|Eisaku|E|;Yamada|Yuta|Y|;Nakamura|Masaki|M|;Yamada|Daisuke|D|;Suzuki|Motofumi|M|;Murata|Takashi|T|;Kume|Haruki|H|",
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"fulltext": "\n==== Front\nBMC Urol\nBMC Urol\nBMC Urology\n1471-2490 BioMed Central London \n\n779\n10.1186/s12894-020-00779-z\nCase Report\nDermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation\nMinagawa Hideyuki 12 Kawai Taketo taketokawai@yahoo.co.jp 2 Matsumoto Akihiko 2 Makino Katsuhiro 12 Sato Yusuke 2 Nagasaka Kenji 3 Tokura Masami 3 Tanaka Nao 3 Ito Eisaku 4 Yamada Yuta 2 Nakamura Masaki 2 Yamada Daisuke 2 Suzuki Motofumi 2 Murata Takashi 1 Kume Haruki 2 1 grid.416773.00000 0004 1764 8671Department of Urology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042 Japan \n2 grid.26999.3d0000 0001 2151 536XDepartment of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655 Japan \n3 grid.416773.00000 0004 1764 8671Department of Rheumatology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042 Japan \n4 grid.416773.00000 0004 1764 8671Department of Pathology, Ome Municipal General Hospital, 4-16-5, Higashiome Ome, Ome, Tokyo, 1980042 Japan \n7 1 2021 \n7 1 2021 \n2021 \n21 825 5 2020 29 12 2020 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nAlthough it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.\n\nCase presentation\nA 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.\n\nConclusions\nWe successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.\n\nKeywords\nDermatomyositisProstate cancerNeuroendocrine differentiationDysphagiaGlucocorticoidADTEPDocetaxelAbirateroneEnzalutamideissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nApproximately 20% of all dermatomyositis cases are accompanied by malignancies [1–3]. Furthermore, among patients with dermatomyositis, those with malignancies have a poor prognosis [1, 2]. Although there are several reports of prostate cancer with dermatomyositis [1, 3, 4], we are aware of only one case of neuroendocrine prostate cancer with dermatomyositis [5], who responded poorly to treatment and died within 4 months after initiation of treatment. Here, we report a case of long-term survival of dermatomyositis with severe dysphagia which was associated with prostate adenocarcinoma with neuroendocrine differentiation.\n\nCase presentation\nA 63-year-old man visited our hospital complaining of frequent urination and hesitancy, which had worsened a year prior to the visit. He also complained of muscle weakness and pain in the upper arms. Blood tests revealed abnormally high PSA (147.7 ng/mL), NSE (60.9 ng/mL), and CK (647 IU/L) (Fig. 1). Prostate biopsy revealed adenocarcinoma with Gleason score 4 + 5 accompanied by neuroendocrine differentiation, which was positive for PSA, synaptophysin, and NCAM1/CD56 by immunohistochemistry (Fig. 2). Contrast-enhanced computed tomography (CT) revealed prostate cancer which showed invasion to the bladder, seminal vesicles, and rectum. Multiple metastases to the liver (Fig. 3a), pelvic lymph nodes, and bone were observed. The patient was diagnosed with prostate adenocarcinoma with neuroendocrine differentiation, cT4N1M1. At the time of diagnosis, the use of abiraterone and docetaxel for high-risk metastatic hormone-sensitive prostate cancer (HSPC) was not yet approved in medical insurance in Japan. Therefore, combined androgen blockade (CAB) therapy with surgical castration and bicalutamide was initiated as the most intense treatment available in Japan at that time for high-risk metastatic HSPC. Chemotherapy with etoposide and cisplatin (EP) was not performed at this time because pure adenocarcinoma components dominated, few with neuroendocrine differentiation in the prostate biopsy.Fig. 1 Temporal changes in PSA, NSE and CK. The treatments performed are indicated above the graph\n\nFig. 2 Immunohistochemical findings of prostate biopsy; hematoxylin and eosin (a, b), PSA (c, d), synaptophysin (e), and NCAM1/CD56 (f). Hematoxylin and eosin staining reveals adenocarcinoma with Gleason score 4 + 5 (a) and components of neuroendocrine differentiation (b). The components of typical adenocarcinoma (c) and neuroendocrine differentiation (d) are highly and weakly positive for PSA, respectively. The components of neuroendocrine differentiation are positive for synaptophysin (e) and NCAM1/CD56 (f). The bar indicates 100 μm\n\nFig. 3 CT findings of liver metastases before ADT (a), before EP therapy (b), and after 4 courses of EP therapy (c)\n\n\n\nTwo weeks later, dysphagia, edema of both upper limbs, and erythema on the skin were identified. Bicalutamide was discontinued and high-dose glucocorticoid therapy with methylprednisolone (mPSL) was initiated at a dose of 125 mg/day intravenously (IV) for the first 3 days, 80 mg/day IV for the next 3 days, and 40 mg/day IV for the next 3 days. At this time, the symptoms were suspected to be bicalutamide-induced adverse events. One week after the initiation of mPSL, dysphagia and erythema of the skin and muscle weakness of both arms did not improve. Physical examination revealed erythema on the back of the finger joints (Gottron’s sign) (Fig. 4a), from the shoulder to the upper back (shawl sign) (Fig. 4b) and around the neck (V-neck sign) (Fig. 4c), and edematous erythema on the bilateral eyelids (heliotrope rash) (Fig. 4d). Blood tests revealed abnormally high values of CK (1727 IU/L, Fig. 1), aldolase (14.5 U/L), and myoglobin (435.8 ng/mL). Anti-nuclear antibody was positive at titers of 1:640, anti-ARS antibody was negative, and anti-TIF1-γ antibody was positive. Based on these findings, the patient was diagnosed with malignancy-associated dermatomyositis. He was presented with dysphagia, which was severe and required temporary fasting and central parenteral nutrition. Glucocorticoid administration was changed from mPSL to prednisolone (PSL) at a dose of 60 mg/day IV.Fig. 4 Various skin symptoms observed in the patient. Erythema on the back of the finger joint (Gottron’s sign) (a), erythema from shoulder to upper back (shawl sign) (b), erythema around the neck (V-neck sign) (c), and edematous erythema on the bilateral eyelids (heliotrope rash) (d)\n\n\n\nFour weeks after the start of androgen deprivation therapy (ADT), CT showed residual multiple liver metastases (Fig. 3b), although PSA and NSE decreased to 7.0 ng/mL and 21.9 ng/mL, respectively (Fig. 1). Then, EP therapy (etoposide 100 mg/m2 and cisplatin 20 mg/m2, every 3 weeks) was commenced, resulting in a rapid decrease of PSA and NSE to < 1 ng/mL and < 13 ng/mL, respectively (Fig. 1). Two weeks after EP therapy started, swallowing function improved with a decrease in CK (Fig. 1) and oral intake became possible. PSL administration was gradually tapered to 5 mg/day.\n\nAfter 4 courses of EP therapy, CT showed marked reduction of the primary tumor and all metastases including those in the liver (Fig. 3c), but EP therapy was discontinued due to grade 3 malaise. Although the metastases had shrunk, they did not disappear, and we supposed that a small amount of cancer progression could lead to a relapse of dermatomyositis. The patient was therefore switched to docetaxel therapy (70 mg/m2, every 3 weeks). After 4 courses, docetaxel was also discontinued due to grade 3 malaise, and abiraterone acetate treatment was initiated. Abiraterone acetate treatment was ceased after one month because erythema on his face and extremities and serum CK level worsened (246 IU/L). Enzalutamide treatment and dose escalation of PSL to 30 mg/day were started, and dermatomyositis improved. PSA and NSE were consistently low, and no progressions were observed during the administration of docetaxel, abiraterone, and enzalutamide. At present, 31 months after the start of enzalutamide administration, no cancer progression has been observed. Dermatomyositis is in remission, and the patient is on PSL at 10 mg/day.\n\nDiscussion and conclusions\nIt is difficult to obtain a good therapeutic effect in patients with dermatomyositis complicated by malignant tumors, as long as the tumor is present; conversely, radical treatment of malignancy may improve muscle and skin symptoms. Therefore, treatment of malignancy is prioritized in order to improve dermatomyositis [3]. In the present case, dermatomyositis was improved by treatment for prostate cancer in addition to high-dose glucocorticoid therapy. ADT was initially performed to treat prostate cancer with neuroendocrine differentiation and the treatment had limited effects on dermatomyositis, and dysphagia became apparent. Although dermatomyositis tends to improve with high-dose glucocorticoid therapy, oral intake was possible after EP therapy was commenced. These findings suggest that EP therapy was required to address the component of neuroendocrine differentiation.\n\nPure neuroendocrine prostate cancer (including small cell carcinoma and large cell carcinoma) has a poor prognosis. However, it is controversial whether neuroendocrine differentiation in adenocarcinomas worsens the prognosis [6, 7]. In the present case, multiple liver metastases were observed from the first visit, suggesting that the cancer was aggressive. ADT was followed by EP therapy and other strong treatments with docetaxel, abiraterone, and enzalutamide before the onset of castration resistance. We believe that the ability to control aggressive cancers with these treatments may have led to an improvement in disease activity of dermatomyositis.\n\nIn conclusion, we encountered a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation. The patient was successfully treated with ADT and subsequent EP therapy for prostate cancer and high-dose glucocorticoid therapy for dermatomyositis.\n\nAbbreviations\nPSAProstate specific antigen\n\nNSENeuron specific enolase\n\nCKCreatinine kinase\n\nNCAM1Neural cell adhesion molecule 1\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nHM collected data and wrote the manuscripts. TK contributed to concept of this paper, interpreted the data, and prepared the manuscripts. AM, KM, and YS contributed to concept of this paper. KN, MT, and NT collected data regarding the dermatomyositis, and reviewed the manuscripts. EI performed the histological examination. YY, MN, DY, MS, TM, and HK reviewed the manuscripts. All authors read and approved the final manuscript.\n\nFunding\nNo funding.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article and available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis report was approved by the Ethics Committee at the Ome Municipal General Hospital (Approval number: 54). Informed consent to participate was obtained from the patient.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Motomura K Yamashita H Yamada S Takahashi Y Kaneko H Clinical characteristics and prognosis of polymyositis and dermatomyositis associated with malignancy: a 25-year retrospective study Rheumatol Int 2019 39 10 1733 1739 10.1007/s00296-019-04428-z 31444556 \n2. Liu Y Xu L Wu H Zhao N Tang Y Li X Liang Y Characteristics and predictors of malignancy in dermatomyositis: analysis of 239 patients from northern China Oncol Lett 2018 16 5 5960 5968 30344746 \n3. Zerdes I Tolia M Nikolaou M Tsoukalas N Velentza L Hajiioannou J Mitsis M Kyrgias G How can we effectively address the paraneoplastic dermatomyositis: diagnosis, risk factors and treatment options J BUON 2017 22 4 1073 1080 28952230 \n4. Yang Z Lin F Qin B Liang Y Zhong R Polymyositis/dermatomyositis and malignancy risk: a metaanalysis study J Rheumatol 2015 42 2 282 291 10.3899/jrheum.140566 25448790 \n5. Papagoras C Arelaki S Botis I Chrysafis I Giannopoulos S Skendros P Co-occurrence of dermatomyositis and polycythemia unveiling rare de novo neuroendocrine prostate tumor Front Oncol 2018 8 534 10.3389/fonc.2018.00534 30524963 \n6. Epstein JI Amin MB Beltran H Lotan TL Mosquera JM Reuter VE Robinson BD Troncoso P Rubin MA Proposed morphologic classification of prostate cancer with neuroendocrine differentiation Am J Surg Pathol 2014 38 6 756 767 10.1097/PAS.0000000000000208 24705311 \n7. Shariff AH Ather MH Neuroendocrine differentiation in prostate cancer Urology 2006 68 1 2 8 10.1016/j.urology.2006.02.002\n\n",
"fulltext_license": "CC BY",
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"issue": "21(1)",
"journal": "BMC urology",
"keywords": "ADT; Abiraterone; Dermatomyositis; Docetaxel; Dysphagia; EP; Enzalutamide; Glucocorticoid; Neuroendocrine differentiation; Prostate cancer",
"medline_ta": "BMC Urol",
"mesh_terms": "D000230:Adenocarcinoma; D003882:Dermatomyositis; D006801:Humans; D008297:Male; D008875:Middle Aged; D055099:Neuroendocrine Cells; D011471:Prostatic Neoplasms",
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"title": "Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.",
"title_normalized": "dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation"
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"abstract": "BACKGROUND\nCardiac sarcoidosis (CS) is an increasingly recognized cause of cardiomyopathy; however, data on immunosuppressive strategies are limited. Treatment with tumor necrosis factor (TNF) alpha inhibitors is not well described; moreover, there may be heart failure-related safety concerns.\n\n\nMETHODS\nRetrospective multicenter study of patients with CS treated with TNF alpha inhibitors. Baseline characteristics, treatments, and outcomes were adjudicated.\n\n\nRESULTS\nThirty-eight patients with CS (mean age 49.9 years, 42% women, 53% African American) were treated with TNF alpha inhibitor (30 infliximab, 8 adalimumab). Prednisone dose decreased from time of TNF alpha inhibitor initiation (21.7 ± 17.5 mg) to 6 months (10.4 ± 6.1 mg, P = .001) and 12 months (7.3 ± 7.3 mg, P = .002) after treatment. On pre-TNF alpha inhibitor treatment positron emission tomography with 18-flourodoxyglucose (FDG-PET), 84% of patients had cardiac FDG uptake. After treatment, there was a significant decrease in number of segments involved (3.5 ± 3.8 to 1.0 ± 2.5, P = .008) and maximum standardized uptake value (3.59 ± 3.70 to 0.57 ± 1.60, P = .0005), with 73% of patients demonstrating complete resolution or improvement of cardiac FDG uptake. The left ventricular ejection fraction remained stable (45.0 ± 16.5% to 47.0 ± 15.0%, P = .10). Four patients required inpatient heart failure treatment, and 8 had infections; 2 required treatment cessation.\n\n\nCONCLUSIONS\nTNF alpha inhibitor treatment guided by FDG-PET imaging may minimize corticosteroid use and effectively reduce cardiac inflammation without significant adverse effect on cardiac function. However, infections were common, some of which were serious, and therefore patients require close monitoring for both infection and cardiac symptoms.",
"affiliations": "Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: naggarw2@jhmi.edu.;Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Divison of Rheumatology, Medstar Washington Hospital Center, Washington, DC.;Medstar Heart and Vascular Institute, Washington, DC.;Johns Hopkins University School of Nursing, Baltimore, Maryland.;Medstar Heart and Vascular Institute, Washington, DC.;Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiology, Medstar Washington Hospital Center, Washington, DC.;Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Divison of Rheumatology, Medstar Washington Hospital Center, Washington, DC.;Medstar Heart and Vascular Institute, Washington, DC.;Division of Cardiology, Columbia University School of Medicine, New York, New York.;Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Medstar Heart and Vascular Institute, Washington, DC.",
"authors": "Gilotra|Nisha A|NA|;Wand|Alison L|AL|;Pillarisetty|Anjani|A|;Devraj|Mithun|M|;Pavlovic|Noelle|N|;Ahmed|Sara|S|;Saad|Elie|E|;Solnes|Lilja|L|;Garcia|Carlos|C|;Okada|David R|DR|;Constantinescu|Florina|F|;Mohammed|Selma F|SF|;Griffin|Jan M|JM|;Kasper|Edward K|EK|;Chen|Edward S|ES|;Sheikh|Farooq H|FH|",
"chemical_list": "D019275:Radiopharmaceuticals; D014409:Tumor Necrosis Factor-alpha; D019788:Fluorodeoxyglucose F18",
"country": "United States",
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"doi": "10.1016/j.cardfail.2020.08.013",
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"issn_linking": "1071-9164",
"issue": "27(1)",
"journal": "Journal of cardiac failure",
"keywords": "Sarcoidosis; arrhythmia; cytokine; heart failure; inflammation",
"medline_ta": "J Card Fail",
"mesh_terms": "D009202:Cardiomyopathies; D005260:Female; D019788:Fluorodeoxyglucose F18; D006333:Heart Failure; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012189:Retrospective Studies; D012507:Sarcoidosis; D013318:Stroke Volume; D014409:Tumor Necrosis Factor-alpha; D016277:Ventricular Function, Left",
"nlm_unique_id": "9442138",
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"pages": "83-91",
"pmc": null,
"pmid": "32889044",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "16840744;2647299;7540941;27924643;31538835;2299255;15023878;29482029;27813028;26428728;11354550;12672326;27614001;27400984;3799813;27886616;28109920;16157536;26847095;30825644;16705109;29030454;28765228;31806154;31954655;25527698;18256069;24819193;12796126;31233331;24751450;2195340;30446173;31500815;23623644;30378224;24140661;19884472;27215507",
"title": "Clinical and Imaging Response to Tumor Necrosis Factor Alpha Inhibitors in Treatment of Cardiac Sarcoidosis: A Multicenter Experience.",
"title_normalized": "clinical and imaging response to tumor necrosis factor alpha inhibitors in treatment of cardiac sarcoidosis a multicenter experience"
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"companynumb": "US-CELLTRION INC.-2021US003739",
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"abstract": "Surgical correction of hyperparathyroidism after kidney transplantation has been associated with significant graft function decline. We examined the effects of parathyroidectomy on short- and long-term graft function and its potential predictors.\n\n\n\nFor this retrospective, monocentric study we identified 48 (5.5%) out of 892 patients from our protocol biopsy program who received renal transplantation between 2000 and 2007, with parathyroidectomy after transplantation. Data from up to three years after parathyroidectomy was collected and analyzed with multivariable linear regression analyses.\n\n\n\nMain indications for parathyroidectomy were hypercalcemia and graft calcifications. Parathyroidectomy was successful in 47 patients, with a median drop in serum intact parathormone (iPTH) from 394 to 21 pg/ml. Mean estimated glomerular fitration rate (eGFR) before parathyroidectomy was 60 ± 26 ml/min. At three months after parathyroidectomy, the eGFR was 46 ± 18 ml/min (p < 0.001) but remained stable at one and three years (50 ± 20; 49 ± 20 ml/min). The median annual eGFR change was - 0.5 ml/min before and + 1.0 ml/min after parathyroidectomy. Multivariable modeling identified high iPTH levels and higher eGFR before parathyroidectomy as predictors of the eGFR drop after parathyroidectomy. Lower graft function twelve months after parathyroidectomy was predicted by the eGFR before and the iPTH drop after surgery.\n\n\n\nThese results indicate that the extent of parathyroidectomy is critical and too much lowering of iPTH should be avoided by timely parathyroidectomy, before reaching extreme high iPTH values. In view of the observed loss of eGFR, parathyroidectomy can be considered safe in patients with an eGFR above 30 ml/min.",
"affiliations": "Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Straße 1, 30635, Hannover, Germany. patecki.margret@mh-hannover.de.;Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Straße 1, 30635, Hannover, Germany.;Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Straße 1, 30635, Hannover, Germany.;Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Straße 1, 30635, Hannover, Germany.",
"authors": "Patecki|Margret|M|0000-0002-1421-3432;Scheffner|Irina|I|;Haller|Hermann|H|;Gwinner|Wilfried|W|",
"chemical_list": "D010281:Parathyroid Hormone; D002118:Calcium",
"country": "England",
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"doi": "10.1186/s12882-020-01723-x",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 172310.1186/s12882-020-01723-xResearch ArticleLong-term renal graft outcome after parathyroidectomy - a retrospective single centre study http://orcid.org/0000-0002-1421-3432Patecki Margret patecki.margret@mh-hannover.de Scheffner Irina Haller Hermann Gwinner Wilfried grid.10423.340000 0000 9529 9877Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Straße 1, 30635 Hannover, Germany 18 2 2020 18 2 2020 2020 21 5320 10 2019 11 2 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\nSurgical correction of hyperparathyroidism after kidney transplantation has been associated with significant graft function decline. We examined the effects of parathyroidectomy on short- and long-term graft function and its potential predictors.\n\nMethods\nFor this retrospective, monocentric study we identified 48 (5.5%) out of 892 patients from our protocol biopsy program who received renal transplantation between 2000 and 2007, with parathyroidectomy after transplantation. Data from up to three years after parathyroidectomy was collected and analyzed with multivariable linear regression analyses.\n\nResults\nMain indications for parathyroidectomy were hypercalcemia and graft calcifications. Parathyroidectomy was successful in 47 patients, with a median drop in serum intact parathormone (iPTH) from 394 to 21 pg/ml. Mean estimated glomerular fitration rate (eGFR) before parathyroidectomy was 60 ± 26 ml/min. At three months after parathyroidectomy, the eGFR was 46 ± 18 ml/min (p < 0.001) but remained stable at one and three years (50 ± 20; 49 ± 20 ml/min). The median annual eGFR change was − 0.5 ml/min before and + 1.0 ml/min after parathyroidectomy.\n\nMultivariable modeling identified high iPTH levels and higher eGFR before parathyroidectomy as predictors of the eGFR drop after parathyroidectomy. Lower graft function twelve months after parathyroidectomy was predicted by the eGFR before and the iPTH drop after surgery.\n\nConclusions\nThese results indicate that the extent of parathyroidectomy is critical and too much lowering of iPTH should be avoided by timely parathyroidectomy, before reaching extreme high iPTH values. In view of the observed loss of eGFR, parathyroidectomy can be considered safe in patients with an eGFR above 30 ml/min.\n\nKeywords\nRenal transplantationParathyroidectomyHyperparathyroidismHypercalcemiaKidney functionissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPersisting or even worsening hyperparathyroidism after kidney transplantation affects between 17 and 50% [1–5] of the transplant population and can lead to worsening graft function, bone disease and extraskeletal calcifications [1, 6–10]. Despite its off-label character, calcimimetics are increasingly used in this condition to control serum calcium and parathormone levels [11]. Nevertheless, the long-term consequences on bone metabolism are unknown [12, 13] and side effects or lacking efficacy are frequent problems. These patients may benefit from parathyroidectomy which is reported with rates of about 5% in the transplant population, thus avoiding the above mentioned complications [1, 7, 14].\n\nPrevious studies have reported differing results of parathyroidectomy after kidney transplantation. Although regarded as an efficient treatment, concerns have been raised that parathyroidectomy adversely affects the graft. In the retrospective study of Schwarz et al. a decrease in creatinine clearance by 10% was reported, without relevant recovery during a 12-month follow-up [15]. Evenepoel et al. also reported an increase in serum creatinine by 16% in the first 6 months after parathyroidectomy, with partial reversal and stabilization of graft function in the long term over 4 years [16]. In another study, patients with parathyroidectomy had 6-year graft survival of less than 15%, whereas patients without had a graft survival of approximately 70%. However, in the multivariable analysis, parathyroidectomy was not a significant factor [17].\n\nCurrently, it is not possible to predict which patient will suffer from a temporary or persistent decline in graft function after parathyroidectomy. To this end, (i) a greater iPTH drop (ii) lower serum calcium, (iii) and requirement for more intense substitution with calcium and vitamin D analogues for hypocalcemia after parathyroidectomy, (iv) lower baseline creatinine before parathyroidectomy, (v) and the time interval between parathyroidectomy and transplantation have been inconsistently reported as potential factors of a declining renal function after parathyroidectomy [3, 15, 18, 19]. Furthermore, the effects of different extents of parathyroid tissue resection on the graft function are still under discussion [15, 19, 20].\n\nAims of this study were to examine the effect of parathyroidectomy on the graft function and to explore potential determinants of the loss of transplant function and recovery in a well-documented patient cohort with protocol biopsies and long-term follow-up.\n\nMethods\nPatients\nIn this retrospective study, adult patients were included who received a kidney transplant alone or in combination with another solid organ at Hannover Medical School between 2000 and 2007 and who participated in our protocol biopsy program. Protocol biopsies were performed 6 weeks, 3 and 6 months after transplantation. Data were collected prior to and at the time of transplantation, at the time points of protocol biopsies and any additional biopsies, and in yearly intervals after transplantation. For patients who were followed-up elsewhere, data were retrieved by contacting their local caregivers. Data collection and analysis was performed with informed consent of the patients and with approval of the ethic board (no 2765) of the Hannover Medical School.\n\nMethods\nRenal function was assessed by the estimated glomerular filtration rate using the Cockcroft&Gault formula. All parathormone levels were analyzed as intact PTH (normal limits: 10–65 pg/mL; Advia Centauer System, Siemens Corp., Germany). Serum calcium and phosphate levels were determined by an autoanalyzer of the hospital’s laboratory (normal ranges: 2.15–2.60 mmol/L; 0.73–1.35 mmol/L, respectively), without correcting serum calcium for albumin concentrations. Delayed graft function was defined as urine output of less than 500 ml in the first 24 h after transplantation and/or need of dialysis because of graft dysfunction within the first week after transplantation. Biopsies were evaluated according to the Banff classification. Besides routine stainings, von Kossa stain was performed on those cases which had tubular or interstitial crystalloid deposits [21]. Calcifications were roughly characterized as ‘mild’ with up to 2 foci of crystalloid deposits per microscopic section of the biopsy at 200fold magnification and ‘severe’ with > 2 foci. There was no specific medical treatment for calcification. Rejections were treated as reported elsewhere in detail [22].\n\nStatistical analysis\nThe IBM SPSS statistical software package version 24 was used for statistical analysis. Continuous variables with normal distribution are given as means±SD, data without normal distribution as medians. Continuous data were compared with the Kruskal-Wallis and Mann-Whitney test. The Spearman rank test was used for correlation analyses. Kaplan–Meier analysis and the log-rank test were used to compare graft survival of patients with and without parathyroidectomy. Multivariable linear regression analyses were performed to assess the effect of clinical and laboratory factors on eGFR, using backward selection and a cutoff p value of < 0.05. Alternative models using forward selection or no variable selection were tested in comparison. Variables chosen for the multivariable modeling were selected from Table 2, using a cutoff p value of < 0.15, but excluding variables with redundant information (such as serial eGFR measurements) or variables with clear causality secondary to another, significant variable (e.g. low serum phosphate caused by parathormone). Further, the large list of candidate variables shown in Table 2 and Additional file 1 was thoroughly examined for variables with potential bearing on parathyroidectomy associated adverse effects on graft, even without showing a p value of < 0.15. Statistical significance was assumed for p < 0.05.\n\nResults\nIn a cohort of 892 patients in our database who were transplanted between 2000 and 2007, 48 patients (5.4%; n = 23 female, n = 25 male) were identified with parathyroidectomy after kidney transplantation. Pretransplant and perioperative data of these patients are depicted in Table 1. Five patients had their second kidney transplantation. Three patients received combined pancreas and kidney transplantation. Delayed graft function occurred in 14 patients (29%). 40 patients (83%) received a graft from a deceased donor. Low parathormone levels in the year before transplantation, defined as parathormone levels below 2.5 times above the upper normal value were observed in only three patients. The highest eGFR within the first 6 months after transplantation was 67 ± 25 ml/min. Five patients were on therapy with cinacalcet, seven patients were treated with bisphosphonates, and one patient with calcitonin directly before parathyroidectomy.\nTable 1 Description of patients\n\nAge (mean ± SD)\t47.7 ± 11.4\t\nGender (male/female)\t25 / 23 (52.1 / 47.9)\t\nRenal replacement therapy before transplantation hemodialysis / peritoneal dialysis\t44 / 4 (91.7 / 8.3)\t\nTime on dialysis (months; mean ± SD)\t78.7 ± 32.8\t\nBody mass index at transplantation (mean ± SD)\t24.2 ± 3.7\t\nTransplantation data\t\n Donor serum creatinine (μmol/l; mean ± SD)\t80.1 ± 36.5\t\n Donor age (mean ± SD)\t45 ± 17\t\n Donor gender (male; female)\t20 (43)/ 27 (57)\t\n Heterogeneous / homogeneous donor/recipient gender (female donor / male donor)\t20 (13 / 7) / 26 (15 / 11)\t\n Second or third kidney transplantation\t5 (10.4)\t\n Additional pancreas transplantation\t3 (6.3)\t\n Living donor transplantation\t8 (16.7)\t\n Eurotransplant Senior Program\t1 (2)\t\n Pre-formed antibodies > 0%\t3 (6)\t\n Mean number of HLA mismatches (A/B/DR)\t2.21 ± 1.3\t\n Cold ischemic time (hours; mean ± SD)\t16.3 ± 9.5\t\n Delayed graft function\t14 (29.2)\t\n CMV IgG positive recipient\t26 (55)\t\n Donor CMV IgG positive\t25 (53)\t\nImmunosuppressive therapy\t\n Induction therapy: IL-2 AB / ATG / none / unknown\t38 / 3 / 6 / 1\n\n(79.2 / 6.3 / 12.5 / 2.1)\n\n\t\n Ciclosporin A\t35 (72.9)\t\n Tacrolimus\t9 (18.8)\t\n Mycophenolate mofetil\t30 (62.5)\t\n Rapamycin\t4 (8.3)\t\n Steroids\t46 (95.8)\t\nMain reason for ESRF\t\n Unknown\t17 (35.4)\t\n Glomerulonephritis\t15 (31.3)\t\n Tubulointerstitial disease\t4 (8.3)\t\n Hypertensive or diabetic nephropathy\t3 (6.3)\t\n Congenital disease\t8 (16.7)\t\n Other\t1 (2.1)\t\nComorbidities before or at transplantation\t\n Heart failure\t1 (2)\t\n Hypertension\t46 (95.8)\t\n Peripheral arterial disease\t5 (10.4)\t\n Coronary heart disease\t4 (8.3)\t\n Stroke\t1 (2.1)\t\n Hepatitis C\t2 (4.2)\t\n Diabetes type I / II\t4 (8.3) / 1 (2.1)\t\n Hypercholesterolemia\t20 (41.7)\t\n Smoking still present / given up / never / unknown\t4 / 11 / 25 / 8\n\n(8.3 / 22.9 / 52.1 / 16.7)\n\n\t\n Pregnancies before actual transplantation\t19 (40)\t\n Blood transfusions before transplantation\t14 (30)\t\nProportions are depicted as number of patients, with percentages in brackets\n\nATG Anti-thymocyte globulin, CMV Cytomegalovirus, ESRF End stage renal failure, HLA human leukocyte antigen, IL-2 AB Interleukin-2 antibodies, SD Standard deviation\n\n\n\nParathyroidectomy was intended as subtotal resection in 14 cases, as total resection with auto-transplantation in 28 cases, and as total resection without auto-transplantation in 4 cases; in 2 patients further information was not available. Five patients had recurrent hyperparathyroidism after parathyroidectomy performed before transplantation. In one patient, two parathyreoidectomies after transplantation were necessary. The median time between transplantation and parathyroidectomy was 19.5 months (range: 4–80 months), with 15 patients receiving the parathyroidectomy within the first year, 17 patients within the second year, and 15 patients after the second year post-transplantation. Main indication for parathyroidectomy was repeated hypercalcemia due to hyperparathyroidism not responsive to medical management (n = 34; 71%). Calcification in the renal graft (in one or more preceding biopsies) in the presence of high serum calcium and/or elevated parathormone levels was another reason for parathyroidectomy in 31 (65%) patients. Calcification was observed as single finding in one biopsy in 14 patients, in two biopsies in 14 patients and in 3 biopsies in 3 patients. 19 cases had mild calcification and 8 severe calcifications and four were without grading.\n\nThe post-transplant course of parathormone and serum calcium values is shown in Figs. 1 and 2. At 6 weeks, the median iPTH was 296 pg/ml (range: 57–1028 pg/ml) and 385 pg/ml (range: 31–1780 pg/ml) at 6 months. Mean serum calcium levels at 6 weeks after transplantation were 2.53 ± 0.21 mmol/l (normal range: 2.15–2.6 mmol/l) and 2.65 ± 0.17 mmol/l at 6 months. Mean serum phosphate levels were 0.63 ± 0.29 (normal range: 0.73–1.35 mmol/l) and 0.94 ± 0.27 mmol/l at 6 weeks and 6 months post-transplantation, respectively (not shown). Directly before parathyroidectomy, median iPTH was 394 pg/ml (range: 71–1699 pg/ml), mean serum calcium 2.63 ± 0.20 mmol/l, and phosphate 0.89 ± 0.26 mmol/l. One patient had hypocalcemia due to a high dose of cinacalcet at this time. iPTH values showed a weak inverse correlation with serum calcium (r = − 0.36; p < 0.05) at this time. This correlation was not observed at 6 weeks and 6 months posttransplantation (Fig. 3). Serum phosphate correlated with iPTH levels, with r = − 0.33 at 6 weeks and r = − 0.32 at 6 months (p < 0.05) (not shown).\nFig. 1 Intact parathormone levels before and after parathyroidectomy. Blue lines represent individual values; the red line represents the median course of all patients. iPTH; intact parathormone\n\nFig. 2 Serum calcium before and after parathyroidectomy. Green lines represent individual values; the red line represents the mean\n\nFig. 3 Correlation between parathormone levels and serum calcium before and after parathyroidectomy. Note different scales for iPTH values pre- and post-parathyroidectomy. iPTH; intact parathormone\n\n\n\nAt 3 months after parathyroidectomy, iPTH values had dropped in all patients, showing a median of 21 pg/ml (range: 1–467 pg/ml) (Fig. 1). For three patients there were no iPTH values available at 3 months after parathyroidectomy. In twenty-three patients (48%) iPTH values were in the normal range of 10–65 pg/ml, in eleven patients (23%) below the lower normal, and eleven patients (23%) had iPTH values between the upper normal and 300 pg/ml. One year after parathyroidectomy, median iPTH was 24 pg/ml (range: 1–245 pg/ml) and mean serum calcium was 2.23 ± 0.26 mmol/l. Calcium and parathormone levels were moderately correlated after parathyroidectomy (Fig. 3). Serum calcium fell in most patients, with an average of 2.29 ± 0.27 mmol/l at 3 months after parathyroidectomy (Fig. 2), and phosphate rose to 1.16 ± 0.35 mmol/l. Hypercalcemia above 2.6 mmol/l was present in only 3 patients (6.3%). Hypocalcemia below 2.15 mmol/l occurred in eleven patients (23%). At one year after parathyroidectomy, 16 patients had calcium supplements, 37 patients had calcitriol or calcidiol and 2 patients colecalciferol to maintain calcium homeostasis. None of the patients received cinacalcet.\n\nThe changes in estimated eGFR are shown in Fig. 4. Directly before parathyroidectomy the mean eGFR was 60 ± 26 ml/min. Within the first 3 months, the eGFR dropped to 46 ± 18 ml/min (p < 0.001) but remained stable at one and three years after parathyroidectomy (50 ± 20; 49 ± 20 ml/min) (Fig. 4). There were no graft losses during follow-up of three years after parathyroidectomy. The median annual eGFR change was − 0.5 ml/min before and + 1.0 ml/min in the time interval between parathyroidectomy and the following 3 years. For comparison, overall 15-year death-censored graft survival and eGFR decline were similar to that of the 844 patients who had not undergone parathyroidectomy (cumulative survival of 76 vs. 71%, p = 0.356; median annual loss of eGFR of − 2.47 vs. -2.05 ml/min, p = 0.877; for patients with and without parathyroidectomy).\nFig. 4 eGFR before and up to 3 years after parathyroidectomy. Black lines represent individual eGFR values, the red line the mean eGFR. eGFR estimated glomerular filtration rate\n\n\n\nIn a comprehensive analysis, several pre-, peri-, and posttransplant variables were explored for possible relationship with the graft function at 3 months and 12 months after parathyroidectomy. In univariable analyses (Table 2) the time interval between transplantation and parathyroidectomy and the serum calcium concentration before parathyroidectomy were not correlated with the eGFR loss (p = 0.183; p = 0.200). Younger age and higher body weight were weakly associated with a greater loss of eGFR (p = 0.055 and p = 0.065 respectively). Male patients had a greater loss of eGFR (p = 0.002). Calcification of the renal graft tissue was not linked with a greater loss of eGFR after parathyroidectomy (− 16.45 ml/min compared with − 8.8 ml/min in patients without calcifications, p = 0.461). Also, severity and frequency of calcification findings were not associated with the loss of eGFR (p = 0.266 and 0.589 respectively). Interestingly, we also did not observe an association of the frequency or severity of calcification findings with interstitial fibrosis and tubular atrophy or with arteriolar hyalinosis (p < 0.539 and p < 0.821). Multivariable analysis identified higher eGFR and iPTH values directly before parathyroidectomy as predictors of a greater loss of eGFR at 3 months after parathyroidectomy (R = 0.625) (Table 3a). Alternative models without variable selection or with less stringent cutoffs for selection had lower or not relevantly higher R values and showed no changes in the ß-coefficient of the significant variables (not shown). Variables that were not significant in univariate analyses and not considered in the different multivariable models were shown in an additional file (see Additional file 1).\nTable 2 Correlation of the GFR-change with pretransplant, peri- and posttransplant clinical factors which were considered as candidate variables in the multivariable modeling\n\n\teGFR change at 3 months post para-thyroidectomy\tP value\teGFR change at 12 months post para-thyroidectomy\tP value\t\nRecipient at transplantation\t\n Age\t0.281\t0.055\t0.153\t0.303\t\n Gender (male/female)\t−19.40; −8.22\t0.002\t12.93; −6.83\t0.053\t\n Hyperparathyroidism before transplantation, yes; no\t−14.10; −21,54\t0.414\t−10.59; −13.93\t0.414\t\n Parathyroidectomy before transplantation, yes; no\t−16.87; −11.29\t0.568\t−14.78; −9.88\t0.158\t\n Time on dialysis before transplantation\t−0.078\t0.603\t− 0.195\t0.189\t\n Re-transplanted patients, 2nd or 3rd transplantation; 1st transplantation\t−20.34; − 11.68\t0.372\t−13.93; − 10.23\t0.535\t\n Body weight at transplantation\t−0.277\t0.065\t−0.265\t0.078\t\n Body mass index at transplantation\t−0.146\t0.340\t−0.239\t0.114\t\nEarly post-transplantation course\t\n Delayed graft function, yes; no\t−12.42; −16;57\t0.924\t−10.23; −11.76\t0.505\t\n Best eGFR in the first 6 weeks post- transplantation\t−0.542\t< 0.001\t−0.239\t0.055\t\nPost-transplant-related factors\t\n Last serum calcium before parathyroidectomy\t0.190\t0.200\t0.290\t0.048\t\n Mean serum calcium within the first 6 months after transplantation\t0.143\t0.338\t0.220\t0.137\t\n Last serum phosphate before parathyroidectomy\t−0.034\t0.832\t−0.132\t0.412\t\n Mean serum phosphate within the first 6 months after transplantation\t0.031\t0.836\t−0.115\t0.441\t\n Last iPTH before parathyroidectomy\t−0.226\t0.127\t−0.409\t0.004\t\n Mean iPTH within the first 6 months after transplantation\t−0.146\t0.328\t−0.278\t0.058\t\n iPTH change after parathyroidectomy\t0.199\t0.190\t0.374\t0.011\t\n Months between transplantation and parathyroidectomy\t0.198\t0.183\t0.193\t0.194\t\n eGFR 6 weeks after transplantation\t−0.464\t0.001\t− 0.207\t0.162\t\n eGFR 3 months after transplantation\t−0.524\t< 0.001\t− 0.227\t0.124\t\n eGFR 6 months after transplantation\t− 0.373\t0.010\t−0.129\t0.386\t\n eGFR 3 months before parathyroidectomy\t−0.501\t< 0.001\t−0.361\t0.013\t\n Last eGFR before parathyroidectomy\t−0.500\t< 0.001\t−0.398\t0.006\t\n eGFR change before parathyroidectomy\t−0.050\t0.741\t−0.159\t0.285\t\n Nephrocalcinosis at biopsy, yes; no\t−16.45; −8.8\t0.461\t−11.5; −7.9\t0.242\t\n Rejections until parathyroidectomy yes; no\t−14.2; −10.5\t0.749\t−7.7; − 11.3\t0.701\t\nThe change in eGFR 3 months and 12 months after parathyroidectomy was calculated individually for each patient as the difference between the post-parathyroidectomy value and the eGFR before parathyroidectomy, with negative values representing a loss of eGFR. PTH change: decrease in iPTH is defined as negative value. Shown are r values for continuous factors and grouped medians for categorical variables. eGFR estimated glomerular filtration rate, iPTH intact parathormone\n\nTable 3 Factors predictive of eGFR loss at 3 (A) and 12 (B) months after parathyroidectomy\n\n(A) Model for eGFR loss at 3 months\n\nOverall fit: R = 0.625\n\n\tUnivariable linear regression\tMultivariable linear backward stepwise regression\t\n\tß\tCI 95%\tp value\tß\tCI 95%\tp value\t\nAge at transplantation (years)\t0.305\t0.038 0.573\t0.026\t\t\t\t\nFemale gender\t10.046\t4.460 15.632\t0.001\t\t\t\t\nBody weight at transplantation (kg)\t−0.205\t−0.419 0.009\t0.060\t\t\t\t\nLast iPTH before parathyroidectomy (pg/ml)\t−0.005\t−0.013 0.002\t0.165\t−0.006\t− 0,012 0.000\t0.043\t\nTime between parathyroidectomy and transplantation (months)\t0.114\t−0.094 0.321\t0.275\t\t\t\t\nLast eGFR before parathyroidectomy (ml/min)\t−0.280\t−0.399 -0.160\t0.000\t−0.288\t− 0.404 0.172\t0.000\t\n(B) Model for eGFR loss at 12 months\n\nOverall fit: R = 0.545\n\n\tUnivariable linear regression\tMultivariable linear backward stepwise regression\t\nß\tCI 95%\tp value\tß\tCI 95%\tp value\t\nFemale gender\t4.866\t−0.556 10.288\t0.077\t\t\t\t\nBody weight at transplantation (kg)\t−0.163\t−0.354 0.027\t0.092\t\t\t\t\nParathyroidectomy before transplantation\t−5.522\t−15.444 4.400\t0.268\t\t\t\t\nLast iPTH before parathyroidectomy (pg/ml)\t−0.008\t−0.014 -0.002\t0.016\t\t\t\t\niPTH change after parathyroidectomy (pg/ml)\t0.007\t0.000 0.014\t0.043\t0.009\t0.002 0.015\t0.008\t\nLast serum calcium before parathyroidectomy (mmol/l)\t12.473\t−1.336 26.282\t0.076\t\t\t\t\nLast eGFR before parathyroidectomy (ml/min)\t−0.178\t−0.296 -0.060\t0.004\t−0.193\t−0.304 -0.082\t0.001\t\nThe change in eGFR after parathyroidectomy was calculated individually for each patient as the difference between the post-parathyroidectomy value and the eGFR before parathyroidectomy, with negative values representing a loss of eGFR\n\nThe overall fit of the models is given in the left upper column head\n\niPTH change: decrease in iPTH is defined as negative value\n\nCI Confidence interval, eGFR estimated glomerular filtration rate, iPTH intact parathormone\n\n\n\nRecovery from the observed loss in graft function determines the longterm outcome. Therefore, we examined factors which determine the lower graft function one year after parathyroidectomy. In univariable analyses (Table 2), most factors were comparable with the 3 months results, including male gender (p = 0.053), body weight (p = 0.078), iPTH and eGFR before parathyroidectomy (p = 0.004 and p = 0.006, respectively). In addition, the decrease of iPTH after parathyroidectomy was a significant factor (p = 0.011). The multivariable analysis (Table 3b) identified higher eGFR before and greater iPTH drop after parathyroidectomy as a predictor of a greater loss in eGFR at 12 months (R = 0.545). Similarly, as described above alternative models did not show improved prediction of eGFR.\n\nDiscussion\nPersistent Hyperparathyroidism is frequent after kidney transplantation, with approximately 17–50%, mostly occurring as tertiary hyperparathyroidism [1–5]. Tertiary hyperparathyroidism represents a relevant clinical problem due to adverse effects of hypercalcemia in terms of extraosseous calcification and worsening of graft function [1, 6–10]. In this study, the main indications for parathyroidectomy were hypercalcemia which was present in 34 of 48 patients (71%) and calcification of the renal graft (n = 31). Parathyroidectomy was successful in the majority of patients. Only one patient had to undergo re-parathyroidectomy and 3 patients had serum calcium levels above the upper normal value after surgery.\n\nThe adverse short-term effect of parathyroidectomy on renal graft function is well-known [15, 16, 19]. We were interested in the longterm graft function of patients with parathyroidectomy and the factors that determine this outcome.\n\nRenal graft function in the whole group of patients appeared to be relatively stable before parathyroidectomy with an eGFR slope of − 0.5 ml/min*year. This loss is less than reported in studies that analyzed graft function over longer follow-up periods after transplantation, with an annual GFR decline of 1.1–1.7 ml/min [23, 24]. However, most patients were in an early period after transplantation in which gain of graft function is usually observed within the first year (unpublished data). Also, parathormone has been suggested as a driver of glomerular filtration [25–29] which may have obscured a decline in GFR. After parathyroidectomy, a uniform and significant decrease in eGFR by 25% was observed. This loss of eGFR is greater than reported in other studies showing a 10% decline in eGFR [16, 19]. The course of renal function after the initial loss of eGFR is unknown. Our study clearly shows that renal graft function stabilizes in patients with parathyroidectomy. Over the course of three years, the median eGFR was comparable with the eGFR three months after parathyroidectomy. Moreover, individual calculation of the eGFR slope before and after surgery showed that the eGFR slope changed to positive values after parathyroidectomy, with an average increase of 1.0 ml/min*year, which could reflect an improvement or recovery after correction of hyperparathyroidism. Yet, because of the substantial initial drop of eGFR, complete recovery of renal function to pre-parathyroidectomy eGFR values was not observed. Despite this incomplete recovery, graft survival and annual eGFR loss over the entire course of 15 years after transplantation was comparable with patients who had no parathyroidectomy after transplantation. Subanalysis of patients with renal graft calcification showed that there is no difference in the initial drop in eGFR after parathyroidectomy and the further course of graft function compared with patients without graft calcification. Due to the lack of systematic re-biopsies we were not able to determine whether calcifications decrease after normalization of the calcium-phosphate metabolism. Also, no systematic study was possible by biopsies performed after parathyroidectomy to associate the functional impairment with histomorphological changes.\n\nPre-parathyroidectomy parathormone concentration, glomerular filtration rate, serum calcium levels and the time between transplantation and parathyroidectomy have been proposed as important influencing factors for the eGFR loss after parathyroidectomy. We used the comprehensive documentation of clinical, laboratory and biopsy data of this patient cohort to explore if further factors determine the magnitude of eGFR loss after parathyroidectomy. Our univariable analyses largely confirmed the reported associations and identified only gender as an additional factor. The time point of parathyroidectomy was not a relevant factor in the present time range of 4–80 months posttransplantation. The small number of patients precluded establishing separate models for predicting the eGFR loss in subgroups with different time periods between parathyroidectomy and transplantation. However, univariate sensitivity analyses showed that patients with parathyroidectomy beyond the second year after transplantation had a lower eGFR before parathyroidectomy and a smaller loss of eGFR after parathyroidectomy, compatible with our multivariable model (not shown). Further, neither the univariate analysis (Table 2) nor the multivariable modeling (Table 3) identified the timing of parathyroidectomy as a significant factor. Therefore, parathyroidectomy may be decided at any time when conservative therapy fails and thus an indication for surgical therapy is present. Linear regression analysis showed that the loss in eGFR is significantly determined by the renal graft function and the serum parathormone concentration immediately before parathyroidectomy. The outcome at one year was best predicted by the eGFR before parathyroidectomy and the drop in parathormone by the surgery.\n\nWe recognize the limitations of our study which is retrospective and cannot prove causality of the observed associations. Results may not directly applicable to transplant settings in other centers and not to all patients with potential indication for parathyroidectomy as our study included only forty-eight patients.\n\nConclusions\nSeveral conclusions can be drawn from our results. First, because the average eGFR loss was 14 ml/min, indication for parathyroidectomy can be considered safe only in patients with an eGFR above 30 ml/min because otherwise, expected eGFR after parathyroidectomy will be in the range of stage V of chronic kidney disease. This is important because renal function is a highly significant factor of patient and graft survival [22, 30]. Second, as the magnitude of iPTH elevation before parathyroidectomy and the drop in iPTH values after parathyroidectomy are major determinants of the loss in eGFR, timely parathyroidectomy –before reaching extreme high iPTH values– may be beneficial, thus avoiding the adverse effect of a steep drop in iPTH. Also important in this line, an appropriate extend of parathyroidectomy could help to avoid a steep drop in iPTH after surgery. In our patient group, 23% of patients experienced hypocalcemia and 23% had serum parathormone concentrations below the lower normal limit, implicating that a substantial proportion probably had an inordinate removal of parathyroid tissue. This point is also highlighted by the fact that one third of patients required calcium supplementation one year after parathyroidectomy and 77% were treated with vitamin D compounds. Intraoperative iPTH monitoring could help to avoid an excessive parathyroid tissue removal that can lead to too low iPTH levels after surgery [31].\n\nIt should be noted that current guidelines do not give specific recommendations regarding target iPTH values after parathyroidectomy, the extent of parathyroid tissue removal and its timing after kidney transplantation [32–34]. For patients with chronic kidney disease of all stages but without dialysis treatment, iPTH concentrations within the normal range were suggested. Lowering of iPTH values below the lower normal limit as present in a substantial proportion in our patients should be certainly prevented.\n\nSupplementary information\n\nAdditional file 1. Correlation of the GFR-change with clinical factors. The table displays the variables that were not significant in univariate analyses and not considered in the different multivariable models.\n\n \n\n\nAbbreviations\nATGanti-thymocyte globulin\n\nCIconfidence interval\n\nCMVcytomegalovirus\n\neGFRestimated glomerular filtration rate\n\nESRFend stage renal failure\n\nHLAhuman leukocyte antigen\n\nIL-2 ABinterleukin-2 antibodies\n\niPTHintact parathormone\n\nSDstandard deviation\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/s12882-020-01723-x.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nPM, SI and GW collected and analyzed the data. PM, WG and HH designed the study and wrote the paper. All authors read and approved the final manuscript.\n\nAuthors’ information\nnone\n\nFunding\nNo funding.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the last author (Gwinner.Wilfried@mh-hannover.de) on reasonable request.\n\nEthics approval and consent to participate\nData collection and analysis was performed with written informed consent of the patients and with approval of the ethic board (no 2765) of the Hannover Medical School.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Copley JB Wüthrich RP Therapeutic management of post-kidney transplant hyperparathyroidism Clin Transpl 2011 25 24 10.1111/j.1399-0012.2010.01287.x \n2. 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Gwinner W Suppa S Mengel M Early calcification of renal allografts detected by protocol biopsies: causes and clinical implications Am J Transplant 2005 5 1934 10.1111/j.1600-6143.2005.00938.x 15996242 \n8. Torres A Lorenzo V Salido E Calcium metabolism and skeletal problems after transplantation J Am Soc Nephrol 2002 13 551 11805187 \n9. Mazzaferro Sandro Pasquali Marzia Taggi Franco Baldinelli Matteo Conte Carmina Muci Maria Luisa Pirozzi Nicola Carbone Iacopo Francone Marco Pugliese Francesco Progression of Coronary Artery Calcification in Renal Transplantation and the Role of Secondary Hyperparathyroidism and Inflammation Clinical Journal of the American Society of Nephrology 2009 4 3 685 690 10.2215/CJN.03930808 19211668 \n10. Schwarz A Mengel M Gwinner W Risk factors for chronic allograft nephropathy after renal transplantation: a protocol biopsy study Kidney Int 2005 67 341 10.1111/j.1523-1755.2005.00087.x 15610260 \n11. Cohen J Gordon C Balk E Francis JM Cinacalcet for the treatment of hyperparathyroidism in kidney transplant recipients: a systematic review and meta-analysis Transp J 2012 94 10 1041 10.1097/TP.0b013e31826c3968 \n12. Behets GJ Spasovski G Sterling LR Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism Kidney Int 2015 87 4 846 10.1038/ki.2014.349 25337774 \n13. Perrin Peggy Kiener Clotilde Javier Rose-Marie Braun Laura Cognard Noelle Gautier-Vargas Gabriela Heibel Francoise Muller Clotilde Olagne Jerome Moulin Bruno Ohlmann Sophie Recent Changes in Chronic Kidney Disease–Mineral and Bone Disorders and Associated Fractures After Kidney Transplantation Transplantation 2017 101 8 1897 1905 10.1097/TP.0000000000001449 27547867 \n14. Ivarsson KM Akaberi S Isaksson E Cardiovascular and cerebrovascular events after Parathyroidectomy in patients on renal replacement therapy World J Surg 2019 43 8 1981 10.1007/s00268-019-05020-z 31087130 \n15. Schwarz A. Rustien G. Merkel S. Radermacher J. Haller H. Decreased renal transplant function after parathyroidectomy Nephrology Dialysis Transplantation 2006 22 2 584 591 10.1093/ndt/gfl583 \n16. Evenepoel P Claes K Kuypers DR Debruyne F Vanrenterghem Y Parathyroidectomy after successful kidney transplantation: a single Centre study NDT 2007 22 1730 17371780 \n17. Lee PP Schiffmann L Offermann G Beige J Effects of Parathyroidectomy on renal allograft survival Kidney Blood Press Res 2004 27 191 10.1159/000079810 15256817 \n18. Parikh S Nagaraja H Agarwal A Impact of post-kidney transplant parathyroidectomy on allograft function Clin Transpl 2013 27 3 397 10.1111/ctr.12099 \n19. Littbarski SA Kaltenborn A Gwiasda J Timing of parathyroidectomy in kidney transplant candidates with secondary hyperparathryroidism: effect of pretransplant versus early or late post-transplant parathyroidectomy Surgery 2018 163 2 373 10.1016/j.surg.2017.10.016 29284591 \n20. Jäger MD Kaaden S Emmanouilidis N Effect of incomplete Parathyroidectomy preserving entire parathyroid glands on renal graft function Arch Surg 2011 146 6 704 10.1001/archsurg.2011.138 21690447 \n21. Von Kossa J Ueber die im Organismus kuenstlich erzeugbaren Verkalkungen Beitr Pathol Anat Allg Pathol 1901 29 163 \n22. Abeling T, Scheffner I, Karch A, et al. Risk factors for death in kidney transplant patients: analysis from a large protocol biopsy registry. Nephrol Dial Transplant. 2018;1.\n23. Marcen R. Morales J. M. Fernandez-Rodriguez A. Capdevila L. Pallardo L. Plaza J. J. Cubero J. J. Puig J. M. Sanchez-Fructuoso A. Arias M. Alperovich G. Seron D. Long-term graft function changes in kidney transplant recipients Clinical Kidney Journal 2010 3 suppl 2 ii2 ii8 10.1093/ndtplus/sfq063 \n24. Weekers L Vanderweckene P Pottel H The closure of arteriovenous fistula in kidney transplant recipients is associated with an acceleration of kidney function decline Nephrol Dial Transplant 2017 32 196 27798197 \n25. Esbrit P Santos S Ortega A Parathyroid hormonerelated protein as a renal regulating factor From vessels to glomeruli and tubular epithelium Am J Nephrol 2001 21 179 11423685 \n26. Ellison DH McCarron DA Structural prerequisites for the hypotensive action of parathyroid hormone Am J Phys 1984 246 556 \n27. Endlich K Massfelder T Helwig JJ Steinhausen M Vascular effects of parathyroid hormone and parathyroid hormone-related protein in the split hydronephrotic rat kidney J Physiol 1995 483 2 481 10.1113/jphysiol.1995.sp020599 7650615 \n28. Massfelder T Parekh N Endlich K Saussine C Steinhausen M Helwig JJ Effect of intrarenally infused parathyroid hormone-related protein on renal blood flow and glomerular filtration rate in the anaesthetized rat Br J Pharmacol 1996 118 1995 10.1111/j.1476-5381.1996.tb15635.x 8864534 \n29. Jespersen B Randlov A Abrahamsen J Fogh-Andersen N Kanstrup IL Effects of PTH(1-34) on blood pressure, renal function, and hormones in essential hypertension: the altered pattern of reactivity may counteract raised blood pressure Am J Hypertens 1997 10 1356 9443771 \n30. Morales J. M. Marcen R. del Castillo D. Andres A. Gonzalez-Molina M. Oppenheimer F. Seron D. Gil-Vernet S. Lampreave I. Gainza F. J. Valdes F. Cabello M. Anaya F. Escuin F. Arias M. Pallardo L. Bustamante J. Risk factors for graft loss and mortality after renal transplantation according to recipient age: a prospective multicentre study Nephrology Dialysis Transplantation 2012 27 suppl 4 iv39 iv46 10.1093/ndt/gfs544 \n31. Pitt SC Panneerselvan R Chen H Sippel RS Secondary and tertiary hyperparathyroidism: the utility of ioPTH monitoring World J Surg 2010 34 1343 10.1007/s00268-010-0575-4 20386902 \n32. Ketteler M Block GA Evenepoel P Executive summary of the 2017 KDIGO chronic kidney disease–mineral and bone disorder (CKD-MBD) guideline update: what’s changed and why it matters Kidney Int 2017 92 26 10.1016/j.kint.2017.04.006 28646995 \n33. Moe SM Drüeke TB Block GA KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int Suppl 2009 113 S1 \n34. Isakova T Nickolas TL Denburg M KDOQI US commentary on the 2017 KDIGO clinical practice guidelines update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Am J Kidney Dis 2017 70 6 737 10.1053/j.ajkd.2017.07.019 28941764\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "21(1)",
"journal": "BMC nephrology",
"keywords": "Hypercalcemia; Hyperparathyroidism; Kidney function; Parathyroidectomy; Renal transplantation",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000328:Adult; D002118:Calcium; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006934:Hypercalcemia; D006961:Hyperparathyroidism; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone; D016105:Parathyroidectomy; D012189:Retrospective Studies",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "53",
"pmc": null,
"pmid": "32070317",
"pubdate": "2020-02-18",
"publication_types": "D016428:Journal Article",
"references": "21690447;23448282;19211668;15256817;17371780;9443771;30811012;31087130;20386902;29284591;9568830;7650615;6720960;23020185;26603850;17035377;27798197;27547867;20572835;23069843;28941764;23258810;15996242;29860340;8864534;15610260;11805187;14993493;11423685;25337774;28646995;20508857",
"title": "Long-term renal graft outcome after parathyroidectomy - a retrospective single centre study.",
"title_normalized": "long term renal graft outcome after parathyroidectomy a retrospective single centre study"
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"abstract": "BACKGROUND Anorectal infections occur in 5% to 9% of patients with hematological malignancies, including acute myeloid leukemia, and cause febrile neutropenia and sepsis. Surgical treatments of anorectal abscesses tend to be avoided in patients with leukemia owing to persistent neutropenia and bleeding risks. CASE REPORT A 56-year-old man presented with an ischiorectal abscess. Preoperative laboratory test results revealed leukocytopenia and anemia. He was diagnosed with acute myeloid leukemia. He developed septic shock. Antibiotic treatment was ineffective, and fever persisted. One week later, the abscess was treated by incision and drainage. Two days later, induction chemotherapy was initiated. No pus was drained; cellulitis spread to both buttocks. Pain worsened, and oxycodone was administered. Achievement of complete remission failed. Reinduction therapy was started, followed by fistulotomy of the abscess with extensive debridement of cellulitis on day 6. Granulation was observed on day 17. The patient's fever resolved on day 21. Although hematopoietic recovery was observed, bone marrow examination demonstrated partial remission. Two additional courses of chemotherapy were administered. Abscess recurrence was not observed, even during febrile neutropenia. The surgical wound shrank to a skin defect along the gluteal cleft. He achieved complete remission and was transferred to another hospital, where he underwent 3 allogeneic stem cell transplants. He died of leukemia progression. CONCLUSIONS Surgical treatments can prevent fatal progression of anorectal abscess, even during neutropenia. Incision and drainage are suitable for fluctuant abscesses. For a non-fluctuant abscess aggravated by sepsis and cellulitis, it is worth considering more invasive surgical interventions, including debridement and fistulotomy.",
"affiliations": "Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan.;Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan.;Department of Coloproctology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan.;Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan.",
"authors": "Ohzu|Masami|M|;Takazawa|Hitomi|H|;Furukawa|Satomi|S|;Komeno|Yukiko|Y|",
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"country": "United States",
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"doi": "10.12659/AJCR.931589",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34218249\n10.12659/AJCR.931589\n931589\nArticles\nAnorectal Abscess in a Patient with Neutropenia and Refractory Acute Myeloid Leukemia: To Operate or not to Operate?\nOhzu Masami BCDEF12\nTakazawa Hitomi BCD13\nFurukawa Satomi ABCD4\nKomeno Yukiko ABCDEF1http://orcid.org/0000-0002-7910-8641\n\n1 Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan\n2 Department of Hematology and Oncology, The University of Tokyo, Bunkyo City, Tokyo, Japan\n3 Department of Internal Medicine, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan\n4 Department of Coloproctology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan\nCorresponding Author: Yukiko Komeno, e-mail: ykomeno-tky@umin.ac.jp\nAuthors’ 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\n2021\n04 7 2021\n22 e931589-1e931589-5\n12 2 2021\n13 5 2021\n25 5 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 56-year-old\n\nFinal Diagnosis: Perianal abscess\n\nSymptoms: Fever • gluteal pain • septic shock\n\nMedication: —\n\nClinical Procedure: Debridement • fistulotomy • incision and drainage\n\nSpecialty: Hematology • Infectious Diseases • Surgery\n\nObjective:\n\nRare disease\n\nBackground:\n\nAnorectal infections occur in 5% to 9% of patients with hematological malignancies, including acute myeloid leukemia, and cause febrile neutropenia and sepsis. Surgical treatments of anorectal abscesses tend to be avoided in patients with leukemia owing to persistent neutropenia and bleeding risks.\n\nCase Report:\n\nA 56-year-old man presented with an ischiorectal abscess. Preoperative laboratory test results revealed leukocytopenia and anemia. He was diagnosed with acute myeloid leukemia. He developed septic shock. Antibiotic treatment was ineffective, and fever persisted. One week later, the abscess was treated by incision and drainage. Two days later, induction chemotherapy was initiated. No pus was drained; cellulitis spread to both buttocks. Pain worsened, and oxycodone was administered. Achievement of complete remission failed. Reinduction therapy was started, followed by fistulotomy of the abscess with extensive debridement of cellulitis on day 6. Granulation was observed on day 17. The patient’s fever resolved on day 21. Although hematopoietic recovery was observed, bone marrow examination demonstrated partial remission. Two additional courses of chemo-therapy were administered. Abscess recurrence was not observed, even during febrile neutropenia. The surgical wound shrank to a skin defect along the gluteal cleft. He achieved complete remission and was transferred to another hospital, where he underwent 3 allogeneic stem cell transplants. He died of leukemia progression.\n\nConclusions:\n\nSurgical treatments can prevent fatal progression of anorectal abscess, even during neutropenia. Incision and drainage are suitable for fluctuant abscesses. For a non-fluctuant abscess aggravated by sepsis and cellulitis, it is worth considering more invasive surgical interventions, including debridement and fistulotomy.\n\nKeywords:\n\nAbscess\nAnus Diseases\nColorectal Surgery\nFebrile Neutropenia\nLeukemia, Myeloid, Acute\nRectal Diseases\n==== Body\nBackground\n\nAnorectal abscesses are caused by infection of the anal glands and are characterized by redness, swelling, and pain of the anal skin. Fistulas, in contrast, are formed by chronic inflammation and the epithelialization of a tract connecting the inciting anal gland with the perianal skin and are characterized by secretions from around the anus [1–3]. Treatments for anorectal abscesses in the general population are prompt incision upon diagnosis and complete drainage [1–3]. These procedures alleviate pain and prevent progressive inflammation (including life-threatening pelvic sepsis and Fournier gangrene), abscess recurrence, and fistula formation. Antibiotic treatment is not required for patients who are immunocompetent but should be administered in the presence of extensive cellulitis in the perianal/perineal area, signs of systemic infection, or other complications (diabetes, valvular heart disease, or immunosuppression, such as human immunodeficiency virus infection and leukemia) [1–3]. Antibiotic therapy can prevent fistula formation after incision and drainage [3], as was shown in a randomized single-blind clinical trial [4] and meta-analysis [5]. Fistulotomy at the time of incision and drainage of a perianal abscess is associated with a significant decrease in abscess recurrence, persistence of fistula or abscess, and the need for subsequent surgery; however, a statistically insignificant increase of continence impairment has been reported [6]. Therefore, primary fistulotomy can be performed in cases of superficial fistulas, by experienced surgeons. Otherwise, it should be performed as a secondary procedure [1–3].\n\nThe frequency of anorectal infections in patients with hematological malignancies, including leukemia, has been reported as 5% to 9% [7–12]. When febrile neutropenia develops in patients with hematological malignancies who suffer from anorectal infections, broad-spectrum antibiotic treatment must be immediately prescribed, with modifications made based on the site of the infection and the identified pathogens [13]. Guidelines for anorectal abscesses and fistulas also recommend that antibiotic treatment be used for patients who are immunocompromised [1–3,14].\n\nHowever, the indications for surgical intervention of anorectal abscesses during neutropenia are still debated. Surgical treatments tend to be avoided in patients with leukemia owing to persistent neutropenia, slow granulation, and bleeding risks. There is no strong evidence-based treatment guideline because there have been no prospective randomized studies on this topic to date [14].\n\nWe report the case of a patient with refractory acute myeloid leukemia (AML) during prolonged myelosuppression who successfully underwent radical abscess surgery (fistulotomy) and extensive debridement for widespread cellulitis after incision and drainage of the ischiorectal abscess.\n\nCase Report\n\nThe patient was a 56-year-old man with an unremarkable past medical history. He denied a history of tobacco use, alcohol use, and substance abuse. He experienced anal pain for 2 weeks before presenting at our hospital. A perianal abscess found on the right buttock had caused spontaneous perforation a week before, and he visited our hospital for colorectal surgery. The abscess was accompanied by erythema and yellow discharge. On admission, laboratory test results showed a low white blood cell count (1.57×103/μL, neutrophils 2.0%, blasts 80.5%) and anemia. Bone marrow aspiration revealed 77% blasts, which led to the diagnosis of AML (subtype M1). His temperature was 40.3°C. We promptly began administering 1 g intravenous (i.v.) doripenem 3 times daily for febrile neutropenia. The gluteal pain was persistent and worsened in a sitting position. For this reason, the patient was always in the lateral decubitus position. The day after admission, septic shock manifested. Pelvic magnetic resonance imaging revealed an ischiorectal abscess. Immunoglobulin 5 g i.v. once daily for 3 days and vancomycin 1 g i.v. twice daily were also administered. Escherichia coli was detected in blood and urine cultures, and E. coli and Enterococcus faecalis were detected in the perianal abscess culture. The fever and gluteal pain persisted. On day 8 of hospitalization, an incision and drainage were performed, with the patient under general anesthesia (Figures 1, 2). The day after surgery, septic shock manifested again. Induction chemotherapy with daunorubicin 38 mg/m2 i.v. once daily for 5 days and continuous cytarabine 100 mg/m2 i.v. for 7 days (body surface area 1.8 m2) was performed on the second day after surgery. The patient’s fever resolved 3 days after surgery. However, cellulitis developed and spread to both buttocks, forming a horseshoe abscess. The gluteal pain worsened, requiring analgesia by oral oxycodone. Liposomal amphotericin B 100 mg i.v. once daily was also administered. The patient had fever on day 23 and thereafter. No pus was observed draining from the abscess. The neutropenia persisted, and bone marrow aspiration revealed no response (blasts 72%).\n\nHigh-dose cytarabine (HD-Ara-C) 2 g/m2 i.v. twice daily for 4 days was initiated as a reinduction therapy. As the cellulitis worsened and sepsis continued after incision, drainage, and prolonged antibiotic therapy, radical fistulotomy and debridement of the abscess were performed on day 6. The abscessed skin and the infected granulation tissues were extensively removed (Figure 2). Perioperatively, the platelet counts were maintained above 50 000/µL with platelet transfusions. E. coli, E. faecalis, methicillin-resistant coagulase-negative staphylococci (MRCNS) and anaerobic gram-negative bacilli were cultured from the removed drainage tube, while only MRCNS was cultured from the blood. The patient’s fever persisted after the surgery. Laboratory test results showed elevated hepatic enzyme levels, for which endotoxin adsorption was performed. Silver sulfadiazine was applied to the open wound. Large volumes of malodorous exudate were observed every day. However, no further extension of cellulitis was observed. On day 17, healthy granulation tissue appeared in the wound, and the gluteal pain improved. The patient’s fever resolved on day 21. The neutrophil levels recovered to >500/µL on day 22, and a bone marrow examination demonstrated partial remission (blasts 25%).\n\nBecause the reinduction chemotherapy was effective for debulking (reducing blasts from 72% to 25%), chemotherapy treatment of HD-Ara-C i.v. for 5 days (1 day longer than previously) was repeated as the third chemotherapy. The surgical wound continued to shrink. The gluteal pain improved, and oxycodone (maximum dose, 25 mg twice daily) was tapered off. From the wound swab, alpha-hemolytic Streptococcus, coryneform bacteria, Enterobacter cloacae, and anaerobic gram-negative bacilli were cultured during myelosuppression, while Enterococcus faecium was cultured during the bone marrow recovery. The neutrophil levels recovered to > 500/µL on day 20. Febrile neutropenia was observed on days 11 to 22. The bone marrow examination showed refractory disease (blasts 26%).\n\nAnother reinduction chemotherapy was administered: modified FLAGM (subcutaneous granulocyte colony-stimulating factor 300 µg on day 1+i.v. fludarabine 1.5 mg/m2 twice daily on days 2 to 5+i.v. HD-Ara-C 2 g/m2 twice daily on days 2 to 5+i.v. mitoxantrone 9.4 mg/m2 once daily on day 6). E. faecalis was detected in blood cultures on day 3. Coryneform bacteria and E. faecalis were detected in the wound culture on day 4, and Morganella morganii was detected in the blood culture on day 11. The surgical wound was closed to the gluteal cleft (Figure 2). Neutrophil levels recovered to >500/µL on day 23. Febrile neutropenia was observed on days 10 to 22. The patient achieved complete remission and was transferred to another hospital for transplantation. However, soon after the transfer, the leukemia relapsed. He underwent an allogeneic peripheral-blood stem cell transplant, followed by 2 cord-blood transplants. There was no abscess recurrence or fistula formation. The patient did not develop fecal incontinence. He died of leukemia 16 months after diagnosis.\n\nDiscussion\n\nSurgical treatments for anorectal infection include incision and drainage, debridement, fistulotomy, and surgeries for other complications, such as fasciotomy for Fournier gangrene and colostomy for a rectovaginal fistula. Incomplete drainage might lead to worsening of cellulitis and sepsis, abscess recurrence, and fistula formation [1–3]. In patients with neutropenia and hematological malignancies, surgical treatments tend to be avoided because of concerns about delayed wound healing, secondary infections, and bleeding risks [8,12,15].\n\nThere are several retrospective studies comparing patient outcomes, with or without surgery, that draw conflicting conclusions. Owing to the retrospective nature of these studies, there were no predefined indications for surgical treatment or principles of antibiotic use, and the clinical course of the underlying disease (de novo, refractory/relapsed, or complete remission) and neutrophil counts could have affected treatment decisions. Some researchers believe surgery is not recommended because there is insufficient data on the impact of surgical interventions on recurrence or survival could not be statistically demonstrated owing to the small number of cases and variable clinical severity [8,12]. However, they do not deny the efficacy of surgical treatments or provide enough evidence to deem surgery inappropriate.\n\nThe minimally invasive surgical treatments of anorectal abscess are incision and drainage, which are recommended in cases of abscesses that are fluctuant or resistant to antibiotics, even during stages of neutropenia [7,9–11,16–18], including cases of stem cell transplantation [17,18].\n\nThe evidence on the application of more invasive surgical treatments (debridement and fistulotomy) for anorectal infections during neutropenia is scarce. These procedures are performed for anorectal non-fluctuant abscesses, induration, cellulitis, and fistulas. In the retrospective studies mentioned above, some patients did undergo these invasive procedures, but detailed information of each case was not available [8,9,12,17,18]. However, Barnes et al reported in detail about 16 patients with acute leukemia with non-fluctuant perirectal infections during severe neutropenia [10]. Eight patients who underwent incision and debridement showed wound healing and granulation, and all but 1 patient were discharged. The patients were receiving induction chemotherapy for de novo acute leukemia or reinduction therapy for relapse, and the time to neutrophil level recovery of > 500/µL ranged between 2 and 15 days after surgery [10]. Loureiro et al reported anorectal infections in 27 patients (abscess in 9 patients, fistula in 13 patients, cellulitis in 5 patients) with hematological malignancies [19]. Of the patients treated with antibiotics alone, 9 of 12 showed improvement or resolution of symptoms, while 14 of 15 patients treated with antibiotics plus surgery (cannulation, seton placement, and fistulotomy in 10 patients and surgical drainage and debridement in 5 patients) showed improvement or resolution of symptoms, suggesting a favorable outcome in the latter group [19]. In the present report, with refractory AML, a horseshoe abscess progressed to cellulitis, sepsis persisted during prolonged myelosuppression, and extensive debridement and fistulotomy were performed. Bleeding was managed by platelet transfusion. Antibiotic treatment was continued even after the surgery because the patient was immunocompromised, with extensive disease and signs of infection [1–3,13]. The time from debridement and fistulotomy to a neutrophil recovery level > 500/µL was 16 days (neutropenia continued for 56 days after admission) (Figure 1). Although the wound closure time was longer than 98 days, the wound was in good enough condition for the patient to undergo 3 transplants without a recurrent abscess.\n\nThese results demonstrate that surgical interventions can prevent progression to a life-threatening infection. Thus, it is important to consider surgical procedures, including debridement and fistulotomy, in patients with leukemia, even in those with persistent neutropenia, if cellulitis, sepsis, and complications worsen despite antimicrobial treatment. Deciding on the appropriate timing for surgery can be challenging but it should be resolved through collaboration between hematologists and surgeons.\n\nWound culture is not necessary in all patients but is typically performed in patients who are at risk of having methicillin-resistant Staphylococcus aureus (MRSA) infection, who have recurrent infection or nonhealing wounds, or who are immuno-suppressed (due to HIV infection or leukemia) and can have resistant or unusual bacteria [1]. Therefore, multiple culture tests were performed from our patient’s abscess and surgical wound.\n\nConclusions\n\nFor anorectal abscesses in patients with neutropenia and hematological malignancies, antibiotic treatment is mandatory. A fluctuant abscess is a good indication for incision and drainage. If the abscess is (or becomes) non-fluctuant, is accompanied by cellulitis or sepsis, and shows antibiotic resistance, it is worth considering further surgical intervention, including debridement and fistulotomy. Surgical interventions can prevent the progression of infection and can be lifesaving; thus, they should not be deemed a contraindication for patients with neutropenia. Prospective multicenter studies are warranted to establish a clear treatment algorithm for this rare disease.\n\nThe authors would like to thank Tomiko Ryu (Department of Hematology) for providing general support. The authors would also like to thank Editage (www.editage.com) for English-language editing.\n\nFigure 1. Clinical course of induction and reinduction chemotherapy. On the X axis, hospital day 1 was set as the day of admission. Ara-C – cytarabine; BT – body temperature; CRP – C-reactive protein; DNR – daunorubicin; HD-Ara-C – high-dose cytarabine; Neu – neutrophils.\n\nFigure 2. Macroscopic appearance of the perianal abscess and the surgical wound. HD – hospital day; HD-Ara-C – high-dose cytarabine; POD – postoperative day.\n\nDepartment and Institution Where Work Was Done\n\nDepartment of Hematology, JCHO Tokyo Yamate Medical Center, Shinjuku City, Tokyo, Japan.\n\nConflicts of Interest\n\nNone.\n==== Refs\nReferences:\n\n1. Vogel JD Johnson EK Morris AM Clinical practice guideline for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula Dis Colon Rectum 2016 59 1117 33 27824697\n2. Ommer A Herold A Berg E German S3 guidelines: Anal abscess and fistula (second revised version) Langenbecks Arch Surg 2017 402 191 201 28251361\n3. Amato A Bottini C De Nardi P Evaluation and management of perianal abscess and anal fistula: SICCR position statement Tech Coloproctol 2020 24 127 43 31974827\n4. Ghahramani L Minaie MR Arasteh P Antibiotic therapy for prevention of fistula in-ano after incision and drainage of simple perianal abscess: A randomized single blind clinical trial Surgery 2017 162 1017 25 28822559\n5. Mocanu V Dang JT Ladak F Antibiotic use in prevention of anal fistulas following incision and drainage of anorectal abscesses: A systematic review and meta-analysis Am J Surg 2019 217 910 17 30773213\n6. Malik AI Nelson RL Tou S Incision and drainage of perianal abscess with or without treatment of anal fistula Cochrane Database Syst Rev 2010 7 CD006827 20614450\n7. Buyukasik Y Ozcebe OI Sayinalp N Perianal infections in patients with leukemia: Importance of the course of neutrophil count Dis Colon Rectum 1998 41 81 85 9510315\n8. Chen CY Cheng A Huang SY Clinical and microbiological characteristics of perianal infections in adult patients with acute leukemia PLoS One 2013 8 e60624 23577135\n9. Grewal H Guillem JG Quan SH Enker WE Cohen AM Anorectal disease in neutropenic leukemic patients. Operative vs. nonoperative management Dis Colon Rectum 1994 37 1095 99 7956576\n10. Barnes SG Sattler FR Ballard JO Perirectal infections in acute leukemia. Improved survival after incision and debridement Ann Intern Med 1984 100 515 18 6703543\n11. Vanhueverzwyn R Delannoy A Michaux JL Dive C Anal lesions in hematologic diseases Dis Colon Rectum 1980 23 310 12 6931029\n12. Chang H Kuo MC Tang TC Clinical features and recurrence pattern of perianal abscess in patients with acute myeloid leukemia Acta Haematol 2017 138 10 13 28586772\n13. Freifeld AG Bow EJ Sepkowitz KA Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America Clin Infect Dis 2011 52 427 31 21205990\n14. Stevens DL Bisno AL Chambers HF Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America Clin Infect Dis 2014 59 147 59 24947530\n15. Schimpff SC Wiernik PH Block JB Rectal abscesses in cancer patients Lancet 1972 2 844 47 4116553\n16. North JH Jr Weber TK Rodriguez-Bigas MA The management of infectious and noninfectious anorectal complications in patients with leukemia J Am Coll Surg 1996 183 322 28 8843260\n17. Morcos B Amarin R Abu Sba A Contemporary management of perianal conditions in febrile neutropenic patients Eur J Surg Oncol 2013 39 404 7 23347777\n18. Cohen JS Paz IB O’Donnell MR Ellenhorn JD Treatment of perianal infection following bone marrow transplantation Dis Colon Rectum 1996 39 981 85 8797645\n19. Loureiro RV Borges VP Tome AL Anorectal complications in patients with haematological malignancies. Eur J Gastroenterol Hepatol 2018 30 722 26\n\n",
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"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000038:Abscess; D001004:Anus Diseases; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D018805:Sepsis",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e931589",
"pmc": null,
"pmid": "34218249",
"pubdate": "2021-07-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7956576;28822559;23347777;21205990;8843260;8797645;27824697;6703543;31974827;4116553;23577135;28586772;20614450;28251361;9510315;6931029;24947530;29659377;30773213",
"title": "Anorectal Abscess in a Patient with Neutropenia and Refractory Acute Myeloid Leukemia: To Operate or not to Operate?",
"title_normalized": "anorectal abscess in a patient with neutropenia and refractory acute myeloid leukemia to operate or not to operate"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2021-22673",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "To identify an optimal cumulative cisplatin dose along with concurrent chemoradiotherapy (CC-CCD) for children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC) using real-world data.\n\n\n\nUsing an NPC-specific database at our center, 157 patients younger than 19 years old with non-disseminated CALANPC and receiving neoadjuvant chemotherapy (NAC) plus cisplatin-based concurrent chemoradiotherapy (CCRT) were enrolled. Confounding factors were controlled by conducting propensity score matching analysis. Primary endpoints include disease-free survival (DFS) and distant metastasis-free survival (DMFS).\n\n\n\nThe optimal threshold for CC-CCD with respect to DFS was 160 mg/m2 based on recursive partitioning analyses (RPA). Therefore, a uniform threshold of 160 mg/m2 (≥160 vs. <160 mg/m2) was selected to classify patients between high and low CC-CCD groups for survival analysis. Patients receiving low CC-CCD showed a significant decrease in 5-year DFS (76.6% vs 91.3%; P = 0.006) and DMFS (81.3% vs 93.5%; P = 0.009) compared to those receiving high CC-CCD. Multivariate analyses indicated that high CC-CCD as an favorable prognostic influence for DFS (P = 0.007) and DMFS (P = 0.008). Further matched analysis identified 65 pairs in both high and low CC-CCD groups. In the matched cohort, high CC-CCD was still identified as a favorable factor for prognosis in DFS (HR, 0.23; 95% CI, 0.08-0.70; P = 0.010) and DMFS (HR, 0.23; 95% CI, 0.06-0.82; P = 0.023).\n\n\n\nCC-CCD exerts significant treatment effects and 160 mg/m2 CC-CCD may be adequate to provide antitumor effects for CALANPC receiving NAC plus CCRT.",
"affiliations": "VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Department of Head and Neck Oncology, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Biomedical Imaging, Zhuhai, China.;VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Department of Pathology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.;State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Department of Environmental Health Sciences, School of Public Health, University at Albany, State University of New York, Rensselaer, United States.;Department of Environmental Health Sciences, School of Public Health, University at Albany, State University of New York, Rensselaer, United States.;VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address: zhangbei@sysucc.org.cn.;VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address: xialp@sysucc.org.cn.",
"authors": "Jin|Ya-Nan|YN|;Yao|Ji-Jin|JJ|;You|Ya-Fei|YF|;Cao|Hui-Jiao|HJ|;Li|Zi-Zi|ZZ|;Dai|Dan-Ling|DL|;Zhang|Wang-Jian|WJ|;Marks|Tia|T|;Zhang|Bei|B|;Xia|Liang-Ping|LP|",
"chemical_list": "D002945:Cisplatin",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.radonc.2021.06.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-8140",
"issue": "161()",
"journal": "Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology",
"keywords": "Children and adolescent; Concurrent chemoradiotherapy; Cumulative cisplatin dose; Nasopharyngeal carcinoma; Prognosis",
"medline_ta": "Radiother Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002648:Child; D002945:Cisplatin; D018572:Disease-Free Survival; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D055815:Young Adult",
"nlm_unique_id": "8407192",
"other_id": null,
"pages": "83-91",
"pmc": null,
"pmid": "34116076",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Optimal cumulative cisplatin dose during concurrent chemoradiotherapy among children and adolescents with locoregionally advanced nasopharyngeal carcinoma: A real-world data study.",
"title_normalized": "optimal cumulative cisplatin dose during concurrent chemoradiotherapy among children and adolescents with locoregionally advanced nasopharyngeal carcinoma a real world data study"
} | [
{
"companynumb": "CN-HQ SPECIALTY-CN-2021INT000210",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nWe studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir.\n\n\nMETHODS\nThis was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional.\n\n\nRESULTS\n31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected.\n\n\nCONCLUSIONS\nDespite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effective concentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis.
ClinicalTrials.gov number NCT00825929.",
"affiliations": "Radboud University Medical Center, Nijmegen, the Netherlands. angela.colbers@radboudumc.nl.",
"authors": "Colbers|Angela|A|;Hawkins|David|D|;Hidalgo-Tenorio|Carmen|C|;van der Ende|Marchina|M|;Gingelmaier|Andrea|A|;Weizsäcker|Katharina|K|;Kabeya|Kabamba|K|;Taylor|Graham|G|;Rockstroh|Jürgen|J|;Lambert|John|J|;Moltó|José|J|;Wyen|Christoph|C|;Sadiq|S Tariq|ST|;Ivanovic|Jelena|J|;Giaquinto|Carlo|C|;Burger|David|D|;|||",
"chemical_list": "D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.3851/IMP2820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "20(1)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005865:Gestational Age; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir; D000068698:Tenofovir; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "57-64",
"pmc": null,
"pmid": "24992294",
"pubdate": "2015",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Atazanavir exposure is effective during pregnancy regardless of tenofovir use.",
"title_normalized": "atazanavir exposure is effective during pregnancy regardless of tenofovir use"
} | [
{
"companynumb": "NL-ABBVIE-15P-114-1381830-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional": null,
... |
{
"abstract": "A 74-year-old woman developed acute renal failure and granulomatous interstitial nephritis associated with hydrochlorothiazide/amiloride. On stopping the drug the renal function improved, but not significantly. Around 20 months after prednisone administration, the renal function had stabilized, with a moderate degree of renal insufficiency. The case is discussed, and some aspects of acute interstitial nephritis induced by diuretics are briefly reviewed.",
"affiliations": "Section of Nephrology, General Hospital of Elche, Spain.",
"authors": "Enríquez|R|R|;Cabezuelo|J B|JB|;González|C|C|;Lacueva|J|J|;Teruel|A|A|;Fernández|J|J|;Arenas|M D|MD|",
"chemical_list": "D006852:Hydrochlorothiazide; D000584:Amiloride; D011241:Prednisone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000168845",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-8095",
"issue": "15(3)",
"journal": "American journal of nephrology",
"keywords": null,
"medline_ta": "Am J Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000584:Amiloride; D005260:Female; D006099:Granuloma; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D009395:Nephritis, Interstitial; D011241:Prednisone",
"nlm_unique_id": "8109361",
"other_id": null,
"pages": "270-3",
"pmc": null,
"pmid": "7618655",
"pubdate": "1995",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Granulomatous interstitial nephritis associated with hydrochlorothiazide/amiloride.",
"title_normalized": "granulomatous interstitial nephritis associated with hydrochlorothiazide amiloride"
} | [
{
"companynumb": "ES-RANBAXY-2013R1-73641",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMILORIDE HYDROCHLORIDE\\HYDROCHLOROTHIAZIDE"
},
... |
{
"abstract": "A 61-year-old man underwent systemic chemotherapy with intravenous infusion of nedaplatin and 5-fluorouracil. On the day after the final drug administration, he suddenly experienced difficulty in speaking followed by left-sided weakness. His National Institutes of Health Stroke Scale score was 12. A computed tomographic scan of the brain performed 4 hours after symptom onset revealed no abnormalities. Because all eligibility criteria were fulfilled, he immediately underwent intravenous recombinant tissue plasminogen activator therapy. He recovered from neurologic complications on day 14. An initial magnetic resonance imaging scan of his brain revealed a hyperintense area in the bilateral white matter and corpus callosum, and these abnormalities had improved on the follow-up scan. We diagnosed him with 5-fluorouracil-induced leukoencephalopathy with acute stroke-like presentation. Our experience suggests that 5-fluorouracil-induced leukoencephalopathy potentially fulfills all eligibility criteria for recombinant tissue plasminogen activator therapy.",
"affiliations": "Department of Internal Medicine, Showa University Northern Yokohama Hospital, Kanagawa, Japan. Electronic address: kinno@med.showa-u.ac.jp.;Department of Rehabilitation Medicine, Showa University Northern Yokohama Hospital, Kanagawa, Japan.;Department of Internal Medicine, Showa University Northern Yokohama Hospital, Kanagawa, Japan.;Department of Internal Medicine, Showa University Northern Yokohama Hospital, Kanagawa, Japan.;Department of Internal Medicine, Showa University Northern Yokohama Hospital, Kanagawa, Japan.;Department of Internal Medicine, Showa University Northern Yokohama Hospital, Kanagawa, Japan.",
"authors": "Kinno|Ryuta|R|;Kii|Yoshitaka|Y|;Uchiyama|Masanobu|M|;Owan|Yoshiyuki|Y|;Yamazaki|Takahiro|T|;Fukui|Toshiya|T|",
"chemical_list": "D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "23(2)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "5-fluorouracil; leukoencephalopathy; recombinant tissue plasminogen activator; stroke-like presentation",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D005343:Fibrinolytic Agents; D005472:Fluorouracil; D006801:Humans; D007262:Infusions, Intravenous; D056784:Leukoencephalopathies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D020127:Recovery of Function; D020521:Stroke; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "387-9",
"pmc": null,
"pmid": "23422344",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "5-fluorouracil-induced leukoencephalopathy with acute stroke-like presentation fulfilling criteria for recombinant tissue plasminogen activator therapy.",
"title_normalized": "5 fluorouracil induced leukoencephalopathy with acute stroke like presentation fulfilling criteria for recombinant tissue plasminogen activator therapy"
} | [
{
"companynumb": "JP-ACCORD-061594",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NEDAPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "FGFR-TACC fusions, including FGFR3-TACC3, have been identified as potential oncogenic drivers and actionable alterations in a number of different cancer types. The clinical relevance of FGFR3-TACC3 fusions in endometrial cancer has not yet been described. Formalin-fixed, paraffin-embedded metastatic endometrial carcinoma from the spleen and peritoneum were sent for comprehensive genomic profiling (CGP) using the FoundationOne platform as part of a prospective tumor genomic profiling protocol. We report the identification of an FGFR3-TACC3 fusion in a case of metastatic endometrioid endometrial cancer. Other potentially actionable alterations detected in this specimen included PIK3CA T1025S and an uncharacterized rearrangement involving TSC2 The patient initially received an FGFR inhibitor as an investigational agent and experienced stable disease with complete resolution of a pelvic nodule; however, treatment had to be discontinued because of intolerable side effects. A PET/CT scan nearly 3 mo after discontinuation showed disease progression. She subsequently received the mTOR inhibitor, temsirolimus, later accompanied by letrozole, and achieved stable disease. Clinical benefit was attributed to the mTOR inhibitor as tumor stained negative for estrogen receptor. Temsirolimus was discontinued after >17 mo because of disease progression. FGFR inhibitors may have clinical benefit in the treatment of endometrial carcinoma with FGFR3-TACC3 fusions. Additionally, clinical benefit from an mTOR inhibitor may reflect a response to targeting the alteration in PIK3CA or TSC2 More research is needed to understand the activity of FGFR3-TACC3 fusions on tumors and to discover additional therapeutic options for endometrial carcinoma patients with this gene fusion.",
"affiliations": "Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.;Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.;Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.;Department of Obstetrics and Gynecology, Hackensack University Medical Center-Hackensack Meridian Health, John Theurer Cancer Center, Hackensack, New Jersey 07601, USA.;Department of Obstetrics and Gynecology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.;Department of Radiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.;Department of Pathology, Monmouth Medical Center, Long Branch, New Jersey 07740, USA.;Department of Pathology, Monmouth Medical Center, Long Branch, New Jersey 07740, USA.;Foundation Medicine, Inc. Cambridge, Massachusetts 02141, USA.;Foundation Medicine, Inc. Cambridge, Massachusetts 02141, USA.;Foundation Medicine, Inc. Cambridge, Massachusetts 02141, USA.;Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.",
"authors": "Dhami|Jatinder|J|;Hirshfield|Kim M|KM|;Ganesan|Shridar|S|;Hellmann|Mira|M|;Rojas|Veronica|V|;Amorosa|Judith K|JK|;Riedlinger|Gregory M|GM|;Zhong|Hua|H|;Ali|Siraj M|SM|;Pavlick|Dean|D|;Elvin|Julia A|JA|;Rodriguez-Rodriguez|Lorna|L|",
"chemical_list": "D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a002089",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 10.1101/mcs.a002089MCS002089DhaResearch ReportComprehensive genomic profiling aids in treatment of a metastatic endometrial cancer Targeted therapy for endometrial cancer based on comprehensive genomic profilingTargeted therapy for endometrial cancer based on comprehensive genomic profilingDhami Jatinder 18Hirshfield Kim M. 18Ganesan Shridar 1Hellmann Mira 2Rojas Veronica 3Amorosa Judith K. 4Riedlinger Gregory M. 5Zhong Hua 5Ali Siraj M. 6Pavlick Dean 6Elvin Julia A. 6Rodriguez-Rodriguez Lorna 71 Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA;2 Department of Obstetrics and Gynecology, Hackensack University Medical Center–Hackensack Meridian Health, John Theurer Cancer Center, Hackensack, New Jersey 07601, USA;3 Department of Obstetrics and Gynecology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA;4 Department of Radiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA;5 Department of Pathology, Monmouth Medical Center, Long Branch, New Jersey 07740, USA;6 Foundation Medicine, Inc. Cambridge, Massachusetts 02141, USA;7 Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA8 These authors contributed equally to this work.\n\nCorresponding author: rodriglo@cinj.rutgers.edu4 2018 4 2 a00208926 4 2017 7 2 2018 © 2018 Dhami et al.; Published by Cold Spring Harbor Laboratory Press2018This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.FGFR-TACC fusions, including FGFR3-TACC3, have been identified as potential oncogenic drivers and actionable alterations in a number of different cancer types. The clinical relevance of FGFR3-TACC3 fusions in endometrial cancer has not yet been described. Formalin-fixed, paraffin-embedded metastatic endometrial carcinoma from the spleen and peritoneum were sent for comprehensive genomic profiling (CGP) using the FoundationOne platform as part of a prospective tumor genomic profiling protocol. We report the identification of an FGFR3-TACC3 fusion in a case of metastatic endometrioid endometrial cancer. Other potentially actionable alterations detected in this specimen included PIK3CA T1025S and an uncharacterized rearrangement involving TSC2. The patient initially received an FGFR inhibitor as an investigational agent and experienced stable disease with complete resolution of a pelvic nodule; however, treatment had to be discontinued because of intolerable side effects. A PET/CT scan nearly 3 mo after discontinuation showed disease progression. She subsequently received the mTOR inhibitor, temsirolimus, later accompanied by letrozole, and achieved stable disease. Clinical benefit was attributed to the mTOR inhibitor as tumor stained negative for estrogen receptor. Temsirolimus was discontinued after >17 mo because of disease progression. FGFR inhibitors may have clinical benefit in the treatment of endometrial carcinoma with FGFR3-TACC3 fusions. Additionally, clinical benefit from an mTOR inhibitor may reflect a response to targeting the alteration in PIK3CA or TSC2. More research is needed to understand the activity of FGFR3-TACC3 fusions on tumors and to discover additional therapeutic options for endometrial carcinoma patients with this gene fusion.\n\nendometrial carcinomaRutgers Cancer Institute of New Jersey 10.13039/100007558RUCDR Infinite BiologicsNIH 10.13039/100000002P30CA072720\n==== Body\nINTRODUCTION\nSignificant progress in the development of comprehensive genomic profiling (CGP) platforms, analyses, and targeted therapies has culminated in the use of these modalities to reclassify and to treat many cancers, including endometrial carcinoma. Endometrial cancer, the most common gynecologic cancer, is predicted to account for 61,380 new cases of gynecologic cancers affecting women in the United States in 2017 (Siegel et al. 2016). Risk factors of endometrial cancer include obesity, diabetes mellitus, high blood pressure, tamoxifen treatment, and unopposed estrogen use (McConechy et al. 2012; Trabert et al. 2015; Morice et al. 2016). Current treatment modalities for women with endometrial cancer are surgery or surgery in combination with radiation therapy and/or chemotherapy, hormone therapy, and biologic therapy (National Cancer Institute 2002; National Comprehensive Cancer Network 2014). However, prognosis is worsened for women with recurrent or metastatic disease, as treatment options are limited and suboptimal (Temkin and Fleming 2009; Rauh-Hain and Del Carmen 2010; Lee and Secord 2014).\n\nAdvances in molecular genotyping have not only identified molecular heterogeneity driving tumor behavior (The Cancer Genome Atlas Research Network et al. 2013) but have also shed light on alternative approaches to therapeutically target tumors with specific mutations (Conley 2015; Meric-Bernstam et al. 2015; Tobin et al. 2015). Common alterations seen in endometrial cancers include mutations in the PI3K pathway (occurring in >80% of the endometrioid subtype) (Cheung et al. 2011), copy-number alterations (frequently observed in serous and mixed histology endometrial cancers, but also seen in endometrioid endometrial cancers; seen in such genes as ERBB2, FGFR3, and CCNE1), and frequent TP53 mutations (The Cancer Genome Atlas Research Network et al. 2013). FGFR alterations reported in endometrial cancers most frequently involve FGFR2 (Helsten et al. 2016). According to The Cancer Genome Atlas (TCGA) for data reported in Nature in 2013, the most frequently altered FGFR gene in endometrial cancers was FGFR2, with 12.5% of sequenced samples (n = 248 samples) harboring alterations in this gene. Gene fusions in endometrial cancers, although less common than copy-number alterations and point mutations, involve members of various pathways with recurrent translocations that most frequently involve genes of the BCL-2 family, followed by PI3K, WNT, EGFR, RAS–MAPK, protein kinase A, and retinoblastoma pathways (The Cancer Genome Atlas Research Network et al. 2013).\n\nWe report on a woman with a platinum-resistant recurrence of a metastatic endometrioid endometrial carcinoma with poorly differentiated, widespread carcinomatosis and splenic involvement. CGP performed on a tumor specimen revealed several potentially actionable alterations, including both an FGFR3-TACC3 fusion and a PIK3CA-activating mutation. Consensus opinion from our institutional molecular tumor board (MTB) led to enrollment of this patient on a clinical trial including an FGFR inhibitor and subsequent therapy with an mTOR inhibitor, to which she derived a prolonged clinical benefit. This case demonstrates the utility of tumor genomic profiling with the ability to identify gene rearrangements as a method of identifying potentially actionable targets in endometrial cancers.\n\nRESULTS\nClinical Presentation and Family History\nA 57-yr-old nulliparous, postmenopausal female presented with intermittent abnormal vaginal bleeding over 3 yr. Her history was significant for menarche at age 11, menopause at age 50, diabetes managed with metformin, body mass index of 29, and a remote 40 pack/year smoking history where tobacco cessation occurred 20 yr prior to diagnosis. She had no history of exogenous hormone use. She had a dilation and curettage 3 yr prior to the initial cancer diagnosis that showed no pathology. The patient continued to experience abnormal vaginal bleeding, and a second endometrial biopsy revealed moderately differentiated endometrioid adenocarcinoma, FIGO grade II, with extensive necrosis (Fig. 1A,B).\n\nFigure 1. Hematoxylin and eosin (H&E)-stained endometrial biopsy showing endometrial adenocarcinoma with papillary features and necrosis at low (A) and high (B) magnification, respectively.\n\nShe underwent an exploratory laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pathology confirmed a high-grade, 8.5 cm × 8 cm × 5 cm endometrioid adenocarcinoma, FIGO grade II, with extensive necrosis and focal clear cell changes. There was <10% myometrial invasion. No lymphovascular invasion or cervix involvement was noted. Eighteen pelvic and para-aortic lymph nodes showed no metastases. Final staging was 1A (pT1a, N0), based on the 2009 FIGO staging guidelines. Because she had a high risk for recurrence, the patient received whole pelvis radiation therapy and brachytherapy on a clinical trial that was completed 9 mo prior to the presentation of recurrent disease.\n\nA CT scan of the abdomen and pelvis following completion of radiation showed stable hypodensities in the liver that were too small to characterize. However, 9 mo after completion of the trial, a follow-up CT scan showed a new 8-mm hypodense lesion in the splenic hilum and ring-like enhancement along the posterior margin of spleen not seen on the previous exam. A subsequent PET-CT scan revealed two abnormal hypermetabolic foci in the spleen (SUV 3.2 in the hilum, SUV 4.5 in a 1.2 cm hypodense lesion), stable non-FDG-avid liver lesions, and no pelvic adenopathy. The patient underwent splenectomy, and pathology was consistent with metastasis of the original tumor to the spleen (Fig. 2A,B). She received six cycles of intravenous carboplatin (AUC = 5) in combination with paclitaxel (175 mg/m2). Nearly 14 mo later, a CT scan of the chest, abdomen, and pelvis (CAP) revealed an increase in the size of previously visualized abdominal nodules, which were now suspicious for peritoneal carcinomatosis. A fine needle aspiration of the nodules within the abdomen and pelvis confirmed adenocarcinoma with extensive necrosis. A diagnostic laparoscopy was performed to resect tumor nodules (Fig. 3A,B), which were then sent for comprehensive tumor genomic profiling (CGP) under the auspices of a clinical trial.\n\nFigure 2. H&E-stained slide of tissue from splenectomy showing metastatic, moderately differentiated adenocarcinoma with necrosis at low (A) and high (B) magnification, respectively.\n\nFigure 3. H&E-stained slide showing metastatic adenocarcinoma with necrosis and calcifications following diagnostic laparoscopy with removal of the anterior abdominal wall nodule at low (A) and high (B) magnification, respectively; specimen from this procedure was sent for comprehensive genomic profiling.\n\nGenomic Analyses\nThe patient provided informed consent to participate in the Rutgers CINJ genomic tumor profiling protocol (NCT02688517), which was approved by the Institutional Review Board (IRB) of Rutgers University New Brunswick Health Sciences (Pro2012002075). The specimen from the patient's laparoscopy underwent CGP using the FoundationOne platform, which consisted of whole-exon sequencing of a panel of 236 genes and 47 introns of 19 genes involved in translocations. Tumor genomic profiling revealed an FGFR3-TACC3 fusion (breakpoints at FGFR3 exon 17 and TACC3 exon 8), a missense mutation in PIK3CA (T1025S), and an uncharacterized rearrangement involving TSC2 (Table 1). A subthreshold amplification of the entire coding region of FGFR3 (copy number 6) was also detected, further validating the rearrangement. The results of tumor genomic profiling, clinical course, and pathology were reviewed at the Rutgers Cancer Institute of New Jersey Molecular Tumor Board (RCINJ MTB).\n\nTable 1. Variants identified from comprehensive genomic profiling\n\nGene\tChromosome\tHGVS DNA reference\tHGVS protein reference\tVariant type\tPredicted effect\t\nFGFR3\t4\tt(4;4)\nChr 4 duplication fragment: 5′-FGFR3 (ex1-17 NM_000142)-TACC3 (ex8-16 NM_006342) Breakpoints: FGFR3 exon 17, TACC3 exon 8\tN/A\tFusion\tFunctional\t\nPIK3CA\t3\tN/A\tp.T1025S\tSubstitution\tPredicted functional\t\nTSC2\t16\tt(16;16)\n∼206-kbp duplication fragment: 3′-TSC2 (NM_000548), Breakpoints: TSC2 exon 26, ABCA3 intron 25\tN/A\tFusion\tUnknown\t\nTargeted sequencing of the entire coding sequence was done for 236 genes and 47 introns of 19 genes involved in fusions at a depth of 500–1000× (median exon depth of 792×; 100% of the baited region was sequenced at a depth of at least 100×; sequence alignment error of only 0.27%). The depth of variant call reads was 59×; these 59 chimeric reads equate to an independently validated variant calling method described in Frampton et al. (2013). The depth of wild-type reads was 1155×.\n\nHGVS, Human Genome Variation Society; N/A, not available.\n\nData suggest that FGFR3 fusion-containing cells are addicted to FGFR kinase activity and are sensitive to FGFR pan-inhibitors, such as pazopanib and PD173074 (Pollock et al. 2007; Lamont et al. 2011; Dieci et al. 2013; Williams et al. 2013). Given the preclinical study results, MTB recommendations to the treating oncologist included consideration of a trial using an FGFR inhibitor, a phase I trial of the combination carboplatin/paclitaxel/pazopanib, a trial with a PIK3CA inhibitor, an mTOR inhibitor, and off-label use of ponatinib or pazopanib.\n\nIntriguingly, several variants of unknown significance were also reported in the tumor of this patient and included a TSC2 rearrangement. The TSC2 rearrangement was a 3′ tandem duplication of TSC2 with breakpoints in exon 26 and ABCA3 intron 25. This is an out of strand fusion event, because TSC2 and ABCA3 are transcribed in the positive and negative directions, respectively. The reciprocal event was not seen for this rearrangement. Additionally, there was a subthreshold amplification in TSC2 exons 26–42 (copy number 7) that further validate the rearrangement.\n\nTreatment Outcomes\nThe patient was enrolled into a phase I clinical trial with an FGFR inhibitor. This MTB recommendation was based on the inference that the FGFR3-TACC3 fusion-containing tumor would be addicted to FGFR kinase activity. The patient experienced stable disease over the course of nearly 2 mo with complete resolution of a pelvic nodule, as observed in CT scans (Fig. 4A–D). However, at nearly four full cycles, the patient was removed from the study for grade 3 palmar-plantar erythrodysesthesia. The patient showed disease progression on a PET/CT scan about 3 mo following cessation of the FGFR inhibitor on trial (Fig. 5A–D).\n\nFigure 4. CT scans of the abdomen and pelvis with contrast prior to initiation of an FGFR inhibitor on trial. (A) Axial CT image with oral and intravenous contrast at the level of the mid pelvis shows a 3-cm soft tissue mass with minimal calcifications (red arrow). (B) Coronal reconstructed CT image with oral and intravenous contrast through the anterior abdomen and pelvis shows the 3-cm soft tissue mass with minimal calcifications (red arrow). CT scans of the abdomen and pelvis with contrast obtained during treatment with FGFR inhibitor on trial. (C) Axial CT image with oral and intravenous contrast at the level of the mid pelvis shows no measurable mass. (D) Coronal reconstructed CT image with oral and intravenous contrast through the anterior abdomen and pelvis shows no measurable mass.\n\nFigure 5. CT scans of the abdomen and pelvis with contrast shortly following discontinuation of trial with FGFR inhibitor. (A) Axial CT image shows no measurable mass. (B) Coronal reconstructed CT image shows no measurable mass. PET/CT scans 3 mo following cessation of the FGFR inhibitor on trial. (C) Axial CT image without oral or intravenous contrast at the mid pelvis shows a 3-cm mass with calcifications. (D) PET scan with coronal display shows an area of increased abnormal metabolic activity corresponding to the soft tissue mass (red arrow).\n\nThe patient was subsequently treated with the mTOR inhibitor temsirolimus based on recommendations from the MTB as an inferred downstream target of the PIK3CA alteration. Recommendations were not based on the TSC2 alteration, as this was a variant of unknown significance. She received temsirolimus for >17 mo with a few instances of the drug being withheld because of fever and neuropathy. Because of stable disease after >8 mo with foci showing mixed response and evidence from the treatment of breast cancer that mTOR inhibitors enhance the response to antiestrogen therapy, letrozole (2.5 mg/d orally) was added to the weekly regimen of temsirolimus (Baselga et al. 2009; Liu et al. 2014). The patient continued on temsirolimus and letrozole for nearly 9 additional months until disease progression was detected.\n\nDISCUSSION\nThe FGFR family is made up of four active members, FGFR1, FGFR2, FGFR3, and FGFR4 (Turner and Grose 2010). Alterations in these genes, such as amplifications, mutations, or translocations, may lead to the constitutive or increased activation of the tyrosine kinases in their protein products (Dutt et al. 2008; Turner and Grose 2010; Singh et al. 2012). Both in vitro and in vivo studies on cancer cells and tumors containing FGFR fusions suggest oncogenic potential and, therefore, potential growth impairment with FGFR-specific and pan-kinase inhibitors for different tumor subtypes.\n\nBecause of the unusual presentation of recurrent endometrial cancer affecting the spleen, CGP was performed on the tumor in the aforementioned case. This revealed that the tumor contained an FGFR3-TACC3 fusion and a missense mutation in PIK3CA (Table 1). TACC3, or transforming acidic coiled-coil containing protein 3, is involved in mitotic spindle organization and possible stemness properties of cells (Zhou et al. 2015). It is positioned on Chromosome 4 upstream of FGFR3. The FGFR3-TACC3 fusion event is believed to occur through a tandem duplication of a region of the chromosome where both genes exist, 4p16.3 (Parker et al. 2013). The fusion event, through the help of the coiled-coil domain on TACC3, increases autophosphorylation of tyrosine residues on the FGFR3 kinase domain and leads to a constitutively active FGFR3 protein (Fig. 6; Nelson et al. 2016). The frequency of alterations in uterine cancer for the genes altered in our patient case was reported by The Cancer Genome Atlas (TCGA) (Fig. 7; Cerami et al. 2012; Gao et al. 2013).\n\nFigure 6. Diagram of the formation of the FGFR3-TACC3 fusion protein product.\n\nFigure 7. Frequency of alterations found in FGFR3, PIK3CA, or TSC2 reported in uterine corpus endometrial carcinoma (TCGA Provisional) for 242 cases. The results shown here are based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.\n\nAlterations, including amplifications, deletions, and missense and nonsense mutations in FGFR genes, have previously been observed in endometrial cancers (Pollock et al. 2007; Dutt et al. 2008; Byron et al. 2012; Konecny et al. 2013; Helsten et al. 2016). Although the most frequently altered FGFR gene was FGFR2, with ∼15% of cases according to TCGA data, alterations in FGFR1, FGFR3, and FGFR4 have also been observed at a frequency of 6%, 5%, and 5%, respectively, in endometrial cancers (Fig. 8; Cerami et al. 2012; Gao et al. 2013).\n\nFigure 8. Percentages of uterine cancer cases with alterations in FGFR genes, as reported by TCGA for 242 cases (TCGA Provisional). The results shown here are based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.\n\nFGFR fusions, including FGFR-TACC fusions, have been observed among a variety of cancer types. For example, FGFR3-TACC3 fusions have been reported in a subset of bladder cancer (Williams et al. 2013; Wu et al. 2013), low-grade glioma (Granberg et al. 2017), glioblastoma (independently identified and reported by Singh et al. 2012 and Parker et al. 2013), nasopharyngeal carcinoma (Yuan et al. 2014), cervical cancer (Carneiro et al. 2015), head and neck squamous cell carcinoma (Wu et al. 2013), lung squamous cell carcinoma (Wu et al. 2013), and oral cancer (Wu et al. 2013). Helsten et al. (2016) reviewed the genomic profiling of nearly 5000 tumor samples from a variety of cancer types. They found one case out of 80 cases of endometrial cancer with an FGFR3-TACC3 fusion (Helsten et al. 2016). Additionally, data from Foundation Medicine, Inc. found four cases of endometrial cancer that contained an FGFR3-TACC3 fusion. Among 813 patients with endometrial adenocarcinoma (NOS), two patients (0.25%) had an FGFR3-TACC3 fusion. One of these patients included the patient featured in our case study. Additionally, one out of 64 patients (1.60%) with clear cell endometrial adenocarcinoma and one out of 419 patients (0.24%) with papillary serous endometrial adenocarcinoma had an FGFR3-TACC3 fusion. These data highlight the unique nature of these fusions in endometrial cancers. Details on the genomic breakpoints involved in these fusions are listed in Table 2. Our case sheds additional light on this rare but significant fusion event in endometrial cancer and follows the patient through treatment with targeted therapy.\n\nTable 2. Descriptions of the genomic breakpoints for the patients provided by Foundation Medicine, Inc.\n\nDisease ontologya\tGenomic breakpoints\t\nUterus endometrial adenocarcinoma (NOS)\tChr 4 duplication fragment: 5′-FGFR3(ex1-18 UTR NM_000142)-TACC3(ex10-16 NM_006342) Breakpoints FGFR3 exon 18, TACC3 intron 9\t\naUterus endometrial adenocarcinoma (NOS)\tChr 4 duplication fragment: 5′-FGFR3(ex1-17 NM_000142)-TACC3(ex8-16 NM_006342) Breakpoints FGFR3 exon 17, TACC3 exon 8\t\nUterus endometrial adenocarcinoma clear cell\tChr 4 duplication fragment: 5′-FGFR3(ex1-2 NM_000142)-TACC3(ex7-16 NM_006342) Breakpoints FGFR3 exon 2, TACC3 intron 6\t\nUterus endometrial adenocarcinoma papillary serous\tChr 4 duplication fragment: 5′-FGFR3(ex1-18 UTR NM_000142)-TACC3(ex10-16 NM_006342) Breakpoints FGFR3 exon 18, TACC3 intron 9\t\naHighlighted case results.\n\nDi Stefano et al. (2015) illustrated differential effectiveness of the FGFR inhibitor JNJ-42756493 on mouse astrocytes and human glioma stem cells expressing the FGFR3-TACC3 gene fusion versus similar cells lacking this fusion. The authors reported on two patients with recurrent glioblastoma who were found to have FGFR3-TACC3 fusions (breakpoints: FGFR3 exon 17 and TACC3 exon 6; FGFR3 exon 17 and TACC3 exon 8). Following treatment with the FGFR inhibitor JNJ-42756493 in the context of a clinical trial, stabilization of disease was observed for ∼16 and ∼19 wk, respectively, where 2 wk was equivalent to one cycle. Progression of disease was subsequently observed (Di Stefano et al. 2015). This drug has also been shown to lead to partial responses in patients with an FGFR3-TACC3-containing urothelial cancer and a decrease in tumor size in a patient with an adrenal cancer harboring this fusion (Tabernero et al. 2015).\n\nBefore developing toxicity, the patient in the present report was benefiting from the FGFR inhibitor within the context of a clinical trial. Other FGFR-specific inhibitors have been developed, though none has yet been FDA-approved for the treatment of solid tumors. The FGFR inhibitor PD173074 reduced the viability of nasopharyngeal carcinoma cells harboring a FGFR3-TACC3 fusion in a dose-dependent manner (Yuan et al. 2014). FGFR3-TACC3 showed constitutive FGFR kinase activity, followed by the inhibition of this activity with PD173074 in transduced human astrocytes and mouse glioma stemlike cells (Singh et al. 2012). NVP-BGJ398 demonstrated FGFR1-4 inhibition in human embryonic kidney cells (Guagnano et al. 2011), whereas LY2874455 exhibited inhibition of FGFR2 in human gastric carcinoma cell lines (Zhao et al. 2011). These studies and our present case provide the rationale for considering FGFR inhibitors for patients whose tumor genomic profiles indicate this fusion. More research is needed to understand the activity of FGFR3-TACC3 fusions on tumors and, consequently, to discover additional clinically relevant therapeutic options for endometrial cancer patients with this gene fusion.\n\nThis patient's tumor also harbored a PIK3CA mutation, which is another putative targetable alteration. PIK3CA is a gene encoding for a catalytic subunit within the PI3K molecule (Volinia et al. 1994). Alterations in PIK3CA are implicated in 41%–52% of endometrioid endometrial carcinomas and between 33% and 38% of nonendometrioid endometrial carcinomas (e.g., papillary serous histology, clear cell histology) (Slomovitz and Coleman 2012). PI3K inhibitors, although still experimental or in clinical trials, have been developed (Khan et al. 2013).\n\nTumors harboring PIK3CA mutations may benefit from mTOR inhibitors, as mTOR is a target downstream from PI3K (Khan et al. 2013). mTOR inhibitors are a class of drugs that target mutations in the PI3K/AKT/mTOR pathway and limit both tumor cell proliferation and progression through the cell cycle (Husseinzadeh and Husseinzadeh 2014). The predictive value of a PIK3CA mutation for mTOR inhibitor response has been inconsistent across tumor types. Other alterations in this tumor may account for drug response. For example, this tumor also carried a TSC2 rearrangement with a breakpoint in exon 26 but was reported as a variant of unknown significance. Germline mutations in TSC2 result in developmental defects seen in tuberous sclerosis (Jones et al. 1997; Dabora et al. 2001; Langkau et al. 2002). Although tuberous sclerosis is an autosomal dominant disease, the hamartomatous growths associated with this disease often include the loss of heterozygosity of TSC2 (or, less commonly, TSC1) (Carbonara et al. 1996; Kwiatkowski 2003). It is not known if this tumor displays loss of heterozygosity. This alteration disrupts TSC2 upstream of the GTPase-activating protein (GAP)-related domain (exons 34–38) and may confer relevant loss of function (Maheshwar et al. 1997). With loss-of-function mutations in TSC2, the protein is phosphorylated and inhibited by AKT, stimulating Rheb GTPase activity, and leading to the activation of mTOR (Maheshwar et al. 1997; Kwiatkowski 2003; Li et al. 2004; Dibble and Cantley 2015; Huynh et al. 2015). Exceptional responses have been observed in patients with otherwise aggressive, TSC2-mutated tumors with mTOR inhibitor therapy (Wagle et al. 2014). Because retrospective analysis of this tumor did not reveal expression of estrogen receptor (not shown), the 17-mo clinical benefit experienced by this patient was likely due to mTOR inhibition. The observed clinical benefit strongly implicates the TSC2 rearrangement as being functional, although a benefit due to other upstream alterations cannot be ruled out.\n\nMETHODS\nThis patient was evaluated at the Rutgers CINJ and provided informed consent to participate in a prospective study trial for tumor genomic profiling (NCT02688517). This trial was approved by the Rutgers University New Brunswick Health Sciences IRB (Pro2012002075). Clinical records were abstracted for relevant patient history and tumor characteristics; data were abstracted until the end of October 2015, therefore, subsequent data were not reflected in this manuscript. Medical history, pathology, radiology, clinical course, and genomic profiling results were reviewed in an anonymized fashion at a formal MTB. Profiling results were discussed in the context of clinical course, tumor type, mutational frequency, role in cell pathways contributing to cancer biology, and considerations for future therapy including consensus recommendations for clinical trials, FDA-approved therapies (on or off label), and genetic counseling, if appropriate. The patient was followed prospectively for clinical course. The protocol for tumor genomic profiling was approved by the Institutional Review Board of Rutgers Robert Wood Johnson Medical School.\n\nFor the additional patients provided by Foundation Medicine, Inc., approval for this study, including a waiver of informed consent and a HIPAA waiver of authorization, was obtained from the Western Institutional Review Board (Protocol No. 20152817).\n\nComprehensive Genomic Profiling\nDetails on the sequencing methodology used in this study can be found in Frampton et al. (2013). Routine formalin-fixed, paraffin-embedded (FFPE) tissue was sent to Foundation Medicine, Inc. for CGP using the CLIA-certified FoundationOne platform (Frampton et al. 2013). Targeted sequencing of the entire coding sequence was done for 236 genes and 47 introns of 19 genes involved in fusions at a depth of 500×–1000× (median exon depth of 792×; 100% of the baited region was sequenced at a depth of at least 100×; sequence alignment error of only 0.27%). The depth of variant call reads was 59×; these 59 chimeric reads equate to an independently validated variant calling method described in Frampton et al. (2013). The depth of wild-type reads was 1155× (please see Supplemental Table S1).\n\nPathology\nH&E-stained slides of tissue samples at various time points in the clinical care of the case patient were reviewed by Pathology.\n\nRadiology\nCT scans of the abdomen and pelvis (axial and coronal reconstructed), with or without oral/intravenous contrast, were performed at various time points in the clinical care of the case patient. A PET scan with coronal display was also performed. The scans were reviewed by J.K.A. and L.R.-R. RECIST criteria were used to determine response based on CT scan imaging (Eisenhauer et al. 2009).\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe genomic variants for our patient case were deposited into ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV000693748–SCV000693750.\n\nEthics Statement\nThe patient provided informed consent to participate in the Rutgers CINJ genomic tumor profiling protocol (NCT02688517), which was approved by the Institutional Review Board (IRB) of Rutgers University New Brunswick Health Sciences (Pro2012002075).\n\nAcknowledgments\nWe thank the patient, Natasha Nicholson, Frances DiClemente, Joseph Miktus, and service provided by the Biospecimen Repository Service Core Facility. We thank Jennifer Hostettler for assistance with drafting and editing.\n\nAuthor Contributions\nJ.D. contributed to manuscript preparation; K.M.H. contributed to genomic data interpretation and manuscript preparation; S.G. contributed to genomic data interpretation and manuscript preparation; M.H. contributed to patient care and manuscript preparation; V.R. contributed to manuscript preparation; J.K.A. contributed to manuscript preparation and data interpretation; G.M.R. contributed to manuscript preparation and data interpretation; H.Z. contributed to manuscript preparation and data interpretation; S.M.A. contributed to comprehensive genomic profiling, data analysis, and manuscript preparation; D.P. contributed to comprehensive genomic profiling, data analysis, and manuscript preparation; J.A.E. contributed to comprehensive genomic profiling, data analysis, and manuscript preparation; L.R.-R. contributed to patient care, genomic data interpretation, and manuscript preparation.\n\nFunding\nThis research was supported by a generous gift to the Genetics Diagnostics to Cancer Treatment Program of the Rutgers Cancer Institute of New Jersey and RUCDR Infinite Biologics and by the National Institutes of Health (NIH) P30CA072720.\n\nCompeting Interest Statement\nS.G. serves on a scientific advisory board and as consultant to Inspirata, Inc., and has equity in Inspirata, Inc.; serves on an advisory board for Novartis Pharmaceuticals; and has patents on digital imaging technology licensed to Inspirata, Inc. S.M.A. is an employee of Foundation Medicine Inc. D.P. is an employee of Foundation Medicine Inc. J.A.E. is an employee of Foundation Medicine Inc.\n\nReferees\nWei Zhang\n\nAnonymous\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nBaselga J , Semiglazov V , van Dam P , Manikhas A , Bellet M , Mayordomo J , Campone M , Kubista E , Greil R , Bianchi G , \n2009 \nPhase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer . J Clin Oncol \n27 : 2630 –2637 .19380449 \nByron SA , Gartside M , Powell MA , Wellens CL , Gao F , Mutch DG , Goodfellow PJ , Pollock PM . 2012 \nFGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features . 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Eur J Pediatr \n161 : 393 –402 .12111193 \nLee PS , Secord AA . 2014 \nTargeting molecular pathways in endometrial cancer: a focus on the FGFR pathway . Cancer Treat Rev \n40 : 507 –512 .24332498 \nLi Y , Corradetti MN , Inoki K , Guan KL . 2004 \nTSC2: filling the GAP in the mTOR signaling pathway . Trends Biochem Sci \n29 : 32 –38 .14729330 \nLiu Y , Zhang X , Liu J , Hou G , Zhang S , Zhang J . 2014 \nEverolimus in combination with letrozole inhibit human breast cancer MCF-7/Aro stem cells via PI3K/mTOR pathway: an experimental study . Tumour Biol \n35 : 1275 –1286 .24014089 \nMaheshwar MM , Cheadle JP , Jones AC , Myring J , Fryer AE , Harris PC , Sampson JR . 1997 \nThe GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis . Hum Mol Genet \n6 : 1991 –1996 .9302281 \nMcConechy MK , Ding J , Cheang MC , Wiegand KC , Senz J , Tone AA , Yang W , Prentice LM , Tse K , Zeng T , \n2012 \nUse of mutation profiles to refine the classification of endometrial carcinomas . J Pathol \n228 : 20 –30 .22653804 \nMeric-Bernstam F , Johnson A , Holla V , Bailey AM , Brusco L , Chen K , Routbort M , Patel KP , Zeng J , Kopetz S , \n2015 \nA decision support framework for genomically informed investigational cancer therapy . J Natl Cancer Inst \n107 : djv098 .25863335 \nMorice P , Leary A , Creutzberg C , Abu-Rustum N , Darai E . 2016 \nEndometrial cancer . Lancet \n387 : 1094 –1108 .26354523 \nNational Cancer Institute . 2002 \nEndometrial cancer treatment (PDQ®): patient version . In PDQ cancer information summaries , http://www.ncbi.nlm.nih.gov/books/NBK65896/?report=printable .\nNational Comprehensive Cancer Network . 2014 \nNCCN clinical practice guidelines in oncology (NCCN guidelines®): uterine neoplasms . Version 2.2015 \nNational Comprehensive Cancer Network , Fort Washington, PA .\nNelson KN , Meyer AN , Siari A , Campos AR , Motamedchaboki K , Donoghue DJ . 2016 \nOncogenic gene fusion FGFR3-TACC3 is regulated by tyrosine phosphorylation . Mol Cancer Res \n14 : 458 –469 .26869289 \nParker BC , Annala MJ , Cogdell DE , Granberg KJ , Sun Y , Ji P , Li X , Gumin J , Zheng H , Hu L , \n2013 \nThe tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma . J Clin Invest \n123 : 855 –865 .23298836 \nPollock PM , Gartside MG , Dejeza LC , Powell MA , Mallon MA , Cancer Genome Project , Davies H , Mohammadi M , Futreal PA , Stratton MR , Trent JM , \n2007 \nFrequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes . Oncogene \n26 : 7158 –7162 .17525745 \nRauh-Hain JA , Del Carmen MG . 2010 \nTreatment for advanced and recurrent endometrial carcinoma: combined modalities . Oncologist \n15 : 852 –861 .20660059 \nSiegel RL , Miller KD , Jemal A . 2016 \nCancer statistics, 2016 . CA Cancer J Clin \n66 : 7 –30 .26742998 \nSingh D , Chan JM , Zoppoli P , Niola F , Sullivan R , Castano A , Liu EM , Reichel J , Porrati P , Pellegatta S , \n2012 \nTransforming fusions of FGFR and TACC genes in human glioblastoma . Science \n337 : 1231 –1235 .22837387 \nSlomovitz BM , Coleman RL . 2012 \nThe PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer . Clin Cancer Res \n18 : 5856 –5864 .23082003 \nTabernero J , Bahleda R , Dienstmann R , Infante JR , Mita A , Italiano A , Calvo E , Moreno V , Adamo B , Gazzah A , \n2015 \nPhase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors . J Clin Oncol \n33 : 3401 –3408 .26324363 \nTemkin SM , Fleming G . 2009 \nCurrent treatment of metastatic endometrial cancer . Cancer Control \n16 : 38 –45 .19078928 \nThe Cancer Genome Atlas Research Network , Kandoth C , Schultz N , Cherniack AD , Akbani R , Liu Y , Shen H , Robertson AG , Pashtan I , Shen R , \n2013 \nIntegrated genomic characterization of endometrial carcinoma . Nature \n497 : 67 –73 .23636398 \nTobin NP , Foukakis T , De Petris L , Bergh J . 2015 \nThe importance of molecular markers for diagnosis and selection of targeted treatments in patients with cancer . J Intern Med \n278 : 545 –570 .26373821 \nTrabert B , Wentzensen N , Felix AS , Yang HP , Sherman ME , Brinton LA . 2015 \nMetabolic syndrome and risk of endometrial cancer in the United States: a study in the SEER-medicare linked database . Cancer Epidemiol Biomarkers Prev \n24 : 261 –267 .25587111 \nTurner N , Grose R . 2010 \nFibroblast growth factor signalling: from development to cancer . Nat Rev Cancer \n10 : 116 –129 .20094046 \nVolinia S , Hiles I , Ormondroyd E , Nizetic D , Antonacci R , Rocchi M , Waterfield MD . 1994 \nMolecular cloning, cDNA sequence, and chromosomal localization of the human phosphatidylinositol 3-kinase p110 α (PIK3CA) gene . Genomics \n24 : 472 –477 .7713498 \nWagle N , Grabiner BC , Van Allen EM , Amin-Mansour A , Taylor-Weiner A , Rosenberg M , Gray N , Barletta JA , Guo Y , Swanson SJ , \n2014 \nResponse and acquired resistance to everolimus in anaplastic thyroid cancer . N Engl J Med \n371 : 1426 –1433 .25295501 \nWilliams SV , Hurst CD , Knowles MA . 2013 \nOncogenic FGFR3 gene fusions in bladder cancer . Hum Mol Genet \n22 : 795 –803 .23175443 \nWu YM , Su F , Kalyana-Sundaram S , Khazanov N , Ateeq B , Cao X , Lonigro RJ , Vats P , Wang R , Lin SF , \n2013 \nIdentification of targetable FGFR gene fusions in diverse cancers . Cancer Discov \n3 : 636 –647 .23558953 \nYuan L , Liu ZH , Lin ZR , Xu LH , Zhong Q , Zeng MS . 2014 \nRecurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma . Cancer Biol Ther \n15 : 1613 –1621 .25535896 \nZhao G , Li WY , Chen D , Henry JR , Li HY , Chen Z , Zia-Ebrahimi M , Bloem L , Zhai Y , Huss K , \n2011 \nA novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models . Mol Cancer Ther \n10 : 2200 –2210 .21900693 \nZhou DS , Wang HB , Zhou ZG , Zhang YJ , Zhong Q , Xu L , Huang YH , Yeung SC , Chen MS , Zeng MS . 2015 \nTACC3 promotes stemness and is a potential therapeutic target in hepatocellular carcinoma . Oncotarget \n6 : 24163 –24177 .26219398\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "4(2)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "endometrial carcinoma",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D014408:Biomarkers, Tumor; D001706:Biopsy; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion; D000072078:Positron Emission Tomography Computed Tomography; D051498:Receptor, Fibroblast Growth Factor, Type 3; D014057:Tomography, X-Ray Computed; D059467:Transcriptome; D016896:Treatment Outcome",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29588307",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25535896;9302281;23175443;11112665;23418312;12111193;21119661;28379477;26219398;17525745;21900693;26159692;25863335;25724664;25609060;25295501;24556063;18552176;26373821;19380449;20660059;23082003;26023091;23550210;21984976;14729330;21936542;7713498;22653804;26425723;19097774;23298836;8824721;20094046;22837387;24142049;19078928;26373574;24014089;26354523;26869289;22588877;23636398;22383975;9328481;23558953;26742998;14614311;26324363;23443805;24332498;25587111;23642907",
"title": "Comprehensive genomic profiling aids in treatment of a metastatic endometrial cancer.",
"title_normalized": "comprehensive genomic profiling aids in treatment of a metastatic endometrial cancer"
} | [
{
"companynumb": "US-PFIZER INC-2018137714",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nClinical trial data have shown apremilast, an oral phosphodiesterase-4 inhibitor, to be efficacious and safe for the treatment of psoriasis. However, little real-world experience using apremilast in the community setting has been documented.\n\n\nOBJECTIVE\nMany patients with psoriasis are often unresponsive to various treatment modalities, including topical, systemic, and biologic medications. The aim of this chart review was to assess the overall patient experience while using apremilast to treat psoriasis.\n\n\nMETHODS\nA retrospective chart review of electronic medical records was conducted of all patients prescribed apremilast in a community dermatology practice.\n\n\nRESULTS\nOf 99 patients who were prescribed apremilast, 81 patients took at least 1 dose. In 63 patients, apremilast improved clinical disease severity, with 37% of patients achieving a body surface area <1%. As a treatment, it was generally well tolerated and caused no serious adverse events. The most commonly reported side effect resulting in discontinuation of treatment of apremilast was nausea and vomiting.\n\n\nCONCLUSIONS\nOverall, apremilast was a safe and well-tolerated treatment with significant clinical improvement in our patient population.",
"affiliations": "1 University of Manitoba Faculty of Health Sciences, College of Medicine, Winnipeg, MB, Canada.;2 Queen's University, Kingston, ON, Canada.",
"authors": "Mayba|Julia N|JN|;Gooderham|Melinda J|MJ|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013792:Thalidomide; C505730:apremilast",
"country": "United States",
"delete": false,
"doi": "10.1177/1203475416676030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1203-4754",
"issue": "21(2)",
"journal": "Journal of cutaneous medicine and surgery",
"keywords": "apremilast; phosphodiesterase-4 inhibitors; psoriasis; real-world application; systemic therapy",
"medline_ta": "J Cutan Med Surg",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea; D010789:Phototherapy; D011565:Psoriasis; D019233:Retreatment; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013792:Thalidomide; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "9614685",
"other_id": null,
"pages": "145-151",
"pmc": null,
"pmid": "27846617",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-World Experience With Apremilast in Treating Psoriasis.",
"title_normalized": "real world experience with apremilast in treating psoriasis"
} | [
{
"companynumb": "CA-CELGENEUS-CAN-20170606418",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"drugadditional": null,
... |
{
"abstract": "The incidence of spinal surgical site infections (SSIs) remains stable at less than 10%. Surgical reinterventions may be hampered by decubitus, treatment-related adverse events, and cost. In the context of emergence of bacterial resistance, a short duration of antimicrobial treatment is of critical importance. If the duration of treatment for SSI is currently 12 weeks, the aim of our study was to assess the efficacy of an antimicrobial treatment shortened to 6 weeks.\n\n\n\nThis prospective study was carried out from November 2014 to July 2016 in an 827-bed teaching hospital. After surgical management of SSIs, patients received broad-spectrum antibiotics intravenously for 10 days and orally for the remainder, for a total of 6 weeks. Success was defined as absence of relapse, superinfection, or surgical failure at the end of treatment and at 1-year follow-up.\n\n\n\nEighty-five patients were included in this study. The median delay between initial surgery and diagnosis of SSI was 16 days. In 65 cases (76.4%), SSIs were monomicrobial; among these, Staphylococcus aureus was found in 30 cases (46%). Failure was observed in 7 cases (8.2%), with more than half caused by anaerobic bacteria.\n\n\n\nSurgical management of SSI followed by a 6-week antibiotic treatment is associated with favorable outcome. Anaerobic bacteria seem to play a role in the occurrence of relapses. A 6-week reduction in antibiotic treatment leads to reduction in cost and, likely, also to reduction in the emergence and spread of resistant microorganisms.",
"affiliations": "Unité Mobile de Microbiologie Clinique, Service de Microbiologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.;Service d'Orthopédie et de Traumatologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.;Unité Mobile de Microbiologie Clinique, Service de Microbiologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.;Unité Mobile de Microbiologie Clinique, Service de Microbiologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.;Faculté de Médecine, Université Paris Descartes, Paris, France.;Unité Mobile de Microbiologie Clinique, Service de Microbiologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.;Faculté de Médecine, Université Paris Descartes, Paris, France.",
"authors": "Fernandez-Gerlinger|Marie-Paule|MP|;Arvieu|Robin|R|;Lebeaux|David|D|;Rouis|Karama|K|;Guigui|Pierre|P|;Mainardi|Jean-Luc|JL|;Bouyer|Benjamin|B|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciy805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "68(11)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "6-week antibiotic therapy; spinal surgery; surgical site infection",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000368:Aged; D000900:Anti-Bacterial Agents; D001421:Bacteria, Anaerobic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013131:Spine; D013211:Staphylococcus aureus; D013530:Surgical Wound Infection; D062606:Tertiary Care Centers; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1856-1861",
"pmc": null,
"pmid": "30247513",
"pubdate": "2019-05-17",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Successful 6-Week Antibiotic Treatment for Early Surgical-site Infections in Spinal Surgery.",
"title_normalized": "successful 6 week antibiotic treatment for early surgical site infections in spinal surgery"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1076438",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "For most patients suffering from recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), chemotherapy is the main option after considering surgery and reirradiation. Cetuximab combined with a platinum-fluorouracil regimen (EXTREME) has been the standard of care for over a decade. Nevertheless, a significant number of patients remain unfit for this regimen because of age, severe comorbidities, or poor performance status. The aim of this study is to investigate an alternative regimen with sufficient efficacy and safety.\nWe reviewed retrospectively the medical charts of all patients treated with paclitaxel, carboplatin, and cetuximab (PCC) at our institution. Eligibility criteria were as follows: first-line R/M-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx not suitable for local therapy, cisplatin, and/or 5-FU ineligibility, ECOG-PS: 0-2. PCC consisted of paclitaxel 80 mg/m2, carboplatin AUC 2, and cetuximab at an initial dose of 400 mg/m2 then 250 mg/m2, for 16 weekly administrations followed by cetuximab maintenance for patients for whom a disease control was obtained. The primary endpoint was overall survival (OS), and secondary endpoints were overall response rate (ORR), progression free survival (PFS), and safety.\nWe identified 60 consecutive patients treated with PCC between 2010 and 2016 at our institution. Thirty-one patients (52%) were ECOG-PS 2. Fifty-five patients (92%) were cisplatin ineligible. ORR was 43.3% (95% CI, 30.8-55.8), and disease control rate was 65% (95% CI, 52.9-77.1). With a median follow-up of 35.7 months (IQR 28.6-48.8), median PFS was 5.8 months (95% CI, 4.5-7.2), and median OS was 11.7 months (95% CI, 7.5-14.8). For ECOG-PS 0-1 patients, median OS was 14.8 months (95% CI, 12.2-21.7) while it was only 7.5 months (95%CI: 5.5-12.7) for ECOG-PS 2 patients (p < 0.04). Grades III-IV toxicities occurred in 30 patients (50%). Most toxicities were hematologic. Six patients (10%) had febrile neutropenia. Nonhematologic toxicities were reported such as cutaneous toxicities, neuropathy, infusion-related reactions, or electrolyte disorders.\nThe weekly PCC regimen seems to be an interesting option in cisplatin-unfit patients. This study shows favorable PFS and OS when compared with what is achieved with the EXTREME regimen and a high controlled disease rate with predictable and manageable toxicities even in the more fragile population.",
"affiliations": "Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France.;Centre Paul Strauss, Department of Medical Oncology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Radiation Oncology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Radiation Oncology, Strasbourg, France.;Clinique Sainte Barbe, Head and Neck Surgery Unit, Strasbourg, France.;Clinique Sainte Barbe, Head and Neck Surgery Unit, Strasbourg, France.;Hôpitaux Universitaires de Strasbourg, Department of Otorhinolaryngology and Head and Neck Surgery, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Supportive Care Unit, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Biostatistics, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Laboratoire de Biologie Tumorale, Strasbourg, France.;Centre Paul Strauss, Department of Radiology, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Pharmacy Department, Strasbourg, France.;Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France.",
"authors": "Carinato|Hélène|H|;Burgy|Mickaël|M|;Ferry|Régine|R|;Fischbach|Cathie|C|;Kalish|Michal|M|;Guihard|Sébastien|S|;Brahimi|Youssef|Y|;Flesch|Henri|H|;Bronner|Guy|G|;Schultz|Philippe|P|;Frasie|Véronique|V|;Thiéry|Alicia|A|;Demarchi|Martin|M|;Petit|Thierry|T|;Jung|Alain C|AC|;Wagner|Pierre|P|;Coliat|Pierre|P|;Borel|Christian|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.714551",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.714551\nOncology\nOriginal Research\nWeekly Paclitaxel, Carboplatin, and Cetuximab as First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma for Patients Ineligible to Cisplatin-Based Chemotherapy: A Retrospective Monocentric Study in 60 Patients\nCarinato Hélène 1\n\nBurgy Mickaël 1\n\nFerry Régine 2 †\nFischbach Cathie 1\nKalish Michal 1\nGuihard Sébastien 3\nBrahimi Youssef 3\nFlesch Henri 4\nBronner Guy 4\nSchultz Philippe 5\n\nFrasie Véronique 6\n\nThiéry Alicia 7\nDemarchi Martin 1\nPetit Thierry 1\n\nJung Alain C. 8 9\nWagner Pierre 10\nColiat Pierre 11\n\nBorel Christian 1 *\n\n1 Institut de Cancérologie Strasbourg Europe, Department of Medical Oncology, Strasbourg, France\n2 Centre Paul Strauss, Department of Medical Oncology, Strasbourg, France\n3 Institut de Cancérologie Strasbourg Europe, Department of Radiation Oncology, Strasbourg, France\n4 Clinique Sainte Barbe, Head and Neck Surgery Unit, Strasbourg, France\n5 Hôpitaux Universitaires de Strasbourg, Department of Otorhinolaryngology and Head and Neck Surgery, Strasbourg, France\n6 Institut de Cancérologie Strasbourg Europe, Supportive Care Unit, Strasbourg, France\n7 Institut de Cancérologie Strasbourg Europe, Department of Biostatistics, Strasbourg, France\n8 Institut de Cancérologie Strasbourg Europe, Laboratoire de Biologie Tumorale, Strasbourg, France\n9 Université de Strasbourg, Inserm, UMR_S1113, Strasbourg, France\n10 Centre Paul Strauss, Department of Radiology, Strasbourg, France\n11 Institut de Cancérologie Strasbourg Europe, Pharmacy Department, Strasbourg, France\nEdited by: Christophe Le Tourneau, Institut Curie, France\n\nReviewed by: Valerio Voliani, Italian Institute of Technology (IIT), Italy; Jérôme Fayette, Centre Léon Bérard, France\n\n*Correspondence: Christian Borel, c.borel@icans.eu\nThis article was submitted to Head and Neck Cancer, a section of the journal Frontiers in Oncology\n\n†Present Address:Régine Ferry, Hematology Department, CHRU de Nancy Hôpital Brabois, Vandoeuvre les Nancy, France\n\n27 10 2021\n2021\n11 71455125 5 2021\n17 9 2021\nCopyright © 2021 Carinato, Burgy, Ferry, Fischbach, Kalish, Guihard, Brahimi, Flesch, Bronner, Schultz, Frasie, Thiéry, Demarchi, Petit, Jung, Wagner, Coliat and Borel\n2021\nCarinato, Burgy, Ferry, Fischbach, Kalish, Guihard, Brahimi, Flesch, Bronner, Schultz, Frasie, Thiéry, Demarchi, Petit, Jung, Wagner, Coliat and Borel\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nObjective\n\nFor most patients suffering from recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), chemotherapy is the main option after considering surgery and reirradiation. Cetuximab combined with a platinum-fluorouracil regimen (EXTREME) has been the standard of care for over a decade. Nevertheless, a significant number of patients remain unfit for this regimen because of age, severe comorbidities, or poor performance status. The aim of this study is to investigate an alternative regimen with sufficient efficacy and safety.\n\nMethods\n\nWe reviewed retrospectively the medical charts of all patients treated with paclitaxel, carboplatin, and cetuximab (PCC) at our institution. Eligibility criteria were as follows: first-line R/M-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx not suitable for local therapy, cisplatin, and/or 5-FU ineligibility, ECOG-PS: 0–2. PCC consisted of paclitaxel 80 mg/m2, carboplatin AUC 2, and cetuximab at an initial dose of 400 mg/m2 then 250 mg/m2, for 16 weekly administrations followed by cetuximab maintenance for patients for whom a disease control was obtained. The primary endpoint was overall survival (OS), and secondary endpoints were overall response rate (ORR), progression free survival (PFS), and safety.\n\nResults\n\nWe identified 60 consecutive patients treated with PCC between 2010 and 2016 at our institution. Thirty-one patients (52%) were ECOG-PS 2. Fifty-five patients (92%) were cisplatin ineligible. ORR was 43.3% (95% CI, 30.8–55.8), and disease control rate was 65% (95% CI, 52.9–77.1). With a median follow-up of 35.7 months (IQR 28.6–48.8), median PFS was 5.8 months (95% CI, 4.5–7.2), and median OS was 11.7 months (95% CI, 7.5-14.8). For ECOG-PS 0–1 patients, median OS was 14.8 months (95% CI, 12.2–21.7) while it was only 7.5 months (95%CI: 5.5-12.7) for ECOG-PS 2 patients (p < 0.04). Grades III–IV toxicities occurred in 30 patients (50%). Most toxicities were hematologic. Six patients (10%) had febrile neutropenia. Nonhematologic toxicities were reported such as cutaneous toxicities, neuropathy, infusion-related reactions, or electrolyte disorders.\n\nConclusion\n\nThe weekly PCC regimen seems to be an interesting option in cisplatin-unfit patients. This study shows favorable PFS and OS when compared with what is achieved with the EXTREME regimen and a high controlled disease rate with predictable and manageable toxicities even in the more fragile population.\n\nhead and neck squamous cell carcinoma\nrecurrent or metastatic\nchemotherapy\ncetuximab\npaclitaxel\ncarboplatin\nfirst-line\n==== Body\npmcIntroduction\n\nHead and neck squamous cell carcinoma (HNSCC) represent more than 90% of the head and neck tumors. In Europe, approximately 140,000 new cases were diagnosed in 2014, corresponding to an annual incidence of 43/100,000. The main risk factors of HNSSC are tobacco with alcohol heavy/frequent consumption and HPV infection (1). In France, most patients are active or former smokers frequently in association with a high consumption of alcohol. Thus, they are likely to suffer from several active tobacco/alcohol-related comorbidities, undernourishment, and other active carcinomas. Considering significant concomitant nonmalignant diseases, age and general condition are crucial in oncological decision-making because a vast majority of patients turns out to be ineligible for clinical trial or standard of care (2).\n\nConcerning recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M HNSCC), palliative chemotherapy is the standard of care if local treatment (surgery or radiotherapy) cannot be curative. There is a need to find an optimal strategy to achieve the highest possible overall survival and patient’s quality of life. In 2008, the EXTREME trial (3) showed the benefits of adding cetuximab to a platinum-5-FU chemotherapy in R/M HNSCC first-line treatment. An overall response rate (ORR) of 36% was achieved, median progression free survival (PFS) was 5.6 months, and median overall survival (OS) was 10.1 months. The EXTREME regimen has emerged as the standard of care for fit R/M HNSCC patients. Nevertheless, numerous patients remain unfit for this regimen because of frailties such as age, ECOG-PS >1, or heavy comorbidities, as evidenced by 82% of grades III–IV toxicities (3).\n\nOther treatments consisting of a platinum-based chemotherapy associated with taxanes (docetaxel or paclitaxel) were investigated for HNSCC including R/M HNSCC (4). In a phase II trial (5), docetaxel combined with a cisplatin and cetuximab regimen (TPEx) achieved promising outcomes with a 44.4% ORR and a 79.6% disease control rate (DCR). Thus, the same authors carried out a phase II randomized trial (TPExtreme), comparing TPEx with EXTREME in terms of efficacy and safety (6). Results suggest that taxanes are an option in first-line treatment. However, this regimen should be used exclusively in cisplatin fit patients.\n\nTherefore, some studies investigated alternative polychemotherapies in nonfit patients. Carboplatin with weekly paclitaxel is a safe and recommended option in the elderly population affected by advanced nonsmall cell lung cancer (7). In R/M HNSCC as well, some smaller nonrandomized studies demonstrated that first-line weekly carboplatin and paclitaxel could be safely used and improved efficacy when compared with monotherapy schedules in unfit patients (8). The paclitaxel, carboplatin, and cetuximab (PCE) regimen showed a 40% ORR, 5.2 months median PFS, and a 14.7-month median OS as first-line treatment in R/M HNSCC patients (9). The weekly paclitaxel, carboplatin, and cetuximab (PCC) regimen was first reported with promising results by Kies et al. in the locally advanced setting with a high dose of paclitaxel (10). The aim of this study is to provide a deeper insight into the weekly PCC efficacy and safety in the first-line R/M setting.\n\nPatients and Methods\n\nPatient Selection\n\nWe retrospectively reviewed data from medical charts at our institution (Centre Paul Strauss, Strasbourg, France) between January 2010 and December 2016 to identify patients treated with paclitaxel, carboplatin, and cetuximab and suffering from histologically confirmed SCC of the oral cavity, oropharynx, larynx, hypopharynx, or cervical lymph node from assumed HNSCC. Patients with skin SCC and sinus or nasopharynx carcinoma with poor differentiation were not selected.\n\nAdult patients (aged 18 or older) in first-line treatment of a metastatic and/or recurrent HNSCC with no curative intent, ECOG-PS 0-2, and cisplatin and/or 5-FU ineligibility were included. Patients were considered cisplatin ineligible if at least one of the following criteria was met: age ≥70 or ECOG-PS 2 or creatinine clearance <60 ml/min or significant active comorbidities or cisplatin free interval <6 months. Patients were considered 5-FU ineligible in case of severe cardiovascular previous history including coronary insufficiency whether or not complicated by myocardial infarction, heart insufficiency, or lower limb arteriopathy of at least stage II. A treatment by radiotherapy or surgery for a previous locoregional relapse was permitted.\n\nInduction regimen and palliative second-line or further treatment by PCC were excluded of the analysis.\n\nThe selection process is shown in Figure 1 .\n\nFigure 1 Selection process.\n\nTreatment\n\nFrom January 2010 to January 2012, we administered the PCC regimen as follows: carboplatin AUC 5 on day 1; paclitaxel 80 mg/m² on days 1, 8, and 15; and cetuximab 400 mg/m² loading dose then 250 mg/m² weekly. This pattern was repeated on day 22. A maximum of six cycles was administrated followed by a cetuximab maintenance given weekly or biweekly until progressive disease or unacceptable toxicities. However, administering carboplatin once every 3 weeks caused hematologic toxicity to such an extent that it became frequently impossible to administer paclitaxel on D15 and even sometime on D8.\n\nThus, from February 2012 to December 2016, the carboplatin infusion schedule was modified switching to a weekly administration: weekly carboplatin AUC 2 (maximum dose of 220 mg); paclitaxel 80 mg/m²; and cetuximab 400 mg/m² loading dose then 250 mg/m². A maximum of 16 cycles was performed followed by a cetuximab maintenance given weekly (250 mg/m²) or every 2 weeks (500 mg/m²) until progressive disease or unacceptable toxicities.\n\nDoses could be reduced initially or during treatment according to patient’s comorbidities or toxicities.\n\nAssessment\n\nThe efficacy of the protocol was assessed on the basis of response rate, progression-free survival and overall survival. A computed tomographic scan (or 18F-FDG PET/CT if needed) was performed at baseline, then every eight weeks. Measurements were compared between baseline and 8th-week CT scan (or 18F-FDG PET/CT) according to RECIST 1.1 criteria. The ORR is the complete response (CR) rate plus the partial response (PR) rate. The DCR is the ORR plus the stable disease (SD) rate. Radiologically, unevaluable patients were considered progressive if clinical reports mentioned it.\n\nToxicities were monitored weekly throughout the treatment and evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Dose intensity data were calculated in order to assess regimen feasibility.\n\nStatistical Analysis\n\nPFS (time from first PCC infusion to progression or death) and OS (time from first PCC infusion to death) were estimated by the Kaplan-Meier method. If progression or death did not occur before the cutoff date, data were censored at the time of the last valid assessment.\n\nThe follow-up time is calculated from first PCC infusion to data cutoff (16 Jun 2018).\n\nResults\n\nPatient Characteristics\n\nSixty patients were treated with the first-line combination of paclitaxel and carboplatin plus cetuximab for a R/M HNSCC at our institution between January 2010 and December 2016. Median age was 61, with 10 patients (17%) aged 70 or more. Sex ratio was 5:1. In our study, the main risk factor was tobacco smoking as 80% of patients were former or current smokers. HPV infection was only assessed in two patients with oropharyngeal SCC by using p16 immunohistochemistry as a surrogate marker: one patient was p16 positive, the other one was not.\n\nFive patients were diagnosed with distant metastases at the initial assessment and received PCC as a first treatment. Fifty-five patients had been pretreated with surgery and/or chemoradiotherapy. Fifteen patients in a recurrent setting had received locoregional treatments with a curative intent (such as surgery or reirradiation).\n\nForty-six patients (77%) were diagnosed with a locoregional relapse, among whom 38 patients in the field of an earlier irradiation. Twenty-nine patients (48%) had been already treated with platinum-based regimen in a neoadjuvant setting (18%) and/or with concurrent radiotherapy (32%) as a multimodality treatment of their initial tumor. Platinum-free interval was less than 3 months in 11 patients (18% of the whole patient population), between 3 and 6 months in three patients (5%) and longer than 6 months in 15 patients (25%). Because of a cisplatin-related kidney failure after a single course of TPEx, one patient received subsequently a PCC regimen. Patient characteristics are summarized in Table 1 .\n\nTable 1 Baseline characteristics of the patients.\n\nVariable\t\tN = 60\t\nGender [n (%)]\tn\t60\t\n\tMale\t50 (83)\t\n\tFemale\t10 (17)\t\nAge (years)\tMedian\t61\t\n\tRange\t23–79\t\nAge [n (%)]\tn\t60\t\n\t<65 years\t36 (60)\t\n\t65–69 years\t14 (23)\t\n\t≥70 years\t10 (17)\t\nECOG-PS [n (%)]\tn\t60\t\n\t0\t9 (15)\t\n\t1\t20 (33)\t\n\t2\t31 (52)\t\nTobacco status [n (%)]\tn\t60\t\n\tNonsmoker\t12 (20)\t\n\tCurrent or former smoker\t48 (80)\t\nPrimary tumor localization [n (%)]\tn\t60\t\n\tOropharynx\t23 (40)\t\n\tOral cavity\t17 (28)\t\n\tHypopharynx\t12 (20)\t\n\tLarynx\t7 (12)\t\n\tUnknown\t1 (2)\t\nHistologic type [n (%)]\tn (not specified or missing)\t38 (22)\t\n\tWell differentiated\t8 (21)\t\n\tModerately differentiated\t23 (60)\t\n\tPoorly differentiated\t7 (18)\t\nInitial treatment [n (%)]\tn\t60\t\n\tNeoadjuvant chemotherapy + Surgery\t5 (8)\t\n\tNeoadjuvant chemotherapy + Surgery + CRT\t1 (2)\t\n\tNeoadjuvant chemotherapy + CRT (cetuximab)\t5 (8)\t\n\tSurgery\t9 (15)\t\n\tSurgery + RT\t6 (10)\t\n\tSurgery + CRT (platin-based)\t15 (25)\t\n\tSurgery + CRT (other)\t7 (12)\t\n\tRT alone\t2 (3)\t\n\tCRT (cisplatin)\t3 (5)\t\n\tCRT (cetuximab)\t2 (3)\t\n\tNo prior treatment\t5 (8)\t\nLocal treatment for first relapse with a curative intent [n (%)]\tSurgery\t11 (18)\t\n\tReirradiation\t4 (7)\t\nTumor extension at baseline [n (%)]\tn\t60\t\n\tLoco regional only\t33 (55)\t\n\tLoco regional and metastatic\t13 (22)\t\n\tMetastatic only\t14 (23)\t\nCharacteristics of relapse [n (%)]\tn\t60\t\n\tRelapse in RT field\t38 (63)\t\n\tRelapse after platinum-based regimen (neoadjuvant, CRT)\t29 (48)\t\nPlatinum free interval before baseline [n (%)]\tn\t29\t\n\t<3 months\t11 (38)\t\n\t3–5.9 months\t3 (10)\t\n\t≥6 months\t15 (52)\t\nChemotherapy ineligibility [n (%)]\tn\t60\t\n\tCisplatin\t55 (92)\t\n\t5-FU\t34 (57)\t\nECOG PS, Eastern Cooperative Oncology Group Performance Status; CRT, concurrent chemoradiotherapy; RT, radiotherapy.\n\nTwenty-nine patients (48%) were ECOG-PS 0–1 and 31 patients (52%) were ECOG-PS 2 at treatment onset. Frailty characteristics such as undernourishment and active comorbidities are reported in Table 2 .\n\nTable 2 Frailty criteria of patients.\n\nList of frailty criteria [n (%)]\tn\t60\t\n\tAge >70 years\t10 (17)\t\n\tECOG-PS = 2\t31 (52)\t\n\tUndernourishment a\t45 (75)\t\n\tSignificant active associated comorbidities\t\t\n\tSevere atheroma\t32 (53)\t\n\tHeart insufficiency\t10 (17)\t\n\tChronic obstructive lung disease, ≥ stage 2\t19 (32)\t\n\tKidney insufficiency\t2 (3)\t\n\tPre-existing neuropathy\t5 (8)\t\n\tPreviously cured cancer\t17 (28)\t\n\tSynchronous active cancer\t6 (10)\t\n\tOthers (psychiatric disorder, cirrhosis, organ transplant, etc.)\t35 (58)\t\nNumber of criteria [n (%)]\tn\t60\t\n\tNone\t1 (2)\t\n\t1 criterion\t10 (17)\t\n\t2 criteria\t12 (20)\t\n\t3 or more criteria\t37 (62)\t\na Undernourishment: albumin <30 g/L or weight loss over 5% in 6 months or weight loss over 2% if BMI >20 or BMI <18.5 or BMI <21 in 70 years and more aged patients.\n\nAs defined in the inclusion criteria, 55 patients (92%) were ineligible to cisplatin. Thirty-four patients (57%) were ineligible to 5-FU because of severe cardiovascular comorbidities.\n\nA second primary cancer arose in six patients during follow-up: two patients with a nonsmall cell lung cancer, one patient with a cutaneous melanoma and a nonsmall cell lung cancer, one patient with a hepatocellular carcinoma, one patient with a cutaneous squamous cell carcinoma, and one patient with a prostate adenocarcinoma.\n\nPCC Delivery\n\nAmong the 60 patients included, six were treated with the first pattern to be used (carboplatin AUC 5 every 3 weeks, weekly paclitaxel 80 mg/m², and cetuximab 400 mg/m2 initial dose, followed by weekly 250 mg/m2). Starting in 2012, the 54 following patients were treated with weekly carboplatin AUC 2 (maximum dose of 220 mg: 49 patients were involved in dose limiting), paclitaxel 80 mg/m², and cetuximab 400 mg/m² loading dose then 250 mg/m². A maximum of 16 cycles was performed followed by a maintenance administration of cetuximab given weekly (250 mg/m²) or biweekly (500 mg/m²) until progressive disease or unacceptable toxicities.\n\nA first clinical and radiological evaluation was done after eight cycles of PCC. As shown in Table 3 , seven patients (12%) did not resume chemotherapy due to unacceptable toxicities and 16 patients (27%) because of progressive disease. A focal treatment (neck and/or metastasis) was carried out in seven patients (12%) because of a particularly good partial response. Cetuximab maintenance began after this assessment in eight patients (13%).\n\nTable 3 PCC delivery before cetuximab maintenance.\n\nVariable\tN = 60\tPaclitaxel 80 mg/m²/week\tCarboplatin AUC2/week\tCetuximab 400 mg/m² then 250 mg/m²/week\t\nNumber of cycles\tMedian\t9.5\t9.5\t10.5\t\n\tRange\t1–19\t1–21\t1–21\t\nEarly discontinuation of treatment (≤8 cycles):\t\t\t24 (40)\t\t\n- Due to unacceptable toxicities\tn (%)\t\t7 (12)\t\t\n- Due to progressive disease\tn (%)\t\t16 (27)\t\t\n- Change of treatment (local treatment, etc.)\tn (%)\t\t7 (12)\t\t\nDelivery completed (≥16 cycles)\tn (%)\t\t24 (40)\t\t\nPatients with dose reductions\tn (%)\t19 (32)\t37 (62)\t3 (5)\t\nPatients with ≥1 dose held for ≥7 days\tn (%)\t27 (45)\t27 (45)\t23 (38)\t\nDose intensity a\tMedian\t65\t1.6\t250\t\n\tRange\t40–80\t0.8–2\t125–250\t\nAUC, area under the curve. aDose delivered per week, accounting for treatment delays and dose reductions. Units of measure are as follows: paclitaxel: mg/m²/week; carboplatin: AUC/week; cetuximab: mg/m²/week. The loading dose of cetuximab (i.e., 400amg/m²) was not included in the calculation of dose density.\n\nMedian number of delivered cycles was 9.5 for chemotherapy and 10.5 for cetuximab. Twenty-four patients (40%) completed the 16 cycles of treatment, of whom 17 patients (28%) with the three drugs, while carboplatin or paclitaxel had to be stopped in seven patients.\n\nDoses of paclitaxel and/or carboplatin and/or cetuximab had to be reduced in 19 patients, 37 patients, and three patients, respectively. Forty-five percent of patients experienced delayed chemotherapy due to side effects. PCC had to be stopped in 16 patients (27%) because of severe toxicities.\n\nToxicities are reported in Table 4 . Thirty patients (50%) showed grades III–IV toxicities. Most toxicities were hematologic. Blood transfusions were required in 18 patients (30%). EPO and G-CSF were used as secondary prophylaxis in respectively nine (15%) and 30 patients (50%). Sixteen unexpected hospitalizations occurred due to infection, including six febrile neutropenia (10%). Four infections (6.6%), mostly pneumopathies, led to death which occurred only in ECOG-PS 2 patients. No other toxicity brought toxic death about. We observed 15 grades III–IV (25%) nonhematologic toxicities. Hypokalemia and hypomagnesemia are the most noticeable nonhematologic toxic effects in our study.\n\nTable 4 Maximal toxicity per patient.\n\n\tGrade I-II\tGrade III\tGrade IV\t\nOverall toxicities [n (%)]\t21 (35)\t30 (50)\t\nNon hematologic toxicities [n (%)]\t14 (23)\t15 (25)\t\nCutaneous\t12 (20)\t7 (12)\t0\t\nNeuropathy\t3 (5)\t2 (3)\t0\t\nElectrolytes disorders\t3 (5)\t5 (8)\t2 (3)\t\nInfusion reaction\t3(5)\t1 (2)\t0\t\nNausea\t5 (8)\t0\t0\t\nDiarrhea\t4 (7)\t1 (2)\t0\t\nHematologic toxicities [n (%)]\t17 (28)\t21 (35)\t\nNeutropenia\t30 (50)\t8 (13)\t7 (12)\t\nAnemia\t26 (43)\t7 (12)\t0\t\nThrombopenia\t7 (12)\t1 (2)\t0\t\nToxicity-related data [n (%)]\t\nBlood transfusion\t18 (30)\t\nEPO (secondary prophylaxis)\t9 (15)\t\nG-CSF (primary prophylaxis)\t4 (7)\t\nG-CSF required (secondary prophylaxis)\t30 (50)\t\nFebrile neutropenia\t6 (10)\t\nHospitalisation due to infection\t16 (27)\t\nHospitalisation\t26 (43)\t\nDeaths in association with AEs\t4 (6,6)\t\n\nPCC Efficacy\n\nPCC achieved a 43.3% (i.e., 26 responses) ORR (95% CI: 30.8–55.8) with three complete responses and 23 partial responses. Thirteen patients experienced stable disease. DCR came out at 65% (i.e., 39 controlled patients) (95% CI: 52.9–77.1). Progression occurred in 16 patients (26.7%): seven patients experienced clinical progression but could not be radiologically evaluated, six patients experienced CT-scan-proved disease progression, and three patients showed dissociated responses with appearance of new metastases despite partial responses on target lesions. Five patients were not evaluable because of nonmeasurable lesions ( Table 5 ). The ORR is similar in the 38 patients with a locoregional relapse in a previously irradiated area; in this population, we observe 14 responses, i.e., a response rate of 36.8%. Among the 14 patients for whom the cisplatin free interval was less than 6 months, we observed three partial responses.\n\nTable 5 Efficacy after 8 weeks of treatment.\n\n\tn = 60\t\nOverall response rate (95% CI)\t43.3% (30.8–55.8)\t\nComplete response\t3 (5%)\t\nPartial response\t23 (38.3%)\t\nDisease control rate (95% CI)\t65% (52.9–77.1)\t\nStable disease\t13 (21.7%)\t\nProgressive disease\t16 (26.7%)\t\nNon evaluable\t5 (8.3%)\t\n\nChange in target lesions was not evaluable in 12 patients: five patients died before evaluation (four due to progressive disease, one due to infection); one patient was not compliant; one patient could not be re-evaluated due to clinical deterioration; and five patients did not have any measurable lesion according to RECIST criteria. Change in target lesions is shown in Figure 2 .\n\nFigure 2 Waterfall plot of 48 assessable patients for change in target lesions.\n\nWith a median follow-up of 35.7 months (IQR 28.6–48.8), we observed a median OS of 11.7 months (95% CI: 7.5–14.8) and a median PFS of 5.8 months (95% CI: 4.5–7.2). Kaplan-Meier curve-line estimate of PFS and OS are shown in Figures 3 , 4 .\n\nFigure 3 Progression-free survival (PFS) total population (A); PFS according to performance status (PS) (B).\n\nFigure 4 Overall survival (OS) total population (A); OS according to performance status (PS) (B).\n\nIn the ECOG-PS 0–1 population (i.e., 29 patients), median OS was 14.8 months (95% CI: 12.2–21.7) and median PFS was 7.1 months (95% CI: 6.3–9.0 months). In ECOG-PS 2 patients (i.e., 31 patients), median OS was 7.5 months (95% CI, 5.5–12.7; p < 0.04) and median PFS was 4.6 months (95% CI: 3.5–6.9; p = 0.07).\n\nDiscussion\n\nOur study shows that in first-line R/M HNSCC, a combination of paclitaxel, carboplatin, and cetuximab makes it possible to achieve results comparing favorably with what may be obtained through chemotherapies based on platinum-5-FU and cetuximab (3) or cisplatin-docetaxel and cetuximab (5, 6), and this, with particularly frail patients.\n\nIndeed, in our study, 55 patients (92%) are cisplatin ineligible: ECOG-PS 2: 52%, platinum free interval <6 months: 23%, at least three frailty criteria: 62%, age ≥70: 17%; however, a 43.3% ORR, a 5.8-month median PFS, and a 11.7-month median OS are achieved.\n\nAlthough a 11.7-month median OS compares favorably with the 10.1 months obtained through the EXTREME regimen (3), it seems however shorter than the 14.5 months observed with the TPEx (6) and the 14.7 months with the PCE regimens (9). It should be noted however that these two latter studies concern a more favorable population of patients ECOG-PS 0 or 1 and that patients who were enrolled into the TPExtreme study were cisplatin fit and under age 70. In our study, when we consider the ECOG-PS 0–1 patients, the 14.8 months median OS is very similar to that reported with the TPEx or PCE regimens.\n\nPêtre et al. reported on a weekly paclitaxel and carboplatin combination in a particularly frail and heavily pretreated population that produced a 40% ORR, a median PFS of 4.7 months, and a median OS of 9.1 months (11). Interestingly, this study confirms the major impact of cisplatin eligibility and ECOG-PS on survival outcomes: median OS is 13.7 months for cisplatin-eligible patients whereas it is only 8 months for cisplatin-ineligible patients. For cisplatin-ineligible patients, median overall survival decreases from 11.5 to 3.6 months in patients ECOG-PS 0–1 and ECOG-PS 2–3, respectively (11).\n\nThe number of administered weekly PCC cycles, cetuximab maintenance, and subsequent treatments seem to be important factors of survival. Indeed, in the retrospective study reported by Narveson et al, where treatment is limited to six weekly cycles of PCC, although a similar ORR of 37% is reported, median PFS is 4.6 months and median OS is only 5.25 months (12).\n\nWeekly paclitaxel is a well-established regimen which allows high dose intensity with low hematologic toxicity (13). Likewise, fractionated administration of carboplatin allows also to decrease the hematologic toxicity and thus to maintain continuous weekly administration of chemotherapy with as few toxicity-related interruptions as possible (9, 11). Nevertheless, in our study, although toxicity is noteworthy, it is however mostly hematologic and may be managed. It is caused to a large extent by the frailty of the treated population. We observed 10% of febrile neutropenia, 50% of secondary prophylaxis using G-CSF, and 27% of hospital readmission for sepsis which resulted in four deaths (6.6%). It should be noted however that deaths in association with adverse events are only observed in ECOG-PS 2 patients. Likewise, in the TPExtreme study, a 7.7% rate of deaths in association with adverse events is reported in the EXTREME arm and 5.9% in the TPEx arm (6). We are now proposing G-CSF as a primary prophylaxis which significantly reduces infectious toxicity. Indeed, weekly administration of G-CSF is safe and effective as reported by Kies et al. in the first publication of the weekly PCC (10).\n\nResults of our study like these observed with the TPEx and the PCE regimens as well as in the CETMET trial show that it is possible to replace advantageously 5-FU by a taxane. The CETMET trial is a randomized phase II study which shows that the replacement of 5-FU by paclitaxel allows to decrease toxicity: 60% of the grades III–V reported toxicities being in the EXTREME arm (p = 0.034). Moreover, authors observed an increasing trend in the median PFS from 4.37 months in the EXTREME arm to 6.5 months in the paclitaxel, carboplatin, and cetuximab arm (p = 0.064) (14). The randomized phase II study TPExtreme did not show however any survival advantage when compared with the EXTREME protocol but confirms a high median survival of 14.5 months and a favorable safety profile in the TPEx arm (6).\n\nThe EXTREME protocol has remained the standard of care for first-line R/M until 2019 when the KEYNOTE-048 study has demonstrated, as far as survival is concerned, the superiority of immunotherapy by the anti-PD-1 pembrolizumab for the CPS ≥1 population and of the combination of pembrolizumab, platinum, and 5-FU in all patients (15). Nevertheless, platinum and cetuximab associations may remain relevant as first- or second-line R/M treatments in situations such as described hereunder. As first-line treatment, the association of platinum and cetuximab is appropriate when using an anti-PD-1 which is not suitable because of insufficient efficacy whenever the combined positive score (CPS) is inferior to 1 (which in Europe precludes its use in association with chemotherapy as well) or in case the patient is considered ineligible for immunotherapy particularly with an active autoimmune disease treated by immunosuppressive agents. In first-line treatment, there remains a need to address the problem of fragile patient, particularly cisplatin unfit or ECOG-PS 2 patients for whom the toxicity of the pembrolizumab combined to platinum/5-FU is too severe to be considered (85% of grades III–IV). Pembrolizumab alone may be proposed (55% of grades III–IV toxicity, 17% related to treatment), but the ORR is only 19% for the CPS ≥1 population (15) which appears inappropriate for severely symptomatic patients (16), whereas the response rate provided by the weekly PCC regimen is 43%. Moreover, the efficacy of pembrolizumab for ECOG-PS 2 patients has not been formally studied. As a second-line R/M treatment, following the administration of pembrolizumab alone, platinum and cetuximab combinations remain perfectly relevant and this especially since increased efficacy of chemotherapy following the use of anti-PD-1 agents has been reported (17). The weekly PCC may be then an interesting option for cisplatin-unfit patient, even for those who are ECOG-PS 2.\n\nDespite its two main advantages (response duration and low toxicity), immunotherapy by pembrolizumab alone benefits only a minority of patients, and the determination of PD-L1 by combined positive score (CPS) remains an imperfect predictive factor (23% of response for CPS >20). Moreover, progression rate at first evaluation is high (around 40%) which makes it risky to propose immunotherapy alone to severely symptomatic patients. Combining pembrolizumab to chemotherapy makes it possible to improve results (ORR 36%, median OS of 13 months). There remain however two drawbacks: high toxicity (85% grades III–IV) and when compared with EXTREME, a survival benefit which is not clearly demonstrated for all subgroups (CPS <20) (18).\n\nConsidering the above, it remains clearly necessary to improve the immunotherapy combination or the associated chemotherapy. The combination of weekly paclitaxel, carboplatin, and durvalumab which is intended specifically for frail patients in first-line R/M is presently being studied in the frail-immune trial (19).\n\nCombining monalizumab with cetuximab in at least second-line R/M patients pretreated with platinum, 45% of whom had also received an antiPD-1, has shown promising results which still remain to be confirmed in a randomized phase II study (20). A probable synergy of an anti-PD-1 with cetuximab (21) would justify the next step of studying a combination of PCC with an anti-PD-1 or also PCC with monalizumab.\n\nIn addition, the PCC regimen showed promising results in the neoadjuvant setting with an ORR ranging from 70% to 97% (10, 22, 23). Haddad et al. showed in a phase II randomized study, in the neoadjuvant setting, that weekly PCC is as effective and less toxic than cetuximab–Taxotere/platin/5-FU (C-TPF) making weekly PCC an option of choice for TPF-unfit patients (24).\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nHC and CB conceptualized and drafted the study and the manuscript. MB and AJ critically reviewed the manuscript. HC, MB, RF, CF, and MK collected patients’ data. CB and PW reviewed all CT scans. AT realized statistical analysis. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nCB is advisory board consultant for BMS and Astra Zeneca, and has received honoraria for consulting from Merck, BMS, Astra Zeneca and MSD. MB has received honoraria for consulting from BMS, Ipsen and MSD.\n\nThe remaining 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\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nSpecial thanks to Patrick Borel for his work of proofreading and correcting the text in English.\n==== Refs\nReferences\n\n1 Shaw R Beasley N . Aetiology and Risk Factors for Head and Neck Cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol (2016) 130 (S2 ):S9–12. doi: 10.1017/S0022215116000360 27841107\n2 Brom L De Snoo-Trimp JC Onwuteaka-Philipsen BD Widdershoven GAM Stiggelbout AM Pasman HRW . Challenges in Shared Decision Making in Advanced Cancer Care: A Qualitative Longitudinal Observational and Interview Study. Health Expect (2017) 20 (1 ):69−84. doi: 10.1111/hex.12434 26669902\n3 Vermorken JB Mesia R Rivera F Remenar E Kawecki A Rottey S . Platinum-Based Chemotherapy Plus Cetuximab in Head and Neck Cancer. N Engl J Med (2008) 359 (11 ):1116−27. doi: 10.1056/NEJMoa0802656 18784101\n4 Gibson MK Li Y Murphy B Hussain MHA DeConti RC Ensley J . Randomized Phase III Evaluation of Cisplatin Plus Fluorouracil Versus Cisplatin Plus Paclitaxel in Advanced Head and Neck Cancer (E1395): An Intergroup Trial of the Eastern Cooperative Oncology Group. J Clin Oncol (2005) 23 (15 ):3562−7. doi: 10.1200/JCO.2005.01.057 15908667\n5 Guigay J Fayette J Dillies AF Sire C Kerger JN Tennevet I . Cetuximab, Docetaxel, and Cisplatin as First-Line Treatment in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Multicenter, Phase II GORTEC Study. Ann Oncol (2015) 26 (9 ):1941−7. doi: 10.1093/annonc/mdv268 26109631\n6 Guigay J Aupérin A Fayette J Saada-Bouzid E Lafond C Taberna M . Cetuximab, Docetaxel, and Cisplatin Versus Platinum, Fluorouracil, and Cetuximab as First-Line Treatment in Patients With Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma (GORTEC 2014-01 TPExtreme): A Multicentre, Open-Label, Randomised, Phase 2 Trial. Lancet Oncol (2021) 22 (4 ):463–75. doi: 10.1016/S1470-2045(20)30755-5\n7 Quoix E Zalcman G Oster J-P Westeel V Pichon E Lavolé A . Carboplatin and Weekly Paclitaxel Doublet Chemotherapy Compared With Monotherapy in Elderly Patients With Advanced Non-Small-Cell Lung Cancer: IFCT-0501 Randomised, Phase 3 Trial. Lancet Lond Engl (2011) 378 (9796 ):1079−88. doi: 10.1016/S0140-6736(11)60780-0\n8 Moosmann P Egli F Stahel RA Jost L . Weekly Paclitaxel and Carboplatin Combination Chemotherapy in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck. Onkologie (2003) 26 (6 ):568−72. doi: 10.1159/000074153 14709932\n9 Tahara M Kiyota N Yokota T Hasegawa Y Muro K Takahashi S . Phase II Trial of Combination Treatment With Paclitaxel, Carboplatin and Cetuximab (PCE) as First-Line Treatment in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (CSPOR-Hn02). Ann Oncol (2018) 29 (4 ):1004−9. doi: 10.1093/annonc/mdy040 29408977\n10 Kies MS Jack Lee J William WN Jr. Glisson BS Lin YH Lewin JS . Induction Chemotherapy and Cetuximab for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Results From a Phase II Prospective Trial. J Clin Oncol (2010) 28 (1 ):8–14. doi: 10.1200/JCO.2009.23.0425 19917840\n11 Pêtre A Dalban C Karabajakian A Neidhardt E-M Roux PE Poupart M . Carboplatin in Combination With Weekly Paclitaxel as First-Line Therapy in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Unfit to EXTREME Schedule. Oncotarget (2018) 9 (31 ):22038−46. doi: 10.18632/oncotarget.25157 29774120\n12 Narveson L Kathol E Rockey M Henry D Grauer D Neupane P . Evaluation of Weekly Paclitaxel, Carboplatin, and Cetuximab in Head and Neck Cancer Patients With Incurable Disease. Med Oncol (2016) 33 (10 ):107. doi: 10.1007/s12032-016-0822-0 27568333\n13 Tahara M Minami H Hasegawa Y Tomita K Watanabe A Nibu K . Weekly Paclitaxel in Patients With Recurrent or Metastatic Head and Neck Cancer. Cancer Chemother Pharmacol (2011) 68 (3 ):769–76. doi: 10.1007/s00280-010-1550-3\n14 Tsakonas G Specht L Kristensen CA Herlestam Calero Moreno M Haugen Cange H Soderstrom K . Randomized Phase II Study With Cetuximab in Combination With 5-FU and Cisplatin or Carboplatin Vs. Cetuximab in Combination With Paclitaxel and Carboplatin for Treatment of Patients With Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck (CETMET Trial). Cancers (Basel) (2020) 12 (11 ):3110. doi: 10.3390/cancers12113110\n15 Burtness B Harrington KJ Greil R Soulières D Tahara M de Castro G . Pembrolizumab Alone or With Chemotherapy Versus Cetuximab With Chemotherapy for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (KEYNOTE-048): A Randomised, Open-Label, Phase 3 Study. Lancet (2019) 394 (10212 ):1915−28. doi: 10.1016/S0140-6736(19)32591-7 31679945\n16 Peyrade F Borel C Daste A Even C Saada-Bouzid E Guigay J . Systemic Treatment of Metastatic Squamous Cell Carcinoma of the Head and Neck: Proposal for Management Changes. Curr Opin Oncol (2021) 33 (3 ):160–7. doi: 10.1097/CCO.0000000000000738\n17 Saleh K Daste A Martin N Pons-Tostivint E Auperin A Herrera-Gomez RG . Response to Salvage Chemotherapy After Progression on Immune Checkpoint Inhibitors in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck. Eur J Cancer (2019) 121 :123–9. doi: 10.1016/j.ejca.2019.08.026\n18 Borel C Jung AC Burgy M . Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Cancers (Basel) (2020) 12 (9 ):2691. doi: 10.3390/cancers12092691\n19 FRAIL-IMMUNE (GORTEC 2018-03) - Combination of Durvalumab With Carboplatin/Paclitaxel - Full Text View - ClinicalTrials.Gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03723967 (Accessed on 26 Apr 2020).\n20 Cohen RB Lefebvre G Posner MR Bauman JR Salas S Even C . 1134p-Monalizumab in Combination With Cetuximab in Patients (Pts) With Recurrent or Metastatic (R/M) Head and Neck Cancer (SCCHN) Previously Treated or Not With PD-(L)1 Inhibitors (IO): 1-Year Survival Data. Ann Oncol (2019) 30 (Suppl. 5 ):v460. doi: 10.1093/annonc/mdz252.026\n21 Sacco AG Chen R Ghosh D Wong DJL Worden FP Adkins D . An Open Label, Nonrandomized, Multi-Arm, Phase II Trial Evaluating Pembrolizumab Combined With Cetuximab in Patients With Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC): Results of Cohort 1 Interim Analysis. J Clin Oncol (2019) 37 (Suppl.15 ):6033. doi: 10.1200/JCO.2019.37.15_suppl.6033\n22 Bauman J Langer C Quon H Algazy K Lin A Desai A . Induction Chemotherapy With Cetuximab, Carboplatin and Paclitaxel for the Treatment of Locally Advanced Squamous Cell Carcinoma of the Head and Neck. Exp Ther Med (2013) 5 (4 ):1247–53. doi: 10.3892/etm.2013.948\n23 Wanebo HJ Lee J Burtness BA Ridge JA Ghebremichael M Spencer SA . Induction Cetuximab, Paclitaxel, and Carboplatin Followed by Chemoradiation With Cetuximab, Paclitaxel, and Carboplatin for Stage III/IV Head and Neck Squamous Cancer: A Phase II ECOG-ACRIN Trial (E2303). Ann Oncol (2014) 25 (10 ):2035–41. doi: 10.1093/annonc/mdu248\n24 Haddad RI Massarelli E Lee JJ Lin HY Hutcheson K Lewis J . Weekly Paclitaxel, Carboplatin, Cetuximab, and Cetuximab, Docetaxel, Cisplatin, and Fluorouracil, Followed by Local Therapy in Previously Untreated, Locally Advanced Head and Neck Squamous Cell Carcinoma. Ann Oncol (2019) 30 (3 ):471–7. doi: 10.1093/annonc/mdy549\n\n",
"fulltext_license": "CC BY",
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"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "carboplatin; cetuximab; chemotherapy; first-line; head and neck squamous cell carcinoma; paclitaxel; recurrent or metastatic",
"medline_ta": "Front Oncol",
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"pubdate": "2021",
"publication_types": "D016428:Journal Article",
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"title": "Weekly Paclitaxel, Carboplatin, and Cetuximab as First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma for Patients Ineligible to Cisplatin-Based Chemotherapy: A Retrospective Monocentric Study in 60 Patients.",
"title_normalized": "weekly paclitaxel carboplatin and cetuximab as first line treatment of recurrent and or metastatic head and neck squamous cell carcinoma for patients ineligible to cisplatin based chemotherapy a retrospective monocentric study in 60 patients"
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"abstract": "Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are not well studied.\n\n\n\nTo compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly.\n\n\n\nProspective, randomized, open-label, parallel arm study at a tertiary referral pituitary center.\n\n\n\nAdults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment.\n\n\n\nCombination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release [LAR] 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day).\n\n\n\nMonthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy.\n\n\n\nSixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 [93.3%]; arm B, 22/23 [95.7%]; arm C, 14/14 [100%]). Arm B was least costly (mean, $9837 ± 1375 per month), arm C was most expensive (mean, $22543 ± 11158 per month), and arm A had an intermediate cost (mean, $14261 ± 1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all < 10%.\n\n\n\nLow-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy.",
"affiliations": "Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.;Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.;Division of Endocrinology and Metabolism, Keck School of Medicine, University of Southern California, Los Angeles, California.;Department of Neuroendocrinology and Neurosurgery, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton School of Medicine, Phoenix, Arizona.;Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota.;Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.",
"authors": "Bonert|Vivien|V|;Mirocha|James|J|;Carmichael|John|J|;Yuen|Kevin C J|KCJ|;Araki|Takako|T|;Melmed|Shlomo|S|",
"chemical_list": "D003692:Delayed-Action Preparations; D004304:Dosage Forms; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C060347:lanreotide; D019382:Human Growth Hormone; D013004:Somatostatin; C406545:pegvisomant; D015282:Octreotide",
"country": "United States",
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"issue": "105(9)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": " Acromegaly; combination therapy; pegvisomant; somatostatin receptor ligand",
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000172:Acromegaly; D000328:Adult; D003362:Cost-Benefit Analysis; D003692:Delayed-Action Preparations; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016527:Drug Costs; D004359:Drug Therapy, Combination; D005260:Female; D019382:Human Growth Hormone; D006801:Humans; D008297:Male; D008875:Middle Aged; D015282:Octreotide; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D013004:Somatostatin; D035703:Therapies, Investigational; D016896:Treatment Outcome",
"nlm_unique_id": "0375362",
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"pmid": "32754748",
"pubdate": "2020-09-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cost-Effectiveness and Efficacy of a Novel Combination Regimen in Acromegaly: A Prospective, Randomized Trial.",
"title_normalized": "cost effectiveness and efficacy of a novel combination regimen in acromegaly a prospective randomized trial"
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"abstract": "A 43-year-old man was diagnosed with acromegaly due to pituitary GH-secreting macroadenoma, and underwent craniotomy surgery. After surgery, he was given octreotide long-acting release (LAR) to treat the residual tumor. Eighteen months later, he presented polydipsia and polyuria due to diabetic ketoacidosis (DKA) and central diabetes insipidus (CDI). His casual plasma glucose level was 570 mg/dL, his HbA1c was 14.9%, and his urine was strongly positive for ketone bodies. We discuss a causal relationship among DKA, CDI, and treatment with LAR in this case with residual GH-secreting tumor from the perspective of insulin secretion and resistance.",
"affiliations": "The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan.",
"authors": "Inaba|Hidefumi|H|;Funahashi|Tomomi|T|;Ariyasu|Hiroyuki|H|;Iwakura|Hiroshi|H|;Furuta|Hiroto|H|;Nishi|Masahiro|M|;Akamizu|Takashi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13340-016-0301-z",
"fulltext": null,
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"issn_linking": "2190-1678",
"issue": "8(2)",
"journal": "Diabetology international",
"keywords": "Acromegaly; Central diabetes insipidus; Diabetic ketoacidosis; Octreotide LAR",
"medline_ta": "Diabetol Int",
"mesh_terms": null,
"nlm_unique_id": "101553224",
"other_id": null,
"pages": "237-242",
"pmc": null,
"pmid": "30603327",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": "14510913;14769829;17339747;18611118;21264808;23186966;23508726;24423324;24461109;25356808;26361517;27039081;8822314;9483371",
"title": "Diabetic ketoacidosis in a patient with acromegaly and central diabetes insipidus treated with octreotide long-acting release.",
"title_normalized": "diabetic ketoacidosis in a patient with acromegaly and central diabetes insipidus treated with octreotide long acting release"
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"abstract": "Skeletal muscle sodium channelopathies are a group of neuromuscular disorders associated with mutations in the SCN4A gene. Because principal sodium channel isoforms expressed in the skeletal muscles and the heart are distinct one from the other, this condition usually spares cardiac functioning. Nonetheless, evidence on a possible link between skeletal muscle and cardiac sodium channelopathies has emerged in recent years. To date, eight patients bearing pathogenetic mutations in the SCN4A gene and manifesting cardiac electrophysiological alterations have been reported in literature. Among these patients, three presented a phenotype compatible with Brugada syndrome. We report the case of a 29-year-old patient affected by non-dystrophic myotonia associated with a p.G1306E mutation in the SCN4A gene, who presented symptoms of syncope and palpitation after the introduction of flecainide as an anti-myotonic agent. ECG and ajmaline challenge were consistent with the diagnosis of Brugada syndrome, leading to the implantation of a cardioverter defibrillator. No mutation in causative genes for Brugada syndrome was detected. Mexiletine treatment reduced myotonia without any cardiac adverse events. This case report highlights the clinical relevance of the recognition of cardiac electrophysiological alterations in skeletal muscle sodium channelopathies. The discovery of a possible pathogenetic linkage between skeletal muscle and cardiac sodium channelopathies may have significant implications in patients' management, also in light of the fact that class 1C anti-arrhythmics are potential triggers for life-threatening arrhythmias in patients with Brugada syndrome.",
"affiliations": "Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.;Department of Neurology, IRCCS Policlinico San Donato, Milan, Italy.;Clinical Arrhythmology and Electrophysiology Department, IRCCS Policlinico San Donato, Milan, Italy.;Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.;Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.;Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.;Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, Milan, Italy.;Clinical Arrhythmology and Electrophysiology Department, IRCCS Policlinico San Donato, Milan, Italy.;Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.",
"authors": "Cavalli|Michele|M|;Fossati|Barbara|B|;Vitale|Raffaele|R|;Brigonzi|Elisa|E|;Ricigliano|Vito A G|VAG|;Saraceno|Lorenzo|L|;Cardani|Rosanna|R|;Pappone|Carlo|C|;Meola|Giovanni|G|",
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"doi": "10.3389/fneur.2018.00385",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2018.00385NeurologyCase ReportFlecainide-Induced Brugada Syndrome in a Patient With Skeletal Muscle Sodium Channelopathy: A Case Report With Critical Therapeutical Implications and Review of the Literature Cavalli Michele 1Fossati Barbara 2Vitale Raffaele 3Brigonzi Elisa 1Ricigliano Vito A. G. 1Saraceno Lorenzo 1Cardani Rosanna 4Pappone Carlo 3Meola Giovanni 12*1Department of Biomedical Sciences for Health, University of Milan, Milan, Italy2Department of Neurology, IRCCS Policlinico San Donato, Milan, Italy3Clinical Arrhythmology and Electrophysiology Department, IRCCS Policlinico San Donato, Milan, Italy4Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, Milan, ItalyEdited by: Ghazala Hayat, Saint Louis University, United States\n\nReviewed by: Adrien Moreau, École Normale Supérieure de Lyon, France; Margherita Milone, Mayo Clinic, United States\n\n*Correspondence: Giovanni Meola giovanni.meola@unimi.itThis article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology\n\n30 5 2018 2018 9 38512 2 2018 11 5 2018 Copyright © 2018 Cavalli, Fossati, Vitale, Brigonzi, Ricigliano, Saraceno, Cardani, Pappone and Meola.2018Cavalli, Fossati, Vitale, Brigonzi, Ricigliano, Saraceno, Cardani, Pappone and MeolaThis 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 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.Skeletal muscle sodium channelopathies are a group of neuromuscular disorders associated with mutations in the SCN4A gene. Because principal sodium channel isoforms expressed in the skeletal muscles and the heart are distinct one from the other, this condition usually spares cardiac functioning. Nonetheless, evidence on a possible link between skeletal muscle and cardiac sodium channelopathies has emerged in recent years. To date, eight patients bearing pathogenetic mutations in the SCN4A gene and manifesting cardiac electrophysiological alterations have been reported in literature. Among these patients, three presented a phenotype compatible with Brugada syndrome. We report the case of a 29-year-old patient affected by non-dystrophic myotonia associated with a p.G1306E mutation in the SCN4A gene, who presented symptoms of syncope and palpitation after the introduction of flecainide as an anti-myotonic agent. ECG and ajmaline challenge were consistent with the diagnosis of Brugada syndrome, leading to the implantation of a cardioverter defibrillator. No mutation in causative genes for Brugada syndrome was detected. Mexiletine treatment reduced myotonia without any cardiac adverse events. This case report highlights the clinical relevance of the recognition of cardiac electrophysiological alterations in skeletal muscle sodium channelopathies. The discovery of a possible pathogenetic linkage between skeletal muscle and cardiac sodium channelopathies may have significant implications in patients' management, also in light of the fact that class 1C anti-arrhythmics are potential triggers for life-threatening arrhythmias in patients with Brugada syndrome.\n\nsodium skeletal muscle channelopathySCN4ABrugada syndromeflecainidemexiletine\n==== Body\nBackground\nBrugada syndrome is a dominantly inherited cardiac channelopathy, associated with symptoms of syncope, ventricular arrhythmia and sudden cardiac death (SCD). These symptoms are triggered in time by specific agents, such as fever or the use of sodium channel-blocking drugs. The prevalence is estimated to be worldwide, equal to 1–4 out of 2,000 people. Frequently, patients are initially asymptomatic showing a normal basal ECG, but subsequently they experience aborted SCD or they are diagnosed during a familial screening. A pathogenetic mutation in SCN5A gene, coding for cardiac voltage-gated sodium channel (Nav1.5), is recognized in 20-25% of cases (1).\n\nMutations in SCN4A gene, encoding for skeletal muscle voltage-gated sodium channel (Nav1.4), are known to produce non-dystrophic myotonia, hyper- or hypokalemic periodic paralysis, or congenital myasthenic syndrome (2). Such mutations are usually thought to spare myocardial functioning. This postulate has been questioned by four case reports of patients with T wave alterations and/or QT prolongation in a family with all members affected by paramyotonia congenita (3). Sinus bradycardia with right bundle branch block and QT prolongation were found in a patient affected by hypokalemic periodic paralysis associated with a SCN4A mutation (4). More recently, a work by Bissay and colleagues reported the occurrence of Brugada phenocopy in three patients with SCN4A gene mutations and in two patients with a mutation variant of uncertain significance (VUS) in the same gene. Notably, none of them showed pathogenetic mutations in SCN5A gene (5) (Table 1).\n\nTable 1 Reported arrhythmic complications with SCN4A mutations.\n\n\tNM diagnosis\tSCN4A mutation\tSymptoms\tECG\tAjmaline challenge\tEPS\tSCN5A mutation\tDevices\t\nPéréon Y et al. (3)\tPMC\tR1448C\tMyotonia, episodic weakness\tT wave alteration\tn.a.\tn.a.\tn.a.\tNone\t\nPéréon Y et al. (3)\tPMC\tR1448C\tMyotonia, muscular hypertrophy\tT wave alteration\tn.a.\tn.a.\tn.a.\tNone\t\nPéréon Y et al. (3)\tPMC\tR1448C\tMyotonia\tT wave alteration, long QT\tn.a.\tn.a.\tn.a.\tNone\t\nPéréon Y et al. (3)\tPMC\tR1448C\tMyotonia\tT wave alteration, long QT\tn.a.\tn.a.\tn.a.\tNone\t\nMaffè et al. (4)\tHypo-PP\tR669H\tEpisodic weakness, syncope\tSinus bradycardia, RBBB, long QT\tn.a.\tn.a.\tn.a.\tTemporary PM\t\nBissay et al. (5)\tSCM\tL1436P\tMyotonia, syncope\tNormal\tPositive\tNo inducibility\tH558R 1141–3 C>A\tICD\t\nBissay et al. (5)\tSCM\tL1436P\tMyotonia\tNormal\tPositive\tNo inducibility\tH558R 1141–3 C>A\tNone\t\nBissay et al. (5)\tSCM\tL1436P\tMyotonia\tNormal\tPositive\tNo inducibility\t–\tNone\t\nBissay et al. (5)\t–\tQ1301del (VUS)\tAborted SCD, myotonia\tBrugada pattern I\tn.a.\tn.a.\t–\tICD\t\nBissay et al. (5)\t–\tQ1301del (VUS)\tMyotonia\tNormal\tPositive\tn.a.\tn.a.\tNone\t\nPresent case\tSCM (SNEL phenotype)\tG1306E\tMyotonia, muscular hypertrophy, syncope and palpitation under flecainde\tBrugada pattern I under flecainde\tPositive\tNo inducibility\t–\tICD\t\nNM, neuromuscular; EPS, electrophysiological study; PMC, paramyotonia congenita; PM, pacemaker; RBBB, right bundle branch block; Hypo-PP, hypokalemic periodic paralysis; SCM, sodium channel myotonia; SCD, sudden cardiac death; ICD, implantable cardioverter; VUS, variant of uncertain significance; SNEL, severe neonatal episodic laryngospasm.\n\nCase presentation\nWe report the case of a 29-year-old male affected by non-dystrophic myotonia due to a sporadic p.G1306E mutation in the SCN4A gene (6). During neonatal period he presented paroxysms of laryngospasm and respiratory distress, depicting the peculiar features of severe neonatal episodic laryngospasm (SNEL) phenotype (7). These episodes ceased several weeks after birth, consequently to the introduction of an anti-myotonic treatment with mexiletine, 30 mg quater in die (qid) per os. Since that intervention, the patients progressively developed diffuse muscular hypertrophy and a myotonia permanens phenotype. Only a few transient adynamic episodes occurred during adolescence. An adjustment of mexiletine dosage up to 400 mg ter in die (tid) led to a satisfactory control of the myotonic phenomenon, leaving just a minimal disability. Skeletal muscle biopsy, performed at the age of 14, revealed only moderate fiber size variability, with mild atrophy of type 1 fibers and rare centralized nuclei (Figure 1). A periodical annual cardiological assessment performed with echocardiogram and a 24-h ambulatory ECG showed to be normal.\n\nFigure 1 H&E staining of skeletal muscle transverse section performed at the age of 14. Rare atrophic fibers and few centralized nuclei were present.\n\nA therapeutical shift from mexiletine to flecainide was conducted to improve the patient's compliance by reducing his multiple daily administrations. This choice was in agreement with a mutation-targeted approach proposed by Desaphy et al. (8, 9) and clinically reproduced by Portaro et al. (10). Flecainide treatment was started in an outpatient clinical setting and the daily dosage was gradually increased. After reaching a 100 mg bis in die (bid) dosage amount, the patient came to our Emergency Department showing symptoms of syncope and palpitation. At the admission the neurological evaluation was normal except for a diffuse muscular hypertrophy, while clinical myotonia was undetectable. A standard 12 lead ECG revealed a prominent coved-type ST elevation with a T wave inversion in the first precordial leads consistent with Brugada pattern type I. Serum electrolytes and other routine blood analyses were normal, except for an awaited hyperCKemia (579 U/l). The flecainide therapy was immediately interrupted and, as a consequence, the coved-type ST elevation noted on the right precordial leads disappeared during the following hours. In parallel with the ECG normalization, myotonia symptoms showed, becoming more and more invalidating as the days passed.\n\nAfter an appropriate pharmacological wash-out, ajmaline challenge was performed and resulted positive for the appearance of Brugada pattern type I (Figure 2). Programmed ventricular stimulation during electrophysiological study (EPS) was negative for inducible sustained ventricular arrhythmias. Diagnosis of Brugada syndrome was formulated and, given the history of syncope, an implantable cardioverter defibrillator (ICD) was implanted for primary prevention. Next generation sequencing (NGS) genetic analysis with TruSight Cardio Sequencing kit Illumina excluded the presence of sequence variants in SCN5A gene and in other 15 genes associated to Brugada syndrome (ABCC9, CACNA1C, CACNA2D1, CACNB2, GPD1L, HCN4, KCND3, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF/MOG1, SCN1B, SCN3B, TRAPM4) (11). The analysis revealed two variants of uncertain significance (VUS) in two other genes, namely a p.G678A substitution in DSG2 and a p.R1013W substitution in RYR2. DSG2 encodes for desmoglein-2, a cadherin family member, and is related to arrhythmogenic right ventricular dysplasia (ARVD) (12). RYR2 encodes for ryanodine receptor 2, found in myocardial sarcoplasmatic reticulum, and mutations in its sequence are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) (13). The same variant in DSG2 was found in patient's mother, while the one in RYR2 was present in the father. Both parents were asymptomatic for syncope or palpitation, and their ECGs were normal.\n\nFigure 2 (A) Baseline 12 lead ECG; (B) ECG while starting ajmaline infusion; (C) ECG 5 min after ajmaline infusion starting.\n\nIn consideration of the favorable pharmacodynamic profile in Brugada syndrome (14), an oral regimen of hydroquinidine, that is a class 1A anti-arrhythmic drug, was introduced as a potential anti-myotonic agent and was titrated up to 150 mg bid in a few days. This regimen appreciably reduced myotonia, but had to be interrupted due to the appearance of diarrhea. Consequently, the previous mexiletine regimen was restarted. Since then both clinical myotonia and cardiological symptoms disappeared, the ECG remained unaltered and no shock has been delivered by ICD.\n\nDiscussion\nOur case suggests that mutations in SCN4A may produce per se a Brugada phenotype. In the four confirmed cases two different mutations were implicated, therefore currently no genotype-phenotype correlation can be confirmed. The p.G1306E mutation, present in our patient, is located in the sequence coding for the sodium channel inactivation gate and it profoundly alters the channel's electrophysiology (6, 15). Consistently, p.G1306E mutation is associated with severe myotonic phenotypes, such as SNEL (10). We speculate that a severe affection of the Nav1.4 physiology could also impair cardiac ion currents and, consequently, have a role in Brugada phenotype expression.\n\nSince a pathogenetic mutation is found only in 20-30% of patients affected by Brugada syndrome, we could not exclude the coexistence of different mutations in the same patient, affecting independently both ion currents in skeletal muscle and in cardiac cells. However, to the best of our knowledge, this is the first report of a potentially arrhythmic condition linked to p.G1306E Nav1.4 mutation.\n\nIn current literature only two cases of patients with a pathogenetic mutations in SCN4A have been reported to manifest syncope, while several subjects presenting positive challenge with class 1C anti-arrhythmics were asymptomatic in the Bissay and colleagues' series. To note, Bissay and colleagues have reported two myotonic patients bearing a VUS in SCN4A and presenting Brugada pattern I on baseline ECG; one of the two patients was rescued from a cardiac arrest (5).\n\nIn our case, Brugada-associated symptoms showed after the introduction of a twice a day flecainide regimen, initiated in order to mitigate a massive myotonic phenomenon.\n\nWhile in previous cases only the SCN5A gene had been screened, our patient underwent extensive genetic analysis with the NGS technique. This approach revealed the presence of two VUS in two different genes linked to arrhythmic diseases other than Brugada syndrome.\n\nMoreover, two patients who had been reported by Bissay et al. (5) had two polymorphisms in the SCN5A gene, which were characterized as possible disease modifying variants (16, 17). If considered altogether, these results suggest a potential role of modifier genes in the determination of Brugada phenotype linked to SCN4A mutations.\n\nThe putative pro-arrhythmic effect of SCN4A mutations is corroborated by the demonstration of Nav1.4 expression in human cardiomyocytes (18, 19). However, its real electrophysiological relevance remains to be defined. Notably, reported arrhythmic complications in skeletal muscle sodium channelopathies seem to reproduce the spectrum of electrophysiological alterations associated to SCN5A mutations, such as Brugada syndrome and long QT syndrome (20).\n\nIt should be remarked that in SCN4A gene mutations myotonia is due to a gain-of-function effect in the voltage-gated sodium channel, while in Brugada syndrome there is a loss of function of Nav1.5. Moreover, Nav1.4 expression in human myocardium appears to be quantitatively marginal, accounting for 1.1–2.6% of all sodium channels (18, 19). Latter assumptions stand against a single-agent effect of Nav1.4 in cardiac electrophysiology alterations. Possibly, the Nav1.4 contribution to transmembrane ion fluxes in myocardiocytes may become functionally relevant in presence of sodium-channel blocking agents.\n\nAltogether the considerations expressed above suggest an interactive pathogenetic mechanism rather than a direct causative role of Nav1.4 dysfunction in Brugada syndrome; in this view, modifier genes may be crucial. We cannot definitively establish if Brugada syndrome and myotonia (or periodic paralysis) could be organ-specific manifestations of the same process.\n\nIn a recent study Mannikko et al. found SCN4A pathogenetic mutations in four infants out of a cohort of 278 cases of sudden infant death syndrome (SIDS) (21). The authors suggest that acute respiratory dysfunction, which occurs in cases of SNEL, may be the cause of those premature deaths. Given the considerations expressed above, cardiac arrhythmias could be implicated as well, and this hypothesis should be considered for further investigations.\n\nCurrent data do not seem sufficient to support a systematic screening for Brugada syndrome in all patients with skeletal muscle sodium channelopathy. However, since the symptomatic treatment for myotonia involves the use of sodium channel-blocking agents (22), we suggest the initiation of a class 1C anti-arrhythmic therapy in controlled clinical settings. In this view, we advise the systematic recording of ECG with modified precordial leads to enhance the detection of ST-T changes consistent with Brugada syndrome.\n\nThis is the first report of warning symptoms of a potentially life-threatening cardiac condition appearing after the introduction of class 1C anti-arrhythmic therapy in a patient with non-dystrophic myotonia. We do not discourage a flecainide prescription as an anti-myotonic agent in patients with SCN4A mutations, given it is effective: however, we advise a cautious approach to this type of treatment. In such cases, flecainide therapy should possibly be introduced also in outpatient clinical settings, even though ECG should be performed before and 3 hours after the first drug administration. Since the steady state with oral flecainide is reached after several days (23), a further ECG should be performed after 1 week of a full dosage therapy.\n\nAccording to our experience, mexiletine, a class 1B anti-arrhythmic drug, remains a feasible anti-myotonic therapy, in presence of Brugada syndrome. Nonetheless, it should be given under strict cardiological monitoring. In our patient, hydroquinidine was interrupted before reaching full dosage due to gastrointestinal intolerance but showed a clear anti-myotonic effect. Since its pharmacodynamic features, especially the inhibition of Kito current, are favorable in Brugada syndrome, its efficacy as an anti-myotonic agent should be tested in a controlled and larger setting.\n\nIn conclusion, emerging data seem to outline an overlapping spectrum between skeletal muscle and cardiac sodium channelopathies. This could include non-dystrophic myotonias, periodic paralysis, long QT and Brugada syndromes. As demonstrated by our case, this has strong implications in the therapeutical management, however confirmatory studies are still needed.\n\nEthics statement\nThe study protocol was conducted according to the principles expressed in the Declaration of Helsinki, the institutional regulation and Italian laws and guidelines. Written informed consents were obtained from the patients for all blood samples and muscle biopsies used in this study.\n\nAuthor contributions\nMC wrote the manuscript. BF, MC, EB, and RV conducted clinical work-up. RC processed muscle biopsy. MC, EB, and RC made table and figures. MC, BF, EB, LS, VR, and GM reviewed the literature. MC, BF, RV, EB, VR, LS, RC, CP, and GM performed final manuscript review and editing.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Gourraud JB Barc J Thollet A Le Scouarnec S Le Maree H Schott JJ . The Brugada syndrome: a rare arrhythmia disorder with complex inheritance . Front Cardiovasc Med. (2016 ) 3 :9 . 10.3389/fcvm.2016.00009 27200363 \n2. Nicole S Fontaine B . Skeletal muscle sodium channelopathies . Curr Opin Neurol. (2015 ) 28 :508 –14 . 10.1097/WCO.0000000000000238 26285000 \n3. Péréon Y Lande G Demolombe S Nguyen The Tich S Sternberg D Le Marec H . Paramyotonia congenita with an SCN4A mutation affecting cardiac repolarization . Neurology (2003 ) 60 :340 –2 . 10.1212/01.WNL.0000042093.96309.5A 12552059 \n4. Maffè S Signorotti F Perucca A Bielli M Hladnik U Ragazzoni E . Atypical arrhythmic complications in familial hypokalemic periodic paralysis . J Cardiovasc Med. (2009 ) 10 :68 –71 . 10.2459/JCM.0b013e3283189564 19708131 \n5. Bissay V van Malderen SCH Keymolen K Lissens W Peeters U Daneels D . SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies . Eur J Hum Genet. (2016 ) 24 :400 –7 . 10.1038/ejhg.2015.125 26036855 \n6. Groome JR Fujimoto E Ruben PC . K-aggravated myotonia mutations at residue G1306 differentially alter deactivation gating of human skeletal muscle sodium channels . Cell Mol Neurobiol. (2005 ) 25 :1075 –92 . 10.1007/s10571-005-8057-1 16392038 \n7. Lion-Francois L Mignot C Vicart S Manel V Sternberg D Landrieu P . Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder . Neurology (2010 ) 75 :641 –5 . 10.1212/WNL.0b013e3181ed9e96 20713951 \n8. Desaphy JF Luca ADE Didonna MP George AL JrConte Camerino D . Different flecainide sensitivity of hNav1 .4 channels and myotonic mutants explained by state-dependent block. J Physiol. (2004 ) 554 :321 –34 . 10.1113/jphysiol.2003.046995 14608015 \n9. Desaphy JF Modoni A Lo Monaco M Conte Camerino D . Dramatic improvement of myotonia permanens with flecainide: a two-case report of a possible bench-to-bedside pharmacogenetics strategy . Eur J Clin Pharmacol. (2013 ) 69 :1037 –9 . 10.1007/s00228-012-1414-3 23052413 \n10. Portaro S Rodolico C Sinicropi S Musumeci O Valenzise M Toscano A . Flecainide-responsive myotonia permanens with SNEL onset: a new case and literature review . Pediatrics (2016 ) 137 :e20153289 . 10.1542/peds.2015-3289 26944947 \n11. Watanabe H Minamino T . Genetics of Brugada syndrome . J Hum Genet. (2016 ) 61 :57 –60 . 10.1038/jhg.2015.97 26223181 \n12. Campuzano O Alcalde M Allegue C Iglesias A García-Pavía P Partemi S . Genetics of arrhythmogenic right ventricular cardiomyopathy . J Med Genet. (2013 ) 50 :280 –9 . 10.1136/jmedgenet-2013-101523 23468208 \n13. Lieve KV van der Werf C Wilde AA . Catecholaminergic polymorphic ventricular tachycardia . Circ J. (2016 ) 80 :1285 –91 . 10.1253/circj.CJ-16-0326 27180891 \n14. Anguera I Garcia-Aberola A Dellaglio P Toquero J Pérez L Martínez JG . Shock reduction with long-term quinidine in patients with Brugada syndrome and malignant ventricular arrhythmia episodes . J Am Coll Cardiol. (2016 ) 67 :1653 –4 . 10.1016/j.jacc.2016.01.042 27150692 \n15. Mitrović N George AL JrLerche H Wagner S Fahlke C Lehmann-Horn F . Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel . J Physiol. (1995 ) 487 :107 –14 . 10.1113/jphysiol.1995.sp020864 7473241 \n16. Shinlapawittayatorn K Du XX Liu H Ficker E Kaufman ES Deschênes I . A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations . Heart Rhythm (2011 ) 8 :455 –62 . 10.1016/j.hrthm.2010.11.034 21109022 \n17. Gouas L Nicaud V Berthet M Forhan A Tiret L Balkau B . Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population . Eur J Hum Genet. (2005 ) 13 :1213 –22 . 10.1038/sj.ejhg.5201489 16132053 \n18. Blechschmidt S Haufe V Benndorf K Zimmer T . Voltage-gated Na+ channel transcript patterns in the mammalian heart are species-dependent . Prog Biophys Mol Biol. (2008 ) 98 :309 –18 . 10.1016/j.pbiomolbio.2009.01.009 19351521 \n19. Kaufmann SG Westenbroek RE Maass AH Lange V Renner A Wischmeyer E . Distribution and function of sodium channel subtypes in human atrial myocardium . J Mol Cell Cardiol. (2013 ) 61 :133 –41 . 10.1016/j.yjmcc.2013.05.006 23702286 \n20. Liu M Yang KC Dudley SC Jr . Cardiac sodium channel mutations: why so many phenotypes? \nNat Rev Cardiol . (2014 ) 11 :607 –15 . 10.1038/nrcardio.2014.85 24958080 \n21. Mannikko R Wong L Tester DJ Thor MG Sud R Kullmann DM . Dysfunction of Nav1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study . Lancet (2018 ) 391 :1483 –92 . 10.1016/S0140-6736(18)30021-7 29605429 \n22. Meola G Hanna MG Fontaine B . Diagnosis and new treatment in muscle channelopathies . J Neurol Neurosurg Psychiatry (2009 ) 80 :360 –5 . 10.1136/jnnp.2008.164046 19289476 \n23. Tjandra-Maga TB Verbesselt R Van Hecken A Mullie A De Schepper PJ . Flecainide: single and multiple oral dose kinetics, absolute bioavailability and effect of food and antacid in man . Br J Clin Pharmacol. (1986 ) 22 :309 –16 . 10.1111/j.1365-2125.1986.tb02892.x 3094570\n\n",
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"issue": "9()",
"journal": "Frontiers in neurology",
"keywords": "Brugada syndrome; SCN4A; flecainide; mexiletine; sodium skeletal muscle channelopathy",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "385",
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"pmid": "29899727",
"pubdate": "2018",
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"title": "Flecainide-Induced Brugada Syndrome in a Patient With Skeletal Muscle Sodium Channelopathy: A Case Report With Critical Therapeutical Implications and Review of the Literature.",
"title_normalized": "flecainide induced brugada syndrome in a patient with skeletal muscle sodium channelopathy a case report with critical therapeutical implications and review of the literature"
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"abstract": "Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a potential new treatment option in dementias.\n\n\n\nTo assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks.\n\n\n\nWe conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI.\n\n\n\nSurgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network.\n\n\n\nLow frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks.\n\n\n\nNCT02263937.",
"affiliations": "Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Electronic address: j.gratwicke@ucl.ac.uk.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Biomedical Research Building, Newcastle University & Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.;Biomedical Research Building, Newcastle University & Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.;Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Lynsholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Lynsholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Lynsholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Dementia Research Centre, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Newcastle University & Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle Upon Tyne, UK.;Newcastle University & Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle Upon Tyne, UK.;Biomedical Research Building, Newcastle University & Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.;Dementia Research Centre, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Biomedical Research Building, Newcastle University & Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.;Dementia Research Centre, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.;Department of Clinical & Movement Neurosciences, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Electronic address: t.foltynie@ucl.ac.uk.",
"authors": "Gratwicke|James|J|;Zrinzo|Ludvic|L|;Kahan|Joshua|J|;Peters|Amy|A|;Brechany|Una|U|;McNichol|Ann|A|;Beigi|Mazda|M|;Akram|Harith|H|;Hyam|Jonathan|J|;Oswal|Ashwini|A|;Day|Brian|B|;Mancini|Laura|L|;Thornton|John|J|;Yousry|Tarek|T|;Crutch|Sebastian J|SJ|;Taylor|John-Paul|JP|;McKeith|Ian|I|;Rochester|Lynn|L|;Schott|Jonathan M|JM|;Limousin|Patricia|P|;Burn|David|D|;Rossor|Martin N|MN|;Hariz|Marwan|M|;Jahanshahi|Marjan|M|;Foltynie|Thomas|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.brs.2020.04.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4754",
"issue": "13(4)",
"journal": "Brain stimulation",
"keywords": "Cholinergic networks; Deep brain stimulation; Dementia with Lewy bodies; Functional brain networks; Nucleus basalis of Meynert",
"medline_ta": "Brain Stimul",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020532:Basal Nucleus of Meynert; D046690:Deep Brain Stimulation; D005260:Female; D006801:Humans; D020961:Lewy Body Disease; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101465726",
"other_id": null,
"pages": "1031-1039",
"pmc": null,
"pmid": "32334074",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bilateral nucleus basalis of Meynert deep brain stimulation for dementia with Lewy bodies: A randomised clinical trial.",
"title_normalized": "bilateral nucleus basalis of meynert deep brain stimulation for dementia with lewy bodies a randomised clinical trial"
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"abstract": "BACKGROUND\nHydatid cysts are fluid-filled sacs containing immature forms of parastic tapeworms of the genus Echinococcus. The most prevalent and serious complication of hydatid disease is intrabiliary rupture, also known as cystobiliary fistulae. In this study, a sporadic case of biliary obstruction, cholangitis, and septicemia is described secondary to hydatid cyst rupture into the common bile duct and intraperitoneal cavity.\n\n\nMETHODS\nA 21-year-old Iranian man was admitted to the emergency ward with 5 days of serious sickness and a history of right upper quadrant abdominal pain, fatigue, fever, icterus, vomiting, and no appetite. In the physical examination, abdominal tenderness was detected in all four quadrants and in the scleral icterus. Abdominal ultrasound revealed intrahepatic and extrahepatic biliary duct dilation. Gallbladder wall thickening was normal but was very dilated, and large unilocular intact hepatic cysts were detected in segment IV and another one segment II which had detached laminated membranes and was a ruptured or complicated liver cyst.\n\n\nCONCLUSIONS\nIntrabiliary perforation of the liver hydatid cyst is an infrequent event but has severe consequences. Therefore, when patients complain of abdominal pain, fever, peritonitis, decreased appetite, and jaundice, a differential diagnosis of hydatid disease needs to be taken into consideration. Early diagnosis of complications and aggressive treatments, such as endoscopic retrograde cholangiopancreatography and surgery, are vital.",
"affiliations": "Inflammatory Lung Disease Research Center, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.;Razi Clinical Research Development Unit, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran. doctorAshoobi@gmail.com.;Razi Clinical Research Development Unit, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.;Razi Clinical Research Development Unit, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.;Razi Clinical Research Development Unit, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.;Inflammatory Lung Disease Research Center, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.",
"authors": "Aghajanzadeh|Manouchehr|M|;Ashoobi|Mohammad Taghi|MT|;Hemmati|Hossein|H|;Samidoust|Pirooz|P|;Delshad|Mohammad Sadegh Esmaeili|MSE|;Pourahmadi|Yousha|Y|",
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"doi": "10.1186/s13256-021-02822-5",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2822\n10.1186/s13256-021-02822-5\nCase Report\nIntrabiliary and abdominal rupture of hepatic hydatid cyst leading to biliary obstruction, cholangitis, pancreatitis, peritonitis and septicemia: a case report\nAghajanzadeh Manouchehr 1\nAshoobi Mohammad Taghi doctorAshoobi@gmail.com\ntashoobi99@gmail.com\n\n2\nHemmati Hossein 2\nSamidoust Pirooz 2\nDelshad Mohammad Sadegh Esmaeili 2\nPourahmadi Yousha 1\n1 grid.411874.f 0000 0004 0571 1549 Inflammatory Lung Disease Research Center, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran\n2 grid.411874.f 0000 0004 0571 1549 Razi Clinical Research Development Unit, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran\n28 5 2021\n28 5 2021\n2021\n15 31121 1 2021\n24 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nHydatid cysts are fluid-filled sacs containing immature forms of parastic tapeworms of the genus Echinococcus. The most prevalent and serious complication of hydatid disease is intrabiliary rupture, also known as cystobiliary fistulae. In this study, a sporadic case of biliary obstruction, cholangitis, and septicemia is described secondary to hydatid cyst rupture into the common bile duct and intraperitoneal cavity.\n\nCase presentation\n\nA 21-year-old Iranian man was admitted to the emergency ward with 5 days of serious sickness and a history of right upper quadrant abdominal pain, fatigue, fever, icterus, vomiting, and no appetite. In the physical examination, abdominal tenderness was detected in all four quadrants and in the scleral icterus. Abdominal ultrasound revealed intrahepatic and extrahepatic biliary duct dilation. Gallbladder wall thickening was normal but was very dilated, and large unilocular intact hepatic cysts were detected in segment IV and another one segment II which had detached laminated membranes and was a ruptured or complicated liver cyst.\n\nConclusion\n\nIntrabiliary perforation of the liver hydatid cyst is an infrequent event but has severe consequences. Therefore, when patients complain of abdominal pain, fever, peritonitis, decreased appetite, and jaundice, a differential diagnosis of hydatid disease needs to be taken into consideration. Early diagnosis of complications and aggressive treatments, such as endoscopic retrograde cholangiopancreatography and surgery, are vital.\n\nKeywords\n\nHydatid cyst\nLiver\nIntrabiliary rupture\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nHydatid disease, also known as echinococcosis, is a serious and problematic health issue worldwide, and this parasitic disease is widespread in most Mediterranean countries, West Asia, South America, the Far East, Australia, and East Africa [1–3]. Humans are intermediate and incidental hosts and are infected either through the direct route via exposure to or contact with infected dogs or other canines or indirect routes via consumption of food, water, and infected items on the ground [2–4]. Biliary cirrhosis may also be a tardy sequel of intrabiliary perforation of liver hydatid cysts [5–7]. The majority of patients show an individual organ involvement with a single cyst, and 75–85% of cysts are localized in the liver of patients [2, 5]. Some cysts may grow at an average rate of 1–20 mm per year, and these patients survive with no evident changes for a long time; other cysts can become calcified and completely disappear [5, 8]. An enlarging cyst may compress and cause atrophy and fibrosis of the liver [5, 9]. The compression and displacement of biliary ducts can frequently produce a spontaneous rupture in biliary ducts. Timely detection and therapy are mandatory in the case of an intrabiliary perforation or rupture of a liver hydatid cyst, which can result in the obstruction of the biliary duct with 50% mortality [8–10].\n\nImaging tools, such as ultrasonography (U/S), abdominal computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP), are useful devices to diagnose the disease. U/S and CT scans are the first diagnostic tools of choice and can be applied under all conditions [1, 2]. Of the more invasive instruments, ERCP can help establish definitive detection and treatment with sphincterotomy in patients affected by intra-biliary rupture of a cyst, and MRCP can diagnose the site of the obstructions of the biliary system [6, 7, 10, 11]. This case report describes the clinical presentation of a patient with liver echinococcosis, the various complications of a hepatic hydatid cyst, especially its intrabiliary rupture, and the methods of diagnosing and managing cystic biliary fistulae.\n\nCase presentation\n\nA 21-year-old Iranian man presented to the emergency ward of our hospital with 5 days of illness and a history of right upper quadrant abdominal pain, fatigue, fever, icterus, vomiting, and no appetite. He was examined physically, and abdominal tenderness was detected in all four quadrants, and scleral icterus. His blood pressure was normal at 110.70 mmHg and oxygen saturation rate was of 95% on ambient air. Axillary temperature was 38.8 °C. His medical history showed that was being treated with albendasol 800 mg daily for months because of two hydatid cysts in the liver. One of the cysts was located on the dome of liver segment III and the second was on segment VII just over the right kidney (Fig. 1). On the CT scan of the liver, two cysts were observed in segment II and VII with septation, of which one was intact and the other one had ruptured. After 2 weeks on albendazole, fatigue, fever, icterus, and vomiting were present, which was the complication of albendazole since the values for all liver function tests had increased.Fig. 1 Computed tomography scan of the liver showing two cysts in segments II and VII, respectively, with septation, of which one was intact and the other had ruptured\n\nLaboratory findings revealed increased white blood count (WBC; 17,000 K/uL, reference value 4–10.8 K/uL) and elevated liver enzymes (aspartate transaminase [AST] 120 U/L [reference value 11–72 U/L]; alanine transaminase [ALT] 83 IU/L [reference value < 40 IU/L]; alkaline phosphatase [ALP] 1250 IU/L; total bilirubin 9 mg/dL [reference value < 1.2 mg/dL]). The direct and indirect bilirubin measurements were 4 and 5 mg/dL, respectively, C-reactive protein concentration was 11 U/mL (reference value 0–0.5 mg/dL, amylase 320), and lipase was 180 IU/L. A prothrombin time of 42 s (reference value 9.6–14.2 s), activated partial thromboplastin time of 48 s (reference value, 20–38 s), and international normalized ratio of 5 (reference value 0.85–1.2) were also detected in the tests. The remaining laboratory test results were within normal limits. These test results show hepatitis due to albendazole toxicity.\n\nIn addition to considering these test findings and the patient’s ailments, we also used abdominal U/S to arrive at the diagnosis. Abdominal U/S revealed intrahepatic and extrahepatic bile duct dilation; the gallbladder was dilated but had normal wall thickening. Large intact hepatic cysts were observed in segment IV and another one were in segment II with detached laminated membranes, possibly indicative of a ruptured or complicated liver cyst. An intravenous contrast CT scan was performed for more evaluation and revealed unilocular hepatic cysts with segregated laminated membranes that corresponded to hepatic hydatid cysts on segment II and other unilocular intact hepatic cysts on segment IV (Fig. 2). Further observations indicated intrahepatic and extrahepatic biliary duct dilation (Fig. 3).Fig. 2 Axial contrast enhanced computed tomography scan showing unilocular hepatic cysts with detached laminated membranes compatible with hepatic hydatid cysts on segments II and IV. Intrahepatic biliary duct dilation is also seen\n\nFig. 3 Magnetic resonance cholangiopancreatography shows cyst rupture into the common hydatid cyst membranes and hepatic duct in the common bile duct. A hydatid cyst was also observed on segment II. Laparotomy and common biliary duct exploration established that the bile duct was obstructed with hydatid membranes and daughter cysts\n\nThe reason for bile duct dilatation was investigated by MRCP, which showed the rupture of cysts of segment II into the intrahepatic ducts, common hepatic duct, and common biliary duct (CBD). In addition, laminated membranes of the hydatid cyst and daughter cysts were found in the CBD, causing the obstruction (Fig. 3).\n\nThe patient underwent laparotomy due peritonitis resulting from the rupture of the liver hydatid cyst in the abdominal cavity with a right extensive subcostal incision. During exploration, 500 cc bile fluid was aspirated from the abdominal cavity and sent for analysis. The pancreas was inflamed, and its appearance showed pancreatitis. The liver was carefully inspected; one collapsed infected cystic lesion with a small perforation was present in segment II just over the right kidney.\n\nOur approach for surgical treatment began with the aspiration and evacuation of the cyst contents. To explore for any purulent or bile contents, cystostomy and irrigation were performed. Also, fibrotic tissue around the cyst was resected and the site of bile leakage ligated with a non-absorbable suture. Capitonnage, omentoplasty, and insertion of a Foley catheter inside the incision were performed to remove the residual cyst and prevent recurrence. The gall bladder was highly dilated and was full of a white mucous fluid with obstruction of the cystic duct; choledocotomy and drainage of the common bile duct were performed with saline irrigation. Moreover, daughter cysts were removed from the common bile duct and intrabiliary ducts. At the end of the surgery, a T-tube was inserted in the site of choledocotomy and a corrugated drain was fixed. During exploration, another intact cyst was found in segment VII; this cyst was aspirated and the laminated membrane removed; the cavity was then irrigated with betadine 10%. Pricystectomy was performed, and a Foley catheter 18 was put into the remnant cavity and fixed to the abdominal wall. Finally, the CBD (diameter 30 mm) was examined; it was full of laminated membrane, daughter cysts, and debrides of the hydrated cyst. After extraction of all materials from the CBD and subsequent irrigation, a T-tube was placed in the CBD and fixed into place. A Penrose drain was placed in the abdominal cavity, and then the abdomen was closed.\n\nThree days after surgery, the levels of bilirubin, amylase, lipase, AST, ALT, WBC, and ALP had decreased. The patient’s general condition (fever and appetite) was good, and he was discharged 10-day post-operation with good condition. Trans-T-tube cholangiography was performed 20 days after the operation with good results and was then removed (Figure 4)Fig. 4 Pus from collected after exploration of common bilary duct and dilated gallbladder and T-tube cholangiography\n\nDiscussion and conclusion\n\nThe complications of a liver hydatid cyst (LHC) are rupture into the biliary duct, abscess formation, and rupture into the pulmonary parenchyma and pleural space [1, 3–5]. Presentation of an intrabiliary rupture of LHC ranges from no symptoms in a minor perforation to obstructive jaundice, cholecystitis, cholangitis, pancreatitis, peritonitis, and/or septicemia [5, 6, 10]. In 10–37% of patients, the intrabiliary fistulae due to LHC are of the occult type, with 3–17% of patients having the frank type[5]. Rupture of the occult-type fistula rupture is typically asymptomatic and can be seen as a liver abscess or suppuration, or it can be present as a frank rupture [5, 8]. Clinically, observations are not specific at this phase [4, 5, 10]. Ruptured fragments of laminated membranes, daughter cysts, and other debridement of the cyst can penetrate the biliary tree and cause obstructive icterus, acute cholangitis, or, as in our case, septicemia [6, 10]. Additional presentations, such as acute pancreatitis, acute cholecystitis, and peritonitis due to hydatid material, have been discussed in published reports. Although fistulae between the biliary system and LHC are present in 80–90% of patients, the incidence of clinical presentation occurs only in 13–37% of patients [5, 8, 10]. The rate of huge intrabiliary rupture occurs in 5–17% of patients [5, 6, 8, 10]. Although in these conditions, mortality and morbidity are high [3, 5, 6, 10], diagnosis is difficult in occult or minor fistulae between the biliary system and LHC, as the indications and radiological pre-surgical observations are not remarkable [3, 5, 6]. Biliary leakage is the highly frequent consequence of liver hydatid cyst [5, 6, 9, 10]. The patient described here presented with frank intrabiliary rupture.\n\nThe preoperative detection of the consequences of LHC is difficult, but clinical demonstrations and findings of in vitro assays can be suggestive of intrabiliary rupture, as in our case. U/S and CT scans may indicate a minor or huge intrabiliary rupture in the majority of cases, and magnetic resonance imaging is another imaging tool that can facilitate diagnosis. MRCP can show daughter cysts, separation of the membranes, dilated biliary tree, and hydatid cyst material in the biliary system [6–9]. In our case, the cyst had ruptured into both the abdominal cavity and biliary tree. The surgical treatment of LHC includes hepatic resection and total cystostomy, conservative cyst evacuation, resection of fibrotic priciest layer, and capitonnage with external drainage [2, 5–7, 11]. Current approaches for the treatment of LHC are usually aspiration, cyst evacuation followed by, capitonnage with external drainage, or omentoplasty [1, 2, 8]. The aim of surgery for LHC is to remove all cyst elements and prevent the spread of cysts content via minimizing complications [2, 5]. Aspiration and cyst evacuation followed by external drainage is a relatively harmless and easy approach and is helpful in the treatment of uncomplicated LHC [5]. The main disadvantage of this approach is that adverse events occur at high frequency after the surgery, such as cyst-biliary fistulae, bilio-cutaneous fistulae, bilomas, and bile peritonitis (4–28%) in the remnant cavity for a long time [11–13]. In practice, we never perform hepatic resection [1, 2]. After surgery for LHC, external biliary fistulae are usually closed extemporaneously [5]. In a study involving 304 cases, external biliary fistulae closed extemporaneously within 2–4 months [13]. In another report, all fistulae closed extemporaneously within a maximal duration of 38 days; the prolonged fistulae drainage and morbidity weree high [14]. Medical treatment is usually indicated before surgery to sterilize the fistulae and to avoid recurrences. In medical treatment, disseminated hydatidosis has been indicated. To date, drugs of the benzimidazole family (albendazole or mebendazole) are used to treat hydatidosis, but albendazole is the best pharmacological option [14, 15]. In a few patients with post-surgical external biliary fistulae, it is generally accepted that endoscopic sphincterotomy, with or without stenting or naso-biliary drainage, mitigates the high intrabiliary pressure and improves timely closing of these fistulae even when the distal biliary obstruction is not present [11]. In our case, biliary drainage stopped 20 days post-operation, and the T-tube was removed.\n\nIntrabiliary perforation of the LHC is a scarce event but one with severe consequences. Physicians treating patients referred to medical centers while complaining of abdominal pain, fever, peritonitis, decreased appetite, and icterus should recognize the possibility of perforation of LHC, as opposed to hydatid disease. Early diagnosis of complications and aggressive treatments, such as ERCP and surgery, are vital.\n\nAbbreviations\n\nCBD Common biliary duct\n\nCT Computed tomography\n\nU/S Ultrasonography\n\nAcknowledgements\n\nThe authors wish to extend their gratitude to Guilan University of Medical Sciences for financial support and sponsorship.\n\nAuthors' contributions\n\nMA designed the study, reviewed the manuscript, and edited the final version. MTA contributed to the design of the study, collected the data, and drafted the manuscript. HH and PS contributed to the design of the study, collected the data, and participated in drafting the manuscript. YP and MSED analyzed the data, reviewed the manuscript, and edited the final version. All authors read and approved the final manuscript.\n\nFunding\n\nSelf-funding.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe Ethics Committee of Guilan University of Medical Sciences approved the study.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Aghajanzadeh M Asgary MR Foumani AA Alavi SE Rimaz S Banihashemi Z Surgical management of pleural complications of lung and liver hydatid cysts in 34 patients Int J Life Sci 2014 8 15 19 10.3126/ijls.v8i4.10893\n2. Aghajanzadeh M Safarpoor F Amani H Alavi A One-stage procedure for lung and liver hydatid cysts Asian Cardiovasc Thorac Ann 2008 16 392 395 10.1177/021849230801600510 18812348\n3. Spârchez Z Osian G Onica A Bărbântă C Tanţău M Pascu O Ruptured hydatid cyst of the liver with biliary obstruction: presentation of a case and review of the literature Rom J Gastroenterol 2004 13 245 250 15470540\n4. Atli M Kama NA Yuksek YN Doganay M Gozalan U Kologlu M Intrabiliary rupture of a hepatic hydatid cyst: associated clinical factors and proper management Arch Surg 2001 136 1249 1255 10.1001/archsurg.136.11.1249 11695968\n5. Avcu S Ünal Ö Arslan H Intrabiliary rupture of liver hydatid cyst: a case report and review of the literature Cases J 2009 2 6455 10.1186/1757-1626-2-6455 19829807\n6. Sıkar HE Kaptanoğlu L Kement M An unusual appearance of complicated hydatid cyst: necrotizing pancreatitis Ulus Travma Acil Cerrahi Derg 2017 23 81 83 28261778\n7. von Sinner WN Ultrasound, CT and MRI of ruptured and disseminated hydatid cysts Eur J Radiol 1990 11 31 37 10.1016/0720-048X(90)90099-W 2204531\n8. Dolay K Akbulut S Role of endoscopic retrograde cholangiopancreatography in the management of hepatic hydatid disease World J Gastroenterol 2014 20 15253 15261 10.3748/wjg.v20.i41.15253 25386073\n9. Erden A Ormeci N Fitoz S Erden I Tanju S Genç Y Intrabiliary rupture of hepatic hydatid cysts: diagnostic accuracy of MR cholangiopancreatography AJR Am J Roentgenol 2007 189 W84 W89 10.2214/AJR.07.2068 17646444\n10. Ufuk F Duran M Intrabiliary rupture of hepatic hydatid cyst leading to biliary obstruction, cholangitis, and septicemia J Emerg Med 2018 54 e15 e17 10.1016/j.jemermed.2017.09.009 29107478\n11. Akoglu M Hilmioglu F Balay AR Sahin B Davidson BR Endoscopic sphincterotomy in hepatic hydatid disease open to the biliary tree Br J Surg 1990 77 1073 10.1002/bjs.1800770940\n12. Agarwal S Sikora SS Kumar A Saxena R Kapoor VK Bile leaks following surgery for hepatic hydatid disease Indian J Gastroenterol 2005 24 55 58 15879650\n13. Sayek I Yalin R Sanaç Y Surgical treatment of hydatid disease of the liver Arch Surg 1980 115 847 850 10.1001/archsurg.1980.01380070035007 7387376\n14. El-On J Benzimidazole treatment of cystic echinococcosis Acta Trop 2003 85 243 252 10.1016/S0001-706X(02)00217-6 12606103\n15. Horton RJ Albendazole in treatment of human cystic echinococcosis: 12 years of experience Acta Trop 1997 64 79 93 10.1016/S0001-706X(96)00640-7 9095290\n\n",
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"mesh_terms": "D000328:Adult; D002761:Cholangitis; D002779:Cholestasis; D004444:Echinococcosis, Hepatic; D006801:Humans; D007492:Iran; D008297:Male; D010195:Pancreatitis; D010538:Peritonitis; D018805:Sepsis; D055815:Young Adult",
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"title": "Intrabiliary and abdominal rupture of hepatic hydatid cyst leading to biliary obstruction, cholangitis, pancreatitis, peritonitis and septicemia: a case report.",
"title_normalized": "intrabiliary and abdominal rupture of hepatic hydatid cyst leading to biliary obstruction cholangitis pancreatitis peritonitis and septicemia a case report"
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"abstract": "OBJECTIVE\nA case of probable enoxaparin-induced hepatotoxicity is described.\n\n\nCONCLUSIONS\nA 29-year-old woman sought treatment from a pulmonologist for a dry, hacking, constant cough not relieved by fast-acting inhalers or narcotic cough medications that had lasted for three weeks. Her primary care physician had earlier made a preliminary diagnosis of pertussis and prescribed a short course of azithromycin and corticosteroids, which did not help relieve the symptoms. Computed tomography angiography of her chest revealed multiple bilateral pulmonary emboli with a moderate clot burden, which resulted in her hospitalization. The pulmonary emboli were thought to be associated with her oral contraceptive, which was discontinued at hospital admission. Anticoagulant therapy was initiated with subcutaneous enoxaparin and oral warfarin. Beginning the second day of therapy, the patient complained of nausea and associated vomiting. Diagnostic procedures did not reveal any liver, kidney, splenic, or pancreatic abnormalities. The results of laboratory tests revealed elevated levels of hepatic enzymes, including alanine transaminase (ALT) and aspartate transaminase (AST). Tests for hepatitis A, B, and C were negative. Enoxaparin therapy was discontinued, and the patient was maintained on oral warfarin. Clinical and laboratory signs of liver injury resolved over the next few days, with a return to baseline levels of AST and ALT levels over the subsequent months. According to the Naranjo et al. adverse-reaction probability scale, enoxaparin was the probable cause of hepatotoxicity in this patient.\n\n\nCONCLUSIONS\nA woman receiving enoxaparin every 12 hours developed signs and symptoms of hepatotoxicity after the second dose. The case was unusual in the rapidity and magnitude of hepatic enzyme elevation.",
"affiliations": "Evidence-Based Practice Center, Hartford Hospital, Hartford, CT, USA. wbaker01@harthosp.org",
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"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin",
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"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D056486:Chemical and Drug Induced Liver Injury; D017984:Enoxaparin; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008099:Liver; D008111:Liver Function Tests; D011655:Pulmonary Embolism; D014057:Tomography, X-Ray Computed",
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"abstract": "The primary objective of this study was to compare the amount of lidocaine administered for vaginal reconstruction with versus without hysterectomy. The secondary objective was to assess the risk of lidocaine toxicity.\n\n\n\nThis retrospective cohort study compares lidocaine dose in 2 cohorts: women who underwent vaginal hysterectomy with additional vaginal reconstruction (VH + VR) versus those who underwent vaginal reconstruction without hysterectomy (VR only). Total intraoperative lidocaine dose included the intravenous dose from anesthesia and the vaginally injected dose from the surgeon. The risk of toxicity was defined as total dose greater than 7 mg/kg. The primary outcome was the difference in total lidocaine dose for VH + VR versus VR only.\n\n\n\nAmong 372 women included, 140 (37.6%) were in the VH + VR group, and 232 (62.4%) in the VR-only group. For the primary outcome of total lidocaine dose between groups, VH + VR received more total lidocaine than did VR only (228 ± 105 vs 168 ± 78 mg, P < 0.001). This difference was due to the vaginal lidocaine dose (P < 0.001), with no significant difference in the intravenous lidocaine dose (P = 0.68). In a logistic regression model controlling for age, anesthesia type, sling, and anterior repair, posterior repair, and anesthesia type, VH remained an independent risk factor for increased lidocaine dose (P < 0.001). Two women received a toxic dose of lidocaine, and both were in the VH + VR group.\n\n\n\nWomen undergoing vaginal hysterectomy with additional vaginal reconstructive procedures are more likely to receive a higher dose of lidocaine compared with women undergoing vaginal reconstruction alone. The risk of lidocaine toxicity is increased with concomitant procedures.",
"affiliations": "From the Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, Chapel Hill, NC.",
"authors": "Willis-Gray|Marcella G|MG|;Husk|Katherine E|KE|;Brueseke|Taylor J|TJ|;Connolly|AnnaMarie|A|;Geller|Elizabeth J|EJ|",
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"mesh_terms": "D000368:Aged; D000779:Anesthetics, Local; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007902:Length of Stay; D008012:Lidocaine; D008875:Middle Aged; D056887:Pelvic Organ Prolapse; D019651:Reconstructive Surgical Procedures; D012189:Retrospective Studies; D014550:Urinary Incontinence, Stress; D014621:Vagina",
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"publication_types": "D003160:Comparative Study; D016428:Journal Article",
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"title": "Lidocaine Use in Vaginal Surgery and Risk of Toxicity.",
"title_normalized": "lidocaine use in vaginal surgery and risk of toxicity"
} | [
{
"companynumb": "US-MYLANLABS-2020M1094529",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "Pill oesophagitis is a frequent clinical entity that may induce dysphagia and exceptionally oesophageal occlusion. The mechanisms inducing mucosal inflammation are not completely defined, but oesophageal damage occurring when the caustic content of a drug remains in the oesophagus long enough to produce mucosal lesions seems to be a main factor. We report a case of a life-threatening stenosing pill hypopharynx-oesophagitis caused by the ingestion of a capsule of tamsulosin, a drug diffusely used for benign prostatic hyperplasia treatment.",
"affiliations": "Department of Clinical and Experimental Medicine, Federico II University, Via S Pansini 5, 80131 Naples, Italy. luciano@unina.it",
"authors": "D'Agostino|L|L|;Manguso|F|F|;Bennato|R|R|;Scaramuzzo|A|A|",
"chemical_list": "D000317:Adrenergic alpha-Antagonists; D013449:Sulfonamides; D000077409:Tamsulosin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2003.11.032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "36(9)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": null,
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000317:Adrenergic alpha-Antagonists; D000368:Aged; D004940:Esophageal Stenosis; D004941:Esophagitis; D006801:Humans; D007014:Hypophosphatasia; D008297:Male; D010612:Pharyngitis; D011470:Prostatic Hyperplasia; D013449:Sulfonamides; D000077409:Tamsulosin; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "632-4",
"pmc": null,
"pmid": "15460849",
"pubdate": "2004-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A life-threatening case of stenosing pill hypopharynx-oesophagitis caused by a tamsulosin capsule.",
"title_normalized": "a life threatening case of stenosing pill hypopharynx oesophagitis caused by a tamsulosin capsule"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2001-DE-Y0147",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"dru... |
{
"abstract": "West Nile Virus is an arbovirus that has rapidly spread throughout the United States since the first case was described in Queens, New York in 1999. There has been increasing reports of both community-acquired and organ-derived infections in renal transplant recipients. In immunocompromised individuals, WNV infection is a life-threatening disease with significant neurological morbidity. We report the only pediatric case of community-acquired WNV disease in a renal transplant recipient to undergo detailed long-term neuropsychological assessment. Increased surveillance and prompt treatment of WNV meningoencephalitis is critical, and our report highlights the effectiveness of immunosuppression reduction without compromising allograft outcomes.",
"affiliations": "Louisiana State University Health Sciences Center, New Orleans, LA, USA.;Louisiana State University Health Sciences Center, New Orleans, LA, USA.;Louisiana State University Health Sciences Center, New Orleans, LA, USA.;Nephrology, Children's Hospital of New Orleans, New Orleans, LA, USA.",
"authors": "Lambert|S L|SL|;Aviles|D|D|;Vehaskari|V M|VM|;Ashoor|I F|IF|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12768",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "20(6)",
"journal": "Pediatric transplantation",
"keywords": "Encephalitis; West Nile virus; pediatric kidney transplant",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D002648:Child; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008590:Meningoencephalitis; D009483:Neuropsychological Tests; D011183:Postoperative Complications; D012720:Severity of Illness Index; D014901:West Nile Fever",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "836-9",
"pmc": null,
"pmid": "27470315",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Severe West Nile virus meningoencephalitis in a pediatric renal transplant recipient: successful recovery and long-term neuropsychological outcome.",
"title_normalized": "severe west nile virus meningoencephalitis in a pediatric renal transplant recipient successful recovery and long term neuropsychological outcome"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0083741",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugaddition... |
{
"abstract": "The synergistic effect of clonidine with bupivacaine, well established in peripheral nerve blocks, remains controversial in local field block for postoperative analgesia.\n\n\n\nTo investigate the potential analgesic benefit of adding clonidine to bupivacaine during preincisional field block in posterior approaches for spine surgeries.\n\n\n\nTwo hundred twenty-five patients were enrolled in this study and underwent lumbar spinal fusion (n = 80), lumbar laminectomy (n = 25), lumbar microdiscectomy (n = 94), or cervical laminectomy (n = 26). In each surgical subgroup, patients were randomly assigned in a double-blinded fashion to receive either 20 mL of 0.25% bupivacaine alone (control group, n = 109) or with 150 μg clonidine (clonidine group, n = 116) in the form of a preincisional field block. Outcome parameters included area under the curve of pain from postoperative day D0 to D8 and rescue morphine consumption from D0 to D3.\n\n\n\nThe area under the curve was reduced in the clonidine group, particularly in the microdiscectomy subgroup, and without reaching statistical significance in the cervical laminectomy subgroup. Total rescue morphine consumption was reduced in the clonidine group, particularly at D1-D2, a benefit that was exclusive to the lumbar stenosis and lumbar fusion subgroups. Field block with clonidine, surgical subgroup, and the presence of preoperative spinal pain were factors independently influencing postoperative wound pain in multivariate analysis.\n\n\n\nThe addition of clonidine to local preincisional field block with bupivacaine resulted in better and prolonged postoperative analgesia in posterior lumbar spine surgeries, an effect that was more pronounced in patients with no preoperative spinal pain.",
"affiliations": "Laboratory of Neurosciences, Faculty of Medicine (PTS), St Joseph University, Beirut, Lebanon.;Laboratory of Neurosciences, Faculty of Medicine (PTS), St Joseph University, Beirut, Lebanon.;Laboratory of Neurosciences, Faculty of Medicine (PTS), St Joseph University, Beirut, Lebanon.;Department of Neuro-surgery, Hôtel-Dieu de France hospital, Beirut, Lebanon.;Department of Neuro-surgery, Hôtel-Dieu de France hospital, Beirut, Lebanon.;Department of Neuro-surgery, Hôtel-Dieu de France hospital, Beirut, Lebanon.;Department of Neuro-surgery, Hôtel-Dieu de France hospital, Beirut, Lebanon.;Department of Neuro-surgery, Hôtel-Dieu de France hospital, Beirut, Lebanon.;Laboratory of Neurosciences, Faculty of Medicine (PTS), St Joseph University, Beirut, Lebanon.",
"authors": "Abdel Hay|Joe|J|;Kobaiter-Maarrawi|Sandra|S|;Tabet|Patrick|P|;Moussa|Ronald|R|;Rizk|Tony|T|;Nohra|Georges|G|;Okais|Nabil|N|;Samaha|Elie|E|;Maarrawi|Jospeh|J|",
"chemical_list": "D000779:Anesthetics, Local; D003000:Clonidine; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1093/neuros/nyx313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "82(6)",
"journal": "Neurosurgery",
"keywords": null,
"medline_ta": "Neurosurgery",
"mesh_terms": "D000328:Adult; D000779:Anesthetics, Local; D002045:Bupivacaine; D003000:Clonidine; D017586:Diskectomy; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007796:Laminectomy; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D010149:Pain, Postoperative; D013123:Spinal Fusion",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "790-798",
"pmc": null,
"pmid": "28973650",
"pubdate": "2018-06-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Bupivacaine Field Block With Clonidine for Postoperative Pain Control in Posterior Spine Approaches: A Randomized Double-Blind Trial.",
"title_normalized": "bupivacaine field block with clonidine for postoperative pain control in posterior spine approaches a randomized double blind trial"
} | [
{
"companynumb": "LB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-028328",
"fulfillexpeditecriteria": "1",
"occurcountry": "LB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
... |
{
"abstract": "BACKGROUND\nSeveral studies have reported an association between use of over-the-counter antipyretics during pregnancy or infancy and increased asthma risk. An important potential limitation of these observational studies is confounding by indication.\n\n\nOBJECTIVE\nWe investigated the association of antipyretic intake during pregnancy and during the first year of life (infancy) with asthma-related outcomes before and after controlling for early-life respiratory tract infections.\n\n\nMETHODS\nWe included 1490 mother-child pairs in Project Viva, a longitudinal prebirth cohort study. We categorized prenatal acetaminophen exposure as the maximum intake (never, 1-9 times, or ≥10 times) in early pregnancy or midpregnancy and ibuprofen intake as presence or absence in early pregnancy. We expressed intake of antipyretics in infancy as never, 1 to 5 times, 6 to 10 times, or more than 10 times. We examined the associations of acetaminophen and ibuprofen (per unit increase in exposure category) during pregnancy and infancy with wheeze, asthma, and allergen sensitization in early childhood (3-5 years of age, n = 1419) and midchildhood (7-10 years of age, n = 1220).\n\n\nRESULTS\nUnadjusted models showed an increased asthma risk in early childhood for higher infant acetaminophen (odds ratio [OR], 1.21; 95% CI 1.04-1.41) and ibuprofen (OR, 1.35; 95% CI, 1.19-1.52) intake. Controlling for respiratory tract infections attenuated estimates for acetaminophen (OR, 1.03; 95% CI, 0.88-1.22) and ibuprofen (OR, 1.19; 95% CI, 1.05-1.36). Prenatal acetaminophen was associated with increased asthma (OR, 1.26; 95% CI, 1.02-1.58) in early childhood but not midchildhood.\n\n\nCONCLUSIONS\nAdjustment for respiratory tract infections in early life substantially diminished associations between infant antipyretic use and early childhood asthma. Respiratory tract infections should be accounted for in studies of antipyretics and asthma to mitigate bias caused by confounding by indication.",
"affiliations": "Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.;Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.;Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Mass.;Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Mass.;Child Health and Development Institute, Mount Sinai Hospital, New York, NY.;Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.;Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.;Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.;Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. Electronic address: augusto.litonjua@channing.harvard.edu.",
"authors": "Sordillo|Joanne E|JE|;Scirica|Christina V|CV|;Rifas-Shiman|Sheryl L|SL|;Gillman|Matthew W|MW|;Bunyavanich|Supinda|S|;Camargo|Carlos A|CA|;Weiss|Scott T|ST|;Gold|Diane R|DR|;Litonjua|Augusto A|AA|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-6749",
"issue": "135(2)",
"journal": "The Journal of allergy and clinical immunology",
"keywords": "Asthma; analgesic; antipyretic; respiratory infection",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001249:Asthma; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D063868:Patient Outcome Assessment; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012135:Respiratory Sounds; D012306:Risk",
"nlm_unique_id": "1275002",
"other_id": null,
"pages": "441-8",
"pmc": null,
"pmid": "25441647",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "10992559;24718577;11665870;11826230;11941379;12403878;12420904;12911681;14760269;14711794;15365112;3588140;15649261;15735054;16210062;18400839;18814450;18579547;19696122;19935033;19850963;20843914;20888627;21051083;21143295;20709817;21262745;21811632;21767300;22212639;11153577;10722764;23102919",
"title": "Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children.",
"title_normalized": "prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children"
} | [
{
"companynumb": "US-JNJFOC-20150216042",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Drug-induced anaphylaxis is an unpredictable adverse reaction. Although it may occur with any medication, antibiotics induce more cases of anaphylaxis than any other medication class with most cases being induced by β-lactam antibiotics. Clindamycin is an antibiotic with good gram-positive and anaerobe coverage which is often used in patients with β-lactam allergies. We report the case of a 46-year-old female who experienced anaphylaxis after a dose of intravenous (IV) clindamycin. Following treatment with methylprednisolone, epinephrine, diphenhydramine, and albuterol, the patient stabilized. The patient's score on the Naranjo's algorithm was 8 (probable); a score of 9 (definite) limited only by absence of drug re-challenge. To our knowledge, this is the first report of a clindamycin-induced anaphylaxis where the patient was not exposed to any other agent that may have triggered the response, the first case in the United States, and only the third documented case in the literature. Clinicians should be aware of the potential for drug-induced anaphylaxis in all medications.",
"affiliations": "Harrison School of Pharmacy, Auburn University, Auburn, USA. Mjn0004@auburn.edu.;Department of Internal Medicine, College of Community Health Sciences, University of Alabama School of Medicine, Birmingham, USA.;Department of Internal Medicine, College of Community Health Sciences, University of Alabama School of Medicine, Birmingham, USA.",
"authors": "Bulloch|Marilyn N|MN|;Baccas|Jonathan T|JT|;Arnold|Scott|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-015-0826-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "44(3)",
"journal": "Infection",
"keywords": "Allergic reaction; Anaphylaxis; Clindamycin; Hypersensitivity",
"medline_ta": "Infection",
"mesh_terms": "D061605:Administration, Intravenous; D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D002981:Clindamycin; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008875:Middle Aged; D010508:Periodontal Abscess",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "357-9",
"pmc": null,
"pmid": "26216470",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20934625;565379;17116619;21462805;20692689",
"title": "Clindamycin-induced hypersensitivity reaction.",
"title_normalized": "clindamycin induced hypersensitivity reaction"
} | [
{
"companynumb": "US-ZYDUS-011855",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN\\CLINDAMYCIN PHOSPHATE"
},
"drugadditional"... |
{
"abstract": "Rare FGF23-producing mesenchymal tumors lead to paraneoplastic tumor-induced osteomalacia (TIO) presenting with phosphate wasting, hypophosphatemia, chronic hypomineralization of the bone, fragility fractures and muscle weakness. Diagnosis of TIO requires exclusion of other etiologies and careful search for a mesenchymal tumor that often is very small and can appear anywhere in the body. Surgical removal of the tumor is the only definitive treatment of TIO. Surgical complications due to chronic hypophosphatemia are not well recognized.\n\n\n\nThe current case describes severe fragility fractures in a 58-year-old woman, who lost her ability to walk and was bedridden for two years. First, the initial diagnostic laboratory work-up did not include serum phosphorus measurements, second, the suspicion of adverse effects of pioglitazone as an underlying cause delayed correct diagnosis for at least two years. After biochemical discovery of hyperphosphaturic hypophosphatemia at a tertiary referral centre, a FGF23-producing tumor of the mandible was discovered on physical examination, and then surgically removed. Postoperatively, severe hypophosphatemia and muscle weakness prolonged the need for ventilation support, intensive care and phosphate supplementation. After two years of rehabilitation, the patient was able to walk short distances. The tumor has not recurred, and serum phosphate concentration has remained within normal limits during 3.5 years of follow-up.\n\n\n\nThe case report illustrates knowledge gaps in the diagnostic work-up of rare causes of low bone mass and fragility fractures. Compared to other low phosphate conditions, surgical recovery from TIO-induced hypophosphatemia warrants special attention. Increased alkaline phosphatase concentration may indicate impaired postsurgical recovery due to prolonged hypophosphatemia, underlining the need for proactive perioperative correction of hypophosphatemia.",
"affiliations": "Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.;Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.;Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.",
"authors": "Ryhänen|Eeva M|EM|;Schalin-Jäntti|Camilla|C|;Matikainen|Niina|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2021.686135",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.686135\nEndocrinology\nCase Report\nProlonged Hypophosphatemia and Intensive Care After Curative Surgery of Tumor Induced Osteomalacia: A Case Report\nRyhänen Eeva M.\nSchalin-Jäntti Camilla\nMatikainen Niina *\n\nEndocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland\nEdited by: Elizabeth Mary Curtis, MRC Lifecourse Epidemiology Unit (MRC), United Kingdom\n\nReviewed by: Fabio V. Comim, Federal University of Minas Gerais, Brazil; Andrew Folpe, Mayo Clinic, United States\n\n*Correspondence: Niina Matikainen, niina.matikainen@hus.fi\nThis article was submitted to Bone Research, a section of the journal Frontiers in Endocrinology\n\n03 6 2021\n2021\n12 68613526 3 2021\n19 5 2021\nCopyright © 2021 Ryhänen, Schalin-Jäntti and Matikainen\n2021\nRyhänen, Schalin-Jäntti and Matikainen\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nIntroduction\n\nRare FGF23-producing mesenchymal tumors lead to paraneoplastic tumor-induced osteomalacia (TIO) presenting with phosphate wasting, hypophosphatemia, chronic hypomineralization of the bone, fragility fractures and muscle weakness. Diagnosis of TIO requires exclusion of other etiologies and careful search for a mesenchymal tumor that often is very small and can appear anywhere in the body. Surgical removal of the tumor is the only definitive treatment of TIO. Surgical complications due to chronic hypophosphatemia are not well recognized.\n\nCase Description\n\nThe current case describes severe fragility fractures in a 58-year-old woman, who lost her ability to walk and was bedridden for two years. First, the initial diagnostic laboratory work-up did not include serum phosphorus measurements, second, the suspicion of adverse effects of pioglitazone as an underlying cause delayed correct diagnosis for at least two years. After biochemical discovery of hyperphosphaturic hypophosphatemia at a tertiary referral centre, a FGF23-producing tumor of the mandible was discovered on physical examination, and then surgically removed. Postoperatively, severe hypophosphatemia and muscle weakness prolonged the need for ventilation support, intensive care and phosphate supplementation. After two years of rehabilitation, the patient was able to walk short distances. The tumor has not recurred, and serum phosphate concentration has remained within normal limits during 3.5 years of follow-up.\n\nConclusions\n\nThe case report illustrates knowledge gaps in the diagnostic work-up of rare causes of low bone mass and fragility fractures. Compared to other low phosphate conditions, surgical recovery from TIO-induced hypophosphatemia warrants special attention. Increased alkaline phosphatase concentration may indicate impaired postsurgical recovery due to prolonged hypophosphatemia, underlining the need for proactive perioperative correction of hypophosphatemia.\n\ntumor-induced hypophosphatemia\nintensive care\noncogenic osteomalacia\nperioperative hypophosphatemia\nsurgical complications\ntumor-induced osteomalacia\nfibroblast growth factor 23\nHelsingin ja Uudenmaan Sairaanhoitopiiri10.13039/100008376Helsingin ja Uudenmaan Sairaanhoitopiiri10.13039/100008376Helsingin ja Uudenmaan Sairaanhoitopiiri10.13039/100008376Helsingin Yliopisto10.13039/100007797\n==== Body\nIntroduction\n\nTumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by increased Fibroblast growth factor 23 (FGF23) secretion, typically from a small mesenchymal tumor. In TIO, FGF23 excess drives phosphate wasting and leads to hypophosphatemic oncogenic osteomalacia. Patients typically present with severe symptoms of bone pain, skeletal muscle myopathy, multiple fractures or pseudofractures, skeletal deformities, and impaired quality of life (1, 2).\n\nThe diagnosis of TIO is challenging but surgical removal of the phosphaturic mesenchymal neoplasm potentially cures the patient (1, 3). Although the significance of transient phosphate disorders during surgery and intensive care are extensively described, the specific problems associated with chronic hypophosphatemia due to a FGF23-producing tumor in postsurgical patients are poorly described in the literature. The current case underlines the need for careful presurgical planning and active phosphate replacement in severe hypophosphatemia caused by TIO to prevent prolonged need for ventilation assistance, and intensive care.\n\nCase Description\n\nA 58-year-old female had a three year-history of multiple stress fractures and muscle weakness. Her medical history included well-controlled type 2 diabetes (HbA1c 43 mmol/mol) for nearly 20 years. Her BMI was 39 kg/m2 and she was on metformin, long-acting insulin and pioglitazone. She was a current smoker with a smoking history of 27 pack years and her dietary calcium intake was considered normal. Skeletal growth had been normal, and she had not suffered from bone fractures or abnormal skeletal pains previously. She did not have a family history of skeletal, metabolic or hormonal disorders.\n\nThree years prior to diagnosis the patient presented with multiple fragility fractures and increasing bone pain. Fractures were found in the vertebrae ( Figure 1A ), right femur, sacrum and lateral condyle of the right tibia, and in the left talus. She complained of progressive muscle weakness and diffuse bone pains in her back and lower extremities.\n\nFigure 1 Radiological images of the fragility fractures diagnosed before the diagnosis of TIO. Compression fractures and kyphoscoliosis of the spine in CT (A), MRI scan showing fragility fracture of the lateral condyle of the right tibia (B), X-ray of the fragility fracture of left femoral neck (C) and X-ray of pelvis showing arthroplasty of the left hip and osteosynthesis performed after fragility fractures in right femoral shaft and lateral condyle after surgery (D). CT scan of the tumor in the mandible (E), hematoxylin and eosin staining (F) (18.4 x) and vimentin staining (positive) (15.9 x) (G) of the tumor.\n\nOne year later, dual-energy X-ray absorptiometry (DXA) demonstrated osteopenic bone mineral density (T-scores of lumbar vertebrae 3-4 and the femoral neck were -0.8 SD, and -2.3 SD, respectively). Basic biochemistry in primary care was unremarkable (data not shown). Pioglitazone treatment, initiated four years before the first fragility fracture, was suspected to underlie the multiple, low-intensity fractures and therefore discontinued. At this point, type 2 diabetes was considered as another predisposing factor.\n\nDuring the year before the diagnosis, she suffered from a stress fracture of the left femur with significant dislocation ( Figure 1C ), which was treated with total hip arthroplasty, as well as a stress fracture of the right femur that was treated with an intramedullary nail ( Figure 1D ). Within the next months, she also suffered from stress fractures of the right distal femur, tibia ( Figure 1B ) and humerus.\n\nA year before correct diagnosis of TIO, teriparatide, calcium carbonate (1000 mg daily) and cholecalciferol (20 µg daily) supplementations were initiated to enhance recovery of bone strength after pioglitazone treatment.\n\nThe patient was referred to the University Hospital Endocrine Unit. At this time point, the patient had not been able to walk for two years, was bedridden and had lost 30 kg of weight (from 106 to 78kg), and she needed constant pain medication (oxycodone 50 mg, gabapentin 1800 mg and paracetamol 3 grams daily). Biochemical tests revealed hypophosphatemia, combined with high serum FGF23-concentration (C-terminal, EIA-method, MVZ Labor Dr. Limbach & Kollegen, Heidelberg, Germany), inappropriately normal 24-hour urinary phosphate secretion, and increased serum alkaline phosphatase concentration ( Table 1 ). Alphacalcidol (0.25 µg twice daily) and phosphate supplementation (Phosphate Sandoz 500 mg twice daily, reduced dose due to diarrhea) were started. Calcium carbonate 1000 mg and cholecalciferol 20 µg daily were continued and teriparatide was discontinued. A bone biopsy from the iliac crest demonstrated osteomalacia. Genetic testing for hypophosphatemia [mutations in the DMP-1, ENPP1, FGF23, PHEX and SLC34A3 genes (4)] was negative. Computed tomography (CT) of the thorax and abdomen revealed no tumors. An additional, complete physical examination revealed a palpable mass in the right mandible. Ultrasound and CT confirmed a tumor with invasive growth in the right mandible ( Figure 1E ). Cytologic analysis of a fine needle aspiration taken from the tumor demonstrated myoepithelial-like cells.\n\nTable 1 Biochemical findings at diagnosis and 20 months after surgery.\n\nParameter (reference range)\tAt diagnosis\t1 month after surgery\t16 - 20 months after surgery\t\nIonized calcium (1.15-1.30 mmol/l)\t1.28\t1.26\t1.22\t\nPhosphate (0.76-1.41 mmol/l)\t0.39\t1.39\t1.09\t\nPTH (15-65 ng/l)\t40\t73\t51\t\nAlkaline phosphatase (35-105 U/l)\t489\t482\t123\t\nCreatinine (50-90 μmol/l)\t60\t47\t60\t\n25-OH-D (> 50 nmol/l)\t112\t69\t83\t\n1,25-(OH)2D (52-267 pmol/l)\t25\t–\t132\t\n24h urinary phosphate (20-50 mmol)\t12.9\t–\t8.4\t\nFGF23 (26-110 kRU/l)\t2410\t279\t364\t\nPINP (13-116 μg/l)\t188\t(578, 6 mo after surgery)\t63\t\nPTH, parathyroid hormone; FGF23, fibroblast growth factor 23; PINP, Procollagen type 1 N-propeptide.\n\nAfter the diagnosis was confirmed, the tumor of the right mandible was operated. Histopathological examination of formalin-fixed and paraffin-embedded slides demonstrated a 2.6 cm phosphaturic mesenchymal tumor with multinucleated, osteoclast-like cells ( Figure 1F ), with minimum tumor free resection margins of 0.5 mm. The Ki-67 proliferation index in hot spots was 10-15%. Immunohistochemical studies showed positive vimentin staining ( Figure 1G ) but negative CD34, EMA, and CKPAN stainings, compatible with a phosphaturic mesenchymal tumor and the diagnosis of TIO (5). The histologic samples were re-evaluated by an expert pathologist in the National Institutes of Health, USA.\n\nPostoperatively, the patient needed prolonged treatment of 10 days in the intensive care unit. Both intravenous and p.o. phosphate supplementations were warranted to correct for severe hypophosphatemia ( Table 2 ). After surgery, the concentration of serum ionized calcium remained in the normal range, 1.16-1.25 mmol/l (reference range 1.15-1.30 mmol/l). Administration of calcium carbonate 1000 mg and cholecalciferol 20 µg daily was continued. Due to muscle weakness, the patient was dependent on mechanical ventilation for four days. Thereafter, she needed continuous positive airway pressure (CPAP) through a tracheostomy. During that time, to maintain sufficient blood pressure levels, norepinephrine infusion had to be maintained for one week after surgery. She was on enteral nutrition during the postoperative days 1-11 (1500 kcal daily from third postoperative day). On the third postoperative day, the patient presented with respiratory alkalosis for six hours after fiberoptic bronchoscopy, with a pH of 7.52-7.60 and low/normal pCO2 (3.6-4.9 kPa), and elevated pO2 (13.2-59.8 kPa), base excess (BE) (2.5-5.7 mmol/l) and bicarbonate (HCO3) concentrations (27-30 mmol/l) (reference ranges 7.35-7.45, 4.5-6.0 kPa, 9.3-12.3 kPa, -2.5-2.5 mmol/l and 22-24 mmol/l, respectively). From the fourth postoperative day onwards, arterial pH remained within normal range. The patient was decanylated one week postoperatively ( Table 2 ). She received subcutaneous short-acting insulin (4-12 units daily) for hyperglycaemia.\n\nTable 2 Serum phosphate, ionized calcium and PTH concentrations, phosphate substitution and during 10-day postoperative intensive care.\n\nNumber of days after surgery\tS-Pi, mmol/l*\tIonized calcium, mmol/l*\tPTH, ng/l*\tPhosphate substitution (iv.) per 24 hours\tPhosphate substitution (po.)\tMode of ventilation support\t\n1 month preoperatively\t0.45\t1.19\t47\tnone\tPhosphate 1000 mg\tno\t\nSurgery\tnot measured\t1.27\t\t52 mmol\tnone\tventilator\t\nDay 1\tnot measured\t1.26\t\t52 mmol\tnone\tventilator\t\nDay 2\t0.27 (morning) 0.91 (evening)\t1.24\t\t78 mmol\tnone\tventilator\t\nDay 3\t0.38\t1.15\t\t85 mmol\tnone\tventilator\t\nDay 4\t0.59\t1.20\t\t92 mmol\tPhosphate 500 mg\tventilator#\t\nDay 5\t0.56\t1.21\t\t62 mmol\tPhosphate 500 mg\textubated,\nnoninvasive ventilation (CPAP)\t\nDay 6\t0.66\t1.22\t\t62 mmol\tPhosphate 500 mg\tCPAP\t\nDay 7\tnot measured\t1.25\t69\t42 mmol\tPhosphate 500 mg\tCPAP\t\nDay 8\t0.85\t1.26\t\tnone\tPhosphate 1000 mg\tCPAP\t\nDay 9\tnot measured\t1.24\t\tnone\tPhosphate 1000 mg\tOxygen mask\t\nDay 10\t1.00\t1.28\t\tnone\tPhosphate 1000 mg\tOxygen mask\t\nDay 30\t1.30\t1.26\t73\tnone\tPhosphate 1000 mg\tNone\t\n*reference ranges 0.76-1.71 mmol/l, 1.15-1.30 mmol/l, 15-65 ng/l, respectively. #oxandrolone was started and given for one week.\n\nCPAP, Continuous positive air pressure.\n\nCalcium carbonate supplementation of 1000 mg daily remained stable during the pre- and postoperative period.\n\nPhosphate supplementations were administered for eight weeks. The patient received oxandrolone for one week because of extreme weakness and lack of spontaneous respiratory activity in order to improve muscle function and the recovery of lean body mass (6). Skeletal and limb pains relieved soon, and muscle weakness alleviated within the succeeding months. The patient was able to take a few steps after four months of rehabilitation.\n\nAfter two years of rehabilitation, the patient was able to walk 100 meters with a walker and shorter distances without any help. She has not suffered from any further fractures or bone pains. After surgery, serum phosphate concentration has remained normal. Serum FGF23 concentrations decreased immediately after the operation and have remained slightly increased ( Figure 2 ). Due to the vertebral fractures, DXA of the spine was unreliable.\n\nFigure 2 Timeline showing serum phosphate and FGF23 (C-terminus) concentrations at diagnosis and postoperatively. Time of surgery is marked with the black triangle and X-axis presents the time in months relative to surgery. Reference ranges are 0.76-1.41 mmol/l, and 26-110 kRU/l are marked to the y-axes with a bar, respectively.\n\nLiterature Search\n\nWe identified MeSH-terms (https://www.nlm.nih.gov/mesh/meshhome.html) for possible studies reporting postoperative complications during surgery for TIO. The identified MeSH-terms were searched in PubMed/MEDLINE database from 1966 to February 28, 2021. No publications describing postoperative prolonged hypophosphatemia, surgical complications, or prolonged need for intensive care or mechanical ventilation support in TIO patients were found. The electronic search was supplemented by manually searching reference lists of recent review articles that revealed two case reports of postoperative recovery in patients with TIO (1, 3).\n\nDiscussion\n\nHere, we describe a 58-year old patient with TIO, who presented with prolonged postoperative need for phosphate supplements and ventilation support in the intensive care unit because of severe, persistent hypophosphatemia and respiratory muscle weakness. The decrease in postoperative phosphate levels mimicked a transient hungry bone syndrome-like event that resolved after normalization of bone markers including alkaline phosphatase.\n\nAccording to the literature search, persistent hypophosphatemia complicating the recovery from surgical treatment of TIO has not been described previously. In our patient, the post-surgical prolonged hypophosphatemia and muscle weakness required i.v. and p.o. phosphate supplementation up to eight weeks, despite complete removal of the mesenchymal tumor and later permanent normophosphatemia. According to previous publications, after excision of the mesenchymal tumor, serum phosphate and FGF23 concentrations usually return to normal within the first five post-surgical days, with gradual alleviation of symptoms. During the recovery phase, the skeleton is actively remineralizing and patients may transiently require supplemental calcium to prevent hypocalcemia and secondary hyperparathyroidism (1, 7). Chong et al. (7) describe that the severity of the metabolic bone disease correlates with the serum alkaline phosphatase concentrations, and that kidney phosphate reabsorption may recover slowly. In our patient, severe hypophosphatemia was associated with progressive increase in serum alkaline phosphatase concentrations and bone markers, and loss of muscle strength. The bone biopsy revealed severe osteomalacia, which is a typical histological finding in hyperphosphaturic hypophosphatemia (8). In the present case, a multifactorial background probably best explains hypophosphatemia, including gradual recovery of renal proximal tubular dysfunction and increased phosphate uptake by the skeleton leading to a transient hungry bone syndrome-like decrease in postoperative phosphate levels but the precise mechanisms remains unclear (9). A limitation in our case includes lack of measurements of tubular maximum reabsorption of phosphate and 1,25-(OH)2D immediately post-operatively. However, other causes for hypophosphatemia such as alkalosis or the use of norepinephrine or insulin only briefly contributed to hypophosphatemia during the ICU stay and adequate nutrition was maintained to prevent the re-feeding syndrome (10).\n\nSevere hypophosphatemia is a well-known risk factor for delayed postoperative recovery. In our patient, other factors that could have contributed to late weaning from assisted ventilation include smoking, obesity and diabetes. Phosphate is essential for the synthesis of ATP (adenosine triphosphate) and 2,3-diphosphoglycerate, both of which are critical for the regulation of cell metabolism and muscle contractility (11). In intensive care patients, hypophosphatemia is associated with increased morbidity, including longer dependence on mechanical ventilation and prolonged hospitalization. Hypophosphatemia decreases contractility of the diaphragm, left ventricular function, insulin sensitivity, and functions of the central nervous system, which predispose to postoperative complications such as respiratory insufficiency, increased incidence of ventricular tachycardia, impaired glucose metabolism, seizures, and coma (12–17). Respiratory alkalosis, hyperglycemia, insulin and cathecholamines may further worsen hypophosphatemia during intensive care (16–18). These risks are relevant for patients with TIO, in whom the treatment aims at curative surgery.\n\nAlthough the phosphate concentration normalized within two months, the C-terminal FGF23 concentration remained slightly elevated despite biochemical and physical recovery ( Figure 2 ). Previous literature suggests that this may reflect an alteration in FGF23 processing that increases the biologically inactive FGF23 fraction (19).\n\nWe performed a literature search to summarize the current knowledge of surgical complications and identified only three case reports of postoperative problems associated with TIO (20–22), which emphasize the need for careful assessment of cardiovascular and respiratory status both pre- and postoperatively. However, in these cases, postoperative recovery was only mildly disturbed. Our patient presented with long-term myopathy and, postoperatively, needed 10 days of treatment in the intensive care unit due to difficulties in weaning from mechanical ventilation and hypotension, despite continuous intravenous and oral phosphate supplementations. After normalization of plasma phosphate, muscle weakness persisted for months and rehabilitation is still ongoing. In patients with TIO, careful planning of the postsurgical management including measurements of alkaline phosphatase and phosphorus concentrations is thus essential.\n\nFragility fractures are a diagnostic challenge. They are more common after menopause and in patients with type 2 diabetes, both of which increase bone fragility by enhancing the cortical porosity and decreasing the cortical area and bone material strength (23). Glitazone treatment is associated with an augmented risk of fragility fractures, including both upper and lower limb, as well as hip fractures. Both rosiglitazone and pioglitazone appear equally likely to adversely affect bone health (24–26). In our patient, treatment with pioglitazone for 4.5 years before referral to the Endocrine University Hospital Unit was suspected to underlie the multiple fragility fractures. To our knowledge, glitazones are not known to cause osteomalacia in bone histology. In animal studies, histomorphometric analysis of the trabecular bone of the proximal tibia demonstrate increased fat content and number of adipocytes during rosiglitazone administration. In addition, osteoblast activity is decreased and osteoclast activity increased (27, 28). It is unlikely that type 2 diabetes or pioglitazone use alone could have caused the clinical scenario in the present case, which initially was dominated by multiple severe fractures caused by minimal trauma. Speculatively, these factors may have caused additional bone frailty on top of long term TIO.\n\nThe current case demonstrates the importance of thorough assessment of basic low-cost laboratory tests in patients with low energy fragility fractures, since the delay in the diagnosis was partly due to lack of determinations of serum phosphate concentrations. A recent large series of 144 patients with TIO demonstrates that 95% of patients are initially misdiagnosed, or characteristic laboratory findings are neglected (29). Importantly, current European guidance for the diagnosis and management of osteoporosis in postmenopausal women (30) recommend measurement of serum phosphate and alkaline phosphatase to exclude a disease which can mimic osteoporosis, such as any type of osteomalacia. In our patient, other differential diagnostic testing included exclusion of vitamin D deficiency, chronic renal and/or hepatic diseases and, genetic hyperphosphaturic diseases due to mutations in the DMP-1, ENPP1, FGF23, PHEX and SLC34A3 genes. In addition to the clinical picture, the age of our patient, the results of biochemical testing, the finding of impaired bone mineralization on bone biopsy, as well as the significantly increased serum FGF23 concentrations were consistent with the diagnosis of TIO (1, 30).\n\nGiven their small size, FGF23-producing mesenchymal tumors are difficult to detect with anatomic imaging (radiography, ultrasound, CT and MRI). In our patient, physical examination revealed a tumor in left mandible region that was confirmed by ultrasound. A biopsy was obtained but is not generally recommended because it may lead to tumor seeding (31). Currently, a stepwise approach is recommended, including head to toe functional imaging with Ga-68 DOTATATE PET/CT, the sensitivity of which is better than that of 18F-FDG PET/CT (32). Some centers use selective venous sampling of FGF23, which may be indicated in special situations (33, 34). Most tumors reside in the extremities, while tumors of the maxilla or mandible have been reported less frequently. In a report of 39 patients from Beijing, 56% of the tumors were found in the lower extremities, 5% in the upper extremities, 3% in the hip, 31% in the head, and 5% in the thoracic region (35). Eight of 12 tumors found in the head were located in the mandible or the maxilla. Two tumors were detected on physical examination, and one of them was located in the mandible (35). In another series of 17 Chinese patients, 53% of the tumors were revealed on physical examination, one of which was found in the mandible (36). In the current case, the mesenchymal phosphaturic tumor involving the mandible was detected by palpation, which underlines the importance of thorough basic physical examination.\n\nPhosphaturic mesenchymal tumors are characterized by distinct molecular genetic features with high prevalence of fibronectin 1 (FN1)-FGFR1 fusion gene and less frequently a FN1-FGF1 fusion, which are detected in in 42% and 6% of cases, respectively and may aid the pathologic diagnosis (37). We could not obtain a molecular genetic testing of these fusion gene rearrangements in our case. However, the histologic samples were re-evaluated by an expert pathologist in the National Institutes of Health, USA, to confirm the histological diagnosis.\n\nThe current case illustrates knowledge gaps in the diagnostic work-up of rare causes of low bone mass and fragility fractures. Phosphorus was measured only after referral to a tertiary center. Pioglitazone use possibly further worsened the clinical course and certainly delayed the diagnosis of TIO in our patient. We emphasize the need to recognize that severe myopathy, longstanding presurgical hypophosphatemia and elevated alkaline phosphatase concentrations may indicate major difficulties in postsurgical weaning from the ventilator, and delayed recovery. In such cases, perioperative hypophosphatemia should be corrected proactively. In the future, novel FGF23-antagonists may prove useful in the preoperative treatment of severe hypophosphatemia when other approaches fail (38, 39).\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nNM and CS-J designed the case report. ER and NM collected the data and NM reviewed the literature. ER, CS-J, and NM drafted and revised the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThe authors declare that this study received funding from independent research grants from Finska Läkaresällskapet (to CS-J) and the Helsinki University Hospital Research Funds (TYH2017138 and TYH2018223 to CS-J) and (TYH TYH2020402 and M1021YLI31 to NM). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.\n\nConflict of Interest\n\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\nAcknowledgments\n\nWe thank M.D. Ph.D. Helena Leijon for histological images.\n\nAbbreviations\n\nATP, adenosine triphosphate; BMI, body mass index; CKPAN, Pan-cytokeratin; CPAP, continuous positive airway pressure; CT, computed tomography; DXA, dual-energy absorptiometry; EIA, enzyme immunoassay; FGF23, fibroblast growth factor 23; MRI, magnetic resonance imaging; TIO, tumor-induced osteomalacia.\n==== Refs\nReferences\n\n1 Florenzano P Gafni RI Collins MT . Tumor-Induced Osteomalacia. Bone Rep (2017) 7 :90–7. 10.1016/j.bonr.2017.09.002\n2 Jerkovich F Nuñez S Mocarbel Y Pignatta A Elías N Cassinelli H . 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"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "12()",
"journal": "Frontiers in endocrinology",
"keywords": "fibroblast growth factor 23; intensive care; oncogenic osteomalacia; perioperative hypophosphatemia; surgical complications; tumor-induced hypophosphatemia; tumor-induced osteomalacia",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "686135",
"pmc": null,
"pmid": "34149623",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "20421625;29280738;26958749;22247037;20519122;24999675;27443518;32185436;29955631;6999353;23396031;24123088;3860734;23362135;26478788;21490240;33615105;29947083;25173606;14500573;28703220;26773077;29021995;20682049;31924563;28794533;30324412;29446010;30078476;20590749;30218014;17090245;31382017;28450684;27085966;22945303;22532501;23026174",
"title": "Prolonged Hypophosphatemia and Intensive Care After Curative Surgery of Tumor Induced Osteomalacia: A Case Report.",
"title_normalized": "prolonged hypophosphatemia and intensive care after curative surgery of tumor induced osteomalacia a case report"
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"abstract": "The presented analytical method enabled the Toxicology Department at the Cuyahoga County Medical Examiner's Office to identify 26 and quantitatively report 24 compounds in 500 μL of whole blood, including fentanyl analogues (fentalogues) such as methoxyacetyl fentanyl (MeOAF) and cyclopropyl fentanyl (CPF). This second-generation method (FG2) was developed with the objective to improve the existing analysis (FG1) by decreasing sample size, lowering limits of detection (LOD) and lower limit of quantitation, minimizing ion suppression and resolving chromatographic interferences. Interferences may occur in the analysis of fentanyl, MeOAF, CPF, 3-methylfentanyl (3MF), butyryl fentanyl and isobutyryl fentanyl due to isobars and structural or geometric isomerism with another analogue or metabolite. The isomeric and isobaric fentalogues were grouped into three sets. The LOD established for Set 1 [MeOAF, para-methoxyacetyl fentanyl, para-fluoro acryl fentanyl (isobar), fentanyl carbamate], 2-furanyl fentanyl, Set 2 [CPF, (E)-crotonyl fentanyl] and carfentanil was 0.0125 ng/mL. The LOD established for N-methyl norfentanyl, norfentanyl, norcarfentanil, despropionyl fentanyl (4-ANPP), acetyl fentanyl, β-hydroxy fentanyl, benzyl fentanyl, acryl fentanyl, alfentanil, fentanyl, para-fluoro fentanyl, Set 3 [(±)-trans-3MF, (±)-cis-3MF, isobutyryl and butyryl fentanyl], para-fluoroisobutyryl fentanyl, sufentanil, phenyl fentanyl and cyclopentenyl fentanyl was 0.0625 ng/mL. Seven-point linear calibration curves were established between 0.025 and 4.0 ng/mL for the 8 analytes with the lower LOD and 0.125 and 20 ng/mL for the 18 analytes with the higher LOD. 4-ANPP and cyclopentenyl fentanyl met qualitative reporting criteria only. The results for five postmortem and two driving under the influence of drugs authentic case samples are presented. To the authors' knowledge, FG2 is the first published method that achieved baseline resolution of the nine structural/stereo isomers and one isobar by ultra-high performance liquid chromatography-MS-MS and provided quantitative validation data for nine compounds. FG2 may be used as the new baseline for future isomers that need to be chromatographically separated.",
"affiliations": "Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Phenomenex®, 411 Madrid Avenue, Torrance, CA 90501, USA.;Phenomenex®, 411 Madrid Avenue, Torrance, CA 90501, USA.;Phenomenex®, 411 Madrid Avenue, Torrance, CA 90501, USA.;Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.",
"authors": "Sofalvi|Szabolcs|S|;Lavins|Eric S|ES|;Brooker|Ian T|IT|;Kaspar|Claire K|CK|;Kucmanic|John|J|;Mazzola|Carrie D|CD|;Mitchell-Mata|Christie L|CL|;Clyde|Cassandra L|CL|;Rico|Rindi N|RN|;Apollonio|Luigino G|LG|;Goggin|Charissa|C|;Marshall|Brittany|B|;Moore|Danielle|D|;Gilson|Thomas P|TP|",
"chemical_list": "D000701:Analgesics, Opioid; C000610976:butyrfentanyl; C080127:norfentanyl; C000594854:N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide; C017114:carfentanil; C030592:3-methylfentanyl; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkz056",
"fulltext": null,
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"issn_linking": "0146-4760",
"issue": "43(9)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000701:Analgesics, Opioid; D001344:Autopsy; D002851:Chromatography, High Pressure Liquid; D005283:Fentanyl; D006801:Humans; D007536:Isomerism; D057230:Limit of Detection; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7705085",
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"pages": "673-687",
"pmc": null,
"pmid": "31504606",
"pubdate": "2019-10-17",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Unique Structural/Stereo-Isomer and Isobar Analysis of Novel Fentanyl Analogues in Postmortem and DUID Whole Blood by UHPLC-MS-MS.",
"title_normalized": "unique structural stereo isomer and isobar analysis of novel fentanyl analogues in postmortem and duid whole blood by uhplc ms ms"
} | [
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"companynumb": "US-PFIZER INC-2020144775",
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"activesubstancename": "FENTANYL CITRATE"
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"abstract": "As clinicians, we need to be vigilant about these rare and atypical presentations given the endemic nature of scrub typhus in southern belt of the country. Timely diagnosis and appropriate treatment is the key aspect to prevent further complications.",
"affiliations": "Department of Obstetrics & Gynecology Jigme Dorji Wangchuck National Referral Hospital Thimphu Bhutan.;Department of Obstetrics & Gynecology Jigme Dorji Wangchuck National Referral Hospital Thimphu Bhutan.;Faculty of Post Graduate Medicine Khesar Gyalpo University of Medical Sciences of Bhutan Thimphu Bhutan.;Faculty of Post Graduate Medicine Khesar Gyalpo University of Medical Sciences of Bhutan Thimphu Bhutan.",
"authors": "Tshering|Sangay|S|https://orcid.org/0000-0002-2506-2748;Dorji|Namkha|N|https://orcid.org/0000-0003-3594-3159;Dem|Dago|D|;Om|Tandin|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4451",
"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/ccr3.4451\nCCR34451\nCase Report\nCase Reports\nScrub typhus in pregnancy presenting with permanent hearing loss: A case report\nTSHERING et al.\nTshering Sangay https://orcid.org/0000-0002-2506-2748\n1 sangaytshering6080@gmail.com\n\nDorji Namkha https://orcid.org/0000-0003-3594-3159\n1\nDem Dago 2\nOm Tandin 2\n1 Department of Obstetrics & Gynecology Jigme Dorji Wangchuck National Referral Hospital Thimphu Bhutan\n2 Faculty of Post Graduate Medicine Khesar Gyalpo University of Medical Sciences of Bhutan Thimphu Bhutan\n* Correspondence\nSangay Tshering, Department of Obstetrics & Gynecology, Jigme Dorji Wangchuck National Referral Hospital, Thimphu, Bhutan.\nEmail: sangaytshering6080@gmail.com\n\n21 7 2021\n7 2021\n9 7 10.1002/ccr3.v9.7 e0445102 5 2021\n08 3 2021\n30 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\nAs clinicians, we need to be vigilant about these rare and atypical presentations given the endemic nature of scrub typhus in southern belt of the country. Timely diagnosis and appropriate treatment is the key aspect to prevent further complications.\n\nAs clinicians, we need to be vigilant about these rare and atypical presentations given the endemic nature of scrub typhus in southern belt of the country. Timely diagnosis and appropriate treatment is the key aspect to prevent further complications.\n\nhearing loss\npregnancy\nscrub typhus\nsource-schema-version-number2.0\ncover-dateJuly 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:21.07.2021\nTshering S , Dorji N , Dem D , Om T . Scrub typhus in pregnancy presenting with permanent hearing loss: A case report. Clin Case Rep. 2021;9 :e04451. 10.1002/ccr3.4451\n==== Body\n1 INTRODUCTION\n\nScrub typhus can present with audiological symptoms. A pregnant mother presented with fever, pneumonia, delirium, and hearing loss. Investigation showed positive serology for scrub typhus. Clinicians must be aware of audiological presentations in scrub typhus. Possibly, permanent hearing loss resulted from synergistic effect of pregnancy‐induced changes.\n\nScrub typhus is a mite borne infectious disease caused by Orientia tsutsugamushi. The vector and reservoir for this disease are the larval trombiculid mites also known as chiggers. The southern belt of Bhutan is seasonally endemic to scrub typhus with highest occurrence in farmers. 1\n\nThe clinical manifestations of this nonspecific febrile illness are intense headache and myalgia. Some patients develop generalized lymphadenopathy, macular or maculopapular nonpruritic rashes, and an eschar. Rare and atypical presentations such as acute reversible auditory symptoms like sensorineural hearing loss, tinnitus, and otalgia have been reported. 2 , 3 Possible mechanism for such presentations is immune‐mediated vasculitis leading to cochlear neuroinflammation resulting from exaggerated Th1 cellular immune response. 3 , 4 The severity of infection can vary from mild symptoms to severe multiorgan failure. Mortality rates were higher in those developing pneumonia, delirium, myocarditis, and elderly population. 5 , 6\n\nThe clinical diagnosis accuracy remains nonspecific due to largely overlapping symptoms seen in other tropical infections like dengue, malaria, and leptospirosis. Most patients develop thrombocytopenia, elevated hepatic enzymes, and deranged renal functions. Leukopenia or leukocytosis may develop but most patients present normal total leucocyte count. 7\n\nSince the audiological symptoms related to scrub typhus discussed in the literature were transient or reversible, we hereby present this case with permanent hearing loss in a pregnant woman following scrub typhus infection.\n\n2 CASE PRESENTATION\n\nA previously healthy 39‐year‐old G6P5 farmer at 34 weeks gestation was referred from Punakha District Hospital with 5 days history of fever, headache, generalized bodyache, shortness of breath, and cough. There were no audiological, gastrointestinal, or urinary symptoms. On admission to the maternity ward, she was ill‐looking but conscious with tachypnea, high‐grade fever, and pallor. There was no cervical lymphadenopathy, icterus, body rashes, eschar, or ear infection. Her respiratory rate was 26–30/min, pulse rate of 120 beats per minute, and blood pressure of 110/70 mm Hg. Cardiac auscultation revealed ejection systolic murmur at left lower sternal edge, which was probably due to hyperdynamic circulation in anemia. There was coarse crepitation noted in bilateral lung fields. Abdominal examination revealed no hepatosplenomegaly. Cardiotocograph was reassuring.\n\nPresumptive diagnosis of community‐acquired pneumonia was made and empirical treatment started with intravenous ceftriaxone and oral erythromycin. Antenatal corticosteroid was administered as per the hospital protocol. One unit of packed red cell was transfused.\n\nLaboratory investigation reports showed moderate anemia (Hb 7.9 gm%), raised C‐reactive protein (19.9 mg/L), and mild transaminitis. Renal function was normal. Sputum culture showed Klebsiella pneumoniae, which was sensitive to Ciprofloxacin and resistant to Ceftriaxone. Blood and urine culture were sterile. Dengue serology and malaria parasite smear were negative. Chest X‐ray (Figure 1) showed features suggestive of pneumonia. Echocardiogram was done to rule out cardiac causes of febrile illness, and the findings were normal.\n\nFIGURE 1 CXR posteroanterior view showing segmental consolidation of right lower zone\n\nThere was no clinical improvement after 72 h of antibiotic therapy. Intravenous ciprofloxacin was administered based on sputum culture and antibiotic sensitivity test for 3 days. Her respiratory symptoms improved but still remained febrile. She complained of bilateral hearing loss after 3–4 days of admission and appeared delirious on examination. She did not complain of tinnitus or otalgia. Urgent MRI brain showed no significant abnormalities although minor details could not be reported due to frequent motion by the agitated patient. Repeat serological investigation showed positive IgM for scrub typhus. Other hematological investigations including complete blood count, liver functions, and renal functions did not show significant changes compared with previous results. She responded to oral azithromycin 1 g daily for 03 days. Induction of labor was done in view of fetal jeopardy and delivered a male baby weighing 2100 g with Apgar score of 9 and 10 at 1 and 5 min, respectively. There were no intrapartum and immediate postpartum complications. Audiology examination done postpartum 3rd day showed profound sensorineural bilateral hearing loss (Figure 2A). Audiology re‐assessment was done at 6 and 12 weeks postpartum.\n\nFIGURE 2 Pure tone audiometry (A) Initial (B) 12 weeks postpartum\n\nClinically, there was no improvement in her hearing and repeat pure tone audiometry (PTA) at 12 weeks (Figure 2B) still showed profound bilateral sensorineural hearing loss similar to the initial assessment. A retrospective diagnosis of permanent sensorineural hearing loss following scrub typhus in pregnancy was made. Auditory brainstem response (ABR) was not performed as MRI brain performed earlier did not identify any retrocochlear lesions and PTA findings were sufficient to assess the hearing threshold. She was advised to adopt total communication as an alternative.\n\n3 DISCUSSION\n\nThis is a case of scrub typhus in pregnancy presenting with respiratory symptoms. The diagnosis of scrub typhus in our case was delayed due to predominant respiratory symptoms, absence of eschar, and the initial false‐negative serology result with SD Bioline Tsutsugamushi RDT (Standard Diagnostics Inc). 8 The appearance of audiological symptoms such as hearing loss in acute undifferentiated febrile illness should raise suspicion for scrub typhus infection. 2 Audiological symptoms were present in almost 30% of the cases. 9 A hospital‐based review of records of 33 pregnant women with scrub typhus infection reported 4.5% incidence although none of the cases reported hearing loss. 10 Similar to nonpregnant patients, the severity of disease is associated with delayed diagnosis and treatment leading to multiorgan failure. It is associated with poor obstetric outcome such as maternal admission to intensive care unit, miscarriage, fetal demise, and preterm birth especially in 3rd trimester in at least 50% of the cases. 10 , 11 Consistent with other studies, maternal, fetal, and neonatal outcomes were favorable in our case as there was no multi‐organ dysfunction. There are also few case reports on vertical transmission. 12 However, the baby's serology in our case came negative for scrub typhus infection. Case series reported by Premaratna et al. 2 have shown objective improvement in hearing loss in those who recovered without any complications. All cases except one responded to course of tetracycline/chloramphenicol. One patient died due to myocarditis and meningoencephalitis due to delayed diagnosis. One hypothetic explanation on rarity of literature on permanent hearing loss due to scrub typhus in pregnancy may be due to a shift in Th 1 to Th 2 immune modulation. 13 A balanced Th1/Th2 immune response has been noted in animal studies with milder form of scrub typhus infection. 4 On the contrary, an exaggerated Th1 and suppressed Th2 response has been noted in severe infection. Possibly, neuroinflammation may be more pronounced due to the Th1 to Th2 shift in early stage of infection followed by overwhelming infection at later stage. A reasonable postpartum time period of 3 months was allowed to recover from pregnancy‐associated hearing loss as seen in some healthy women. 14 Telephonic follow‐up with spouse at 6 months revealed no subjective improvement in hearing as hearing recovery took up to 6 months in the case series by Premaratna et al. 2\n\nXu et al. 15 reported about 40% of the women in second half of pregnancy experienced profound sensorineural hearing loss when followed up at 6 months postpartum. They cited hormone‐induced fluid and electrolyte imbalance in the inner ear as the only etiology. However, the hearing loss was unilateral and associated with tinnitus in majority of the cases. Farming occupation is the most important risk factor for scrub typhus infection in our country. 1 Pregnancy per se is not a risk factor for scrub typhus infection but a risk factor for hearing loss. 15 Association between macro and micronutrient deficiencies and hearing loss is well documented, and this effect certainly would be more profound in nutrient‐deficient state like pregnancy in developing countries. 16 , 17 Pregnancy‐induced physiological changes in immunomodulation, nutritional deficiencies, and fluid‐electrolyte changes would have played synergistic role in permanent nature of hearing loss in scrub typhus infection (Figure 3). Our case report is limited by the lack of laboratory investigations to confirm the nutritional status of the mother.\n\nFIGURE 3 Mechanism of permanent hearing loss in pregnancy and scrub typhus infection\n\n4 CONCLUSION\n\nAs clinicians, we need to be vigilant about these rare and atypical presentations given the endemic nature of scrub typhus in southern belt of the country. Timely diagnosis and appropriate treatment is the key aspect to prevent further complications.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHORS CONTRIBUTION\n\nST was involved in conception and design, acquisition of data, analysis and interpretation of data, revising it critically for important intellectual content, final approval of the version to be published, and agreed to be accountable for all aspects of the work. ND was involved in conception and design, acquisition of data, revising it critically for important intellectual content, final approval of the version to be published, and agreed to be accountable for all aspects of the work. DD was involved in conception and design, acquisition of data, interpretation of data, revising it critically for important intellectual content, final approval of the version to be published, and agreed to be accountable for all aspects of the work. TO was involved in conception and design, acquisition of data, interpretation of data, revising it critically for important intellectual content, final approval of the version to be published, and agreed to be accountable for all aspects of the work.\n\nETHICAL APPROVAL\n\nEthical approval is not needed for case report in de‐identified patients.\n\nACKNOWLEDGMENT\n\nWe would like to thank Mr. Sangay Tshering, Audiologist at the JDWNRH, Thimphu for the providing the results of pure tone audiometry in digital form. Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing not applicable as this article did not generate or analyzed dataset.\n==== Refs\nREFERENCES\n\n1 Dorji K , Phuentshok Y , Zangpo T , et al. Clinical and epidemiological patterns of scrub typhus, an emerging disease in Bhutan. Trop Med Infect Dis. 2019;4 (2 ):56.\n2 Premaratna R , Chandrasena TG , Dassayake AS , Loftis AD , Dasch GA , de Silva HJ . Acute hearing loss due to scrub typhus: a forgotten complication of a reemerging disease. Clin Infect Dis. 2006;42 (1 ):6‐8.\n3 Kang JI , Kim DM , Lee J . Acute sensorineural hearing loss and severe otalgia due to scrub typhus. BMC Infect Dis. 2009;9 :173.19849842\n4 Soong L . Dysregulated Th1 immune and vascular responses in scrub typhus pathogenesis. J Immunol. 2018;200 (4 ):1233‐1240.29431689\n5 Peter JV , Sudarsan TI , Prakash JAJ , Varghese GM . Severe scrub typhus infection: Clinical features, diagnostic challenges and management. World J Crit care Med. 2015;4 (3 ):244‐250.26261776\n6 Taylor AJ , Paris DH , Newton PN . A systematic review of mortality from untreated scrub typhus (Orientia tsutsugamushi). PLoS Negl Trop Dis. 2015;9 (8 ):e0003971.26274584\n7 Kim D‐M , Kim SW , Choi S‐H , Yun NR . Clinical and laboratory findings associated with severe scrub typhus. BMC Infect Dis. 2010;10 :108.20433689\n8 Pote K , Narang R , Deshmukh P . Diagnostic performance of serological tests to detect antibodies against acute scrub typhus infection in central India. Indian J Med Microbiol. 2018;36 (1 ):108‐112.29735837\n9 Noad KB , Haymaker W . The neurological features of Tsutsugamushi fever with special reference to deafness. Brain. 1953;76 (1 ):113‐131. 10.1093/brain/76.1.113 13041926\n10 Rajan SJ , Sathyendra S , Mathuram AJ . Scrub typhus in pregnancy: maternal and fetal outcomes. Obstet Med. 2016;9 (4 ):164‐166.27829876\n11 Kumar R , Thakur S , Bhawani R , Kanga A , Ranjan A . Clinical profile of scrub typhus in pregnancy in Sub‐Himalayan region. J Obstet Gynaecol India. 2016;66 (Suppl 1 ):82‐87.27651583\n12 Suntharasaj T , Janjindamai W , Krisanapan S . Pregnancy with scrub typhus and vertical transmission: a case report. J Obstet Gynaecol Res. 1997;23 (1 ):75‐78.9094822\n13 Wang W , Sung N , Gilman‐Sachs A , Kwak‐Kim J . T Helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh cells. Front Immunol. 2020;11 :1‐14.32038653\n14 Sharma K , Sharma S , Chander D . Evaluation of audio‐rhinological changes during pregnancy. Indian J Otolaryngol Head Neck Surg. 2011;63 (1 ):74‐78.22319721\n15 Xu M , Jiang Q , Tang H . Sudden sensorineural hearing loss during pregnancy: clinical characteristics, management and outcome. Acta Otolaryngol. 2019;139 (1 ):38‐41. 10.1080/00016489.2018.1535192 30664387\n16 Puga AM , Pajares MA , Varela‐Moreiras G , Partearroyo T . Interplay between nutrition and hearing loss: state of art. Nutrients. 2019;11 (1 ):1‐26.\n17 Gernand AD , Schulze KJ , Stewart CP , West KP , Christian P . Effects and prevention. Nat Rev Endocrinol. 2016;12 (5 ):274‐289.27032981\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "9(7)",
"journal": "Clinical case reports",
"keywords": "hearing loss; pregnancy; scrub typhus",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"pages": "e04451",
"pmc": null,
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"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "19849842;29431689;27032981;22319721;16323083;20433689;9094822;26261776;30664387;27651583;32973809;27829876;13041926;26274584;29735837;30934849",
"title": "Scrub typhus in pregnancy presenting with permanent hearing loss: A case report.",
"title_normalized": "scrub typhus in pregnancy presenting with permanent hearing loss a case report"
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"abstract": "BACKGROUND\nTalimogene laherparepvec (TVEC) is an injectable attenuated oncolytic herpes simplex virus (HSV-1) used in the treatment of loco regionally metastatic melanoma. Lesions managed by TVEC are generally considered unresectable at time of initiation of intralesional therapy; however, a subset of patients go on to have surgical resection of loco regionally controlled disease. We sought to review our experience with surgical excision of treated lesions to offer an insight into the radiologic correlate, treatment effect, and pathological findings of intralesional TVEC therapy.\n\n\nMETHODS\nThis is a retrospective descriptive case series of patients who underwent TVEC injection at Mayo Clinic, Rochester, MN, between October 2016 and July 2020. Institutional Institutional Review Board approval was obtained.\n\n\nRESULTS\nTwenty-one patients underwent intralesional TVEC, met inclusion criteria, and were included in this series. Seven went on to surgical excision of the injected lesions after an initial course of TVEC. Of those 7 patients, 4 had residual melanoma in the specimen on final pathology, while 3 had a complete pathologic response. All 3 patients who had no residual disease on pathology continued to have fluorodeoxyglucose (FDG) avidity on preoperative positron emission tomography scan of the excised lesions.\n\n\nCONCLUSIONS\nDespite ongoing FDG avidity on PET scan, patients who have well-controlled disease and stability over time of the injected lesions may benefit from surgical excision following a course of TVEC. This may render the patient clinically disease free and/or allow them a reprieve from TVEC treatment.",
"affiliations": "Department of Surgery, Mayo Clinic, Rochester, MN, USA.;Department of Surgery, Mayo Clinic, Rochester, MN, USA.;Department of Surgery, Mayo Clinic, Rochester, MN, USA.",
"authors": "MacArthur|Taleen A|TA|;Fahy|Aodhnait S|AS|;Jakub|James W|JW|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; D019275:Radiopharmaceuticals; C000629782:talimogene laherparepvec; D019788:Fluorodeoxyglucose F18",
"country": "United States",
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"issue": "87(6)",
"journal": "The American surgeon",
"keywords": "general surgery; melanoma; surgical oncology",
"medline_ta": "Am Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; D003131:Combined Modality Therapy; D019788:Fluorodeoxyglucose F18; D018259:Herpesvirus 1, Human; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D008910:Minnesota; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012189:Retrospective Studies; D012878:Skin Neoplasms; D014463:Ultrasonography",
"nlm_unique_id": "0370522",
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"title": "Surgical Resection After Talimogene Laherparepvec for Melanoma: Persistent Fuorodeoxyglucose Avidity on Positron Emission Tomography Despite No Viable Disease.",
"title_normalized": "surgical resection after talimogene laherparepvec for melanoma persistent fuorodeoxyglucose avidity on positron emission tomography despite no viable disease"
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"abstract": "OBJECTIVE\nThe main purpose of this study was to evaluate the risk of major malformations after aripiprazole exposure during the embryonic period. The secondary purposes were to assess the risk of miscarriage, prematurity, fetal growth retardation and maternal complications and to describe possible neonatal adverse effects.\n\n\nMETHODS\nWe conducted a cohort study using data prospectively collected by the French Pharmacovigilance Centres participating to the Terappel program and the Centre de Référence sur les Agents Tératogènes between 2004 and 2011. The exposed group consisted of pregnant women exposed to aripiprazole during embryogenesis, and the unexposed group consisted of pregnant women without exposure or exposed to non-teratogenic agents. Two unexposed patients, matched for age and gestational age at call, were randomly selected for each exposed patient.\n\n\nRESULTS\nEighty-six patients were included in the exposed group and 172 in the unexposed group. Exposure to aripiprazole was not significantly associated with an increased rate of major malformations (OR 2.30, 95%CI 0.32-16.7) or miscarriage (1.66, 0.63-4.38) or gestational diabetes (1.15, 0.33-4.04) compared to non-exposure. The study revealed significantly increased rates of prematurity (OR 2.57, 95%CI 1.06-6.27) and fetal growth retardation (2.97, 1.23-7.16) in exposed newborns, difficult to interpret because of the short duration of maternal exposure. Two cases of neonatal complications were reported among the 19 newborns exposed to aripiprazole near delivery.\n\n\nCONCLUSIONS\nThis study failed to demonstrate a significant association between aripiprazole exposure during the embryonic period and major malformations. More powerful prospective studies are required to clarify the reproductive safety profile of aripiprazole.",
"affiliations": "Centre Régional de Pharmacovigilance, Centre Hospitalo-Universitaire, Saint-Etienne, France.",
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"abstract": "Ceftriaxone is widely used in patients for the treatment of serious gram-negative infections. Ceftriaxone can induce some potential side effects, including neurotoxicity, however, nonconvulsive status epilepticus has rarely been reported. We report a case of acute reversible neurotoxicity associated with ceftriaxone. A 65-yr-old woman with chronic kidney disease developed altered consciousness during ceftriaxone treatment for urinary tract infection. The electroencephalogram demonstrated continuous bursts of generalized, high-voltage, 1 to 2 Hz sharp wave activity. Neurologic symptoms disappeared following withdrawal of ceftriaxone. The possibility of ceftriaxone-induced neurotoxicity should be considered in patients developing neurological impairment during ceftriaxone use, and the discontinuation of the drug could lead to complete neurological improvement.",
"affiliations": "Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.",
"authors": "Kim|Ki Bae|KB|;Kim|Sun Moon|SM|;Park|Woori|W|;Kim|Ji Seon|JS|;Kwon|Soon Kil|SK|;Kim|Hye-Young|HY|",
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"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 10.3346/jkms.2012.27.9.1120Case ReportNeuroscienceCeftiaxone-Induced Neurotoxicity: Case Report, Pharmacokinetic Considerations, and Literature Review Kim Ki Bae 1Kim Sun Moon 1Park Woori 1Kim Ji Seon 2Kwon Soon Kil 13Kim Hye-Young 131 Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.2 Department of Neurology, Chungbuk National University College of Medicine, Cheongju, Korea.3 Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea.\nAddress for Correspondence: Sun Moon Kim, MD. Department of Internal Medicine, Chungbuk National University Hospital, 776 1Sunhwan-ro, Heungdeok-gu, Cheongju 361-711, Korea. Tel: +82.43-269-6351, Fax: +82.43-273-3252, uptoyousm@gmail.com9 2012 22 8 2012 27 9 1120 1123 16 1 2012 19 4 2012 © 2012 The Korean Academy of Medical Sciences.2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Ceftriaxone is widely used in patients for the treatment of serious gram-negative infections. Ceftriaxone can induce some potential side effects, including neurotoxicity, however, nonconvulsive status epilepticus has rarely been reported. We report a case of acute reversible neurotoxicity associated with ceftriaxone. A 65-yr-old woman with chronic kidney disease developed altered consciousness during ceftriaxone treatment for urinary tract infection. The electroencephalogram demonstrated continuous bursts of generalized, high-voltage, 1 to 2 Hz sharp wave activity. Neurologic symptoms disappeared following withdrawal of ceftriaxone. The possibility of ceftriaxone-induced neurotoxicity should be considered in patients developing neurological impairment during ceftriaxone use, and the discontinuation of the drug could lead to complete neurological improvement.\n\nCeftriaxoneCephalosporinsChronic Kidney FailureSeizures\n==== Body\nINTRODUCTION\nCeftriaxone is a third-generation cephalosporin, commonly used in the treatment of serious gram-negative infections due to its broad antimicrobial spectrum, long half-life, and easy penetration into the cerebrospinal fluid (1, 2). Contrary to other cephalosporins, a dose adjustment is not required for ceftriaxone even in the presence of renal insufficiency, thus it is prescribed conveniently for patients with chronic kidney disease (CKD) (3). Neurologic adverse effects of ceftriaxone are infrequent, however, encephalopathy, myoclonus, and seizures may occur as exemplified in other cephalosporins (4-6). Here, we describe a case of ceftriaxone-induced nonconvulsive status epilepticus (NCSE) with characteristic electroencephalogram (EEG) findings and discuss with literature review.\n\nCASE DESCRIPTION\nA 65-yr-old woman with CKD was admitted to our hospital because of abdominal pain and poor oral intake on November 18, 2010. She had been diagnosed with idiopathic membranous glomerulonephropathy on renal biopsy six months prior to admission. Her abdominal discomfort began two weeks earlier and was located predominantly in the right lower quadrant, and was associated with lower back discomfort. She described a constant pressure unrelated to food intake that was associated with intermittent nausea and vomiting. Her symptoms were not relieved by the administration of antacid, acetaminophen, or defecation. Laboratory data at patient admission were as follows: serum creatinine 3.2 mg/dL (1.7 mg/dL, 8 weeks before admission), albumin 1.8 g/dL (2.7 g/dL, 8 weeks before admission), and random urine protein-to-creatinine ratio 10.4 g/g (3.3 g/g, 8 weeks before admission), which demonstrated the deterioration of renal function and increase in urinary protein excretion. Gastroscopy exhibited superficial gastritis and the colonoscopy revealed no observable mucosal lesions. To identify other potential causes of abdominal pain and exacerbation of renal insufficiency, such as renal vein thrombosis, computed tomography (CT) scan of abdomen and pelvis was recommended, however she refused further work up being afraid of hemodialysis following CT scan. On day 15 of the hospitalization, she developed a chill, and her temperature rose to 38.5℃. Because she complained of vague urinary symptoms and urinalysis demonstrated pyuria and bacteriuria, ceftriaxone (2 g/day) was administered intravenously for empirical treatment of urinary tract infection. Her temperature returned to normal after three days. On day 20 of the patient's hospitalization, her mental status deteriorated suddenly into stupor and generalized myoclonic jerks were appeared. There was no history of seizures, and no other relevant neurological features observed upon neurological examination. The patient exhibited no fever and the C-reactive protein was 3.2 mg/dL (normal range < 0.3). The serum creatinine level rose to 6.7 mg/dL and the daily urine amount decreased to 300 mL, therefore an emergent hemodialysis was initiated for progressive uremia. Her consciousness did not improve despite 24-hr intensive hemodialysis. A Brain CT demonstrated no abnormalities to explain these neurologic findings. An EEG recording on the next day showed generalized slowing with superimposed almost continuous or periodic bursts of sharp waves or sharp and slow wave activity (Fig. 1A). Under the impression of ceftriaxone-induced NCSE, ceftriaxone was discontinued on day 22 of the hospitalization, and she returned to a completely alert, cooperative, and oriented state within two days of cessation of the drug. The EEG on day 24 showed slowing of the background without epileptiform discharges (Fig. 1B). In addition, the abdomen/pelvis CT revealed extensive thrombosis at the inferior vena cava, both renal veins, right ovarian vein, and both external iliac veins (Fig. 2), thus anticoagulation was started. The patient was discharged on day 58 without any neurologic signs or symptoms.\n\nDISCUSSION\nIn this report, we described a case of NCSE following the administration of ceftriaxone in a patient with progressive renal impairment. The temporal relationship between the start of ceftriaxone therapy and the manifestation of NCSE as well as the withdrawal of ceftriaxone and the disappearance of the symptom strongly indicated that ceftriaxone was a causative agent. Moreover, hemodialysis did not improve her mental status, and we could not find any other factors that could explain the neurologic symptom observed.\n\nNeurotoxicity has been reported with both third-generation and fourth-generation cephalosporins (7-9). Epileptogenic activity of β-lactam antibiotics was first shown in 1945, when seizures were reported in experimental animals following intraventricular injection of penicillin (10), particularly in the settings of renal failure and excessive dosage (11). The exact mechanism is not fully understood, but it has been proposed to be mediated by competitive antagonism of brain γ-aminobutyric acid (GABA), which is the principal inhibitory neurotransmitter in the brain (12). Inhibition of GABA action could lead to a low neuronal threshold and subsequent excitation. Other authors (13) have proposed that cephalosporins might induce the release of cytokines including tumor necrosis factor-α, which could cause direct cerebral toxicity.\n\nCephalosporin-induced neurotoxicity may manifest in a variety of clinical presentations, such as encephalopathy or mental status changes, myoclonus, asterixis, and seizures (4-8). The latency of neurotoxicity, the period between the start of cephalosporin treatment and the resulting neurologic manifestations, varied between one and ten days. All reported neurologic symptoms typically resolved within two to seven days after discontinuation of the drug. The ceftriaxone-associated neurologic syndrome observed in our patients was similar to studies previously described in the literature (6-8). Predisposing factors for cephalosporins-induced neurotoxicity include excessive dosage, renal insufficiency, pre-existing central nervous system (CNS) abnormalities, and increased cerebral penetration of the drug (12, 14, 15). Different EEG patterns have been described in association with cephalosporin neurotoxicity. EEG findings include diffuse slow-wave delta activity, semi-periodic triphasic sharp wave activity, or frank periodic discharges (7). These EEG abnormalities serve as evidence supporting the impact of cephalosporins on the CNS. Given that the majority of patients using cephaloporins have co-morbidity associated with mental alteration, EEG could be of benefit in the diagnosis and management of antibiotics-associated neurotoxicity.\n\nThe prevention of cephalosporin-induced neurotoxicity in high risk patients, as discussed above, is of the utmost importance. The careful monitoring of medication dosages and serum levels may be helpful in the minimization of this risk (7). As seen in this case report, many symptoms resolved completely only with discontinuation of the drug. Anticonvulsants such as phenytoin or valproate were administered in two previously reported cases, and their symptoms improved five days after stopping ceftriaxone (4). Besides, we did not use any anticonvulsants because of the rapid (< 2 days) clinical improvement after discontinuation of ceftriaxone. Data are still lacking as to whether patients with cephalosporin-induced NCSE require antiepileptic drug therapy or simple cessation of drugs results in improvement. However, some authors recommend that anticonvulsant therapy including lorazepam and/or phenytoin might be considered in NCSE until the patient's mental status returns to normal and periodic discharges or NCSE shown on EEG resolve (7). Since neurotoxicity related to cephalosporins is reversible, it is unlikely that patients would need long-term anticonvulsant therapy.\n\nCeftriaxone has a distinctive pharmacokinetic property unlike other cephalsporins (3). While most of cephalosporins are highly dialyzable (70% of a given dose over a 3-hr hemodialysis session), ceftriaxone is not dialyzed during hemodialysis (3, 7). Moreover, the pharmacokinetics of ceftriaxone in patients with renal insufficiency differ markedly from those of other cephalosporins. Compared to values in healthy subjects, the half-life of other cephalosporins is prolonged 6- to 8-fold in patients with end-stage renal disease. However, the half-life of ceftriaxone is not greatly affected by a progressive decrease in the renal function (3). Accordingly, dose adjustment of ceftriaxone is not required for CKD patients. These pharmacokinetic characteristics might be related to the characteristics of ceftriaxone neurotoxicity. Only seven cases of ceftriaxone-induced neurotoxicity have been reported to date (Table 1). All the previous cases had renal impairment and 4 cases of those cases were on hemodialysis. There were 4 cases of choreoathetosis, 2 cases of NCSE, and one case of encephalopathy. Notably, there was no case of which the observed neurologic symptoms and signs were improved by dialysis. These findings are compatible with the pharmacokinetic property of ceftriaxone that is not removable by dialysis. Moreover, given that no dose adjustment is required for ceftriaxone in the patient with renal impairment, overdose did not seem to play a role in ceftriaxone-associated neurotoxicity. In the previous reports, the elimination half-life of ceftriaxone was markedly prolonged in some dialysis patients, it might be due to an impaired biliary excretion process that is the alternative pathway of elimination for ceftriaxone in CKD patients (7,16). These might contribute to the development of infrequent ceftriaxone neurotoxicity in patients with renal insufficiency.\n\nCeftriaxone can cause NCSE in patients with impaired renal function. This neurotoxicity should be considered carefully in patients with reduced renal function or prior CNS abnormalities. In addition, EEG should be performed when a patient receiving ceftriaxone develops neurological symptoms. Early recognition is of the utmost importance because the discontinuation of ceftriaxone reverts the symptoms completely.\n\nFig. 1 Electroencephalogram (EEG) findings during nonconvulsive status epilepticus and recovery state. (A) EEG on day 22, when the patient presented an altered mental state. An EEG showed generalized slowing of the background with superimposed almost continuous bursts of generalized, moderate to high amplitude that had an almost periodic pattern (arrows). (B) EEG on day 24, when the patient's neurologic symptoms resolved completely. Epileptiform discharges had disappeared.\n\nFig. 2 Abdomen/Pevis CT showing the extensive thrombosis (arrowheads). (A) Thrombosis in the inferior vena cava. (B) Thrombosis in the renal vein.\n\nTable 1 Summary of reported cases of ceftriaxone-induced neurotoxicity\n\n*Latency is the period between the start of ceftriaxone treatment and the onset of neurologic features; †Days to improvement are the period between the cessation of ceftriaxone and improvement of neurologic findings. RI, renal impairment; CVA, cerebro vascular accident; UTI, urinary tract infection; NCSE, non-convulsive status epilepticus; NA, not available; AED, anti-epileptic drug.\n==== Refs\n1 Rockowitz J Tunkel AR Bacterial meningitis. Practical guidelines for management Drugs 1995 50 838 853 8586029 \n2 Weisfelt M de Gans J van de Beek D Bacterial meningitis: a review of effective pharmacotherapy Expert Opin Pharmacother 2007 8 1493 1504 17661731 \n3 Patel IH Sugihara JG Weinfeld RE Wong EG Siemsen AW Berman SJ Ceftriaxone pharmacokinetics in patients with various degrees of renal impairment Antimicrob Agents Chemother 1984 25 438 442 6329080 \n4 Martinez-Rodriguez JE Barriga FJ Santamaria J Iranzo A Pareja JA Revilla M dela Rosa CR Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure Am J Med 2001 111 115 119 11498064 \n5 Sato Y Morita H Wakasugi H Iijima S Kawashima E Wakayama Y Yoshimura A Reversible chreoathetosis after the administration of ceftriaxone sodium in patients with end-stage renal disease Am J Med Sci 2010 340 382 384 20724905 \n6 Roncon-Albuquerque R Jr Pires I Martins R Real R Sousa G von Hafe P Ceftriaxone-induced acute reversible encephalopathy in a patient treated for a urinary tract infection Neth J Med 2009 67 72 75 19299850 \n7 Grill MF Maganti R Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring Ann Pharmacother 2008 42 1843 1850 19033476 \n8 Lam S Gomolin IH Cefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review Pharmacotherapy 2006 26 1169 1174 16863493 \n9 Kim SY Lee IS Park SL Lee J Cefepime neurotoxicity in patients with renal insufficiency Ann Rehabil Med 2012 36 159 162 22506251 \n10 Johnson H Walker A Intraventricular penicillin: a note of warning JAMA 1945 127 217 219 \n11 De Sarro A Ammendola D Zappala M Grasso S De Sarro GB Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats Antimicrob Agents Chemother 1995 39 232 237 7695312 \n12 Wallace KL Antibiotics-induced convulsions Crit Care Clin 1997 13 741 762 9330839 \n13 Alkharfy KM Kellum JA Frye RF Matzke GR Effect of ceftazidime on systemic cytokine concentrations in rats Antimicrob Agents Chemother 2000 44 3217 3219 11036058 \n14 Schliamser SE Cars O Norrby R Neurotoxicity of beta-lactam antibiotics: predisposing factors and pathogenesis J Antimicrob Chemother 1991 27 405 425 1856121 \n15 Calandra G Lydick E Carrigan J Weiss L Guess H Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin Am J Med 1988 84 911 918 3284342 \n16 Cohen D Appel GB Scully B Neu HC Pharmacokinetics of ceftriaxone in patients with renal failure and in those undergoing hemodialysis Antimicrob Agents Chemother 1983 24 529 532 6316845\n\n",
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"keywords": "Ceftriaxone; Cephalosporins; Chronic Kidney Failure; Seizures",
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"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D002443:Ceftriaxone; D004569:Electroencephalography; D005260:Female; D006801:Humans; D009422:Nervous System Diseases; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic; D012640:Seizures; D013927:Thrombosis; D014057:Tomography, X-Ray Computed; D016482:Urinalysis; D014552:Urinary Tract Infections",
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"title": "Ceftiaxone-induced neurotoxicity: case report, pharmacokinetic considerations, and literature review.",
"title_normalized": "ceftiaxone induced neurotoxicity case report pharmacokinetic considerations and literature review"
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"abstract": "Isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. We recently identified three adolescent/young adult (AYA) patients with IDH-mutant low grade gliomas of the brainstem with several key clinicopathologic and molecular features in common. We discuss these three cases and review the current literature.",
"affiliations": "Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.;Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA.;Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.;Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.;Division of Neurosurgery, Children's Hospital Los Angeles, Los Angeles, CA, USA.;Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA.;Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.;Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.",
"authors": "Chang|Ellen K|EK|0000-0001-6403-9068;Smith-Cohn|Matthew A|MA|;Tamrazi|Benita|B|;Ji|Jianling|J|;Krieger|Mark|M|;Holdhoff|Matthias|M|;Eberhart|Charles G|CG|;Margol|Ashley S|AS|;Cotter|Jennifer A|JA|",
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"fulltext": "\n==== Front\nBrain Pathol\nBrain Pathol\n10.1111/(ISSN)1750-3639\nBPA\nBrain Pathology\n1015-6305\n1750-3639\nJohn Wiley and Sons Inc. Hoboken\n\n10.1111/bpa.12959\nBPA12959\nLetter to the Editor\nLetters to the Editor\nIDH‐mutant brainstem gliomas in adolescent and young adult patients: Report of three cases and review of the literature\nChang Ellen K. https://orcid.org/0000-0001-6403-9068\n1\nSmith‐Cohn Matthew A. 2 3\nTamrazi Benita 4\nJi Jianling 5\nKrieger Mark 6\nHoldhoff Matthias 7\nEberhart Charles G. 8\nMargol Ashley S. 1\nCotter Jennifer A. 5 jcotter@chla.usc.edu\n\n1 Division of Hematology, Oncology and Blood & Marrow Transplantation Children’s Center for Cancer and Blood Diseases Children’s Hospital Los Angeles Los Angeles CA USA\n2 Department of Neurology Johns Hopkins Hospital Baltimore MD USA\n3 Neuro‐Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD USA\n4 Department of Radiology Children’s Hospital Los Angeles Los Angeles CA USA\n5 Department of Pathology and Laboratory Medicine Children’s Hospital Los Angeles Los Angeles CA USA\n6 Division of Neurosurgery Children’s Hospital Los Angeles Los Angeles CA USA\n7 Department of Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD USA\n8 Department of Pathology Johns Hopkins Hospital Baltimore MD USA\n* Correspondence\nJennifer A. Cotter, Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.\nEmail address: jcotter@chla.usc.edu\n\n07 5 2021\n7 2021\n31 4 10.1111/bpa.v31.4 e1295905 2 2021\n23 3 2021\n© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nIsocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. We recently identified three adolescent/young adult (AYA) patients with IDH‐mutant low grade gliomas of the brainstem with several key clinicopathologic and molecular features in common. We discuss these three cases and review the current literature.\n\nbrain biopsy\nbrainstem glioma\nIDH\nisocitrate dehydrogenase\nlow grade glioma\nyoung adult\nDavid Stroud Postgraduate AYA Oncology Fellowship (EKC) source-schema-version-number2.0\ncover-dateJuly 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:31.08.2021\nFunding information\n\nSupport for this work was provided by the David Stroud Postgraduate AYA Oncology Fellowship (EKC)\n==== Body\npmcIn contrast to adult gliomas, isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. In a recent series of over 1000 pediatric low grade gliomas (LGG), the IDH1 R132H mutation was found in only 0.8% of studied cases, with those identified occurring in older children/adolescents (median 15.7 years) and exclusively in the cerebral hemispheres (1). Other studies show a slightly higher incidence (up to 16%) of IDH mutations in pediatric high grade gliomas (HGG), with comparable age range and exclusivity to hemispheric locations (2).\n\nIDH‐mutant gliomas arising in the brainstem are exceedingly rare in both the adult and pediatric population. Infratentorial location is uncommon in diffuse gliomas, with 5% or less occurring in the brainstem, cerebellum, or spinal cord, and IDH mutations in the infratentorial compartment appear to be rare (7%) (3, 4, 5). Brainstem gliomas are very rare in adults, but approximately 10% of pediatric CNS tumors occur in this location, with diffuse midline glioma, K27M‐mutant representing most cases.\n\nWe recently identified three adolescent/young adult (AYA) patients (Figure 1A) with IDH‐mutant glioma of the brainstem with several key clinicopathologic and molecular features in common (summarized in Table S1). Patient #1 was a 19‐year‐old female who presented with left ptosis, left facial palsy, headache, diplopia, ataxia, and dysarthria. Magnetic resonance imaging (MRI) of the brain revealed a diffusely infiltrating and enlarging space‐occupying lesions within the brainstem without enhancement. She did not have a biopsy on initial presentation because of concerns for significant morbidity and was initially treated with focal intensity‐modulated radiation therapy (IMRT) with concurrent temozolomide (TMZ) after magnetic resonance spectroscopy (MRS) showed findings consistent with LGG. Three years after completing radiation therapy, she developed worsening neurological symptoms and was found to have progressive disease on MRI with extension of the tumor into the facial colliculi bilaterally. MRS findings remained consistent with LGG and she was treated with carboplatin, vincristine, and TMZ per ACNS0223. After five cycles of chemotherapy (56 months from initial diagnosis), she underwent tissue sampling due to disease progression with MRI findings of new areas of infiltrative T2/FLAIR signal hyperintensity throughout the right cerebellar parenchyma. Histopathology and molecular analysis led to an integrated diagnosis of anaplastic astrocytoma, IDH1‐mutant, WHO grade 3. Despite aggressive therapy, Patient #1 progressed on treatment and died 62 months after initial diagnosis.\n\nFIGURE 1 IDH‐mutant brainstem gliomas in adolescent/young adult patients. (A) Clinicopathologic features of the three patients with IDH‐mutant brainstem gliomas and associated genetic alterations identified in tumor tissue. (B and C) Preoperative axial MRI, (B) T2‐weighted, and (C) T1‐weighted post‐contrast of Patient 3. (D–G) Histologic and immunohistochemical features of tumor from Patient #3. (D) H&E staining, (E) IDH R132H immunostaining, (F) H3K27me3 immunostaining, and (G) Ki‐67 immunostaining\n\nPatient #2 was a 17‐year‐old male who presented with left leg weakness, headache, diplopia, ataxia, and left facial palsy. MRI of the brain demonstrated an expansile, diffusion‐restricted lesion in the right pons with no evidence of contrast enhancement. He received up‐front biopsy with histopathology and molecular analyses that were consistent with an infiltrating astrocytoma, IDH1‐mutant, WHO grade 2. He was treated with concurrent chemoradiation using focal IMRT and TMZ. He received adjuvant cycles of TMZ and continues to have stable disease 3 years after diagnosis.\n\nPatient #3 was a 24‐year‐old male who presented with right facial palsy and diplopia. Brain MRI showed an infiltrative, expansile lesion of the brainstem with small areas of enhancement (Figure 1B,C). He underwent biopsy, which led to the integrated diagnosis of infiltrating glioma, IDH1‐mutant, WHO grade 2. Similar to Patient #2, he was treated with concurrent chemoradiation using focal IMRT and TMZ with adjuvant cycles of TMZ. He continues to have stable disease 1.5 years after diagnosis.\n\nAs shown in Figure 1D–G and Figure S1, the three cases by histology were diffuse gliomas with low to moderate Ki‐67 labeling indices. Tumors from Patients #2 and #3 were positive for IDH1 R132H by immunohistochemistry and confirmatory sequencing, while Patient #1 had a noncanonical IDH1 R132S mutation by next‐generation sequencing. The tumors of Patients #1 and #3 showed diminution or loss of immunoexpression of H3K27me3. None of the three tumors demonstrated loss of ATRX immunoreactivity or ATRX mutation. Pathogenic variants of TP53 were identified in all three cases. Other genetic alterations identified included MET exon 14 skipping (Patient #1) and MYCN amplification (Patient #2) (gene content for next‐generation sequencing panels is provided in Tables S3 and S4). None of the tumors showed evidence of 1p/19q codeletion.\n\nWhen compared with pediatric LGG, adult LGG more frequently harbor IDH mutations and demonstrate poorer long‐term survival with a higher risk of malignant transformation and death (6). The relative survival advantage conferred by IDH mutation in other anatomic locations is not observed in the brainstem, with overall survival similar to supratentorial IDH wild‐type gliomas (7). Generally, pediatric LGG patients have excellent long‐term overall survival with rare malignant transformation, leading to the practice of monitoring select patients with expectant observation to prevent treatment‐associated morbidity (8). However, compared to other pediatric LGG patients, young people with IDH‐mutant LGG appear to have a higher risk for malignant transformation, similar to their adult counterparts. For this reason, pediatric IDH‐mutant LGG has been considered “intermediate risk” by some groups (1).\n\nIDH‐mutant gliomas of the infratentorial compartment may be an under‐recognized category of brain tumors due to historical reluctance to biopsy this location and presumption of tumor grade based on MRI features. In a recent study of brainstem gliomas, IDH‐mutant tumors composed a small but distinct subset (9), with a median age of 39, and the most frequent histologic patterns being WHO grade 2 (66.7%) or WHO grade 3 (26.7%). DNA methylation studies and copy number profiling suggest that IDH‐mutant infratentorial gliomas are molecularly distinct and may arise from a different cell of origin than their supratentorial counterparts (7). The same study also showed that infratentorial IDH‐mutant astrocytomas have a predominance of noncanonical IDH variants and a low rate of ATRX loss compared to supratentorial tumors. Outcome analysis showed overall survival in patients with infratentorial IDH‐mutant astrocytomas to be longer than those with diffuse midline gliomas, but shorter than patients with supratentorial IDH‐mutant astrocytomas, specifically those classified as “low grade” by methylation subclass. The existing literature on IDH‐mutant brainstem gliomas in pediatric and AYA patients is summarized in Table S2.\n\nRecognition of this category of tumors has practical implications for neuropathology practice and requires special attention to immunohistochemical workup. Two of three cases in our series showed partial or complete loss of H3K27me3 protein expression (Figure S1). In the context of brainstem glioma, this pattern is typically considered supportive or diagnostic of diffuse midline glioma. These cases demonstrate that caution should be taken in interpreting this stain without confirmation of a diffuse midline glioma‐associated alteration (e.g., H3 K27M or EGFR mutation, EZHIP overexpression). ATRX mutations and thus ATRX loss were not observed in this group, in contrast to the typical pattern for supratentorial IDH‐mutant astrocytomas, suggesting ATRX immunohistochemistry may be less useful in these cases. Finally, there is evidence that noncanonical IDH1 mutations are enriched in IDH‐mutant infratentorial tumors, making IDH1 immunohistochemistry of more limited utility (as demonstrated by Patient #1) (5, 7, 9). Still, Patients #2 and #3 illustrate the importance of IDH1 R132H immunohistochemistry in the setting of AYA brainstem glioma.\n\nWhile not present in the cases we identified, two brainstem gliomas with co‐occurring IDH and H3 K27M mutations have been recently reported ((7), Table S2). Previously, IDH and H3 K27M mutations had been considered mutually exclusive. Both of the reported cases with co‐occurring IDH1 and H3 K27M mutations harbored noncanonical IDH1 mutations (R132C), underscoring the importance of sequencing‐based assays for these tumors. Both tumors had short overall survival and methylation profiles generally aligned with other IDH‐mutant infratentorial gliomas.\n\nWithout biopsy, there is currently no method to distinguish IDH‐mutant brainstem gliomas from other LGG or HGG entities with a wide range of prognoses. Of note, MET exon 14 skipping or MYCN amplification, which were identified in our patients' tumors, are uncommon findings in LGG, and MYCN amplification is associated with poor prognosis in IDH‐mutant gliomas (10). This series highlights that, while uncommon, IDH‐mutant tumors occur in the brainstem of AYA patients, can show low grade histologic features, and should be identified by up‐front immunohistochemical and molecular testing. In our patients, the detection of IDH mutations did not directly impact treatment decisions due to the patients’ severe symptomatology requiring urgent radiation therapy. However, in patients for whom avoidance of radiation therapy is feasible, the presence of IDH mutations could lead to a chemotherapy‐only approach given the tumors’ potential to undergo malignant transformation. In the near future, knowledge of the presence of IDH mutations will enable consideration of emerging therapies. Biopsy is critical for patient selection in the recurrent setting, for example, imipridone (ONC201) in H3 K27M‐mutant gliomas and ongoing investigations with IDH inhibitors and vaccines in IDH‐mutant LGG. Additionally, preclinical studies have shown that IDH mutations may be predictive of response to PARP inhibitors through synthetic lethality, which is currently being evaluated (NCT03212274). Overall, these findings underscore the importance of performing biopsies of brainstem tumors to establish a specific diagnosis, more accurate prognostication, and appropriate treatment.\n\nCONFLICT OF INTEREST\n\nThe authors declare no conflict of interest.\n\nSupporting information\n\nFIGURE S1 Histologic features of tumors from Patients #1‐3. Biopsy of recurrent tumor from Patient #1 (top row) showed tumor cells infiltrating the cerebellar white matter. IDH1 R132H immunohistochemistry was negative, concordant with the observed R132S mutation in this patient. H3K27me3 showed diminished nuclear immunoexpression with a subset of tumor cells appearing negative. Ki‐67 labeling index was moderate to high. The overall features were consistent with an anaplastic astrocytoma, WHO grade 3. Biopsy from the brainstem of Patient #2 (middle row) showed increased cellularity with an infiltrative growth pattern of tumor cells marked by irregular nuclear contours. The findings were consistent with an infiltrative astrocytoma, WHO grade 2. Immunohistochemistry for IDH1 R132H was positive in the scattered tumor cells, H3K27me3 expression was retained, and Ki‐67 labeling index was low. Biopsy from Patient #3 (bottom row) showed an infiltrating glioma with mild nuclear atypia. Immunohistochemistry for IDH1 R132H was positive in scattered cells. H3K27me3 expression was lost in tumor nuclei. Ki‐67 labeling index was low to moderate\n\nClick here for additional data file.\n\nTABLE S1 Pathogenic genetic alterations identified in the three brainstem gliomas\n\nClick here for additional data file.\n\nTABLE S2 Summarized clinicopathologic and genetic data from Patients #1‐3 and review of the literature. Includes reported grade 2‐4 IDH‐mutant tumors arising in the brainstem in patients under age 30\n\nClick here for additional data file.\n\nTABLE S3 List of targeted genes in CHLA OncoKids Cancer Panel\n\nTABLE S4 List of targeted genes in Johns Hopkins Molecular Diagnostics Laboratory Solid Tumor Panel.\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nThe authors thank the patients and their caregivers.\n\nThe inclusion of two cases in Table S2 was possible in part due to The Children’s Brain Tumor Network (CBTN). Thanks to Adam Walker (CHLA) for data collection and analysis from the CBTN dataset.\n\nDATA AVAILABILITY STATEMENT\n\nThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 RyallS, ZapotockyM, FukuokaK, NobreL, Guerreiro StucklinA, BennettJ, et al. Integrated molecular and clinical analysis of 1,000 pediatric low‐grade gliomas. Cancer Cell. 2020;37 :569–583.e565. 10.1016/j.ccell.2020.03.011.32289278\n2 KorshunovA, RyzhovaM, HovestadtV, BenderS, SturmD, CapperD, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015;129 :669–78. 10.1007/s00401-015-1405-4.25752754\n3 EllezamB, TheelerBJ, WalbertT, MammoserAG, HorbinskiC, Kleinschmidt‐DeMastersBK, et al. Low rate of R132H IDH1 mutation in infratentorial and spinal cord grade II and III diffuse gliomas. Acta Neuropathol. 2012;124 :449–51. 10.1007/s00401-012-1011-7.22772980\n4 IdaCM, LambertSR, RodriguezFJ, VossJS, Mc CannBE, SeysAR, et al. BRAF alterations are frequent in cerebellar low‐grade astrocytomas with diffuse growth pattern. J Neuropathol Exp Neurol. 2012;71 :631–9. 10.1097/NEN.0b013e31825c448a.22710963\n5 JavadiSA, HartmannC, WalterGF, BananR, SamiiA. IDH1 mutation in brain stem glioma: case report and review of literature. Asian J Neurosurg. 2018;13 :414–7. 10.4103/1793-5482.228540.29682047\n6 JohnsonDR, BrownPD, GalanisE, HammackJE. Pilocytic astrocytoma survival in adults: analysis of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. J Neurooncol. 2012;108 :187–93. 10.1007/s11060-012-0829-0.22367412\n7 BananR, StichelD, BleckA, HongB, LehmannU, SuwalaA, et al. Infratentorial IDH‐mutant astrocytoma is a distinct subtype. Acta Neuropathol. 2020;140 :569–81. 10.1007/s00401-020-02194-y.32776277\n8 HolzapfelJ, KandelsD, SchmidtR, PietschT, Warmuth‐MetzM, BisonB, et al. Favorable prognosis in pediatric brainstem low‐grade glioma: Report from the German SIOP‐LGG 2004 cohort. Int J Cancer. 2020;146 :3385–96. 10.1002/ijc.32734.31613986\n9 ChenLH, PanC, DiplasBH, XuC, HansenLJ, WuY, et al. The integrated genomic and epigenomic landscape of brainstem glioma. Nat Commun. 2020;11 :3077. 10.1038/s41467-020-16682-y.32555164\n10 ShirahataM, OnoT, StichelD, SchrimpfD, ReussDE, SahmF, et al. Novel, improved grading system(s) for IDH‐mutant astrocytic gliomas. Acta Neuropathol. 2018;136 :153–66. 10.1007/s00401-018-1849-4.29687258\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1015-6305",
"issue": "31(4)",
"journal": "Brain pathology (Zurich, Switzerland)",
"keywords": "IDH; brain biopsy; brainstem glioma; isocitrate dehydrogenase; low grade glioma; young adult",
"medline_ta": "Brain Pathol",
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"nlm_unique_id": "9216781",
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"pmid": "33960568",
"pubdate": "2021-07",
"publication_types": "D016422:Letter; D013485:Research Support, Non-U.S. Gov't",
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"title": "IDH-mutant brainstem gliomas in adolescent and young adult patients: Report of three cases and review of the literature.",
"title_normalized": "idh mutant brainstem gliomas in adolescent and young adult patients report of three cases and review of the literature"
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"abstract": "The rapid expansion of access to antiretroviral therapy (ART) has led to the emergence of multi-class drug resistance (MDR) in people living with HIV (PLWH). However, the viral evolutionary dynamics of the development of MDR has not been well documented. For this study, plasma and peripheral blood mononuclear cells (PBMC) were longitudinally collected at different time points from a PLWH who suffered several periods of ART failure. Next generation sequencing (NGS) was used to analyze the distribution and percent of drug resistance mutations in PBMC and plasma. The results showed the gradual replacement of the wild type protease and integrase genotype by protease inhibitors (PI) and integrase strand transfer inhibitor (INSTI) drug resistant mutations when patient's ART regimen was changed - driving the increase of genetic variability in HIV DNA. Sampling for this study was initiated after the patient was first diagnosed with ART failure, five years after ART treatment was first initiated. By that time, mutants resistant to the reverse transcriptase inhibitor nevirapine (NVP) had already replaced almost 100% of wild type. After the introduction of the protease inhibitor lopinavir/ritonavir (LPV/r) to the patient's ART, resistant protease inhibitor (PI) mutants developed slowly. After one month, none were found in PMBC DNA; after sixteen months, less than 20% were mutants; and after three years (two months prior to the patient's death) PI mutants were still under 50%. However, integrase strand transfer inhibitor (INSTI) mutations evolved much more quickly, replacing approximately 75% of the wild genotype in HIV DNA one year after addition of the integrase inhibitor raltegravir to the patient's ART, and almost 100% after two years. In summary, our dataset provides the first analysis of the distribution and percent of drug resistance mutations in PBMC and plasma during the development of a four-class drug resistant HIV-1 CRF01_AE virion. The study also showed that months before drug resistant mutants could be found in plasma, NGS identified them in HIV DNA, demonstrating that this can be a very effective tool for early detection of the development of drug resistance.",
"affiliations": "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.",
"authors": "Peng|Xiaorong|X|;Xu|Yufan|Y|;Huang|Ying|Y|;Zhu|Biao|B|",
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"doi": "10.2147/IDR.S323762",
"fulltext": "\n==== Front\nInfect Drug Resist\nInfect Drug Resist\nidr\nidr\nInfection and Drug Resistance\n1178-6973\nDove\n\n323762\n10.2147/IDR.S323762\nCase Report\nIntrapatient Development of Multi-Class Drug Resistance in an Individual Infected with HIV-1 CRF01_AE\nPeng et al\nPeng et al\nPeng Xiaorong 1*\nXu Yufan 1*\nHuang Ying 1\nZhu Biao 1\n1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China\nCorrespondence: Biao Zhu State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China Email zhubiao1207@zju.edu.cn\n* These authors contributed equally to this work\n\n25 8 2021\n2021\n14 34413448\n21 6 2021\n06 8 2021\n© 2021 Peng et al.\n2021\nPeng et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nThe rapid expansion of access to antiretroviral therapy (ART) has led to the emergence of multi-class drug resistance (MDR) in people living with HIV (PLWH). However, the viral evolutionary dynamics of the development of MDR has not been well documented. For this study, plasma and peripheral blood mononuclear cells (PBMC) were longitudinally collected at different time points from a PLWH who suffered several periods of ART failure. Next generation sequencing (NGS) was used to analyze the distribution and percent of drug resistance mutations in PBMC and plasma. The results showed the gradual replacement of the wild type protease and integrase genotype by protease inhibitors (PI) and integrase strand transfer inhibitor (INSTI) drug resistant mutations when patient’s ART regimen was changed – driving the increase of genetic variability in HIV DNA. Sampling for this study was initiated after the patient was first diagnosed with ART failure, five years after ART treatment was first initiated. By that time, mutants resistant to the reverse transcriptase inhibitor nevirapine (NVP) had already replaced almost 100% of wild type. After the introduction of the protease inhibitor lopinavir/ritonavir (LPV/r) to the patient’s ART, resistant protease inhibitor (PI) mutants developed slowly. After one month, none were found in PMBC DNA; after sixteen months, less than 20% were mutants; and after three years (two months prior to the patient’s death) PI mutants were still under 50%. However, integrase strand transfer inhibitor (INSTI) mutations evolved much more quickly, replacing approximately 75% of the wild genotype in HIV DNA one year after addition of the integrase inhibitor raltegravir to the patient’s ART, and almost 100% after two years. In summary, our dataset provides the first analysis of the distribution and percent of drug resistance mutations in PBMC and plasma during the development of a four-class drug resistant HIV-1 CRF01_AE virion. The study also showed that months before drug resistant mutants could be found in plasma, NGS identified them in HIV DNA, demonstrating that this can be a very effective tool for early detection of the development of drug resistance.\n\nKeywords\n\nmulti-class drug resistance\nHIV\nCRF01_AE\nART\nNGS\nHIV DNA\nNational Special Research Program for Important Infectious Diseases This study was supported by National Special Research Program for Important Infectious Diseases (No. 2017ZX10202102-002-002).\n==== Body\nIntroduction\n\nThe lifelong administration of combination antiretroviral therapy (ART) can effectively suppress viral replication and reduce morbidity and mortality of people living with HIV (PLWH).1 There are multiple classes of ART drugs, including nucleoside reverse transcriptase inhibitors (NRTI) including lamivudine (3TC) and azidothymidine (AZT), non-nucleoside reverse transcriptase inhibitors (NNRTI) including nevirapine (NVP), protease inhibitors (PI) including Lopinavir/Ritonavir (LPV/r) and the integrase strand transfer inhibitor (INSTI) raltegravir (RAL).2 In recent years, the rapid expansion of access to ART has led to the emergence of multi-class drug resistance (MDR), defined as a virus mutant with resistance to at least three different drug classes.3\n\nA previous study of a large cohort of cART-experienced patients in Italy showed a dramatic drop in drug resistance from 80–85% in 1999 to around 36% in 2018. In recent years (2011–18), the percentage of isolates with at least three classes of drug resistance has remained stable at around 5% (range 3–6%).4 The majority of these patients have been found to have a long history of HIV infection, with previous exposure to suboptimal therapies, and to have, over time, accumulated many mutations resistant to several drug classes.4 The viral evolutionary dynamics within these patients that leads to the development of MDR has not been well documented.\n\nMost drug resistance data have been collected from patients infected with HIV-1 subtype B in the United States, Oceania, and Europe. When ART has become increasingly available in new geographic areas, drug resistance in a diverse group of M subtypes and distinct circulating recombinant forms (CRFs) has evolved. CRF01_AE emerged in Southeast Asia in the 1990s, expanded rapidly in China, and is now the most prevalent HIV-1 form in Southeast Asia.5,6 Previous studies have identified a 9–20% higher resistance mutation frequency at reverse transcriptase positions in CRF01_AE than in subtype B, and a 12–18% higher predicted cross-resistance to future therapy options.7 The influence of genetic variation across subtypes has therefore become an active area of research into resistance evolution and disease progression.\n\nIn our previous study of the evolutionary patterns during ART failure, plasma and peripheral blood mononuclear cells (PBMC) were longitudinally sampled at different time points from a single patient who suffered several periods of ART failure before successful reduction of viral load. The different intrapatient evolutionary dynamics patterns of env and pol viral segments witness not only the emergence of drug resistant mutants, but also the switch of tropism.8\n\nIn the current study, the same longitudinal approach was applied to learn more about the viral evolutionary dynamics during the development of four-class MDR in a single patient infected with the CRF01_AE experiencing ART failure and subsequent mortality. The distribution and percent of drug resistance mutants in the reverse transcriptase (RT), protease (PR) and integrase (IN) genes were determined by next generation sequencing, and the demographic history of the HIV DNA reservoir in PBMC was reconstructed by applying phylodynamics methods.\n\nCase Presentation\n\nA 27-year-old patient was diagnosed as HIV-positive in August 2008. PBMC and plasma samples were collected at different time points from September, 2013 to June, 2017 (Figure 1). The study was approved by the institutional review boards of the First Affiliated Hospital, School of Medicine, Zhejiang University (Reference Number: 2020265). Written informed consent was provided by the patient to allow the case details and any accompanying images to be published.Figure 1 Schematic representing the treatment and sampling protocols used in this study. This patient initiated antiretroviral therapy with 3TC+AZT+NVP in August 2008, switched to 3TC+AZT+LPV/r in August 2013, and to 3TC+AZT+LPV/r+RAL in March 2015. Samples used in the study were collected at different time points shown on top of the schematic. Rectangles represent plasma and circles represent PBMC.\n\nPlasma samples were tested for viral load during treatment. The patient had been diagnosed as HIV-positive in August 2008 and initiated ART with 3TC+AZT+NVP. The ART regimen was switched to 3TC+AZT+LPV/r in August 2013 because of unsuppressed viral load (1*105 copies/mL) and detection of reverse transcriptase resistant mutations, both to NRTI and NNRTI. One month later, in September, 2013, viral load decreased to about 1.4*103 copies/mL, and was under the detection limit (50 copies/mL) from March, 2014 to December 2014. In March, 2015, the ART regimen was changed, to 3TC+AZT+LPV/r+RAL, again due to unsuppressed viral load (5.4*104 copies/mL). By June, 2017, two years later, the viral load had increased, to 1.8*105 copies/mL (Table 1), and was followed by the patient’s death in August, 2017.Table 1 Characteristics of Drug-Resistant Mutant Sequences Isolated from Plasma\n\nSample Type\tSample Date\tDrug-Resistance Mutant (RT)\tDrug-Resistance Mutant (PR)\tDrug-Resistance Mutant (IN)\tViral Load (Copies/mL)\t\nPlasma\t2013–09\tNot applied\t1407.92\t\n2014–03\tNot applied\tUnder LOD\t\n2014–12\tNot applied\tUnder LOD\t\n2015–03\tM41L (99.8%), K65R (99.8%), K70T (99.9%), Y181C (99.7%), G190A (88.8%)\tM46I (92.9%), I54L (40.9%), L76V (90.3%), I84V (90.9%)\tNone\t54,065.67\t\n2017–06\tM41L (99.9%), K65R (99.9%), K70T (99.9%), Y181C (99.8%), G190A(99.9%)\tM46I (99.9%), I54L (62.2%), L76V (99.8%), I84V (99.8%)\tE138K (99.6%), G140A (99.5%), S147G (99.6%), Q148R (99.6%)\t181,920.92\t\n\nSanger Sequencing and Next Generation Sequencing\n\nAll collected samples during treatment were sequenced by Sanger sequencing and Next Generation Sequencing (NGS) techniques. The purified PR/RT amplicon and IN amplicon were randomly interrupted by Covaris ultrasonic breaker and then used for library preparation (NEBNext® Ultra™ II DNA Library Prep Kit for Illumina) according to manufacturer’s instructions. Sequencing was carried out by the Illumina high-throughput sequencing platform (Nova-Seq). After data processing and quality filtering performed to obtain clean data, fastq files were aligned and generated the codon frequency tables using fastq2codfreq script (https://hivdb.stanford.edu/page/codfreq/). Then, the codon frequency tables were submitted to HIVdb-NGS beta for genotypic resistance interpretations and quality control analysis. Minimum detection threshold was set to 1% for all samples, because detection below a frequency of 1% may cause failed quality assessment. ShoRAH was applied to convert NGS sequence variants into haplotypes.9\n\nPhylogenetic Analysis\n\nMUSCLE software (v3.8.31)10 was used to align all RT, PR and IN sequences from plasma viral RNA and cellular DNA collected during the ART therapy. Alignments were manually edited and trimmed to 297 nucleotides for PR (HBX2: 2253–2549), 903 nucleotides for RT (HBX2: 2550–3452) and 780 nucleotides for IN (HBX2: 4290–5069) using BioEdit software (v7.0.9). Shorter sequences and sequences with stop codons or gaps larger than a nucleotide triplet were removed from the alignments. The best-fitting nucleotide substitution model was selected with jModeltest software (v2.1.7),11 using the Akaike Information Criterion (AIC). Phylogenetic trees were inferred using PhyML software (v3.0).12 Bootstrap analysis was performed on 1000 replicates.\n\nDemographic Reconstructions\n\nThe demographic history of the HIV reservoir in PBMC was estimated using the BEAST software13 and implemented in the Bayesian Markov chain Monte Carlo (MCMC) method. The Bayesian skyline model14 and strict clock model were incorporated in the MCMC method. Multiple independent MCMC runs were performed and assessed for consistency. Convergence of relevant parameters and Bayesian skyline results were assessed by effective sample sizes over 200 in Tracer v1.6 (http://tree.bio.ed.ac.uk/software/tracer/).\n\nThe Development of Drug Resistant Mutations\n\nOver the course of three periods of treatment failure, the patient developed a four-class drug resistant virus population, in which we identified thirteen mutations associated with drug resistance. Five were in the RT gene - M41L, K65R, K70T, Y181C and G190A; four in the PR gene - M46I, I54L, L76V, and I84; and four in the IN gene - E138K, G140A, S147G, Q148R.\n\nSampling for this study was initiated after the patient was first diagnosed with ART failure, five years after ART treatment was first initiated. By that time, In September, 2013, almost 100% of PBMC virus already had mutants resistant to NRTI and NNRTI, and these levels persisted throughout periods of treatment, even during 2014, when plasma viral load was under the limit of detection.\n\nAfter the introduction of the protease inhibitor Lopinavir/Ritonavir (LPV/r) to the patient’s ART, PI resistant mutants developed slowly in PMBC DNA. After one month, none were found; after sixteen months, less than 20% were mutants. After three years (two months prior to the patient’s death) PI mutants in PMBC DNA were still under 50%. PI resistant mutants in plasma had a different pattern. At sixteen months after the introduction of the PI no sequences could yet be identified because the viral level was too low for amplification. Eventually, substantially higher PI mutant levels were able to be found in plasma - almost 100% two years after a PI drug was switched to ART, by which time viral load had increased to 5.4*104 copies/mL.\n\nIntegrase strand transfer inhibitor (INSTI) mutations evolved much more quickly, replacing approximately 75% of the wild genotype in HIV DNA one year after addition of the integrase inhibitor raltegravir to the patient’s ART, and almost 100% after two years.\n\nINSTI-resistant mutations, E138K, G140A, S147G and Q148R, replaced approximately 75% of the wild genotype in HIV DNA one year after addition of RAL to ART, and almost 100% 14 months later, by which time viral load reached 1.8*105 copies/mL. These results are displayed in Table 1 and Figure 2.Figure 2 The development of Drug Resistant Mutants in Reverse Transcriptase (RT), Protease (PR) and Integrase (IN) Sequences in DNA from PBMC. Change in percent of drug resistant mutations in RT sequences, PR sequences and IN sequences. The vertical axes represent the percent of drug resistant mutants. Time scale is in calendar years and months.\n\nDrug Resistance Genotype\n\nIn the RT gene, K65R and K70T mutations cause low resistance to 3TC and increased susceptibility to AZT. The Y181C and G190A mutants are associated with high-level resistance to NVP. M41L is a non-polymorphic mutation selected by thymidine analogs AZT. In the PR gene, M46I, L76V and I84V are non-polymorphic mutants selected by protease inhibitors. These mutants reduce susceptibility to LPV/r. In the IN gene, E138K, G140A and Q148R are also non-polymorphic mutants, selected by INSTI (RAL). Q148R is associated with high-level reductions in RAL susceptibility, particularly when it occurs in combination with E138K or G140A mutants (Table 2). All drug resistant mutation associations are based on the Stanford drug resistance database.15Table 2 Characteristics of Drug-Resistant Mutant Sequences Isolated from PBMC\n\nSample Type\tSample Date\tDrug-Resistance Mutant (RT)\tDrug-Resistance Mutant (PR)\tDrug-Resistance Mutant (IN)\tViral Load (Copies/mL)\t\nPBMC\t2013–09\tM41L (79.4%), K65R (99.5%), K70T (99.3%), Y181C (99.3%), G190A (99.4%)\tNone\tNone\tNot applied\t\n2014–03\tM41L (87.3%), K65R (99.8%), K70T (99.7%). Y181C (99.0%), G190A (99.8%)\tNone\tNone\t\n2014–12\tM41L (80.9%), K65R (98.9%), K70T (99.6%), Y181C (99.7%), G190A (98.1%)\tM46I (19.1%), I54L (7.1%), L76V (14.7%), I84V (15.5%)\tNone\t\n2016–04\tM41L (84.5%), K65R (99.9%), K70T (99.9%), Y181C (99.9%), G190A (99.8%)\tM46I (28.0%), I54L (10.2%), L76V (22.5%), I84V (23.5%)\tE138K (76.4%), G140A (73.3%), S147G (75.0%), Q148R (75.0%)\t\n2017–06\tM41L (89.3%), K65R (99.8%), K70T (99.7%), Y181C (99.7%), G190A (99.8%)\tM46I (53.6%), I54L (34.3%), L76V (44.8%), I84V (46.2%)\tE138K (93.4%), G140A (91.2%), S147G (91.9%), Q148R (92.0%)\t\n\nDetecting Evolution Over Treatment Time Points\n\nBecause there were sufficient sequence data points from PBMC HIV DNA, Bayesian skyline plots were reconstructed to infer the dynamic of the effective population of RT, PR, and IN sequences in the PBMC. The effective population of RT sequences was shown to be stable over the entire testing period. However, the effective population of protease and integrase sequences underwent a significant increase in genetic variation during the period of treatment failure. After the switch of LPV/r to ART, the effective population of PR sequences first decreased and then increased with drug mutants selected by LPV/r. The effective population of IN sequences also decreased after the administration of PI, and stayed low for about six months. After the administration of INSTI, the effective population of IN sequences increased because of the drug resistant mutants selected by RAL. (Figure 3).Figure 3 Demographic History of RT, PR and IN Sequences in DNA from PBMC. Bayesian skyline plots showing the effective population in the RT sequences (A), PR sequences (B) and IN sequences (C). Median estimates of the effective number of infections using Bayesian skyline (black curve) are shown in each graphic together with 95% highest probability density intervals of the Bayesian skyline estimates (blue area). The vertical axes represent the estimated effective number of infections on a logarithmic scale. Time scale is in calendar years. Vertical dotted lines indicate when a protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) were added to ART.\n\nDiscussion\n\nIn this study, the mutant sequences have emerged during the development of a new four-class drug resistant HIV-1 CRF01_AE variant in a single patient, during several periods of therapy failure. This is a serious and challenging development since PLWHs harboring multi-class drug resistant virus have a high burden of disease, with a worrying incidence of malignancies and poorer survival after treatment failure.3,16\n\nBy the study’s first sample collection point, almost 100% of viral sequences already had mutants resistant to NRTI and NNRTI in PBMC, so no significant change in the effective population of these sequences was observed over time. However, PI and INSTI drug resistant mutants gradually replaced the wild genotype, and drove the increase of genetic variability in HIV DNA. Demographic histories of these developments were generated by Bayesian skyline plot analysis, and demonstrate the genetic diversity in viral segment sequences over time, expressed as effective population.\n\nThis study’s sequencing data showed significantly reduced genetic variability in both protease and integrase PBMC-derived variants directly following the administration of PI. A study by Besson et al investigated the decay of HIV DNA on ART and showed that the infected cell populations decline initially but then achieve a steady state with the persistence of about 10% of infected cells during effective ART.17 The different phase of decay occurs from the death of infected cells with different half-lives from days to months.18 The effective population increased when the drug resistant mutants were selected.\n\nOne previous study reported that the prevalence of INSTI resistance remained low compared with PI and RT resistance in ART-treated populations, but expanded with increased INSTI use between 2009 and 2016.19 The development of INSTI resistance described in this study suggests how that resistant pathway is evolving. Here the CRF01_AE virion developed INSTI resistant mutants by changes at position Q148, the most common mutant pathways previously described in all subtypes.20 There have been numerous reports of the emergence of substitutions involving position Q148 in response to RAL pressure. As substitutions at position Q148 impart a severe fitness cost,20 they are rapidly compensated for by various secondary resistance mutants, and the addition of at least two secondary mutants seems to confer the highest fold changes in resistance to second-generation INSTIs.21 E138K and G140A, identified in our study, are two of these mutants. The prevalence of the INSTI resistance mutants in CRF01_AE needs further investigation through a larger sample.\n\nDrug-resistant mutants in HIV DNA emerged before they appeared in plasma – through the use of next generation sequencing. The difference could be caused by the higher level of cell-associated HIV-1 RNA than in plasma RNA, which may contribute to the generation of new viral genomes, when plasma virus remains below the limit of detection.22 Some mutants could also remain in HIV DNA through persistence and/or proliferation of infected cells. These integrated and unintegrated provirus in latently infected cells may have a delayed contribution to the pool of resistant virus.23\n\nConclusion\n\nWhile our study is limited to a single patient and several sampling timepoints, our data set and analysis demonstrated for the first time the evolution of sequences in the development of a four-class drug resistant HIV-1 CRF01_AE virion. It revealed dynamic shifts in the viral population and in drug-resistance mutants, while under the influence of complex ART regimens. This study utilized all samples available for this patient. Collection of baseline samples prior to initiation of ART, and at more sampling time points during treatment, will help us analyze evolutionary change in patient viral population. Our findings also suggested that next generation sequencing can be a very effective tool to detect a low level of drug resistance in HIV DNA, which could be critical for the clinical management of patients, especially those already experiencing virological failure while on particular ART regimens.\n\nBoth clinicians and patients need to be aware that a wide pattern of resistance can represent a strong negative prognostic factor for survival. Early detection of the development of drug resistant mutants should become a priority to prevent the further development of resistance through modification of ART regimens and as part of patient education to strengthen adherence to therapy.\n\nAcknowledgments\n\nWe gratefully thank Susan Joyce Herzog for assistance in editing our manuscript.\n\nData Sharing Statement\n\nThe datasets used in this study are available from the corresponding author on reasonable request.\n\nEthics Approval and Consent to Participate\n\nThe study was approved by the institutional review boards of the First Affiliated Hospital, School of Medicine, Zhejiang University (Reference Number: 2020265). Written informed consent was provided by the patient to allow the case details and any accompanying images to be published.\n\nAuthor Contributions\n\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. First co-author: These authors contribute equally to this manuscript: Xiaorong Peng and Yufan Xu.\n\nDisclosure\n\nThe authors declare no conflicts of interest for this work.\n==== Refs\nReferences\n\n1. PalellaFJ, DelaneyKM, MoormanAC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338 :853–860. doi:10.1056/NEJM199803263381301 9516219\n2. SmithSJ, ZhaoXZ, PassosDO, LyumkisD, BurkeTR, HughesSH. Integrase strand transfer inhibitors are effective anti-HIV drugs. Viruses. 2021;13 :205. doi:10.3390/v13020205 33572956\n3. ZaccarelliM, TozziV, LorenziniP, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. Aids. 2005;19 :1081–1089. doi:10.1097/01.aids.0000174455.01369.ad 15958840\n4. ArmeniaD, Di CarloD, FlandreP, et al. HIV MDR is still a relevant issue despite its dramatic drop over the years. J Antimicrob Chemother. 2020;75 :1301–1310. doi:10.1093/jac/dkz554 31976521\n5. FengY, HeX, HsiJH, et al. The rapidly expanding CRF01_AE epidemic in China is driven by multiple lineages of HIV-1 viruses introduced in the 1990s. Aids. 2013;27 :1793–1802. doi:10.1097/QAD.0b013e328360db2d 23807275\n6. PengX, WuH, PengX, JinC, WuN. Heterogeneous evolution of HIV-1 CRF01_AE in men who have sex with men (MSM) and other populations in China. PLoS One. 2015;10 :e0143699. doi:10.1371/journal.pone.0143699 26623642\n7. HuangA, HoganJW, LuoX, et al. Global comparison of drug resistance mutations after first-line antiretroviral therapy across human immunodeficiency virus-1 subtypes. Open Forum Infect Dis. 2016;3 :ofv158. doi:10.1093/ofid/ofv158 27419147\n8. PengX, XuY, HuangY, ZhuB. Intrapatient evolutionary dynamics in an individual infected with HIV-1 CRF01_AE who experienced periods of treatment failure. AIDS Res Hum Retroviruses. 2021;37 :139–146. doi:10.1089/aid.2020.0213 33191758\n9. ZagordiO, BhattacharyaA, ErikssonN, BeerenwinkelN. ShoRAH: estimating the genetic diversity of a mixed sample from next-generation sequencing data. BMC Bioinform. 2011;12 :119. doi:10.1186/1471-2105-12-119\n10. EdgarRC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinform. 2004;5 :113. doi:10.1186/1471-2105-5-113\n11. DarribaD, TaboadaGL, DoalloR, PosadaD. jModelTest 2: more models, new heuristics and parallel computing. Nat Methods. 2012;9 :772. doi:10.1038/nmeth.2109\n12. GuindonS, DufayardJF, LefortV, AnisimovaM, HordijkW, GascuelO. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol. 2010;59 :307–321. doi:10.1093/sysbio/syq010 20525638\n13. DrummondAJ, SuchardMA, XieD, RambautA. Bayesian phylogenetics with BEAUti and the BEAST 1.7. Mol Biol Evol. 2012;29 :1969–1973. doi:10.1093/molbev/mss075 22367748\n14. MininVN, BloomquistEW, SuchardMA. Smooth skyride through a rough skyline: bayesian coalescent-based inference of population dynamics. Mol Biol Evol. 2008;25 :1459–1471. doi:10.1093/molbev/msn090 18408232\n15. ShaferRW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis. 2006;194 (Suppl 1 ):S51–8. doi:10.1086/505356 16921473\n16. GalliL, ParisiMR, PoliA, et al. Burden of disease in PWH harboring a multidrug-resistant virus: data from the PRESTIGIO registry. Open Forum Infect Dis. 2020;7 :ofaa456. doi:10.1093/ofid/ofaa456 33241063\n17. BessonGJ, LalamaCM, BoschRJ, et al. HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis. 2014;59 :1312–1321. doi:10.1093/cid/ciu585 25073894\n18. van ZylG, BaleMJ, KearneyMF. HIV evolution and diversity in ART-treated patients. Retrovirology. 2018;15 :14. doi:10.1186/s12977-018-0395-4 29378595\n19. KamelianK, LepikKJ, ChauW, et al. Prevalence of human immunodeficiency virus-1 integrase strand transfer inhibitor resistance in British Columbia, Canada between 2009 and 2016: a longitudinal analysis. Open Forum Infect Dis. 2019;6 :ofz060. doi:10.1093/ofid/ofz060 30895202\n20. AnstettK, BrennerB, MespledeT, WainbergMA. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology. 2017;14 :36. doi:10.1186/s12977-017-0360-7 28583191\n21. TsiangM, JonesGS, GoldsmithJ, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60 :7086–7097. doi:10.1128/AAC.01474-16 27645238\n22. ScullyEP, GandhiM, JohnstonR, et al. Sex-based differences in human immunodeficiency virus type 1 reservoir activity and residual immune activation. J Infect Dis. 2019;219 :1084–1094. doi:10.1093/infdis/jiy617 30371873\n23. WangYM, DyerWB, WorkmanC, WangB, SullivanJS, SaksenaNK. Molecular evidence for drug-induced compartmentalization of HIV-1 quasispecies in a patient with periodic changes to HAART. Aids. 2000;14 :2265–2272. doi:10.1097/00002030-200010200-00007 11089614\n\n",
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"issn_linking": "1178-6973",
"issue": "14()",
"journal": "Infection and drug resistance",
"keywords": "ART; CRF01_AE; HIV; HIV DNA; NGS; multi-class drug resistance",
"medline_ta": "Infect Drug Resist",
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"title": "Intrapatient Development of Multi-Class Drug Resistance in an Individual Infected with HIV-1 CRF01_AE.",
"title_normalized": "intrapatient development of multi class drug resistance in an individual infected with hiv 1 crf01 ae"
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"abstract": "BACKGROUND\nBrain abscess due to the Nocardia genus is rarely reported and it is usually found in immunocompromised patients. Treatment of Nocardia brain abscess is troublesome and requires consideration of the severity of the underlying systemic disease. The difficulties in identifying the bacterium and the frequent delay in initiating adequate therapy often influence the prognosis of patients.\n\n\nMETHODS\nHere, we report a rare case of brain abscess caused by Nocardia farcinica. The patient's medical history was complicated: he was hospitalized several times, but no pathogens were found. At last, bacteria were found in the culture of brain abscess puncture fluid; the colony was identified as Nocardia farcinica by mass spectrometry. Targeted antibiotic treatment was implemented, brain abscess tended to alleviate, but the patient eventually developed fungal pneumonia and died of acute respiratory distress syndrome (ARDS).\n\n\nCONCLUSIONS\nBrain abscess caused by Nocardia farcinica can appear in non-immunocompromised individuals. Early diagnosis, reasonable surgical intervention, and targeted antibiotic treatment are critical for Nocardia brain abscess treatment. In the treatment of Nocardia brain abscess, attention should paid be to the changes in patients' immunity and infection with other pathogens, especially fungi, avoided.",
"affiliations": "Laboratory Department, The First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;Oncology Department, The First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, China.;Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. 1466041119@qq.com.",
"authors": "Song|Jiangqin|J|;Dong|Lian|L|;Ding|Yan|Y|;Zhou|Junyang|J|http://orcid.org/0000-0002-6999-0781",
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"country": "England",
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"doi": "10.1186/s40001-021-00562-2",
"fulltext": "\n==== Front\nEur J Med Res\nEur J Med Res\nEuropean Journal of Medical Research\n0949-2321\n2047-783X\nBioMed Central London\n\n562\n10.1186/s40001-021-00562-2\nCase Report\nA case report of brain abscess caused by Nocardia farcinica\nSong Jiangqin 1\nDong Lian 2\nDing Yan 3\nhttp://orcid.org/0000-0002-6999-0781\nZhou Junyang 1466041119@qq.com\n\n4\n1 grid.508000.d Laboratory Department, The First People’s Hospital of Tianmen City, Tianmen, 431700 Hubei China\n2 grid.508000.d Oncology Department, The First People’s Hospital of Tianmen City, Tianmen, 431700 Hubei China\n3 grid.443573.2 0000 0004 1799 2448 Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000 Hubei China\n4 grid.417303.2 0000 0000 9927 0537 Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004 Jiangsu China\n3 8 2021\n3 8 2021\n2021\n26 8318 6 2021\n23 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nBrain abscess due to the Nocardia genus is rarely reported and it is usually found in immunocompromised patients. Treatment of Nocardia brain abscess is troublesome and requires consideration of the severity of the underlying systemic disease. The difficulties in identifying the bacterium and the frequent delay in initiating adequate therapy often influence the prognosis of patients.\n\nCase presentation\n\nHere, we report a rare case of brain abscess caused by Nocardia farcinica. The patient’s medical history was complicated: he was hospitalized several times, but no pathogens were found. At last, bacteria were found in the culture of brain abscess puncture fluid; the colony was identified as Nocardia farcinica by mass spectrometry. Targeted antibiotic treatment was implemented, brain abscess tended to alleviate, but the patient eventually developed fungal pneumonia and died of acute respiratory distress syndrome (ARDS).\n\nConclusion\n\nBrain abscess caused by Nocardia farcinica can appear in non-immunocompromised individuals. Early diagnosis, reasonable surgical intervention, and targeted antibiotic treatment are critical for Nocardia brain abscess treatment. In the treatment of Nocardia brain abscess, attention should paid be to the changes in patients’ immunity and infection with other pathogens, especially fungi, avoided.\n\nKeywords\n\nNocardia farcinica\nBrain abscess\nCase report\nhttp://dx.doi.org/10.13039/501100001809 national natural science foundation of china 81602297 Ding Yan guangxi zhuang autonomous natural science foundation2018JJB140322 Ding Yan issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nNocardia is an aerobic filamentous environmental Gram-positive bacterium and is usually considered as an opportunistic pathogen, belonging to the order Actinomycetes [1]. Nocardia brain abscess is rare and typically found in immunocompromised patients [1]. Nocardia infections comprise only 2% of all intracranial abscesses [2], but overall mortality rate can exceed 20% [3, 4]. Brain abscess caused by Nocardia farcinica is rarely reported in clinical practice. The treatment is troublesome and the difficulties lie in the timely identification of the bacterium, its inherent resistance to conventional antibiotics and the frequent delay in initiating an effective therapy [5, 6].\n\nHere, we report a patient who suffered from brain abscess caused by Nocardia farcinica, although his condition improved after targeted antibiotic treatment, due to basic diseases and long-term use of antibiotics, he developed fungal infection in the lungs and eventually died of ARDS. This study hope to provide experience for the clinical diagnosis and treatment of Nocardia brain abscess.\n\nCase presentation\n\nA male aged 61 years was admitted to our hospital for intermittent fever and cough on August 16, 2019. In the past 4 years, the patient had developed pulmonary infection repeatedly, which improved after anti-infection treatment. He had a history of hypertension, coronary heart disease and bronchiectasis. In the past 1 year, the patient intermittently developed cough, sputum, accompanied by fever, with a body temperature of about 38.0 °C, without afternoon low fever, night sweats and hemoptysis. He was hospitalized for many times, no pathogens were detected during hospital stay. The patient continued to cough and fever intermittently outside the hospital.\n\nOn admission, the patient was conscious, with no enlargement of superficial lymph nodes, slightly coarse breathing sounds in both lungs, and a little moist crackles could be heard. On June 19, 2019, chest CT (computed tomography) indicated space occupation in the right upper lung, bilateral lung infective lesion with bronchiectasis, emphysema, bullae of the lung, right pleural effusion (Fig. 1A). On August 16, chest CT indicated that the lesion area of the right upper lung mass was significantly larger than before, accompanied by bronchiectasis, emphysema, and pulmonary bulla (Fig. 1B). After admission, the patient underwent CT-guided percutaneous lung puncture examination, and the tissues were subjected pathological examination and microbial culture. Histopathology showed chronic inflammatory changes accompanied by mild hyperplasia of alveolar epithelium. No bacteria were observed in lung tissue culture. Bronchoscope alveolar lavage fluid (BALF) examination revealed bronchial inflammation. Cytology of lavage fluid exfoliation: no cancer cells detected; mTB-DNA was not detected in BALF by Gene Xpert. No acid-fast bacilli were found in lavage fluid and sputum by acid-fast staining, and no hyphae and spores of bacteria and fungi were found by Gram stain. Mycobacterium culture was negative. IgA, IgG, IgM, C3 and C4 were normal. Blood tests for white blood cells (WBC) 13.6 × 109/L (reference range: 3.5–9.5 × 109/L), C-reactive protein (CRP) 64.67 mg/L (reference range: < 6.0 mg/L), PCT 0.053 mg/L (reference range: 0–0.046 ng/mL).Fig. 1 Chest CT images of the patient. A Chest CT on June 19. B Chest CT August 16. C Chest CT on September 14. D Chest CT on December 9\n\nAfter treatment with cefoperazone sodium + sulbactam sodium, the patient’s symptoms (fever, cough and sputum) improved, but neurological symptoms such as headache, delirium and memory loss appeared on August 16. A magnetic resonance imaging (MRI) scan of the brain suggested space occupation in the left frontal lobe, the maximum cross-sectional area of the lesion was about 35 mm × 52 mm; brain abscess was considered (Fig. 2A). On August 28, the patient underwent minimally invasive puncture drainage under CT-guidance, and about 10 mL yellow purulent fluid was extracted. The puncture fluid was sent to the microorganism laboratory for testing, after 48-h culture, white cotton-like colonies grew (Fig. 3A–C). After smear staining, branching and uneven staining of filamentous bacilli could be seen under the microscope. The mycelia could be wound into clusters to form actinomycetes like particles, Gram stain and the weak acid-fast staining were positive (Fig. 3D–F). The bacteria were identified as Nocardia farcinica by mass spectrometry, with 99.9% credibility. Then, the patient was diagnosed with Nocardia farcinica brain abscess. After 16 days of treatment with trimethoprim/sulfamethoxazole (TMP/SMX) (3.0 g, po, bid) and intravenous amikacin (0.4 g, iv, qd), the patient’s temperature returned to normal and his headache completely disappeared, intracranial mass was significantly reduced (Fig. 2B) and the right upper lung mass was significantly absorbed (Fig. 1C). During subsequent treatment, the patient developed nausea and vomiting for many times, which was considered to be caused by cerebral edema. After treatment with mannitol dehydration, the symptoms were relieved. Re-examination of head MRI on October 23 (Fig. 2B) showed that the brain abscess lesions were smaller than before, the brain edema was significantly better than before. The previous anti-infection treatment regimen was continued.Fig 2 Brain MRI images of the patient. A Brain MRI on August 23. B Brain MRI September 14. C Brain MRI on October 22. D Brain MRI on November 22\n\nFig. 3 Culture and staining of Nocardia farcinica. A Images of puncture fluid after 48 h of culture. B Images of puncture fluid after 72 h of culture. C Images of pure bacteria after 24 h of culture. D Gram stain of Nocardia farcinica. E Acid-fast staining of Nocardia farcinica. F Weak acid-fast staining of Nocardia farcinica\n\nOn December 8, the patient had occasional mild chest tiredness, which relieved spontaneously, intermittent cough, nausea and retching, chest CT showed significant increase in lung lesions, partial bronchiectasis, emphysema and bullous lungs appeared (Fig. 1D). The patient developed dyspnea on December 12 accompanied by wheezing sound in both lungs, sputum culture suggested Candida tropicalis. The patient was given antifungal and antiasthmatic treatment with itraconazole and doxotheophylline. On December 15, he developed ARDS, blood pressure (BP): 100/75 mmHg, arterial blood oxygen saturation (SaO2) 79%. After a series of treatments, including assisted respiration (mask oxygen inhalation), anti-inflammatory (methylprednisolone), antiasthmatic (doxophylline, salbutamol, ipratropium bromide), hyperensort (dopamine), the patient’s dyspnea symptoms were not relieved and blood pressure did not rise (BP 77/52 mmHg). The patient’s family gave up the rescue. Subsequently, the patient went into a deep coma, lost consciousness, and the heart rate dropped. The patient died on the morning of the 16th, and the family refused an autopsy.\n\nDiscussion and conclusion\n\nNocardia is a soil-borne strictly aerobic actinomycete with at least 16 species that can affect human health [7]. Nocardia spp. have a predilection for the lungs and brain as foci of infection, particularly in immunocompromised hosts [8]. In this case, the patient was a 61-year-old male with no immunodeficiency disease, but he had bronchiectasis, hypertension, coronary heart disease. Multiple lung infections, 11 hospitalizations, and prolonged antibiotic use in the past 5 years may be the key factors in the patient’s Nocardia infection.\n\nNocardia farcinica was the most common species in Nocardia infection, accounting for 24.5% [9]. Nocardia farcinica is more prone to affect the central nervous system (CNS) than other species [10, 11]. Clinical manifestations of CNS nocardiosis usually result from local effects of granulomas or abscesses in the brain, less commonly in the spinal cord or meninges [10, 11]. The abscess usually can be identified by CT scan or MRI as a ring enhancement at the capsular phase [12], but needs to be distinguished from tumor, cystic or necrotic foci [13]. In our case, after the patient developed symptom of headache, brain abscess was found by MRI examination. Patient underwent minimally invasive surgery for intracranial abscess puncture and suction under CT-guidance, smear staining and bacterial culture were performed on the drainage fluid, and the cultivated colonies were identified as Nocardia farcinica by mass spectrometry.\n\nNocardia identification can be difficult because of the slowly growing pattern of the germ and low positive rate (colonies usually require at least 48 h of incubation although more commonly 3 to 5 days and up to 14 to 21 days), preferably in selective media [14]. To isolate Nocardia spp., multiple cerebrospinal fluid (CSF) specimens should be cultured to increase the yield, although it is not uncommon for the bacteria to be recovered only when direct pus is cultured [15]. Certain laboratory techniques like mass spectrometry may help to identify the genus and species. The preferred methods for test of Nocardia are 16S rRNA gene analysis and other molecular techniques, such as restriction fragment length polymorphisms and multilocus sequence analysis. Direct abscess drainage seems to be the best method for collection of samples for microbiological confirmation and antibiotic susceptibility testing [16]. Nocardia pneumonia often requires bronchoscopy or percutaneous lung biopsy, and a detailed history and thorough physical examination should be taken to adequately assess the presence of spread of the lesions. Cranial CT or MRI should be performed if symptoms or signs suggest intracranial involvement. The patient was considered to have a pulmonary infection caused by inhalation of the bacterium through the respiratory tract and a cerebral abscess caused by haematogenous spread to the brain. In our case, the patient’s repeated sputum culture and BALF tests showed no bacterial growth. Test was negative in the first percutaneous lung biopsy tissue culture, possibly because no valuable lesion tissue was collected at the biopsy site or the use of antibiotics affected the detection rate. This also suggests that Nocardia is more difficult to identify than more common bacteria. Bacterial grew after 24 h of culture of puncture fluid, indicating a severe brain infection and suggested that abscess drainage may be good for isolating and culturing Nocardia.\n\nDirect smears from surgical samples show Gram-positive, beaded, branching filaments that are partially acid-fast, and thus need to be differentiated from mycobacteria. Colonies usually have a chalky white cotton-like appearance because of the abundant aerial filaments. The smell of moist or wet soil is very characteristic of Nocardia spp. colonies [4]. Nocardia spp. exhibit variable morphologic appearances depending on the species, the incubation conditions and the duration of incubation. In routine culture media, Nocardia spp. appears as bacilli with ramifications and sub-ramifications at right angles that may form coccus in thioglycolate medium after prolonged incubation [7]. The colonies we obtained from the puncture fluid were positive for Gram staining and weak acid resistance for acid-fast staining (Fig. 3D–F). The characteristics of bacterial culture and growth (Fig. 3A–C) are consistent with the above literature reports.\n\nNocardia farcinica brain abscess has a high mortality rate, as high as 20% in immunocompetent patients and 55% in immunocompromised patients. These high rates are attributed to the severity of underlying disease, difficulties in identifying the pathogen, and its inherent resistance to antibiotics, leading to inappropriate or late initiation of therapy [5]. In a study of Nocardia isolated from human samples in France, N. farcinica was the most frequently isolated species in blood cultures and brain abscesses (21/39, 54% and 19/43, 44.2%, respectively. In the French data, N. farcinica was frequently not susceptible to cefotaxime (80% of the isolates), meropenem (73% of isolates) and aminoglycosides (more than 90%) [17]. Taking into account the inherent resistance of Nocardia farcinica to third-generation cephalosporins, TMP/SMX’s ability to cross the blood–brain barrier, most authorities recommend TMP/SMX as part of first-line therapy for nocardiosis [18, 19]. Abscesses > 25 mm in diameter and that fail to shrink after 4 weeks of antibiotic therapy should be aspirated to confirm the diagnosis regardless of the immune status of the patient [5]. Empiric treatment of cerebral nocardiosis is well established with the use of parenteral TMP/SMX, amikacin, and imipenem–cilastatin [20, 21]. Recently, extended-spectrum fluoroquinolones such as moxifloxacin have been used successfully against N. farcinica cerebral abscess [22]. Because of its ability to cross the blood–brain barrier, TMP/SMX is the treatment of choice and may be effective even when in vitro studies show resistance [20, 23–25]. The abscesses in our patient’s brain was about 35 mm × 52 mm, far more than 25 mm, minimally invasive puncture drainage is of great significance for the identification of pathogenic bacteria and the treatment of patients. After 16 days of treatment with TMP/SMX, the patient’s condition was significantly improved, the lesions in lung and head were also significantly reduced, show a good clinical response (Figs. 1C and 2C). This also suggests that the lung lesions were caused by Nocardia farcinica.\n\nWhen the patient was identified with Nocardia infection, the lung lesions and brain abscesses were very severe, which affected the patient’s prognosis. After 2 months of continuous antibiotic treatment, the patient suddenly developed dyspnea, an acute outbreak of pulmonary fungal infection (Fig. 1D), laboratory tests identified the pathogen as Candida tropicalis, which is also an opportunistic pathogen. The patient developed repeated lung infections, merge a variety of basic diseases, long-term use of many kinds of antibiotics, with low immunity; all these factors may cause patients to have severe fungal infections at the latest stage of treatment. After routine use of antifungal drug, the disease deteriorated and oxygen saturation decreased, eventually resulting in death from ARDS.\n\nIn conclusion, brain abscess can be caused by Nocardia farcinica in non-immunocompromised individuals and it rarely occurs in clinical. In our case, although the patient’s condition improved after targeted antibiotic treatment (TMP/SMX), due to underlying diseases and long-term use of antibiotics, the central nervous system symptoms appeared lately and delayed diagnosis, the patient eventually died. For pneumonia of unknown cause, a variety of technical means should be used to determine the pathogen as soon as possible: instituting targeted treatment, paying attention to the examination of the brain and other organs. Minimally invasive puncture drainage is of great significance for the diagnosis and treatment of Nocardia brain abscess. Because the treatment of Nocardia brain abscess requires long-term use of antibiotics, attention should be paid to the changes in patients’ immunity and infection with other pathogens, especially fungi, avoided. Early diagnosis and targeted antibiotic treatment are critical for Nocardia brain abscess treatment and prognosis.\n\nAbbreviations\n\nARDS Acute respiratory distress syndrome\n\nCT Computed tomography\n\nMRI Magnetic resonance imaging\n\nBALF Bronchoscope alveolar lavage fluid\n\nBP Blood pressure\n\nSaO2 Arterial blood oxygen saturation\n\nCNS Central nervous system\n\nCSF Multiple cerebrospinal fluid\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nJS and JZ contributed to thesis selection and design, data collection; LD participated in data analysis and interpretation; YD contributed to critical review of the intellectual content of this article; JZ contributed to the manuscript writing. All authors read and approved the final manuscript.\n\nFunding\n\nThe present study was supported by National Natural Science Foundation of China (NO. 81602297), Guangxi Zhuang Autonomous Natural Science Foundation (NO. 2018JJB140322). Funder YD contributed to critical review of the intellectual content of this article and gave financial support.\n\nAvailability of data and materials\n\nAll data are included in this article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the patient’s daughter for the publication of this case report.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s daughter for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nJiangqin Song and Lian Dong contributed equally to this work\n==== Refs\nReferences\n\n1. Fatahi-Bafghi M Nocardiosis from 1888 to 2017 Microb Pathog 2018 114 369 384 10.1016/j.micpath.2017.11.012 29146497\n2. Grond SE Schaller A Kalinowski A Tyler KA Jha P Nocardia farcinica brain abscess in an immunocompetent host with pulmonary alveolar proteinosis: a case report and review of the literature Cureus 2020 12 11 e11494 33354440\n3. Kumar VA Augustine D Panikar D Nandakumar A Dinesh KR Karim S Philip R Nocardia farcinica brain abscess: epidemiology, pathophysiology, and literature review Surg Infect (Larchmt) 2014 15 5 640 646 10.1089/sur.2012.205 25126828\n4. Corti ME Villafañe-Fioti MF Nocardiosis: a review Int J Infect Dis 2003 7 4 243 250 10.1016/S1201-9712(03)90102-0 14656414\n5. Mamelak AN Obana WG Flaherty JF Rosenblum ML Nocardial brain abscess: treatment strategies and factors influencing outcome Neurosurgery 1994 35 4 622 631 10.1227/00006123-199410000-00007 7808604\n6. Wilson JW Nocardiosis: updates and clinical overview Mayo Clin Proc 2012 87 4 403 407 10.1016/j.mayocp.2011.11.016 22469352\n7. Sabuncuoğlu H Cibali AZZ Caydere M Ustün H Semih KI Nocardia farcinica brain abscess: a case report and review of the literature Neurocirugia (Astur) 2004 15 6 600 603 10.1016/S1130-1473(04)70453-4 15632997\n8. Restrepo A Clark NM Nocardia infections in solid organ transplantation: guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation Clin Transplant 2019 33 9 e13509 10.1111/ctr.13509 30817024\n9. Huang L Chen X Xu H Sun L Li C Guo W Xiang L Luo G Cui Y Lu B Clinical features, identification, antimicrobial resistance patterns of Nocardia species in China: 2009–2017 Diagn Microbiol Infect Dis 2019 94 2 165 172 10.1016/j.diagmicrobio.2018.12.007 30679058\n10. Peters BR Saubolle MA Costantino JM Disseminated and cerebral infection due to Nocardia farcinica: diagnosis by blood culture and cure with antibiotics alone Clin Infect Dis 1996 23 5 1165 1167 10.1093/clinids/23.5.1165 8922819\n11. Miralles GD Disseminated Nocardia farcinica infection in an AIDS patient Eur J Clin Microbiol Infect Dis 1994 13 6 497 500 10.1007/BF01974641 7957271\n12. Moorthy RK Rajshekhar V Management of brain abscess: an overview Neurosurg Focus 2008 24 6 E3 10.3171/FOC/2008/24/6/E3\n13. Zhu JW Zhou H Jia WQ You J Xu RX A clinical case report of brain abscess caused by Nocardia brasiliensis in a non-immunocompromised patient and a relevant literature review BMC Infect Dis 2020 20 1 328 10.1186/s12879-020-05052-0 32381049\n14. Pascual-Gallego M Alonso-Lera P Arribi A Barcia JA Marco J Nocardia farcinica abscess of the cerebellum in an immunocompetent patient: a case report and review of the literature Asian J Neurosurg 2016 11 4 454 10.4103/1793-5482.145179 27695569\n15. Chow FC Marson A Liu C Successful medical management of a Nocardia farcinica multiloculated pontine abscess BMJ Case Rep 2013 10.1136/bcr-2013-201308 24311420\n16. Galacho-Harriero A Delgado-López PD Ortega-Lafont MP Martín-Alonso J Castilla-Díez JM Sánchez-Borge B Nocardia farcinica brain abscess: report of 3 cases World Neurosurg 2017 106 1015 1053 10.1016/j.wneu.2017.07.033 28985656\n17. Lebeaux D Bergeron E Berthet J Djadi-Prat J Mouniée D Boiron P Lortholary O Rodriguez-Nava V Antibiotic susceptibility testing and species identification of Nocardia isolates: a retrospective analysis of data from a French expert laboratory, 2010–2015 Clin Microbiol Infect 2019 25 4 489 495 10.1016/j.cmi.2018.06.013 29933049\n18. Budzik JM Hosseini M Mackinnon AJ Taxy JB Disseminated Nocardia farcinica: literature review and fatal outcome in an immunocompetent patient Surg Infect (Larchmt) 2012 13 3 163 170 10.1089/sur.2011.012 22612440\n19. Viganò SM Edefonti A Ferraresso M Ranzi ML Grossi P Righini A Rusconi R Santambrogio L Ghio L Successful medical treatment of multiple brain abscesses due to Nocardia farcinica in a paediatric renal transplant recipient Pediatr Nephrol 2005 20 8 1186 1188 10.1007/s00467-005-1978-6 15947983\n20. Brown-Elliott BA Brown JM Conville PS Wallace RJ Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy Clin Microbiol Rev 2006 19 2 259 282 10.1128/CMR.19.2.259-282.2006 16614249\n21. Fellows GA Kalsi PS Martin AJ Nocardia farcinica brain abscess in a patient without immunocompromise Br J Neurosurg 2007 21 3 301 303 10.1080/02688690701365770 17612924\n22. Miksits K Stoltenburg G Neumayer HH Spiegel H Schaal KP Cervós-Navarro J Distler A Stein H Hahn H Disseminated infection of the central nervous system caused by Nocardia farcinica Nephrol Dial Transplant 1991 6 3 209 214 10.1093/ndt/6.3.209 1866050\n23. Delvenne E Farnir F Guiot J Giot JB Von Frenckell C Brain abscesses associated with a systemic infection by Nocardia farcinica Rev Med Liege 2017 72 7–8 340 343 28795545\n24. Lin YJ Yang KY Ho JT Lee TC Wang HC Su FW Nocardial brain abscess J Clin Neurosci 2010 17 2 250 253 10.1016/j.jocn.2009.01.032 20005722\n25. Buelte D Noth J Mull M Sellhaus B Koch A Queider M Hünger F Gobbelé R Different manifestations of the cerebral nocardiosis Nervenarzt 2008 79 12 1432 1435 10.1007/s00115-008-2601-4 19020850\n\n",
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"title": "A case report of brain abscess caused by Nocardia farcinica.",
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"abstract": "Ligands for the proinflammatory C-C chemokine receptor types 2 and 5 (CCR2 and CCR5) are elevated in the eyes of patients with diabetic macular edema (DME). We evaluated the efficacy and safety of PF-04634817, an oral CCR2/5 dual antagonist, versus intravitreal ranibizumab, in adult subjects with DME.\n\n\n\nIn this phase II, randomized, placebo-controlled, double-masked study, eligible subjects (≥18 years of age) had type 1 or 2 diabetes and DME with best-corrected visual acuity (BCVA) of 20/32 or worse (letter score ≤ 78), and up to 20/320 or better (≥24 letter score), in the study eye. Subjects were assigned randomly 1:1 to once-daily (QD) oral PF-04634817 200 mg plus masked sham therapy as placebo or monthly intravitreal ranibizumab 0.3/0.5 mg plus QD oral placebo. The primary objective was to evaluate the efficacy of PF-04634817 compared with ranibizumab in change from baseline in BCVA after 12 weeks in a noninferiority design. Noninferiority was based on BCVA 80% confidence interval (CI): there had to be a less than three letter loss in the PF-04634817 arm compared with the ranibizumab arm.\n\n\n\nA total of 199 subjects were randomized. Least squares mean difference in change in BCVA from baseline to week 12 in the study eye for the PF-04634817 arm was -2.41 letters (80% CI: -3.91, -0.91; P = 0.04) compared with ranibizumab. PF-04634817 was well tolerated.\n\n\n\nTreatment with oral CCR2/5 receptor dual antagonist PF-04634817 was associated with a modest improvement in BCVA, but did not meet the predefined noninferiority criteria compared with intravitreal ranibizumab.",
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"title": "A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema.",
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"abstract": "Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies to coagulation factor VIII (FVIII). AHA onset during the induction of dialysis is extremely rare, and the management of blood access is difficult. We present a case of AHA that developed during induction of dialysis and treatment with double filtration plasmapheresis (DFPP). An 86-year-old man with chronic kidney disease was admitted to our hospital with multiple subcutaneous hemorrhages. Because of his prolonged activated partial thromboplastin time (aPTT) and high titer of inhibitors to FVIII, he was diagnosed with AHA, and prednisolone treatment was started. After 3 weeks of steroid therapy, his renal function deteriorated, and dialysis was needed. We performed femoral catheter placement under administration of recombinant activated factor VII (rFVIIa) to prevent bleeding. The patient developed catheter-related bloodstream infection and needed arteriovenous fistula (AVF) immediately. After 4 DFPP sessions, his hemostasis recovered to normal. AVF placement did not cause any complication, and he could safely undergo maintenance hemodialysis. Clinicians should suspect AHA in end-stage renal disease patients with acute onset of bleeding and an unexplained prolonged aPTT. DFPP is useful in patients with AHA that develops during induction of dialysis and requires surgical treatment.
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"abstract": "Adoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a 'cold' tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.\n\n\n\nWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.\n\n\n\nWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.\n\n\n\nNCT04177021, NCT01957709, and NCT03063632.",
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"authors": "Schroeder|Brett A|BA|0000-0001-6019-2022;Black|Ralph Graeme|RG|;Spadinger|Sydney|S|0000-0002-5160-9794;Zhang|Shihong|S|;Kohli|Karan|K|;Cao|Jianhong|J|;Mantilla|Jose G|JG|;Conrad|Ernest U|EU|;Riddell|Stanley R|SR|;Jones|Robin L|RL|;Yee|Cassian|C|;Pollack|Seth M|SM|0000-0002-2466-0607",
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"doi": "10.1136/jitc-2019-000247",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32269142\njitc-2019-000247\n10.1136/jitc-2019-000247\nCase Report\n1506\nHistiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy\nhttp://orcid.org/0000-0001-6019-2022Schroeder Brett A 12 Black Ralph Graeme 1 http://orcid.org/0000-0002-5160-9794Spadinger Sydney 1 Zhang Shihong 1 Kohli Karan 1 Cao Jianhong 3 Mantilla Jose G 4 Conrad Ernest U 5 Riddell Stanley R 16 Jones Robin L 7 Yee Cassian 8 http://orcid.org/0000-0002-2466-0607Pollack Seth M 16 1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA\n2 Virginia Mason Medical Center, Seattle, Washington, USA\n3 Fred Hutchinson Cancer Research Center, Seattle, Washington, USA\n4 Pathology, University of Washington Medical Center, Seattle, Washington, USA\n5 Orthopedic Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USA\n6 Oncology, University of Washington Medical Center, Seattle, Washington, USA\n7 Sarcoma, Royal Marsden Hospital NHS Trust, London, UK\n8 Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA\nCorrespondence to Dr Seth M Pollack; spollack@fredhutch.org\n2020 \n8 4 2020 \n8 1 e00024702 3 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This 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, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.\n\nCase presentation\nWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.\n\nConclusion\nWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.\n\nTrial registration numbers\nNCT04177021, NCT01957709, and NCT03063632.\n\noncologyimmunotherapy, adoptiveCD8-positive T-lymphocytessarcomaGillman Sarcoma FoundationNIHK23CA175167special-featureunlocked\n==== Body\nBackground\nSynovial sarcoma (SS) is a soft-tissue malignancy with few available treatments, and overall survival is often less than 2 years when metastatic.1 2 However, SS maybe an ideal tumor type for adoptive cellular therapy (ACT), given frequent and homogeneous expression of NY-ESO-1. Importantly, the NY-ESO-1 protein is routinely expressed only in testicular germ cells and in some cancers, but not in healthy adult tissues.3 4 Multiple trials targeting the A*0201 restricted NY-ESO-1 (157–165) epitope have demonstrated greater than 50% responses, with some showing durable and/or reinducible responses at the time of progression.5–7 Unfortunately, in almost all cases, patients who initially respond ultimately progress. We previously reported that SS has an immunologically ‘cold’ tumor microenvironment, with few infiltrating T cells, and low levels of gene expression related to antigen presentation, including constituents of the major histocompatibility complex (MHC).8 However, treatment of patients with SS with systemic interferon gamma (IFN-γ) increased MHC expression and increased T-cell infiltration in matched tumor biopsies in a phase 0 clinical trial.9\n\nHere we describe a pilot study integrating weekly IFN-γ with ACT in the context of high-dose cyclophosphamide (HD Cy)-based lymphodepletion and low-dose IL-2. While the first patient (IFN#1) had an impressive regression of pulmonary tumors, the second patient (IFN#2) developed a fatal histiocytic myocarditis. Although we concluded that this conditioning regimen was not safe moving forward, IFN-γ could still play an important role in future immunotherapy trials; thus, future investigators must be aware of this toxicity.\n\nMethods\nPatients, leukapheresis acquisition and clinical T-cell products\nHLA typing of patient samples was performed at the Puget Sound Blood Center (PSBC). The interventional and pilot studies using either NY-ESO-1-specific T cells or IFN-γ were registered with clinicaltrials.gov.\n\nLeukapheresis was performed at either PSBC or at the University of Washington (UW) General Clinical Research Center if the patient expressed HLA A*0201, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and if tumor biopsies stained positive for NY-ESO-1 in >25% of cells by immunohistochemistry (IHC). Subsequent processing of leukapheresed product was performed at FHCRC, including the cell processing facility (CPF), under current good manufacturing practice (GMP) guidelines. This form of ACT using peripheral blood as a source of antigen-specific T cells is known as endogenous T-cell (ETC) therapy and yields a T-cell product of near uniform specificity with central memory properties.10 ETC has been used in first-in-human studies targeting tumor-associated antigens with evidence of clinical efficacy.11 12\n\nTo facilitate detailed functional analysis, an aliquot of T-cell product was removed from the CPF and then expanded in the research laboratory. In vitro assays were used to assess recognition of target cells pulsed with various peptide concentrations and to assess cytokine production secondary to antigen stimulation. Cell surface phenotype and T cell receptor beta chain variable region (TCR Vβ) sequencing were performed on aliquots from the second expansion.13 Specificity of expanded T-cell products was confirmed using chromium release assays performed on day 12 of the rapid expansion protocol. T2 target cells were cultured alone for 2 hours or in media with target peptide; when relevant, the HLA A*0201+, NY-ESO-1+tumor line, Mel A375 (A375), was also used as target cell.\n\nFlow cytometry and functional analysis of antigen specific T cells\nCell surface phenotype of persisting cells was determined by costaining with NY-ESO-1 tetramer (FHCRC, Seattle, Washington, USA) and fluorochrome-conjugated monoclonal antibodies (mAbs). Multicolor flow cytometry data were collected using a LSRII (Becton Dickinson, Franklin Lakes, New Jersey, USA) and FlowJo software. For staining, cells were fixed and stained for CD8 (BD Bioscience, Franklin Lakes, New Jersey, USA).\n\nTCR Vβ sequencing\nTCR Vβ sequencing and normalization was performed on suspensions of tumor-infiltrating lymphocytes, as well as paraffin-mbedded specimens by Adaptive Biotechnologies (Seattle, Washington, USA). The number of total cells, T cells, T-cell fraction, the number of unique rearrangements, and clonality were calculated for each sample as previously described.14\n\nImmunohistochemistry\nImmunohistochemical analyses of myocardium for CD3, CD4, CD8, CD20, and CD68 expression were performed using an automated immunostainer (Bond III) and the following mAbs: CD3 (clone LN10, dilution 1:100; Novacastra, Newcastle, UK), CD4 (clone SP35, dilution 1:25; Cell Marque, Rocklin, California, USA), CD8 (clone 4B11, dilution 1:200; Novacastra), CD20 (clone L26, dilution 1:800; Dako, Glostrup, Denmark), and CD68 (clone Kp-1, dilution 1:1000; Cell Marque). Tonsils were used as positive controls.\n\nImmunohistochemical expression to confirm eligibility of patients for treatment with NY-ESO-1-specific T cells was performed at the UW Pathology Lab with mAb specific for NY-ESO-1 (1:100, E978 clone; Life Technologies, Grand Island, New York, USA), CD3 (clone LN10, dilution 1:200; Novacastra), and MHC class I (1:8000, EMR8-5 clone; Abcam, Cambridge, Massachusetts, USA).\n\nResults\nTo test whether systemic weekly IFN-γ could be safely combined with ACT using NY-ESO-1-specific T cells, we designed a phase I trial using weekly IFN-γ (100 µg/m2) beginning 2 weeks prior to cell infusion and continuing for 2 weeks after the cell infusion. Lymphodepletion consisted of HD Cy (2 g/m2/day) on days −3 and −2, prior to the T cell infusion (day 0). To augment in vivo proliferation, low-dose IL-2 (250 000 U/m2 every 12 hours) was administered for 2 weeks after the infusion (figure 1).\n\nFigure 1 Trial schema. IFN-γ, interferon gamma.\n\nPatient 1\nIFN#1 was a man in his mid-40s with intractable pain in his left shoulder. He visited a local emergency department, and an investigative chest X-ray showed a hilar mass. Subsequent CT of the chest, abdomen, and pelvis again demonstrated the hilar mass, along with a 2.5×3.6 cm pelvic mass. Biopsy showed diffuse expression of Bcl-2, vimentin, CD99, and neoplastic cells expressing TLE-1, indicative of SS. He received two cycles of doxorubicin and ifosfamide, with disease progression. Next, he received two cycles of trabectedin, again with disease progression (table 1).\n\nTable 1 Tumor and treatment information.\n\nIdentifier\tSarcoma subtype\tPrior treatment\tSites of disease\tCell dose (×109)\tVα gene\tCDR3 α-chain\tVβ gene\tBest tumor response\t\nIncluding IFN-γ and low-dose interleukin-2\t\nIFN#1\tSS\tA/I, trabectedin\tSoft tissue, lung, brain\t22\tTRAV-8*02\tCALSAVALGMCCI\tTRBD1*01\t32% lung\t\nIFN#2\tSS\tA/I/vincristine, Rtx/Ifos\tLung\t12.9\tTRAV21*01\tCAVMGDNDMRF\tTRBV12-3*01\tN/A\t\n*part of dual alpha, only this alpha sequence was productive based on tetramer staining and functional assays.\n\nIFN#2, second patient; IFN-γ, interferon gamma; IFN#1, first patient; Ifos, ifosfamide; N/A, not applicable; Rtx, rituximab; SS, synovial sarcoma.\n\nMultiple brain metastases were identified, and the patient underwent gamma knife radiation. Given that his tumor demonstrated strong homogenous NY-ESO-1 expression and that he was HLA-A0201+, he was enrolled in the ACT trial.\n\nDespite the aggressive metastatic chemoresistant disease, 4 weeks after T-cell infusion, all six lung tumors showed a measurable decrease in size. A hilar lymph node decreased from 3.0×3.0 cm to 1.9×3.0 cm, and the small pleural-based lung nodules also decreased in size. The most dramatic response was in a large right upper lobe (RUL) tumor that previously received 3600 cGy of radiation 3 months prior to ACT. This mass was 10.8×8.1 cm prior to radiation and remained stable at 10.4×8.0 cm 3 months after radiation therapy. However, 4 weeks after T-cell therapy, the tumor decreased markedly in size to 6.9×5.3 cm, and by 10 weeks to 6.9×4.5 cm (figure 2B). Importantly, biopsy of lung lesion pretreatment and forehead lesion post-treatment were stained for NY-ESO-1 and MHC class I. The post-treatment sample showed both increased NY-ESO-1 staining (figure 2D) and increased MHC class I expression (figure 2E). No lung tumors (including subcentimeter nodules) had progressed 4 weeks after T-cell therapy. Subjectively, he reported a marked improvement in fatigue and respiratory status following ACT and even returned to work after missing weeks because of fatigue. He experienced common self-limited toxicities of HD Cy (leukopenia, anemia, malaise, and mild mucositis), IFN-γ and IL-2 (fatigue, malaise, and myalgias), but no unexpected toxicities.\n\nFigure 2 (A) Persistence of transferred T cells as absolute values. Percent tetramer positive derived from peripheral CD8+ T cells. (B) CT scan showing pretreatment and post-treatment lung. (C) Forehead soft tissue mass. (D) Pretreatment lung (left) and post-treatment forehead mass (right) stained for NY-ESO-1. (E) Lung (left) stained for HLA-ABC, forehead mass (right) stained for HLA-ABC.\n\nPrior to T-cell infusion, NY-ESO-1 tet+ T cells were undetectable in the blood (<0.01% of CD8+ cells). Four weeks after infusion, following complete reconstitution of the absolute lymphocyte and white blood cell counts and cyclophosphamide conditioning, NY-ESO-1 tet+ T cells represented 5% of all peripheral CD8+ T cells (figure 2A). At 10 weeks postinfusion, this cell population remained detectable.\n\nDespite the marked response of the pulmonary metastases, the overall response was mixed as a soft tissue lesion on his forehead progressed 10 weeks after ACT (figure 2C). To investigate the lack of response at some tumor sites, his forehead lesion was excised. The pathology demonstrated homogenous staining of NY-ESO-1 by IHC, but few infiltrating T cells were found and the tissue lacked MHC class I expression (data not shown), which was thought to be responsible for the lack of response and may indicate that the impact of IFN-γ in the tumor microenvironment is not durable.\n\nPatient 2\nThe IFN#2 was a man in his mid-40s who first noticed lower back pain. His pain progressed, and a small lump eventually developed. MRI at an outside hospital showed a right flank mass measuring 7.8×8.7×12.9 cm. Subsequent biopsy demonstrated poorly differentiated SS. He underwent six cycles of neoadjuvant doxorubicin with ifosfamide and vincristine, followed by surgical resection. He also received radiation and concurrent ifosfamide for two cycles after the surgical resection. Unfortunately, 2 years later during routine surveillance, lung metastases were discovered in both lungs. After discussing multiple treatment options, the patient elected for ACT.\n\nBefore trial enrollment, his poorly controlled type 2 diabetes was noted with a hemoglobin A1c of 10.1%, complicated by diabetic nephropathy and a baseline serum creatinine of 1.4 mg/dL (1.5 mg/dL was the trial max). Prior to ACT, a cardiac stress echocardiogram was performed and deemed normal. His ECOG performance status was 1.\n\nOn trial initiation, he experienced no symptoms from the single-agent IFN-γ and tolerated Cy well. He had no immediate complications during T-cell infusion. Two days following T-cell infusion, he reported fatigue and was found to have an elevated creatinine of 1.9, attributed to Cy and an underlying renal dysfunction. He received intravenous hydration with normal saline in the outpatient infusion center, and his creatinine returned to baseline. On the evening between days 3 and 4 post-T cell infusion, he developed malaise, a cough with pink-tinged sputum, and a fever to 101°F. CBC performed earlier that day confirmed an appropriate neutrophil count. He took acetaminophen at home and elected not to go to the emergency room, with planned follow-up at the clinic in 1–2 days. On day 4 after T-cell infusion, he suddenly lost consciousness and was found in cardiac arrest. Resuscitation was attempted but was unsuccessful.\n\nAutopsy revealed disease that was more extensive than originally appreciated on CT with innumerable tiny (<0.5 cm) bilateral lung metastases. Autopsy also showed a myocarditis with an immune infiltrate primarily composed of CD68+ cells (figure 3D) and CD3+ cells (figure 3B). Almost no CD4+ or CD8+ cells were detected (data not shown). Since the infusion product was greater than 98% CD8+, his myocarditis was attributed to the conditioning regimen, further complicated by his pre-existing comorbidities. T-cell receptor (TCR) sequencing from myocardial tissue was attempted, but an insufficient number of reads were observed. This was consistent with the IHC that showed only a small fraction of infiltrating T cells, again suggesting that T cell-induced myocardial toxicity was not the cause of death. We also confirmed that the heart tissue did not express NY-ESO-1 and concluded that the addition of IFN-γ to HD Cy and low-dose IL-2 as administered in this regimen was not safe, and this cohort was terminated.\n\nFigure 3 Histological sections of the heart at autopsy demonstrate myocyte necrosis and marked mononuclear inflammation (A, H&E ×200). Immunohistochemical stains highlight a mixed population of inflammatory cells composed of predominantly CD68+ histiocytes (D) and few CD3 +T cells (B). CD20 stain does not demonstrate a significant B-cell population (C).\n\nDiscussion and conclusions\nA variety of treatment modalities including immune checkpoint blockade, tumor-associated macrophage phenotype modulation, chimeric antigen and high-affinity T-cell receptors, along with vaccine therapies, are all under investigation for sarcomas.15 ACT targeting NY-ESO-1 is a promising treatment for SS.5–7 NY-ESO-1 has also been safely targeted using vaccines with potential clinical benefit in sarcoma.16 17 However, SS has a cold tumor immune microenvironment illustrated by low levels of MHC expression and few T-cell infiltrates, which could impede meaningful responses. We previously showed that both MHC expression and T-cell infiltration can be increased using systemic IFN-γ and thus could improve the efficacy of ACT for SS.18 IFN-γ likely also increases programmed death-ligand 1 (PD-L1) expression in SS tumors, and attempts to combine IFN-γ with programmed cell death protein 1 (PD-1) inhibition are ongoing. However, our results show that novel combinations of immunotherapeutic regimens must be explored cautiously, even when using treatments with well-established safety profiles.\n\nIn the original studies of Cy, cardiotoxicity was the dose-limiting toxicity, but this is unusual with routine doses of 2 g/m2/day×2 days used in ACT trials.19 20 Cy-related myocarditis is thought to arise from direct damage to the myocardium and vessels, resulting in edema, hemorrhage and the formation of microthrombi.21–23 Hemorrhage and microthrombi were not observed in this case. Instead, a profound infiltrate of CD68+ histiocytes was discovered. While IFN-γ is Food and Drug Administration approved and has been used safely in the treatment of thousands of patients, IFN-γ can activate macrophages and lead to cardiac trafficking in murine models.24 25 It may be possible that a subclinical Cy-related myocarditis was made clinically relevant through IFN-γ-induced macrophage stimulation.\n\nAlthough we conclude that IFN-γ should not be used concurrently with HD Cy or low-dose IL-2, IFN-γ may still play an important role in sensitizing SS for ACT. Interestingly, another recent ACT study showed the combination of interferon alpha and tumor-infiltrating lymphocyte (TIL) therapy, including Cy pretreatment in a similar dose, reinfusion of TILs, and postinfusion of IL-2 in a higher dose, was found to be safe in 12 patients in a published article by Andersen et al.26 However, future studies should avoid using IFN-γ during the immediate period around cell infusion and instead should consider alternative schedules, such as beginning IFN-γ weeks after cell infusion or at the time of progression.\n\nTwitter: @tcellsrus, @immunosarc\n\nContributors: BAS compiled and analyzed clinical data and helped prepare the manuscript. RGB, SS, SZ, KK, and JC performed experiments. JGM performed pathology. EUC, RLJ and SMP cared for the patient. SMP developed the novel trial. CY and SRR provided leadership and contributed to the preparation of the manuscript.\n\nFunding: This work was supported by the Gilman Sarcoma Foundation as well as K23CA175167.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Not required.\n\nEthics approval: Patients were enrolled on protocols approved by the Fred Hutchinson Cancer Research Center Institutional Review Board for either clinical trials or tissue and blood procurement, and provided informed consent in accordance with the Declaration of Helsinki.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Riedel RF , Jones RL , Italiano A , et al \nSystemic anti-cancer therapy in synovial sarcoma: a systematic review\n. Cancers \n2018 ;10 . 10.3390/cancers10110417 . [Epub ahead of print: 01 Nov 2018].\n2 Moreau L-C , Turcotte R , Ferguson P , et al \nMyxoid\\round cell liposarcoma (MRCLS) revisited: an analysis of 418 primarily managed cases\n. Ann Surg Oncol \n2012 ;19 :1081 –8\n.10.1245/s10434-011-2127-z 22052112 \n3 Jungbluth AA , Antonescu CR , Busam KJ , et al \nMonophasic and biphasic synovial sarcomas abundantly express cancer/testis antigen NY-ESO-1 but not MAGE-A1 or CT7\n. Int J Cancer \n2001 ;94 :252 –6\n.10.1002/ijc.1451 11668506 \n4 Pollack SM , Jungbluth AA , Hoch BL , et al \nNy-Eso-1 is a ubiquitous immunotherapeutic target antigen for patients with myxoid/round cell liposarcoma\n. Cancer \n2012 ;118 :4564 –70\n.10.1002/cncr.27446 22359263 \n5 Robbins PF , Morgan RA , Feldman SA , et al \nTumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1\n. J Clin Oncol \n2011 ;29 :917 –24\n.10.1200/JCO.2010.32.2537 21282551 \n6 Robbins PF , Kassim SH , Tran TLN , et al \nA pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response\n. Clin Cancer Res \n2015 ;21 :1019 –27\n.10.1158/1078-0432.CCR-14-2708 25538264 \n7 D'Angelo SP , Melchiori L , Merchant MS , et al \nAntitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma\n. Cancer Discov \n2018 ;8 :944 –57\n.10.1158/2159-8290.CD-17-1417 29891538 \n8 Pollack SM , He Q , Yearley JH , et al \nT-Cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas\n. Cancer \n2017 ;123 :3291 –304\n.10.1002/cncr.30726 28463396 \n9 Zhang S , Kohli K , Black RG , et al \nSystemic interferon-γ increases MHC class I expression and T-cell infiltration in cold tumors: results of a phase 0 clinical trial\n. Cancer Immunol Res \n2019 ;7 :1237 –43\n.10.1158/2326-6066.CIR-18-0940 31171504 \n10 Li Y , Bleakley M , Yee C \nIl-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response\n. J Immunol \n2005 ;175 :2261 –9\n.10.4049/jimmunol.175.4.2261 16081794 \n11 Chapuis AG , Roberts IM , Thompson JA , et al \nT-Cell therapy using Interleukin-21-Primed cytotoxic T-cell lymphocytes combined with cytotoxic T-cell lymphocyte antigen-4 blockade results in long-term cell persistence and durable tumor regression\n. J Clin Oncol \n2016 ;34 :3787 –95\n.10.1200/JCO.2015.65.5142 27269940 \n12 Yee C , Lizee G , Schueneman AJ \nEndogenous T-cell therapy: clinical experience\n. Cancer J \n2015 ;21 :492 –500\n.10.1097/PPO.0000000000000158 26588682 \n13 Pollack SM , Jones RL , Farrar EA , et al \nTetramer guided, cell sorter assisted production of clinical grade autologous NY-ESO-1 specific CD8(+) T cells\n. J Immunother Cancer \n2014 ;2 :36 .10.1186/s40425-014-0036-y 25317334 \n14 Robins HS , Srivastava SK , Campregher PV , et al \nOverlap and effective size of the human CD8+ T cell receptor repertoire\n. Sci Transl Med \n2010 ; :;2 :ra64. 2 .10.1126/scitranslmed.3001442 \n15 Pollack SM , Ingham M , Spraker MB , et al \nEmerging targeted and immune-based therapies in sarcoma\n. J Clin Oncol \n2018 ;36 :125 –35\n.10.1200/JCO.2017.75.1610 29220291 \n16 Pollack SM , Lu H , Gnjatic S , et al \nFirst-In-Human treatment with a dendritic Cell-targeting lentiviral Vector-expressing NY-ESO-1, LV305, induces deep, durable response in refractory metastatic synovial sarcoma patient\n. J Immunother \n2017 ;40 :1 –306\n.10.1097/CJI.0000000000000183 27828929 \n17 Somaiah N , Block MS , Kim JW , et al \nFirst-In-Class, first-in-human study evaluating LV305, a dendritic-cell tropic lentiviral vector, in sarcoma and other solid tumors expressing NY-ESO-1\n. Clin Cancer Res \n2019 ;25 :5808 –17\n.10.1158/1078-0432.CCR-19-1025 31227504 \n18 Zhang S , Kohli K , Black G , et al \nSystemic interferon gamma increases MCH class one expression and T-cell infiltration in cold tumors: results of a phase 0 clinical trial\n. Cancer Immunol Res \n2019 ;8 :1237 –43\n.\n19 Goldberg MA , Antin JH , Guinan EC , et al \nCyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor\n. Blood \n1986 ;68 :1114 –8\n.10.1182/blood.V68.5.1114.1114 3533179 \n20 Higgins AY , O'Halloran TD , Chang JD \nChemotherapy-Induced cardiomyopathy\n. Heart Fail Rev \n2015 ;20 :721 –30\n.10.1007/s10741-015-9502-y 26338137 \n21 Appelbaum F , Strauchen JA , Graw RG , et al \nAcute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity\n. Lancet \n1976 ;1 :58 –62\n.10.1016/s0140-6736(76)90151-3 54581 \n22 Katayama M , Imai Y , Hashimoto H , et al \nFulminant fatal cardiotoxicity following cyclophosphamide therapy\n. J Cardiol \n2009 ;54 :330 –4\n.10.1016/j.jjcc.2009.01.006 19782276 \n23 Shanholtz C \nAcute life-threatening toxicity of cancer treatment\n. Crit Care Clin \n2001 ;17 :483 –502\n.10.1016/S0749-0704(05)70196-2 11529252 \n24 Reifenberg K , Lehr H-A , Torzewski M , et al \nInterferon-Gamma induces chronic active myocarditis and cardiomyopathy in transgenic mice\n. Am J Pathol \n2007 ;171 :463 –72\n.10.2353/ajpath.2007.060906 17556594 \n25 Torzewski M , Wenzel P , Kleinert H , et al \nChronic inflammatory cardiomyopathy of interferon γ-overexpressing transgenic mice is mediated by tumor necrosis factor-α\n. Am J Pathol \n2012 ;180 :73 –81\n.10.1016/j.ajpath.2011.09.006 22051774 \n26 Andersen R , Borch TH , Draghi A , et al \nT cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression\n. Ann Oncol \n2018 ;29 :1575 –81\n.10.1093/annonc/mdy139 29688262\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "CD8-positive T-lymphocytes; immunotherapy, adoptive; oncology; sarcoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D017321:Clinical Trials, Phase I as Topic; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D006644:Histiocytes; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma; D008212:Lymphocyte Depletion; D008297:Male; D009205:Myocarditis; D011379:Prognosis; D013584:Sarcoma, Synovial",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32269142",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "3533179;11668506;31227504;29220291;25317334;26338137;17556594;29688262;22051774;19782276;27269940;11529252;21282551;54581;25538264;22359263;16081794;31171504;29891538;28891906;28463396;22052112;30388821;20811043;26588682",
"title": "Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy.",
"title_normalized": "histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide based lymphodepletion for adoptive cellular therapy"
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-02054",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"abstract": "OBJECTIVE\nTo compare the use of metformin with that of insulin for the treatment of gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) unresponsive to diet therapy.\n\n\nMETHODS\nIn this prospective observational study, maternal glycemic control and perinatal outcome in diabetic pregnancies were compared between 2 obstetric units, one using insulin therapy and the other using metformin therapy. Baseline pretreatment glycemic profile was done and then repeated weekly throughout pregnancy. The outcome measures studied were glycemic control, maternal complications and perinatal outcome.\n\n\nRESULTS\nSixty women with gestational and type 2 diabetes were enrolled, 30 each for metformin and insulin. Both groups were comparable with respect to age, body mass index (BMI), parity and pretreatment plasma glucose levels. Glycemic control was better with metformin after 1 week of therapy and also throughout gestation (P = 0.03-0.007). There were no major complications or perinatal deaths in this study. Mean gestational age and birth weight (2.9 +/- 0.4 kg versus 3.1 +/- 0.4 kg, P = 0.30) were comparable. However, there was a significant increase in neonatal intensive care unit (NICU) admission and stay for babies born in the insulin group. The cost of treatment was tenfold higher in thethe insulin group.\n\n\nCONCLUSIONS\nMetformin is clinically effective, cheap and a safe alternative to insulin therapy in pregnant diabetic women.",
"affiliations": "Department of Obstetrics and Gynecology, Kasturba Medical College Hospital, Manipal, Karnataka, India. railavanya@yahoo.com",
"authors": "Rai|Lavanya|L|;Meenakshi|D|D|;Kamath|Asha|A|",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin",
"country": "India",
"delete": false,
"doi": "10.4103/0019-5359.58878",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-5359",
"issue": "63(11)",
"journal": "Indian journal of medical sciences",
"keywords": null,
"medline_ta": "Indian J Med Sci",
"mesh_terms": "D000704:Analysis of Variance; D001786:Blood Glucose; D015992:Body Mass Index; D016001:Confidence Intervals; D003924:Diabetes Mellitus, Type 2; D016640:Diabetes, Gestational; D005260:Female; D038321:Glycemic Index; D006801:Humans; D007004:Hypoglycemic Agents; D007194:India; D007328:Insulin; D007333:Insulin Resistance; D007363:Intensive Care Units, Neonatal; D007902:Length of Stay; D008687:Metformin; D011247:Pregnancy; D011446:Prospective Studies",
"nlm_unique_id": "0373023",
"other_id": null,
"pages": "491-7",
"pmc": null,
"pmid": "20075550",
"pubdate": "2009-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Metformin--a convenient alternative to insulin for Indian women with diabetes in pregnancy.",
"title_normalized": "metformin a convenient alternative to insulin for indian women with diabetes in pregnancy"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-IN-ALKEM-2018-05313",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
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... |
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"abstract": "BACKGROUND\nDisseminated herpes zoster infection occurs mostly in immunocompromised hosts. There have been recent reports of disseminated zoster with chemotherapeutic regimens and newer monoclonal antibodies.\n\n\nMETHODS\nThe present case describes a 61-year-old patient presenting with disseminated herpes zoster after initiation of benralizumab, an anti-IL-5 monoclonal antibody for severe persistent asthma. His initial vesicular lesions limited to left lumbar dermatomes progressed extensively resulting in dissemination on his body. The diagnosis was confirmed with PCR and he had remarkable clinical improvement with acyclovir and supportive medical management.\n\n\nCONCLUSIONS\nClinical trials have reported an association of mepolizumab, another anti-IL-5 monoclonal antibody with herpes zoster. This report of herpes zoster following initiation of benralizumab might suggest a possibility of a class effect of anti-IL-5 monoclonal antibody.",
"affiliations": "Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts.;Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts.;Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts.",
"authors": "Mishra|Ajay Kumar|AK|https://orcid.org/0000-0003-4862-5053;Sahu|Kamal Kant|KK|https://orcid.org/0000-0002-0382-6882;James|Atem|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C571386:benralizumab; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1111/crj.12998",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-6981",
"issue": "13(3)",
"journal": "The clinical respiratory journal",
"keywords": "disseminated; immunotherapy; zoster",
"medline_ta": "Clin Respir J",
"mesh_terms": "D000212:Acyclovir; D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "101315570",
"other_id": null,
"pages": "189-191",
"pmc": null,
"pmid": "30666793",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated herpes zoster following treatment with benralizumab.",
"title_normalized": "disseminated herpes zoster following treatment with benralizumab"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-014328",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "ALBUTEROL"
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{
"abstract": "C. striatum is an innocuous inhabitant of the normal human epithelial and mucosal surfaces. The C. striatum ´s thogenic potential is increasingly recognized in our time.\nWe present a rare case of CRBSI by C. striatum in a 57-yr-old male patient. The patient suffered from many basic diseases and was admitted to hospital of shock.\nThe patient finally died of septic shock caused by CRBSI due to multidrug-resistant C. striatum which responded neither to empiric nor to targeted treatment.\nC. striatum can cause CRBSI in immunocompromised patients when they were treated by intravenous catheters.",
"affiliations": "Nanjing Tongren Hospital Affiliated to Medical School of Southeast University, Nanjing 211102, China.;Nanjing Tongren Hospital Affiliated to Medical School of Southeast University, Nanjing 211102, China.;Nanjing Tongren Hospital Affiliated to Medical School of Southeast University, Nanjing 211102, China.;Nanjing Tongren Hospital Affiliated to Medical School of Southeast University, Nanjing 211102, China.;Nanjing Tongren Hospital Affiliated to Medical School of Southeast University, Nanjing 211102, China.",
"authors": "Ge|Yanmei|Y|;Lu|Jingchuan|J|;Feng|Shaozun|S|;Ji|Wenli|W|;Tong|Huacheng|H|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00987",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30295-X\n10.1016/j.idcr.2020.e00987\ne00987\nCase Report\nA case of catheter related bloodstream infection by Corynebacterium striatum\nGe Yanmei geym2@njtrh.org Lu Jingchuan lujc@njtrh.org Feng Shaozun fengsz@njtrh.org Ji Wenli jiwl@njtrh.org Tong Huacheng tonghc@njtrh.org⁎ Nanjing Tongren Hospital Affiliated to Medical School of Southeast University, Nanjing 211102, China\n⁎ Corresponding author. tonghc@njtrh.org\n27 10 2020 \n2020 \n27 10 2020 \n22 e0098712 9 2020 9 10 2020 10 10 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nC. striatum is an innocuous inhabitant of the normal human epithelial and mucosal surfaces. The C. striatum´s thogenic potential is increasingly recognized in our time.\n\nMethods\nWe present a rare case of CRBSI by C. striatum in a 57-yr-old male patient. The patient suffered from many basic diseases and was admitted to hospital of shock.\n\nResults\nThe patient finally died of septic shock caused by CRBSI due to multidrug-resistant C. striatum which responded neither to empiric nor to targeted treatment.\n\nConclusions\nC. striatum can cause CRBSI in immunocompromised patients when they were treated by intravenous catheters.\n\nKeywords\nC. striatumCRBSICVC\n==== Body\nBackground\nCorynebacteria are gram-positive and non-spore forming, usually aerobic or facultatively anaerobic rods [1]. They are commensal organisms of skin and mucosal and traditionally regarded as avirulent members. Like other Corynebacterium species, C. striatum is an innocuous inhabitant of the normal human epithelial and mucosal surfaces. However, the C. striatum´s thogenic potential is recognized and it has been increasingly associated with severe infections in hosts. For example, it has been reported that C. striatum infection outbreaks in long-stay patients with underlying disease in 2007 [2] and 281 cases of prosthetic device-related Corynebacterium infection, including central venous catheters (CVCs) in 2014 [3]. Here, we report a case of catheter related bloodstream infection (CRBSI) by C. striatum in China.\n\nPatient and methods\nA 57-yr-old man presented to the Emergency Department complaining of chest tightness, shortness of breath and difficulty breathing without obvious causes. He was admitted to our hospital of shock in intensive care unit (ICU). He had history of chronic renal impairment (CKD5), lung infection, pleural effusion, cerebral infarction, hypertension, type 2 diabetes, heart failure and other basic diseases. He had been on hemodialysis. Cultures from sputum and pleural fluid yielded no isolates, so there was no etiological basis for his lung infection this time and empiric antimicrobial treatment with piperacillin-tazobactam was given only.\n\nThe main clinical findings of this patient were as follows: temperature (35.6℃), heart rate (48 heats per minute), blood pressure (103/51 mmHg) and breathe (68 breaths per minute). Initial complete blood count revealed (Table 1): WBC count, 11.7 × 109/L (3.5−9.5 × 109/L, 83.76 % segmented neutrophils); hemoglobin, 65 g/L (130−175 g/L); and platelet count, 144 × 109/L (125−350 × 109/L). C-reactive protein (CRP) level was 110.73 mg/L (0−4 mg/L), creatinine level was 598 μmol/L (57−97 μmol/L), procalcitonin level was 1.07 ng/mL (<0.5 ng/mL) and glucose was 6.2 mmol/L (3.9−6.1 mmol/L). His lymphocyte count remained below normal after admission and the indicator helped explain his weakened immunity. A CVC was inserted into his femoral vein to open deep vein access and use of blood pressure drugs. After 48 h, a subclavian access was opened to replace femoral access, and this situation had been remained. Continuous renal replacement therapy (CRRT) treatment was given after his admission and right internal jugular vein catheterization to maintain hemodialysis.Table 1 Patient´s main findings of parameter in blood of hospitalization.\n\nTable 1Parameter in blood(units)\tReference range\tDay 1 morning ICU admission\tDay 1 afternoon\tDay 2 morning\tDay 2 afternoon\tDay 3 morning\tDay 4 morning\tDay 4 afternoon\tDay 6 morning Nephrology admission\tDay 8 morning\tDay 10 morning\tDay 10 afternoon\tDay 11 morning\tDay 12 morning\tDay 13 morning\tDay 14 morning ICU admission\tDay 14 afternoon\tDay 15 morning\t\nWBCs(109/L)\t3.5−9.5\t11.7\t8.3\t6.1\t5.8\t4.9\t4\t4.8\t5.3\t6\t1.3\t1.2\t2.1\t2.3\t1.4\t5.2\t2.8\t5.5\t\nNeus(109/L)\t1.8−6.3\t9.8\t6.9\t5.3\t5.1\t4.1\t3.1\t4\t4.5\t5.1\t0.5\t0.4\t1.4\t1.5\t0.9\t4.4\t1.6\t4.5\t\nLyms(109/L)\t1.1−3.2\t1\t1\t0.5\t0.3\t0.4\t0.4\t0.2\t0.5\t0.5\t0.5\t0.6\t0.4\t0.5\t0.5\t0.8\t0.8\t0.9\t\nPlts(109/L)\t125−350\t144\t89\t70\t76\t56\t60\t34\t28\t24\t16\t18\t15\t34\t15\t27\t14\t28\t\nCRP(mg/L)\t0−4\t110.73\t\t129.86\t\t141.68\t159.73\t\t147.36\t112.17\t210.22\t149.82\t230.13\t185.5\t132.85\t113.49\t\t127.7\t\nPCT(ng/mL)\t< 0.5\t1.07\t\t\t\t\t\t\t2.46\t\t2.39\t\t3.07\t2.81\t2.67\t3.06\t\t4.14\t\nCRE(μmol/L)\t57−97\t595\t515\t435\t471\t484\t549\t444\t551\t552\t636\t\t717\t628\t690\t628\t478\t451\t\nBUN(mmol/L)\t3.1−8\t37.8\t38.3\t29.7\t31.2\t32.1\t32\t25\t26.5\t27.2\t32\t\t38.6\t37.7\t42.3\t37.7\t31.2\t28.9\t\nCK-MB(U/L)\t< 25\t76\t102\t67\t31\t21\t16\t14\t11\t8\t8\t\t19\t6\t7\t14\t25\t38\t\nTNT(ng/L)\t0−14\t2581\t\t3410\t\t3752\t3404\t\t2760\t1645\t1563\t\t1417\t931\t915\t1036\t635\t1284\t\nALT(U/L)\t9−50\t624\t1186\t1506\t1188\t992\t333\t552\t335\t167\t96\t\t75\t11\t49\t48\t196\t265\t\nAST(U/L)\t15−40\t1322\t2803\t3121\t1796\t989\t104\t222\t67\t25\t17\t\t21\t56\t11\t45\t799\t1049\t\nLDH(U/L)\t120−250\t1988\t2218\t2452\t1240\t686\t348\t309\t256\t245\t221\t\t285\t190\t204\t273\t867\t910\t\nGLU(mmol/L)\t3.9−6.1\t4.4\t5.8\t4.1\t5.8\t7.1\t9.7\t8.8\t8.1\t9.9\t11.4\t\t15.7\t19.1\t18\t10.7\t5\t10.7\t\nWBC: white bloodcells, Neu: neutrophils, Lym: lymphocytes, Plt: platelets, CRP: C-reactive protein, PCT: procalcitonin, CRE: creatinine, BUN: blood urea nitrogen, CK-MB: creatine kinase-MB, TNT: troponin t, ALT: alanine aminotransferase, AST: aspartate aminotransferase, LDH: lactate dehydrogenase, GLU: glucose, ICU: intensive care unit.\n\n\n\nThe patient´s WBC count decreased to 6.1 × 109/L and neutrophil count was 5.3 × 109/L on day 2. But his blood sugar control was not very good from day 4. His condition had eased in the next few days and transferred to nephrology from ICU on day 6. Continuous of empiric antimicrobial treatment with piperacillin-tazobactamas and other symptomatic treatment measures during this time.\n\nResults\nOn the 10th day, the patient´s condition suddenly deteriorated. His temperature and CRP level increased to 38.9℃and 210.22 mg/L, respectively. The WBC count decreased to 1.3 × 109/L, neutrophil count was 0.5 × 109/L and glucose was 11.4 mmol/L (Table 1). Since the symptoms of infection worsen, empiric antimicrobial treatment with a combination of piperacillin-tazobactam and moxifloxacin. Cultures from sputum and pleural fluid still had no isolates. Two aerobic and two anaerobic blood culture sets were incubated in the automatic blood culture system (BACTEC 9120, Becton, Dickinson and Company, US). Simultaneously, the catheter tip was collected to culture and it had bacterial growing after 24-hr. Bacterial growth after 18-hr was noted in aerobic culture bottles and after 50-hr was noted in anaerobic culture bottles. Blood and catheter tip cultures yielded Corynebacterium spp. The pathogen was gram-positive diphtheroid type rod and was identified as C. striatum by VITEK 2 (bioMérieux, Marcy I´Etoile, France) bacteria identification system (98 % probability,excellent identification). Meanwhile, the VITEK MS (bioMérieux, Marcy I´Etoile, France) system was used to confirm the pathogen (confidence coefficient: 99.9 %). The 16S rRNA genes of the isolates were sequenced to obtain more reliable phenotypic data and species identification. All sequences were analyzed by BLAST (basic local alignment search tool) and ribosomal database project. The sequence showed 99 % similarity to that of C. striatum. Minimal inhibitory concentration (MIC) was determined by using broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) guidelines [4]. The pathogen was susceptible to vancomycin (MIC 0.5 μg/mL) and resistant to penicillin (>32 μg/mL), ciprofloxacin (>32 μg/mL), clindamycin (>256 μg/mL), and erythromycin (>8 μg/mL) (Table 2). While waiting for the microbiological results, the patient´s clinical status and laboratory values continued to deteriorate (Table 1). On day 14, the patient was transferred to ICU again due to septic shock. Treatment was switched to vancomycin, but his symptoms had not improved and died one day later. Lactate level were elevated and remained high when he was in the ICU (Fig. 1). The patient was in a state of persistent acidosis. No other pathogens were isolated from the patient during his hospitalization.Table 2 Antimicrobial susceptibility results of C. striatum.\n\nTable 2Antimicrobials(μg/mL)\tS\tI\tR\tMIC\tResult\t\nPenicillin\t≤1\t2\t≥4\t>32\tR\t\nErythromycin\t≤0.5\t1\t≥2\t8\tR\t\nClindamycin\t0.5\t1∼2\t4\t>256\tR\t\nMoxifloxacin\t–\t–\t–\t16\t–\t\nCiprofloxacin\t≤1\t2\t≥4\t>32\tR\t\nLevofloxacin\t–\t–\t–\t>32\t–\t\nClarithromycin\t–\t–\t–\t12\t–\t\nVancomycin\t≤2\t–\t–\t0.5\tS\t\nS: susceptible, I: intermediate, R: resistant, MIC: minimal inhibitory concentration.\n\nFig. 1 Changes of the patient´s lactate level in blood of hospitalization when he was ICU.\n\nFig. 1\n\nDiscussion\nC. striatum is a non-spore Gram-positive coryneform bacteria, which is considered to be a parasitic bacteria on the skin or mucous membrane surface [5,6]. There have been more researches on infections caused by C. striatum. C. striatum isolates have been included among the etiologic agents of bacteremia [7], such as endocarditis [8], septic arthritis [6], with or without CVC in place [9,10] and other invasive disease.\n\nCVC is a life pathway for effective treatment of critically ill patients in clinical departments such as emergency department and ICU. With the widespread use of CVC, catheter-related infections have also increased and CRBSI is the most common serious infection. There are many pathogenic bacteria which cause CRBSI, such as Staphylococcus aureus, Escherichia coil and Candida albicans, etc [[11], [12], [13]]. However, CRBSI caused by C. striatum is relatively rare.\n\nIn our case, the patient was diagnosed with various underlying diseases when he was admitted to hospital. Deep venous catheters and hemodialysis catheters needed to be reserved for treatment needs. The patient´s condition was relatively stable within a week of admission. After the 10th day, he had fever, lower WBCs and elevated CRP levels. There was no bacterial growth in sputum and pleural fluid culture, but same species C. striatumwas isolated from CVC tip and peripheral venous blood. Three identification systems were used to identify the pathogen as C. striatum. Combined with clinical symptoms and other laboratory values, we considered the patient as CRBSI caused by C. striatum. According to the drug sensitivity results, C. striatum was only sensitive to vancomycin and resistant to penicillin, ciprofloxacin, clindamycin and erythromycin. It was a multidrug-resistant strain, so the empiric antimicrobial treatment didn´t have a good effect. Then, he finally died of septic shock caused by CRBSI due to multidrug-resistant C. striatum which responded neither to empiric nor to targeted treatment.\n\nRetrospective analysis found that the patient had many underlying diseases and lower immunity. During the whole treatment, his lymphocyte count had been below normal and his blood sugar was not well controlled. This may be another important factor causing his bloodstream infection. Due to restrictions on antibiotic use in China, most empirical antibacterial treatment only targets common bacterial infections. Vancomycin is used to treat serious infections for which other antibiotics are ineffective and should be used according to the results of culture and drug sensitivity. So, the patient received vancomycin until Day 14 according to the drug sensitivity results. This is also an important factor in our report of this case. We hope that through the patient’s condition, clinicians could pay attention to infections caused by rare bacteria such as C. striatum and use effective antibiotics as early as possible for treatment.\n\nConclusions\nCRBSI is a common serious infection of CVC, but caused by C. striatum is relatively rare. The culture of C. striatum from peripheral venous blood is an effective method for clinical diagnosis. Therefore, we should pay attention to the following points in the process of clinical diagnosis and treatment. First, the standardized operation of catheterization and nursing of CVC should be improved to prevent the occurrence of CRBSI. Secondly, close collaboration between the laboratory and clinicians is essential to establish a correct diagnosis. Meantime, empirical antibacterial treatment should be performed and then antibiotics should be adjusted according to the results of culture and drug sensitivity. The most important thing is to avoid the outbreak of C. striatum infection in the hospital.\n\nFunding\nNo funding was obtained for this study.\n\nEthical approval\nThe report was approved by the Ethics Committee of Nanjing Tongren Hospital Affiliated to Medical School of Southeast University.\n\nInformed consent\nRetrospective research, informed consent not needed.\n\nAuthors contribution\nJCL and SZF carried out the case collection, WLJ carried out laboratory detection. YMG and HCT drafted and revised the manuscript. All authors read and approved the final manuscript.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n\nAcknowledgments\nWe would like to thank Nanjing Tongren Hospital Affiliated to Medical School of Southeast University for providing the case and Jiangsu Provincial Hospital for laboratory detection by VITEK MS system.\n==== Refs\nReferences\n1 Funke G. von Graevenitz A. Clarridge J.E. 3rd Bernard K.A. Clinical mi_crobiology of coryneform bacteria Clin Microbiol Rev 10 1 1997 125 159 8993861 \n2 Renom F. Garau M. Rubí M. Ramis F. Galmés A. Soriano J.B. Nosocomi_al outbreak of Corynebacterium striatum infection in patients with chron_ic obstructive pulmonary disease J Clin Microbiol 45 6 2007 2064 2067 17409213 \n3 Reece R.M. Cunha C.B. Rich J.D. Corynebacterium minutissimum vascu_lar graft infection: case report and review of 281 cases of prosthetic de_vice-related Corynebacterium infection Scand J Infect Dis 46 9 2014 609 616 24934988 \n4 Clinical and Laboratory Standards Institute Methods for antimicrobial dilution and disk susceptibility testing of infrequently isolated or fastidi_ous bacteria; approved guideline-second edition, M45-A2 2010 Clinical and Laboratory Standards Institute Wayne, PA \n5 Chandran R. Puthukkichal D.R. Suman E. Mangalore S.K. Diphtheroids-important nosocomial pathogens J Clin Diagn Res 10 12 2016 DC28 DC31 \n6 Molina Collada J. Rico Nieto A. Díaz de Bustamante Ussia M. etc. Septicarthritis in a native knee due to Corynebacterium striatum Reumatol Clin 17 2017 30033 30035 \n7 Juliana N.R. Cassius S. Yuri V.F. Bloodstream and catheter-related infections due to different clones of multidrugresistant and biofilm producer Corynebacterium striatum BMC Infect Dis 19 2019 672 31357945 \n8 Sebastien Hascoet Lucia Infectiveendocarditis risk after percutaneous pulmonary valve implantation with themelody and sapien valves JACC Cardiovasc Interv 10 2017 510 517 28279319 \n9 Yoo G. Kim J. Uh Y. Lee H.G. Multidrug-resistantCorynebacterium striatum bacteremia: first case in Korea Ann LabMed 35 2015 472 473 \n10 Daisuke U. Oishi T. Yamane K. Corynebacterium striatumbacteremia associated with a catheter-related blood stream infection CaseRep Infect Dis 2017 2017 1 3 10.1155/2017/2682149 \n11 Cases A. Esforzado N. Lario S. Increased plasma adrenomedullin levels in hemodialysis patients with sustained hypotension Kidney Int 57 2 2000 664 670 10652045 \n12 Tanriover B. Carlton D. Saddekni S. Bacteremia associated with tunneled dialysis catheters: comparison of two treatment strategies Kidney Int 57 5 2000 2151 2155 10792637 \n13 Al-Solaiman Y. Estrada E. Allon M. The spectrum of infections in catheter-dependent hemodialysis patients Clin J Am Soc Nephrol 6 9 2011 2247 2252 21737847\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "22()",
"journal": "IDCases",
"keywords": "C. striatum; CRBSI; CVC",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00987",
"pmc": null,
"pmid": "33194547",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "24934988;28279319;17409213;10792637;21737847;10652045;26131424;28197349;28208859;8993861;31357945",
"title": "A case of catheter related bloodstream infection by Corynebacterium striatum.",
"title_normalized": "a case of catheter related bloodstream infection by corynebacterium striatum"
} | [
{
"companynumb": "CN-PFIZER INC-2021703268",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "A case of valproic acid poisoning with coma and neurological sequelae is presented. The course of the intoxication was severe with affection of the brain, heart and liver. The patient remained in coma for thirteen days. After this he recovered slowly although reduction in vision still persisted after two months. The toxicity of valproate is discussed.",
"affiliations": null,
"authors": "Bigler|D|D|",
"chemical_list": "D014635:Valproic Acid",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1600-0404.1985.tb00884.x",
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"fulltext_license": null,
"issn_linking": "0001-6314",
"issue": "72(3)",
"journal": "Acta neurologica Scandinavica",
"keywords": null,
"medline_ta": "Acta Neurol Scand",
"mesh_terms": "D000328:Adult; D002493:Central Nervous System Diseases; D003128:Coma; D006801:Humans; D008297:Male; D014635:Valproic Acid",
"nlm_unique_id": "0370336",
"other_id": null,
"pages": "351-2",
"pmc": null,
"pmid": "3933275",
"pubdate": "1985-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neurological sequelae after intoxication with sodium valproate.",
"title_normalized": "neurological sequelae after intoxication with sodium valproate"
} | [
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"companynumb": "DK-MYLANLABS-2018M1020612",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.",
"affiliations": "Psychiatric Hospital of the University of Basel, Wilhelm Klein-Strasse 27, 4012, Basel, Switzerland.",
"authors": "Grötsch|Philipp|P|;Lange|Claudia|C|;Wiesbeck|Gerhard A|GA|;Lang|Undine|U|",
"chemical_list": "D018492:Dopamine Antagonists; D005475:Flupenthixol",
"country": "United States",
"delete": false,
"doi": "10.1007/s10899-013-9433-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1050-5350",
"issue": "31(1)",
"journal": "Journal of gambling studies",
"keywords": null,
"medline_ta": "J Gambl Stud",
"mesh_terms": "D000328:Adult; D016739:Behavior, Addictive; D003865:Depressive Disorder, Major; D018492:Dopamine Antagonists; D005475:Flupenthixol; D005715:Gambling; D006801:Humans; D008297:Male; D013313:Stress Disorders, Post-Traumatic",
"nlm_unique_id": "9425991",
"other_id": null,
"pages": "295-7",
"pmc": null,
"pmid": "24356928",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16055768;21804151;22495606;18583430;11729018;17203013;10945141;21853233",
"title": "Pathological gambling induced by dopamine antagonists: a case report.",
"title_normalized": "pathological gambling induced by dopamine antagonists a case report"
} | [
{
"companynumb": "PHHY2015CH106341",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUPENTIXOL"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nTo describe a case of retinal toxicity after intravenous administration of the bisphosphonate medication zoledronic acid.\n\n\nMETHODS\nA 61-year-old woman with known bull's eye chloroquine maculopathy presented with sudden decrease in vision within 1 week of receiving intravenous zoledronic acid (Aclasta). Complete ophthalmic examination including fundus photography, autofluorescence, optical coherence tomography, and visual field testing were performed over 1½ years of follow-up.\n\n\nRESULTS\nDecreased visual acuity, central visual field depression, and loss of the outer retinal layers on optical coherence tomography were seen in the symptomatic eye. The patient's last dose of chloroquine was over 15 years ago, with stable visual acuity and visual fields over this period, making chloroquine maculopathy an unlikely cause for the acute visual decline. The temporal association with the administration of intravenous zoledronic acid suggests a causative role for this mediation.\n\n\nCONCLUSIONS\nExposure to zoledronic acid seems to have precipitated acute visual loss in an eye with known chloroquine toxicity after 15 years of quiescence. Retinal toxicity may represent a rare adverse reaction to zoledronic acid, but this case suggests that caution should be used when administering this medication to patients with compromised retinal integrity.",
"affiliations": "*Department of Ophthalmology, Western University, London, Canada; and †College of Medicine, University of Saskatchewan, Saskatoon, Canada.",
"authors": "Bursztyn|Lulu L C D|LL|;Masri|Moness|M|;Sheidow|Thomas G|TG|",
"chemical_list": "D018501:Antirheumatic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D002738:Chloroquine",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "8(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D018501:Antirheumatic Agents; D050071:Bone Density Conservation Agents; D002738:Chloroquine; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007093:Imidazoles; D008875:Middle Aged; D012164:Retinal Diseases; D014786:Vision Disorders; D000077211:Zoledronic Acid",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "322-5",
"pmc": null,
"pmid": "25372538",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe visual loss secondary to retinal toxicity after intravenous use of bisphosphonate in an eye with known chloroquine maculopathy.",
"title_normalized": "severe visual loss secondary to retinal toxicity after intravenous use of bisphosphonate in an eye with known chloroquine maculopathy"
} | [
{
"companynumb": "PHHY2015CA043543",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "The study aimed to characterize the prevalence and virological features of the rtA181S + T184I + M204I mutant in a large cohort of patients with chronic HBV infection. In total, 22,009 nucleoside/nucleotide analog-treated patients who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2016 were enrolled. Serum samples were collected for HBV reverse-transcriptase gene sequencing. Phenotypic analysis of the viral replication capacity and drug susceptibility was performed. The rtA181S mutation was detected in 0.82% (180/22,009) of samples. rtA181S-positive patients had significantly higher lamivudine (LAM), adefovir (ADV), and entecavir (ETV) exposure than rtA181S-negative patients. Of 180 rtA181S-positive patients, 42 had no coexistent resistance mutations, 34 had coexisting LAM-resistance mutation (LAMr), 17 had coexisting ADV-resistance mutation (ADVr), and 86 had coexisting ETV-resistance mutation (ETVr), and one had ADVr + ETVr. rtA181S + T184I + M204I occurred in 79.1% (68/86) of patients with rtA181S + ETVr and 37.8% (68/180) of all rtA181S-positive patients. Longitudinal analysis of the clinical course of resistant mutant evolution for four representative cases showed that rtA181S + T184I + M204I developed in all patients who had received LAM/telbivudine ± ADV and was receiving ETV or ADV + ETV. Compared with wild-type, the rtA181S + T184I + M204I mutant had 53.7% lower replication capacity and >1000-, 3.9-, and 383.3-fold greater LAM, ADV, and ETV resistance, respectively, but remained sensitive to tenofovir. Artificial elimination of rtA181S from the rtA181S + T184I + M204I mutant restored viral susceptibility to ADV but decreased viral replication capacity. Our study presented the first evidence that HBV rtA181S + T184I + M204I mutation had features of multidrug-resistance that contributed to resistance to both nucleoside and nucleotide analogs.",
"affiliations": "Department of Cell Biology and Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China; Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Department of Cell Biology and Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.;Institute of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. Electronic address: xudongping302@sina.com.;Department of Cell Biology and Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China. Electronic address: duanchzhu@cqmu.edu.cn.",
"authors": "Chen|Rongjuan|R|;Liu|Yan|Y|;Luo|Dan|D|;Si|Lanlan|L|;Huang|Bixia|B|;Wang|Jun|J|;Li|Xiaodong|X|;Cheng|Fengjuan|F|;Xu|Dongping|D|;Duan|Changzhu|C|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000225:Adenine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.antiviral.2020.104852",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0166-3542",
"issue": "180()",
"journal": "Antiviral research",
"keywords": "Adefovir; Entecavir; Hepatitis B virus; Multidrug-resistance; Mutation; rtA181S+T184I+M204I",
"medline_ta": "Antiviral Res",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000998:Antiviral Agents; D044466:Asians; D000068476:Beijing; D015331:Cohort Studies; D004279:DNA, Viral; D024921:Drug Resistance, Multiple, Viral; D005260:Female; D006147:Guanine; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates; D015995:Prevalence",
"nlm_unique_id": "8109699",
"other_id": null,
"pages": "104852",
"pmc": null,
"pmid": "32569703",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hepatitis B virus mutation pattern rtA181S+T184I+M204I may contribute to multidrug resistance in clinical practice: Analysis of a large cohort of Chinese patients.",
"title_normalized": "hepatitis b virus mutation pattern rta181s t184i m204i may contribute to multidrug resistance in clinical practice analysis of a large cohort of chinese patients"
} | [
{
"companynumb": "CN-GILEAD-2019-0398518",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENTECAVIR"
},
"drugadditional": "3",
"... |
{
"abstract": "To present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers.\nSixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings.\nFifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important.\nThis case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice.",
"affiliations": "Atlantic Health Morristown Medical Center, Morristown, NJ, USA.;Hayward Genetics Center, Tulane University Medical School, New Orleans, LA, USA.;Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;Hayward Genetics Center, Tulane University Medical School, New Orleans, LA, USA.;Cooper University Health Care, Camden, NJ, USA.;Indiana University School of Medicine, Indianapolis, IN, USA.;BioMarin Pharmaceutical Inc., Novato, CA, USA.;Phoenix Children's Hospital, Phoenix, AZ, USA.;University of Texas Southwestern Medical Center, Dallas, TX, USA.;University of Texas Medical Branch, Galveston, TX, USA.;The University of Texas Health Science Center at Houston - McGovern Medical School, Houston, TX, USA.;Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.;Rare Disease Institute, Children's National, Washington, DC, USA.;St. Christopher's Hospital for Children, Philadelphia, PA, USA.;University of Colorado School of Medicine, Aurora, CO, USA.;Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.;OHSU Doernbecher Children's Hospital, Portland, OR, USA.;BioMarin Pharmaceutical Inc., Novato, CA, USA.",
"authors": "Adams|Darius|D|;Andersson|Hans C|HC|;Bausell|Heather|H|;Crivelly|Kea|K|;Eggerding|Caroline|C|;Lah|Melissa|M|;Lilienstein|Joshua|J|;Lindstrom|Kristin|K|;McNutt|Markey|M|;Ray|Joseph W|JW|;Saavedra|Heather|H|;Sacharow|Stephanie|S|;Starin|Danielle|D|;Tiffany-Amaro|Jennifer|J|;Thomas|Janet|J|;Vucko|Erika|E|;Wessenberg|Leah B|LB|;Whitehall|Kaleigh|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ymgmr.2021.100790",
"fulltext": "\n==== Front\nMol Genet Metab Rep\nMol Genet Metab Rep\nMolecular Genetics and Metabolism Reports\n2214-4269\nElsevier\n\nS2214-4269(21)00084-7\n10.1016/j.ymgmr.2021.100790\n100790\nResearch Paper\nUse of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics☆\nAdams Darius Darius.Adams@atlantichealth.org\na\nAndersson Hans C. handers@tulane.edu\nkcrivell@tulane.edu\nb\nBausell Heather hbausell@luriechildrens.org\nc\nCrivelly Kea b\nEggerding Caroline d\nLah Melissa mspurr@iu.edu\ne\nLilienstein Joshua joshua.lilienstein@bmrn.com\nf\nLindstrom Kristin klindstrommd@gmail.com\ng⁎\nMcNutt Markey markey.mcnutt@utsouthwestern.edu\nh\nRay Joseph W. jwray@utmb.edu\ni\nSaavedra Heather Heather.Saavedra@uth.tmc.edu\nj\nSacharow Stephanie Stephanie.Sacharow@childrens.harvard.edu\nk\nStarin Danielle Dstarin@childrensnational.org\nl\nTiffany-Amaro Jennifer Jennifer.tiffany-amaro@towerhealth.org\nm\nThomas Janet Janet.Thomas@childrenscolorado.org\nn\nVucko Erika evucko@luriechildrens.org\nc\nWessenberg Leah B. bjornsko@ohsu.edu\no\nWhitehall Kaleigh Kaleigh.Whitehall@bmrn.com\nf\na Atlantic Health Morristown Medical Center, Morristown, NJ, USA\nb Hayward Genetics Center, Tulane University Medical School, New Orleans, LA, USA\nc Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA\nd Cooper University Health Care, Camden, NJ, USA\ne Indiana University School of Medicine, Indianapolis, IN, USA\nf BioMarin Pharmaceutical Inc., Novato, CA, USA\ng Phoenix Children's Hospital, Phoenix, AZ, USA\nh University of Texas Southwestern Medical Center, Dallas, TX, USA\ni University of Texas Medical Branch, Galveston, TX, USA\nj The University of Texas Health Science Center at Houston - McGovern Medical School, Houston, TX, USA\nk Boston Children's Hospital, Harvard Medical School, Boston, MA, USA\nl Rare Disease Institute, Children's National, Washington, DC, USA\nm St. Christopher's Hospital for Children, Philadelphia, PA, USA\nn University of Colorado School of Medicine, Aurora, CO, USA\no OHSU Doernbecher Children's Hospital, Portland, OR, USA\n⁎ Corresponding author at: BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USA. klindstrommd@gmail.com\n14 8 2021\n9 2021\n14 8 2021\n28 1007901 7 2021\n3 8 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nTo present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers.\n\nMethods\n\nSixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings.\n\nResults\n\nFifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important.\n\nConclusion\n\nThis case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice.\n\nKeywords\n\nPhenylketonuria\nCase series\nPegvaliase\nPEGylated phenylalanine ammonia lyase\nPKU diet\nAdverse events\nAbbreviations\n\nACMG, American College of Medical Genetics and Genomics\nAEs, adverse events\nBH4, tetrahydrobiopterin\nHCP, healthcare provider\nI/T/M, induction, titration, and maintenance\nPAH, phenylalanine hydroxylase\nPhe, phenylalanine\nPKU, phenylketonuria\n==== Body\n1 Introduction\n\nPhenylketonuria (PKU) is a genetic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine (Phe) to tyrosine in the liver [1]. Reduction or absence of PAH activity results in elevated levels of Phe in the blood, tissues, and the brain, which can affect brain development and function. Even individuals with early-treated PKU can develop neurologic, cognitive, developmental, psychiatric, and behavioral problems if they are poorly-adherent to treatment [2,3].\n\nPegvaliase (Palynziq®, BioMarin Pharmaceutical Inc., Novato, CA, USA) is a novel enzyme substitution therapy for PKU that has been approved for adults in the United States (US) [4] and for patients ≥16 years of age in Europe [5] who have uncontrolled blood Phe concentrations >600 μmol/L on existing management. Pegvaliase is a PEGylated recombinant phenylalanine ammonia lyase enzyme that is administered via subcutaneous injection [[6], [7], [8]]. Pegvaliase treatment is carried out using an induction, titration, and maintenance (I/T/M) dosing schedule based on individual patient tolerability; dosing starts with a low dose (2.5 mg/week) induction period for several weeks, followed by gradual titration to a maintenance dose up to 60 mg daily [7].\n\nPegvaliase is the first therapeutic option that has the potential to lower blood Phe levels to normal ranges irrespective of residual PAH activity, tetrahydrobiopterin responsiveness (BH4; cofactor for PAH), or genotype (including double null genotypes) [6,9]. In the phase 3 PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) trials (N = 261), 68%, 61%, and 51% of adult patients reached blood Phe concentrations ≤600 μmol/L (recommended level for patients aged >12 years of age in the European guidelines [10]), ≤360 μmol/L (recommended level for all patients in the American College of Medical Genetics and Genomics [ACMG] guidelines [3]), and ≤120 μmol/L (the threshold defining hyperphenylalaninemia or upper limit of normal physiological levels), respectively, within 24 months of treatment [6]. Similarly, improvements from baseline assessments of inattention and mood outcomes were observed over 24 months of treatment [6]. The most common adverse events (AEs) reported in the PRISM studies were hypersensitivity reactions, i.e. arthralgia (70.5%), injection site reaction (62.1%), injection site erythema (47.9%), and headache (47.1%), with most AEs occurring in the first 6 months of treatment [6].\n\nPrior to the commercial approval, a steering committee with extensive pegvaliase clinical trial experience drafted recommendations for the use of pegvaliase based on the existing evidence and their experience with pegvaliase during clinical trials [8]. Pegvaliase is a novel class of therapy and the management of treated patients requires a completely new but manageable paradigm for patient selection, expectation setting, patient and caregiver education, treatment planning, drug titration, management of AEs, dietary and lifestyle modification, and long-term management. Until large-scale registry data from industry or independent researchers become available, clinicians without pegvaliase experience may seek advice and support from colleagues who have successfully managed multiple patients on pegvaliase.\n\nPublished case reports are an important tool to share experiences with the broader medical community and generally the first type of real-world evidence available for novel therapies [11]. We present a case series that illustrates considerations for the real-world use of pegvaliase based on the initial experiences of healthcare providers (HCPs) from across the US with significant clinical experience in treating adult PKU patients with pegvaliase.\n\n2 Materials and methods\n\n2.1 Case selection\n\nSixteen HCPs, representing the 14 clinics in the US with the most substantial real-world experience treating patients with PKU with pegvaliase, provided cases that exemplified important learnings from their initial experiences, relating to the pre-initiation, induction/titration, and/or maintenance phases of treatment. Cases were presented and discussed in an in-person meeting in December 2019 in Nashville, TN, USA. Based on this meeting, key lessons from each case were drafted and shared with the authors for further discussion in a subsequent virtual platform meeting. The case summaries and final takeaway points are shared here.\n\nAuthors received consent from their respective patients to include their treatment experiences and relevant health information in this retrospective case series. No patient identification data are included.\n\n3 Results\n\n3.1 Patient characteristics\n\nFifteen cases, including two brothers (cases 1 and 2), were discussed. Patient and pre-pegvaliase baseline and treatment characteristics for all patients are summarized in and 2. The full extended case reports can be found in the Supplement (see supplementary file). In brief, the 8 male and 7 female adult PKU patients discussed represented a broad spectrum for age, previous PKU care, comorbidities, and socioeconomic situations (Table 1 and Supplement). Age at initiation of pegvaliase treatment ranged from 18 to 53 years; five patients (33%) were students, and at least four lived over 3 h away from their PKU clinic. Before initiating pegvaliase, eleven patients (73%) were following a Phe-restricted diet and were using medical foods, and five (33%) were receiving sapropterin dihydrochloride (sapropterin, Kuvan®; BioMarin Pharmaceutical Inc., Novato, CA, USA). Pre-pegvaliase baseline blood Phe concentrations ranged from 262 μmol/L to 1474 μmol/L (Table 2). Only case 5 had a Phe concentration periodically below the label-recommended value of >600 μmol/L in the last 2 years before initiating pegvaliase, though blood Phe fluctuated considerably (between 160 and 763 μmol/L) due to diet adherence challenges.Table 1 Case overview of demographics and baseline characteristics, and details on induction/titration and maintenance. More details regarding comorbidities, pegvaliase journey, and current status are available in the Supplement (Supplementary file).\n\nTable 1Case\t1a\t2a\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t13\t14\t15\t\nDemographics and baseline characteristics\t\nAge, years\t27\t29\t19\t21\t21\t18\t39\t26\t33\t40\t43\t19\t53\t23\t35\t\nSex\tM\tM\tM\tM\tM\tF\tF\tF\tM\tF\tF\tM\tM\tF\tF\t\nHeight, m\t1.64\t1.64\t1.91\t1.72\t1.67\t1.66\t1.61\t1.60\t1.68\t1.60\t1.58\t1.72\t1.73\t1.65\t1.62\t\nWeight, kg\t59\t68\t119\t62\t57\t56\t79\t64\t74\t65\t64\t71\t106\t78\t111\t\nBMI\t22.0\t25.5\t32.6\t20.8\t20.6\t20.5\t30.6\t25.2\t26.1\t25.5\t25.6\t24.2\t35.5\t28.8\t42.4\t\nPhe-restricted dietb\tNo\tNo\tYes\tYes\tYes\tYes\tNo\tYes\tNo\tYes\tYes\tYes\tYes\tYes\tYes\t\nSapropterin dihydrochloride at baselinec\tFormer\tFormer\tNo\tNo\tNo\tYes\tYes\tNo\tNo\tYes\tNo\tNo\tNo\tNo\tNo\t\n\n\n\t\nInduction/titration\t\nPremedicationd\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\tH1/H2\t\nTemporary dose interruption\tNo\tNo\tNo\tNo\tYes\tYes\tNo\tNo\tYes\tNo\tNo\tNo\tNo\tNo\tNo\t\nReason for interruption\t\t\t\t\tPossible anaphylaxis/anxiety\tRecurrent hives\t\t\tAnaphylaxis\t\t\t\t\t\t\t\nDiscontinuation\tNo\tNo\tNo\tNo\tYes\tYes\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\t\nReason for discontinuation\t\t\t\t\tPossible anaphylaxis/anxiety\tRecurrent hives/patient decision\t\t\t\t\t\t\t\t\t\t\n\n\n\t\nMaintenance\t\nAchieved efficacye\tYes\tYes\tNof\tYes\tNo\tNo\tYes\tYes\tYes\tYes\tYes\tYes\tYes\tYes\tYes\t\nTime to efficacy, weeks\t12\t8\tNAf\t5\t\t\t13\t10\t17\t20\t9\t50\t68\t11\t22\t\nDose at efficacy, mg\t20/day\t10 4×/wk\tNAf\t2.5 2×/wk\t\t\t20/day\t20/day\t10/day\t10 4× & 20 3×/ wk\t10/day\t40/day\t60/day\t20/day\t20/day\t\nDiscontinuation\tNo\tNo\tNo\tNo\t\t\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\t\n\n\n\t\nLast follow-up\t\nPegvaliase treatment status\tMaint.\tMaint.\tTitr.\tMaint.\tDiscont.\tDiscont.\tMaint.\tMaint.\tMaint.\tMaint.\tMaint.\tMaint.\tMaint.\tMaint.\tMaint.\t\nPegvaliase dose, mg\t10/day\t10/day\t10/day\t10 5×/wk\t\t\t20/wk\t20/day\t20/day\t10/day\t10/day\t40/day\t60/day\t20/day\t40/day\t\nBMI: body mass index; F: female; M: male; NA: not available.\n\na Cases 1 and 2 are siblings.\n\nb >75% of protein from medical food.\n\nc Sapropterin dihydrochloride was discontinued after achieving efficacy; patients not receiving sapropterin dihydrochloride were either non-responders or never tried this therapy (see Supplement for further details).\n\nd See Supplement for dosing and duration, if available.\n\ne Efficacy was defined by clinic.\n\nf Titration ongoing.\n\nTable 2 Case overview of blood phenylalanine (Phe) and protein intake at pre-pegvaliase baseline and last follow-up.\n\nTable 2Case\t1\t2\t3\t4\t5a\t6a\t7\t8\t9\t10\t11\t12\t13\t14\t15\t\nBlood Phe, μmol/L\t\nPre-pegvaliase baseline\t1354\t1474\t757\t987\t262\t611\t1174\t923\t1437\t854\t1283\t884\t789\t799\t1223\t\nLast follow-upb\t18\t6\t889d\t321\t\t\t72\t23\t133\t61\t0\t103\t69\t36\t18\t\nChange from baseline\t−1336\t−1468\t+132d\t−666\t\t\t−1102\t−900\t−1304\t−793\t−1283\t−781\t−720\t−763\t−1205\t\n\n\n\t\nNatural protein intake, g/dayc\t\nPre-pegvaliase baseline\t16\t40\t10\t7\t12\t14\t75\t14\tNA\t22\t15\t20\t15\t10\t20\t\nLast follow-up\t73\t100\t10d\t55\t\t\t75–100\t77\t\t95\t65\t73\t65\t70\t20\t\nChange from baseline\t57\t60\t0d\t48\t\t\t0\t63\t\t73\t50\t53\t50\t60\t0\t\n\n\n\t\nMedical food protein, g/day\t\nPre-pegvaliase baseline\t0\t0\t60\t70\t100\t40\t0\t31\t0\t100\t50\t75\t45\t92\t60\t\nLast follow-up\t0\t0\t60d\t0\t\t\t0\t0\t0\t0\t0\t0\t0\t0\t60\t\n\n\n\t\nTotal protein intake, g/day\t\nPre-pegvaliase baseline\t16\t40\t70\t77\t112\t54\t75\t45\t29\t122\t65\tNA\t60\t102\t80\t\nLast follow-up\t73\t100\t70d\t55\t\t\t75–100\t77\t\t95\t65\t73\tNA\t70\t79\t\nChange from baseline\t57\t60\t0d\t−22\t\t\t0\t32\t\t−27\t0\tNA\tNA\t−32\t−1\t\nNA: not available.\n\na Data at last follow-up are not reported for cases 5 and 6 who discontinued treatment.\n\nb If range was reported, upper limit was included.\n\nc If range of natural protein intake was reported, average values are included; if the actual consumption was unavailable, prescription is included.\n\nd Titration ongoing.\n\nSeven patients reported one or more significant neuropsychological or psychiatric comorbidities before treatment initiation, including anxiety (N = 4), attention deficit hyperactivity disorder (N = 2), depression (N = 2), bipolar disorder (N = 2), schizophrenia (N = 1), hallucinations (N = 1), irritability (N = 1), and obsessive compulsive disorder (N = 1). The severity of symptoms varied over time in each patient and across patients. Four of 15 patients reported significant socioeconomic challenges, including economic and/or food insecurity, difficult living and/or care arrangements, and ongoing legal challenges (Supplement).\n\n3.2 Pre-initiation\n\nPatients had different motivations and personal goals for treatment including a desire to eat a normal diet, to increase food choices, or to experience fewer symptoms that they associated with uncontrolled blood Phe levels (Supplement).\n\nTable 1 and the Supplement provide information on premedications used by the patients. No data are available to inform an optimal premedication regimen. The clinical trial study instruction was to use the highest dose of each premedication per their respective labels, as tolerated.\n\n3.3 Induction/titration\n\nWhile for the majority of patients the prescribed standard induction and titration schedule in the label was sufficient, the schedule was revised in three cases (cases 6, 9, and 10) due to AEs. Case 13 had a slower induction regimen due to early AEs. Fourteen patients experienced AEs, including injection site reactions, arthralgia/joint pain, rash/erythema/hives, acute systemic hypersensitivity/anaphylaxis, upper respiratory tract/ear infections, prolonged cough, pedal edema with skin breakdown, chest pain, and leukocytosis (Supplement). Three patients had a temporary dose interruption. One interruption was due to possible non-life-threatening anaphylaxis/anxiety (case 5), one to recurrent hives (case 6), and one to acute systemic hypersensitivity/anaphylaxis (case 9) (Table 1). Eight patients (cases 1, 2, 7, 8, 10, 11, 14, and 15) experienced blood Phe levels below 30 μmol/L upon reaching efficacy (in the titration or maintenance phase) for several weeks, indicated by all sequential blood Phe measurements below this level. Blood Phe increased after protein intake was increased (cases 7 and 10) or after reducing the pegvaliase dose (case 14). Levels were still below 30 μmol/L at last follow-up in cases 1, 2, 8, 11, and 15, but without causing any adverse effects.\n\nMean time to efficacy, as defined by each clinic separately (e.g. blood Phe in the range of 120–360 μmol/L for more than two consecutive levels; blood Phe <360 μmol/L for two consecutive levels; blood Phe <360 μmol/L while on normal diet and off medical food, formula, or sapropterin), was 20.4 weeks (median: 12.5 weeks; range: 5 to 68 weeks) for those who had achieved efficacy. In case 3, titration was still ongoing at 14 weeks after treatment initiation. Two patients discontinued pegvaliase early (case 5 after 18 weeks and case 6 after 33 weeks of treatment) due to AEs (recurrent hives and possible non-life-threatening anaphylaxis/anxiety) (Table 1 and Supplement).\n\n3.4 Maintenance\n\nCases are summarized as of the end of the virtual advisory board. After induction and titration, the 12 patients achieving efficacy were kept on a maintenance dose ranging from 20 mg weekly to 60 mg daily (Table 1). Blood Phe concentration in these patients ranged from 0 to 321 μmol/L (mean 72 μmol/L) (Table 2). Seven patients had required pegvaliase dose adjustments after achieving efficacy (cases 1, 2, 4, 7, 9, 10, and 15). Change from baseline in natural protein intake in those achieving efficacy ranged from 0 to +73 g/day (mean increase 46.7 g/day). At last follow-up, natural protein intake in these patients ranged from 20 to 100 g/day (mean 69.8 g/day), and total protein intake ranged from 55 to 100 g/day (mean 76.2 g/day) (Table 2). Some patients experienced difficulty adjusting to a new diet with higher protein intake (cases 1, 2, 8, 10, 14, and 15); however, 11 of the 12 patients reaching efficacy were no longer on medical food supplementation (Supplement).\n\n4 Discussion: Key learnings of the case series (Table 3)\n\n4.1 Pre-initiation\n\n4.1.1 Patient education\n\nEducation of patients receiving pegvaliase is an ongoing process that starts before initiation of pegvaliase treatment. No assumptions should be made about patients' understanding of expected AEs with pegvaliase treatment, use of premedications, time to efficacy, proper injection technique, dietary changes, or ability to prepare food. All providers and patients must be enrolled in the Palynziq REMS program (www.palynziqrems.com), designed to mitigate the risk of acute systemic hypersensitivity/anaphylaxis, and follow the prescribing and counseling steps outlined in the program, including reinforcing the importance of the presence of a trained observer and discussing the similarity in symptoms between anxiety and anaphylaxis. Patients should be aware that adverse reactions may result in changes to pegvaliase dosing, and that this can considerably prolong the titration process and time to efficacy. In addition, it is important to begin diet education before the initiation of pegvaliase and throughout treatment (i.e. what constitutes a healthy diet; reviewing options for higher protein foods if/when diet changes are warranted). Assessment of a patient's dietary intake and eating behaviors during follow-up visits is essential.Table 3 Key lessons from the case series.\n\nTable 3Pre-initiation\t\n• Patient education is an ongoing process that starts during pre-initiation. No assumptions should be made about patients' understanding of AEs, time to efficacy, diet changes, or ability to prepare food.\n\n• Patient-specific factors that may interfere with treatment success, such as socioeconomic challenges, comorbidities, or prior non-adherence to diet and/or pharmacotherapy, should be identified and addressed before starting pegvaliase, but these factors do not in themselves prohibit success with pegvaliase.\n\n• Socioeconomic barriers and other challenges such as irregular dietary habits and food insecurity that may prevent lifestyle changes should be discussed before initiating pegvaliase.\n\n• Treatment initiation should be planned with the patient's upcoming life events in mind.\n\n• Treatment goals, patient expectations, and planned changes once efficacy is reached should be clearly defined upfront.\n\n\t\n\n\n\t\nInduction/titration\t\n• Initiation of pegvaliase can be challenging in patients living in geographically remote areas. For these patients, it may be difficult to identify an appropriate location and to find and educate local health care providers for the first injection.\n\n• Each patient's titration and diet adjustments are unique; a flexible titration schedule that allows for adjustments when patients experience AEs can help avoid discontinuations.\n\n• While some patients show a reduction in blood Phe level very quickly after treatment initiation with few or no AEs, others require more than a year for an effect to become apparent.\n\n• Patients that experience hypersensitivity reactions early on can still achieve efficacy, but this may require prolonging the titration phase and/or concomitant medication use.\n\n• Patients and caregivers may have a difficult time distinguishing between acute systemic hypersensitivity/anaphylaxis and anxiety. From a safety point of view, it is best to react as if the patient has anaphylaxis.\n\n\t\n\n\n\t\nMaintenance\t\n• To prevent issues with dietary changes, providers should keep in close communication with their patients, make any changes to diet slowly with specific recommendations of how to increase protein, and avoid making assumptions about patients' understanding or goals for their new diet.\n\n• Providers should continue to discuss injection site rotation with patients and have continued discussion around life events that might impact pegvaliase use during maintenance.\n\n\t\nAEs: adverse events.\n\n4.1.2 Evaluation of patient-specific factors\n\nIn this case series, treatment success was seen in patients across different ages, previous PKU care, comorbidities, and socioeconomic challenges, suggesting that these factors do not prohibit treatment with pegvaliase. However, patients with socioeconomic difficulties, historical non-adherence with treatment/diet, or significant psychiatric comorbidities must be individually assessed for willingness and appropriateness before initiating treatment.\n\nPsychological factors such as anxiety that may interfere with treatment success should be identified, discussed with the patient, and in some cases prophylactically treated before starting pegvaliase. Baseline neuropsychological testing may be performed in the hour-long observational period directly following the first injection. Follow-up visits are an opportunity to reassess patients' psychosocial health comprehensively. For patients with neurocognitive or psychiatric issues, it may be important to develop a “contract” with families, especially during the titration period to optimize treatment success (case 4).\n\nAdditional factors that should be evaluated and discussed before initiating pegvaliase are socioeconomic barriers and other dietary challenges, such as irregular dietary habits and food insecurity, that may hinder lifestyle changes (such as in cases 1, 2, 14, 15).\n\nIn addition, case 6 illustrates that treatment initiation should be planned with the patient's life events in mind. This patient discontinued pegvaliase when she started college as she feared significant side effects while away from home. To avoid similar situations, HCPs should proactively discuss the duration, expectations, and requirements of the induction and titration period, as well as potential AEs, and how these may interfere with the patient's plans during the titration period.\n\nFinally, treatment goals, patient expectations, and planned changes once efficacy is reached (e.g. discontinuation of sapropterin) should be clearly defined during the pre-initiation period. Primary motivations for pegvaliase treatment vary between patients. Some may be motivated by the ability to eat a more normal diet, while others may want to be able to think more clearly (resulting from improved Phe levels). It is recommended to discuss the patient's dietary goals (e.g. decrease medical food/formula, increase natural protein intake) before treatment is initiated. Some patients may not wish to totally normalize diet or may be hesitant to administer two injections a day (case 15). It can be helpful to re-evaluate goals through the course of therapy, since goals can change as experience evolves.\n\n4.2 Induction and titration\n\n4.2.1 Premedication\n\nPremedication regimes have changed considerably over time and vary from clinic to clinic. Some providers prescribe daily premedications during titration even if no injection is given, and some consider discontinuing premedications once a patient has reached efficacy and had not experienced hypersensitivity AEs for 1–2 months, with the plan to resume if hypersensitivity events recur.\n\nRegardless of the premedication regimen, all patients should be counseled on potential side effects of premedications (e.g. sedation may occur even with nominally non-sedating antihistamines); timing of injections in the evening may therefore be preferred (case 7). If premedication is started days before the first injection, the provider can assess any AEs as related to the premedication, as opposed to those related to pegvaliase, and adjust the specific premedication as necessary [12].\n\n4.2.2 Initiation of pegvaliase in patients in geographically remote areas\n\nInitiation of pegvaliase can be challenging in patients living in areas geographically distant from the initial treatment site (case 3). For these patients, it may be helpful to identify a local HCP who is able to provide supervision for the first injection. This can be the patient's primary care provider, or another specialty provider such as urgent care or a local specialist (e.g. an allergist or oncologist) who is comfortable managing hypersensitivity reactions and educated about the risk of and response to anaphylaxis. It is important to make sure that any serious AEs experienced are reported and can be managed adequately. Telehealth tools can increase the cost- and time-efficiency of delivering care to remote areas.\n\n4.2.3 Management of patients during titration\n\nThis case series clearly illustrates that each patient's management needs during titration vary, depending on the occurrence of AEs, personal preferences, and emotional factors. Although AEs may present at any time, most of the AEs that occur during titration, such as injection site reactions and joint pain (arthralgia), are mild to moderate in severity, and decrease in frequency and severity over time [6,7,13]. However, some patients may experience severe (e.g. anaphylaxis) or atypical reactions. Patients with acute systemic hypersensitivity events/anaphylaxis are overrepresented in this case series versus previous reports [6,12] because the guidance shared on these cases is important as they require more specific and tailored care.\n\nAEs related to pegvaliase and best practices for their prevention and management have been described previously [8,13]. HCPs should not be reluctant to increase the dosage of histamine receptor antagonists or prescribe steroids to manage hypersensitivity reactions. Steroids are typically administered over a short period of time, to minimize the effects of long-term use. Patients and caregivers may have a difficult time distinguishing between acute systemic hypersensitivity/anaphylaxis and anxiety (case 5); however, for patient safety, it is best to react as if the patient is having an anaphylactic event in these cases. Managing anxiety by setting proper expectations, offering counseling, and potentially prescribing anxiolytics may help reduce drug discontinuation.\n\nPegvaliase treatment can be restarted and continued after anaphylaxis or other hypersensitivity reactions (after up to 1 week interruption in this case series), but must be considered on a case-by-case basis. In the EU, restarting treatment is contraindicated after severe anaphylaxis. Patients who experience hypersensitivity reactions early on can still achieve efficacy, although this may require prolonging the titration phase and/or concomitant steroid use (case 13). Achieving efficacy may take longer than 1 year and may require higher doses of pegvaliase. It is important to acknowledge patient frustrations and fears until efficacy is reached. Treatment efficacy is often not achieved until after hypersensitivity symptoms abate (cases 9 and 13), but can also occur while the patient is experiencing significant AEs (case 2). Having a “buddy”, either a family member (case 1 and 2) or a friend, can be helpful in coping with AEs, reinforcing instructions and staying adherent to the regimen. Although the brothers in cases 1 and 2 had similar responses to pegvaliase treatment, that is not always the case for relatives.\n\nTwelve out of 15 patients in this case series remained motivated to continue treatment and achieved efficacy (one patient did not yet complete titration), despite the fact that nine of them experienced severe hypersensitivity reactions. A flexible titration schedule that allows for adjustments when patients experience AEs (i.e. waiting for reactions to resolve before restarting therapy, building up tolerability before advancing to a higher pegvaliase dose) can help avoid discontinuations (cases 9, 10, and 12).\n\nBecause of the risk of AEs, travel plans during the titration phase, especially long trips that involve air travel, should be discussed with the patient ahead of time, to plan on timing of the pegvaliase dose in relation to the flight, and to stress the importance of packing medications that may be needed in case of an AE.\n\n4.2.4 Monitoring blood Phe levels and diet\n\nTime to therapeutic response is widely variable between patients, ranging from only five weeks (case 4) to more than a year (case 13). As blood Phe can drop early in some patients, checking levels more than once a month (e.g. every 2 weeks) during induction and titration may be considered. Based on case 11, we also suggest that waiting for two consecutive blood Phe assessments before adjusting the pegvaliase dose may avoid worsening of AEs in some cases.\n\nClose follow-up by a dietitian during titration and maintenance can help with dietary changes and with monitoring weight and body mass index. Early identification and intervention may help prevent rapid weight gain. Initiating dietary changes too early can lead to a “yo-yo” effect in blood Phe levels (case 8).\n\n4.3 Maintenance\n\n4.3.1 Key issues for establishing a healthy, adequate diet\n\nMany patients hope to control their blood Phe without maintaining a Phe-restricted diet with pegvaliase. The case series highlights that patients' goals for their diet vary. Providers can assist patients with this transition by understanding the challenges they may face when changing their diet. Once patients have achieved efficacy, they may not report all dietary changes (case 14), because they either do not think they are important or lack adequate information on protein sources. Patients may have difficulty liberalizing their diet in a healthy, sustainable way. Due to unfamiliarity with intake of higher protein foods, they may experience early protein satiety, which could lead to catabolism and fluctuating blood Phe levels (case 14). In some patients, dietary changes enabled by pegvaliase may result in significant weight gain (case 7). Providers should also be aware that patients may feel a loss of identity as diet restrictions are lifted and may be anxious about getting enough protein to prevent low Phe levels (case 10). Some patients may feel overwhelmed with drastic changes in their diet or may face additional pressure from family and friends to make changes to their diet during the initial response.\n\nTo avoid issues with dietary changes, HCPs should maintain close communication with their patients, make any changes to diet slowly and with specific recommendations of how to increase protein, and avoid making assumptions about the patient's understanding or goals for their new diet. Patients need education on appropriate dietary protein sources and help with healthy eating habits, starting at the time of initial counseling and education for pegvaliase. Medical foods/formula should be maintained until patients can adequately understand and meet their new dietary protein needs, including foods of high biological quality protein sources. Education on nutrition and cooking, with focus on preparation of high protein foods, are imperative for pegvaliase responders. For patients with weight issues, standard weight loss techniques, including weight loss clinics and pharmacotherapy, can be considered and should be coordinated with the metabolic clinic with a proactive approach.\n\n4.3.2 Impact of pegvaliase on patients' lives\n\nThis case series underscores the potential for great improvements in quality of life in patients achieving efficacy on a stable maintenance dose. Cases 1 and 2 who had severe socioeconomic challenges reported improvements in neurocognitive and executive function after achieving efficacy. Both brothers received work promotions and, as a result, had better access to food. Other patients showed improvements in studying abilities (cases 8, 12, and 14) (Supplement). Case 4 who had severe functional impairments at baseline was able to perform his own injections and to drive independently; he also became more independent and social. Other patients felt less irritable and had better focus and more energy (case 7), reported improved quality of life from being able to eat a more normal and spontaneous diet (case10), were able to set and achieve personal health goals (case 11), or noted improvements in overall mood (cases 13 and 15).\n\n4.3.3 Ongoing care during maintenance\n\nSeveral cases underscore the importance of ongoing follow-up of patients during maintenance. Case 12 shows that if unexpected spikes in blood Phe levels are observed in a patient who has responded to pegvaliase, it may be useful to inquire about locations and technique of injections in addition to exploring other factors such as changes in diet or illness. Injecting into areas with dense scar tissue (e.g. when the patient is not rotating injection sites) may limit the dose that enters the patient's bloodstream. Therefore, assessing rotation of injection sites during follow-up visits, as well as offering training to provide more injection site options is important. Patients may also experience blood Phe levels below 30 μmol/L that are not associated with an increase in AEs. In clinical trials, low blood Phe resolved in the majority of subjects with either increased natural protein intake and/or dose adjustments [14]. One patient in this series (case 10) experienced hair loss from telogen effluvium related to low blood Phe that resolved within a few months due to a minor increase in blood Phe after intact protein was increased.\n\nProviders should have continued discussion with patients around life events that might impact pegvaliase use during maintenance, e.g. about birth control and pregnancy plans for women of childbearing years.\n\n4.4 Limitations\n\nThe cases presented here do not represent all potential clinical scenarios, nor do the recommendations provided address all challenges which may be encountered when using pegvaliase. These cases and commentary are intended to supplement published clinical trial results, until additional data from registries and independent research can be made publicly available.\n\n5 Conclusions\n\nThis case series collects the initial experiences of HCPs from across the US with significant experience in treating adults with PKU with pegvaliase. Until further evidence from registries and independent research become available, the data and proposed recommendations presented herein can be a valuable resource for HCPs to support appropriate management of patients receiving pegvaliase. The very early qualitative data presented here can lead to future, more statistically rigorous studies with larger patient numbers on the impact of pegvaliase on diet, quality of life, and psychiatric and cognitive measures.\n\nFunding\n\nThe content of this manuscript was based on presentations and discussions during an advisory board meeting that was coordinated and funded by BioMarin Pharmaceutical Inc. BioMarin also funded the writing of this manuscript.\n\nData sharing statement\n\nResearch data for this case series will not be shared as the data that has been used is confidential.\n\nDeclaration of competing interest\n\nDA reports grants from BioMarin outside the submitted work. HCA and KC received payments from BioMarin to participate in the advisory board meeting related to the submitted work. HB reports personal fees from BioMarin related to the submitted work and personal fees from BioMarin, Cambrooke, Horizon, Nutricia, Ultragenyx, and Vitaflo outside the submitted work. CE received payments from BioMarin to participate in the advisory board meeting related to the submitted work, and payments from BioMarin outside the submitted work. ML received personal fees to participate in the advisory board meeting related to the submitted work; payments from BioMarin outside the submitted work; and is an investigator in clinical trials sponsored by BioMarin. JL and KW are employees of BioMarin. KL received payments from BioMarin for participating in the advisory board meeting related to the submitted work; she is currently an employee of BioMarin. MM reports personal fees and non-financial support from BioMarin related to the submitted work and personal fees from Applied Therapeutics, Cycle Pharmaceuticals and Rhythm Pharmaceuticals, personal fees and non-financial support from Aeglea Biotherapeutics and Horizon Therapeutics, and grants from Censa Pharmaceuticals outside the submitted work. JWR received payments and travel support from BioMarin for participating in the advisory board meeting related to the submitted work. HS received payments and travel support from BioMarin related to the submitted work, was involved as an investigator in clinical trials for BioMarin, and received payments from BioMarin, Vitaflo, MetEd and Symbiotics outside the submitted work. SS received consulting fees, speaker fees, and travel support from BioMarin and was involved as an investigator in clinical trials for BioMarin. DS received personal fees from BioMarin related to the submitted work and personal fees from BioMarin, Cambrooke, Horizon, Nutricia, Ultragenyx, Cycle Pharmaceuticals and Vitaflo outside the submitted work. JT-A received personal fees for participating in the advisory board related to the submitted work and personal fees from BioMarin outside the submitted work. JT was involved as an investigator in clinical trials for BioMarin and was a member of the Phase III advisory board. EV received personal fees for participating in the advisory board related to the submitted work and personal fees from BioMarin outside the submitted work. LBW received personal fees from BioMarin for participating in the advisory board and virtual platform meeting related to the submitted work, and personal fees from BioMarin and Nutricia outside the submitted work.\n\nSupplement\n\nSupplementary material\n\nImage 1\n\nAcknowledgements\n\nThe authors are grateful to Cheryl Clow (Albany Medical Center) for her contribution to the advisory board meeting and to Ismar Healthcare NV for their assistance in the writing of this manuscript, which was funded by BioMarin Pharmaceutical Inc. The authors are also grateful to Sarah Rose (BioMarin) for her assistance in finalizing the case details, Gillian Clague (BioMarin) for her assistance in finalizing the manuscript and implementing graphic updates, and Terry Manspeaker (Show Your Science, LLC) for graphic support. The authors are grateful to BioMarin for coordinating and funding the advisory board meeting related to this publication.\n\n☆ All authors contributed equally, and are listed alphabetically.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ymgmr.2021.100790.\n==== Refs\nReferences\n\n1 Blau N. van Spronsen F.J. Levy H.L. Phenylketonuria Lancet 376 2010 1417 1427 20971365\n2 Brumm V.L. Bilder D. Waisbren S.E. Psychiatric symptoms and disorders in phenylketonuria Mol. Genet. Metab. 99 Suppl. 1 2010 S59 S63 20123472\n3 Vockley J. Andersson H.C. Antshel K.M. Phenylalanine hydroxylase deficiency: diagnosis and management guideline Genet. Med. 16 2014 188 200 24385074\n4 Palynziq (pegvaliase-pqpz) [US prescribing information] 2018 BioMarin Pharmaceutical Inc Novato, CA\n5 Palynziq (pegvaliase) [EU product information] 2019 BioMarin International Ltd Shanbally, Ireland\n6 Thomas J. Levy H. Amato S. Pegvaliase for the treatment of phenylketonuria: results of a long-term phase 3 clinical trial program (PRISM) Mol. Genet. Metab. 124 2018 27 38 29653686\n7 Zori R. Thomas J.A. Shur N. Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria Mol. Genet. Metab. 125 2018 217 227 30146451\n8 Longo N. Dimmock D. Levy H. Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria Genet. Med. 21 2019 1851 1867 30546086\n9 Zori R. Ahring K. Burton B. Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria Mol. Genet. Metab. 128 2019 92 101 31439512\n10 van Wegberg A.M.J. MacDonald A. Ahring K. The complete European guidelines on phenylketonuria: diagnosis and treatment Orphanet. J. Rare Dis. 12 2017 162 29025426\n11 Florek A.G. Dellavalle R.P. Case reports in medical education: a platform for training medical students, residents, and fellows in scientific writing and critical thinking 2016 Springer\n12 Sacharow S. Papaleo C. Almeida K. First 1.5 years of pegvaliase clinic: Experiences and outcomes Mol. Genet. Metab. Rep. 24 2020 100603 32489881\n13 Hausmann O. Daha M. Longo N. Pegvaliase: immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy Mol. Genet. Metab. 128 2019 84 91 31375398\n14 Thomas J.A. Jurecki E. Whitehall K.B. Dietary intakes and adverse events in pegvaliase-treated phenylketonuria adults who had low blood phenylalanine concentrations Poster 183 presented at ACMG 2020 2020 https://www.acmgeducation.net/Users/LearningActivityAssetSingleViewer.aspx?LearningActivityAssetID=xHQ0EkDW9ADf%2fkbgLwwMFw%3d%3d\n\n",
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"keywords": "ACMG, American College of Medical Genetics and Genomics; AEs, adverse events; Adverse events; BH4, tetrahydrobiopterin; Case series; HCP, healthcare provider; I/T/M, induction, titration, and maintenance; PAH, phenylalanine hydroxylase; PEGylated phenylalanine ammonia lyase; PKU diet; PKU, phenylketonuria; Pegvaliase; Phe, phenylalanine; Phenylketonuria",
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"title": "Use of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics.",
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"abstract": "BACKGROUND People with hemophilia A have shown osteomuscular complications that have a significant impact on their quality of life (QoL) and on health care costs. Patients with hemophilia A with inhibitors living in developing countries such as Chile face a high disease and treatment burden. Emicizumab, a humanized bispecific monoclonal antibody, is associated with improvements in QoL and reduction in the financial impact of the disease related to treatment. This case report describes the impact of emicizumab on a patient with severe hemophilia A with inhibitors in terms of breakthrough bleeding control, improvements in QoL, and reduced financial impact after a year of treatment, in a country where this medication is not routinely available. CASE REPORT A 10-year-old child with severe hemophilia A with inhibitors had several restrictions in his daily life due to multiple incidences of breakthrough bleeding. He was on episodic treatment with bypassing agents, and in the year prior to treatment with emicizumab he had 18 bleeding episodes. After 1 year on prophylaxis treatment with emicizumab, the patient had only 1 bleeding episode (94.4% of reduction), improved pain control (5-point reduction on the visual analogue scale), a decrease in the Hemophilia Joint Health Score from 39 to 19, the QoL perception increased by 86% on the standardized Haemo-QoL-kids, and a 70% reduction in treatment costs versus the costs of episodic treatment with bypassing agents. CONCLUSIONS After 1 year of treatment with emicizumab, this patient had substantial improvements in the evaluated parameters. Further investigations with emicizumab are needed to assess its possible effects on public health policies.",
"affiliations": "Department of Pediatrics and Newborns, Hospital San Pablo, Coquimbo, Chile.;Department of Hematology, Hospital Roberto del Río, Santiago, Chile.",
"authors": "Abarca-Villaseca|Viviana|V|;Soto-Arellano|Verónica|V|",
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"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n33883542\n10.12659/AJCR.929598\n929598\nArticles\nBreakthrough Bleeding Episodes at Minimum and Improvement in Quality of Life in a Child with Severe Hemophilia A with Inhibitors Treated with Emicizumab: A Case Report from Chile\nAbarca-Villaseca Viviana ABCDEF1\nSoto-Arellano Verónica ABCDEF2\n1 Department of Pediatrics and Newborns, Hospital San Pablo, Coquimbo, Chile\n2 Department of Hematology, Hospital Roberto del Río, Santiago, Chile\nCorresponding Author: Viviana Abarca-Villaseca, e-mail: vivianabarca@gmail.com\nAuthors’ 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: Writing of this study was supported by Hoffmann-La Roche (Roche-Chile)\n\n2021\n22 4 2021\n22 e929598-1e929598-5\n02 11 2020\n06 2 2021\n19 3 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 10-year-old\n\nFinal Diagnosis: Hemophilia A\n\nSymptoms: Hemorrhage\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Hematology • Pediatrics and Neonatology\n\nObjective:\n\nRare disease\n\nBackground:\n\nPeople with hemophilia A have shown osteomuscular complications that have a significant impact on their quality of life (QoL) and on health care costs. Patients with hemophilia A with inhibitors living in developing countries such as Chile face a high disease and treatment burden. Emicizumab, a humanized bispecific monoclonal antibody, is associated with improvements in QoL and reduction in the financial impact of the disease related to treatment. This case report describes the impact of emicizumab on a patient with severe hemophilia A with inhibitors in terms of breakthrough bleeding control, improvements in QoL, and reduced financial impact after a year of treatment, in a country where this medication is not routinely available.\n\nCase Report:\n\nA 10-year-old child with severe hemophilia A with inhibitors had several restrictions in his daily life due to multiple incidences of breakthrough bleeding. He was on episodic treatment with bypassing agents, and in the year prior to treatment with emicizumab he had 18 bleeding episodes. After 1 year on prophylaxis treatment with emicizumab, the patient had only 1 bleeding episode (94.4% of reduction), improved pain control (5-point reduction on the visual analogue scale), a decrease in the Hemophilia Joint Health Score from 39 to 19, the QoL perception increased by 86% on the standardized Haemo-QoL-kids, and a 70% reduction in treatment costs versus the costs of episodic treatment with bypassing agents.\n\nConclusions:\n\nAfter 1 year of treatment with emicizumab, this patient had substantial improvements in the evaluated parameters. Further investigations with emicizumab are needed to assess its possible effects on public health policies.\n\nKeywords:\n\nBlood Coagulation Factor Inhibitors\nHemophilia A\nQuality of Life\n==== Body\nBackground\n\nHemophilia is a genetic disease linked to the X chromosome that is expressed by a decrease in coagulation factor VIII or IX, corresponding to hemophilia A (HA) or B (HB), respectively. Hemophilia A affects one in 5,000–10,000 males every year [1]. Patients with this disease are prone to breakthrough bleeding with either spontaneous bleeding or traumatic bleeding episodes, particularly in the joints (elbow, knee, and ankle), that negatively affect quality of life (QoL) and provoke hemophilic arthropathy as a frequent complication [2].\n\nHemophilia is classified according to the percentage of deficiency in antihemophiliac factors, specifically, severe hemophilia (<1% of normal), moderate hemophilia (1–5% of normal), and mild hemophilia (5–40% of normal) [3,4]. Globally, data indicate that the cumulative incidence of inhibitor development in severe HA is in the range of 20–30% [5], while in different Latin American countries the prevalence of inhibitors is between 11% and 19% [6,7]. Affected patients have more annual bleeding events and osteomuscular complications than patients with other types of hemophilia, which affects QoL and has a significant impact on health care costs. This disease is challenging for patients, families, and the health care system [8].\n\nThe standard of care in Chile for every patient with the nonhemorrhagic phenotype is on-demand treatment only. For patients with the hemorrhagic phenotype, treatment corresponds to prophylaxis with bypassing agents (BPAs).\n\nAccording to the HAVEN 2 study, once-weekly subcutaneous emicizumab prophylaxis resulted in a very low bleeding rate in children with HA and FVIII inhibitors; 77% of participants did not need treatment for bleeding episodes [9].\n\nCase Report\n\nA 10-year-old boy with severe HA (FVIII: C: <1%), a carrier of an inversion of intron 22 type 1, was diagnosed at 2 months of age. He had a family history of hemophilia in the maternal line, including his grandfather and nephews. However, he was the first one in the family to present inhibitors.\n\nSince he was 2 months of age, he received on-demand plasma-derived FVIII only; inhibitor presence was suspected at 11 months of age, after exposure number 19 due to an uncontrolled bleeding episode. The diagnosis of high-titer FVIII inhibitor was established when a factor VIII inhibitor of 384 Bethesda units (BU) was detected. Once the inhibitor was diagnosed, the management of bleeding events started with recombinant FVIIa (rFVIIa) only while waiting for them to decrease in order to have an initiation of immunotolerance. The first central venous catheter was installed and prophylaxis with rFVIIa was initiated with a significant decrease of bleeding events, although they did not disappear. When hemorrhagic events occurred despite prophylaxis, the response to rFVIIa was variable and often had to be changed to activated prothrombin complex concentrates, and on some occasions, it was used sequentially. Immunotolerance began with 14 BU and receipt of 160 IU/kg of rFVIIa daily. The highest peak after starting induction of immune tolerance was 1190 BU. He experienced 3 years of failure of induction of immune tolerance, during which period the catheters had to be changed twice due to infections, and was maintained with rFVIIa prophylaxis. After that, due to venous access problems, the patient was unable to continue with prophylaxis. In addition, the response to BPAs in episodic cases of bleeding was highly variable, leading to treatment with on-demand BPAs being ended. By the year before initiating treatment with emicizumab, the patient had developed arthropathy in both ankles, a knee, and an elbow, which were assessed by using Hemophilia Joint Health Score (HJHS) tool. Synoviorthesis of the right elbow and right ankle was successfully conducted. Despite the patient’s young age, the use of a wheelchair was required because multiple joints were compromised.\n\nIntervention\n\nIn the year before initiating treatment with emicizumab, the patient received episodic treatment with BPAs and had 18 bleeding episodes. Therefore, the emicizumab prophylactic treatment was started following the manufacturer’s recommendation for administration (loading dose: 3 mg/kg subcutaneously once weekly for 4 weeks; maintenance dose: 1.5 mg/kg subcutaneously once weekly).\n\nPrimary Variables\n\nA year before treatment with emicizumab began, the child’s weight was 24.5 kg and his height was 1.27 m; his body mass index was 15.1 kg/m2, placing him in the 34th percentile for children aged 8 years, indicating a healthy weight. After 1 year of using emicizumab, his weight was 34.4 kg and height 1.4 m, resulting in a body mass index of 17.5, putting the patient in the 66th percentile for children aged 10 years, indicating a healthy weight.\n\nBleeding Episodes\n\nAs mentioned previously, during the year before prophylaxis treatment with emicizumab started, the patient was treated with BPAs and had 18 bleeding episodes (all requiring attention in the Emergency Department). Two breakthrough bleeding episodes resulted in the patient’s hospitalization due to severe hematuria. Eight episodes were related to hemarthrosis, affecting the left ankle 6 times and the right and left elbow 1 time each. The other 8 episodes were related to hematoma, affecting the hand, thigh and right leg, right and left ankles, and big toe and left arm.\n\nDuring the year of prophylactic treatment with emicizumab, the patient experienced only 1 bleeding episode, which did not require treatment with BPAs. It was a mild otorrhagia associated with suppurative otitis, which received the usual otitis treatment.\n\nIn a comparison of the 2 treatment regimens (ie, episodic treatment with BPAs vs prophylaxis with emicizumab) with regard to bleeding episodes, we found a reduction of 94.4% (18 vs 1). It is worth noting the significant 100% reduction in joint bleeds during the prophylaxis period with emicizumab, which was one of the greatest long-term cessation of joint bleeds that this patient has experienced.\n\nAssessment of Joint Health\n\nThe HJHS tool was used to assess the patient’s joint health. During the episodic treatment year (7 months preceding the beginning of the emicizumab treatment) and after 1 year on prophylactic treatment with emicizumab, the scoring was 39 and 19, respectively.\n\nAssessment of Pain\n\nPain was assessed using the visual analogue scale (VAS) at 2 different times: at baseline (a full year of episodic treatment with BPAs) with a score of 5/10, and after 1 year on prophylactic treatment with emicizumab (VAS: 0/10). Both the patient and his caregivers considered him as being free of pain.\n\nQuality of Life\n\nThe short version of the Haemo-QoL instrument for children with hemophilia in the age range of 8 to 17 years of age, containing 35 items, scored on 9 scales was used to assess the QoL [10]. Scoring instructions for Haemo-QoL were analyzed according to the developer’s manual. Mean Haemo-QoL is the sum of coded items divided by 35, when at least 29 items have been answered; the scores obtained here were self-reported by the patient. The dimension values correspond to the standardized score, which falls in a range of 0 to 100. A high value indicates a poor QoL, while a lower value indicates a better QoL (Figure 1). The scores obtained were self-reported by the patient.\n\nPrimary variables are summarized in Table 1.\n\nSecondary Variables\n\nDirect and indirect costs were considered to estimate the economic burden.\n\nDirect Costs\n\nA total savings of US$492 941 (70%) was found in a comparison of the costs of prophylaxis with emicizumab versus the costs of treatment with episodic BPAs (Table 2). We analyzed the related costs in terms of treatments, laboratory tests, hospitalizations, and transfers to health institution. As reported in the literature, we also found that the vast majority of the total cost of the disease is associated with the coagulation factor concentrate used [11].\n\nIndirect Costs\n\nA total of US$15 388 was the increase in the household income after emicizumab was initiated, including savings due to the reduction in bleeding episodes. We considered the work downtime of the mother and the impact on elementary education. Before emicizumab, the mother was exclusively dedicated to childcare.\n\nRegarding education issues, before using emicizumab, the child had hospital classroom support because he was not able to attend school. Once prophylactic treatment was initiated with emicizumab, he was able to attend to school in a usual way, and he was fully integrated in social activities with his peers.\n\nDiscussion\n\nInitially, and due to the frequency of bleeding episodes, the patient described in this case report required continuous visits to the hospital to treat his symptoms. After his treatment with emicizumab, his bleeding episodes were reduced by 94.4%, which had a significant impact in terms of his improved QoL. All dimensions of the Haemo-QoL questionnaire showed a better perception of the child’s QoL after initiating treatment with emicizumab, highlighting the improvement in physical health, which has allowed the child to engage in normal activities of his age. Pain evolution assessed by applying the VAS went from a score of 5 (moderate) to a score of 0 (no pain). It should be noted that pain perception decreased, indicating imminent relief in his daily life. HJHS went from 39 to 19, between episodic and prophylactic periods, which is consistent with VAS descending and improvement of physical health and sport dimensions of QoL, improvements that will decrease long-term morbidity and hopefully decrease the need for costly orthopedic procedures when the patient is older. The standardized QoL score went from 66.4 (1 year before emicizumab) to 9.3 (1 year after emicizumab). This score evolution is mainly explained by the dimensions that showed the greatest improvement, as described in Figure 1. Regarding the treatment dimension, it should be noted that treatment was carried out in a less traumatic way, since the child was administered treatment at home instead of in a hospital Emergency\n\nDepartment. The improvement in the friendship dimension can be explained by the child being able to interact in a fluent and regular way and with higher confidence with his friends after he received treatment with emicizumab. Additionally, the improvement in QoL not only had a positive impact directly on the patient, but also on his parents, especially his mother because she was able to resume normal work activities.\n\nIn terms of economic burden, the use of prophylaxis with emicizumab meant a 70% reduction in total costs versus the costs of the episodic treatment with BPAs. The elevated treatment costs explained practically the entire global cost of the disease, before and after the use of emicizumab in this child. Despite emicizumab having been shown to decrease the bleeding rate, access to this therapy in low-income countries in South America, specifically Chile, has not yet been systematically incorporated into treatment options due to the high cost of its use as a continuous prophylaxis therapy and because it has been on the market for only a short time. Treatment with emicizumab meant a significant reduction in disease total costs compared with previous treatments in this patient. Excluding treatment costs, the savings for the family was US$3548, which meant an 82% reduction compared with the period before using emicizumab. These data show that prophylaxis with emicizumab is a cost-saving measure compared with on-demand treatment with BPAs.\n\nIn this patient, the use of emicizumab had significant effects on pain evolution, improved QoL, and reduced the economic burden after 1 year of treatment.\n\nThe current standard practice in Chile for patients with HA with inhibitors is treatment with BPAs. The results obtained in this case report indicate that emicizumab is not only more cost-effective for this patient, but also for the health care system due to the immediate and likely long-term reduction in direct costs.\n\nEmicizumab is not routinely available in Chile, where its implementation is limited due to concerns about the prohibitive cost. However, health care policy makers should consider the cost-effectiveness of this treatment. Initiating prophylaxis therapy with emicizumab for all patients with HA with inhibitors and for those in whom immunotolerance has failed or for those who do not have the opportunities to have it could generate considerable cost savings for the health care system.\n\nThe new World Federation of Hemophilia treatment guidelines indicate that patients with refractory inhibitors should be on prophylaxis, and emicizumab is the preferred treatment [5].\n\nConclusions\n\nThe data obtained from this study show that, after 1 year of treatment with emicizumab, bleeding events decreased to only 1 per year, the HJHS was reduced from 39 to 19, the intensity of pain was reduced by 5 points, QoL perception increased by 86%, and the total cost of the disease decreased by 70%. Further studies are required to confirm the findings presented in this report indicating that emicizumab prophylaxis in this patient population would be beneficial in countries that currently limit access due to financial concerns.\n\nWe would like to thank to Dr. S. von Mackensen and the Haemo-QoL group for granting their permission to use the Spanish version of Haemo-QoL-kids (8-16) instrument. We would also like to thank to Marcelo Riquelme, Pablo García, and Ricardo Cuevas from B-TRIALS for editorial assistance.\n\nFigure 1. Haemo-QoL standardized score by dimension. The 9 dimensions were sorted from highest to lowest, and the differences between before and after treatment were analyzed for each dimension. Haemo-QoL is a quality of life assessment instrument for children with hemophilia.\n\nTable 1. Primary variables.\n\n\t1 year episodic treatment with BPAs\t1 year prophylactic treatment with emicizumab\t\nNumber of Breakthrough bleeds\t18\t1\t\nNumber of hospitalizations\t2\t0\t\nHospitalizations days\t5\t0\t\nBleeding episodes diagnosis\t\t\t\n Hematuria*\t2\t0\t\n Hematoma*\t7\t0\t\n Hemarthrosis*\t9\t0\t\n Suppurative otitis\t0\t1\t\nVAS Score**\t5\t0\t\nHemophilia Joint Health Score (HJHS)\t39\t19\t\nTotal Haemo-QoL\t128\t48\t\nMean Haemo-QoL\t3.6\t1.37\t\nStandardized Haemo-QoL\t66.4\t9.3\t\n* Spontaneous bleeding;\n\n** Visual Analogue Scale Pain. Haemo-QoL – Quality of life assessment instrument for children with haemophilia.\n\nSource: Author’s elaboration using data from Pediatrics Service, Hospital San Pablo, Coquimbo, Chile.\n\nTable 2. Direct costs.\n\nCosts (USD)\t1 year before emicizumab\t1 year after emicizumab\tVariation\t\nExams\t1,512\t77\t−94.9%\t\nMedical fees\t1,300\t66\t−94.9%\t\nHospitalizations\t632\t0\t−100.0%\t\nMedications\t683,832\t206,279\t−69.8%\t\nTravels\t854\t607\t−29.1%\t\nJob opportunity cost\t11,839\t0\t−100.0%\t\nTotal\t699,969\t207,028\t−70.4%\t\nMedication cost as percentage of total cost\t97.7%\t99.6%\t\t\n\nConflict of Interest\n\nWriting of this study was supported by Hoffmann-La Roche (Roche-Chile).\n==== Refs\nReferences:\n\n1. Ministry of Health of Chile Haemophilia Clinical Guide. MINSAL Clinical Guides Series Santiago Minsal 2013 [cited 2021 Mar 1]. https://www.minsal.cl/sites/default/files/Guia_Hemofilia.pdf\n2. Cassis FR Buzzi A Forsyth A Haemophilia Experiences, Results and Opportunities (HERO) Study: Influence of haemophilia on interpersonal relationships as reported by adults with haemophilia and parents of children with haemophilia Haemophilia 2014 20 04 e287 95 24800872\n3. Srivastava A Brewer AK Mauser-Bunschoten EP Guidelines for the management of hemophilia Haemophilia 2013 19 1 e1 47 22776238\n4. Blanchette VS Key NS Ljung LR Definitions in hemophilia: Communication from the SSC of the ISTH J Thromb Haemost 2014 12 11 1935 39 25059285\n5. Srivastava A Santagostino E Dougall A WFH guidelines for the management of hemophilia, 3rd edition Haemophilia 2020 26 Suppl. 6 1 158 32744769\n6. Rieger A Roisenberg I Prevalence of factor VIII inhibitors in patients with hemophilia A in Brazil Thromb Haemost 1999 81 475 76 10102489\n7. Wight J Paisley S The epidemiology of inhibitors in hemophilia A: A systematic review Haemophilia 2003 9 418 35 12828678\n8. Chen SL Economic costs of hemophilia and the impact of prophylactic treatment on patient management Am J Manag Care 2016 22 S126 33 27266809\n9. Young G Liesner R Chang T A multicenter, open-label, phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors Blood 2019 134 24 2127 38 31697801\n10. von Mackensen S Bullinger M Haemo-QoL Group Development and testing of an instrument to assess the Quality of Life of Children with Haemophilia in Europe (Haemo-QoL) Haemophilia 2004 10 Suppl. 1 17 25\n11. Duncan N Roberson C Lail A A haemophilia disease management programme targeting costs and utilization of specialty pharmaceuticals Haemophilia 2014 20 519 26 24456125\n\n",
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"abstract": "Triptorelin, a gonadotropin releasing hormone analogue, can be administered to postpubertal female individuals with cancer who receive chemotherapy to obtain menstrual suppression and decrease the risk of hemorrhage caused by thrombocytopenia. Our goal was to assess whether triptorelin also has a protective role against the gonadotoxicity of chemotherapy.\n\n\n\nThis retrospective observational study includes all postmenarchal female patients who presented to our Unit from 2000 to 2015 and received chemotherapy for cancer. They were administered depot triptorelin. We evaluated long-term ovarian function in order to detect clinical signs of ovarian damage, miscarriages, and pregnancies. Laboratory follow-up consisted in dosing serum follicle stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone. Ultrasound of the ovaries was performed as well.\n\n\n\nOf 36 evaluable patients, 9 received hematopoietic stem cell transplantation (HSCT). The remaining 27 patients maintained normal ovarian function at clinical, laboratory, and ultrasound assessment. Five of them achieved spontaneous physiological pregnancy. Four of the 9 patients who underwent HSCT developed premature ovarian failure.\n\n\n\nOur study suggests that gonadotropin releasing hormone-a administered during chemotherapy can prevent premature ovarian failure in patients treated without HSCT and that it is not enough to preserve the ovarian function during HSCT. Hence, a prospective randomized trial with a larger population would be recommended.",
"affiliations": "Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.;Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine.",
"authors": "Meli|Mariaclaudia|M|;Caruso-Nicoletti|Manuela|M|;La Spina|Milena|M|;Nigro|Luca Lo|LL|;Samperi|Piera|P|;D'Amico|Salvatore|S|;Bellia|Francesco|F|;Miraglia|Vito|V|;Licciardello|Maria|M|;Cannata|Emanuela|E|;Marino|Silvia|S|;Cimino|Carla|C|;Puglisi|Federica|F|;Valvo|Laura Lo|LL|;Pezzulla|Agnese|A|;Russo|Giovanna|G|;Di Cataldo|Andrea|A|",
"chemical_list": "D000970:Antineoplastic Agents; D017329:Triptorelin Pamoate; D011374:Progesterone; D004958:Estradiol; D011388:Prolactin; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone",
"country": "United States",
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"issn_linking": "1077-4114",
"issue": "40(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D004958:Estradiol; D005260:Female; D059247:Fertility Preservation; D005640:Follicle Stimulating Hormone; D005500:Follow-Up Studies; D006801:Humans; D007986:Luteinizing Hormone; D009369:Neoplasms; D010053:Ovary; D016649:Primary Ovarian Insufficiency; D011374:Progesterone; D011388:Prolactin; D012189:Retrospective Studies; D017329:Triptorelin Pamoate",
"nlm_unique_id": "9505928",
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"pages": "269-276",
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"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Triptorelin for Fertility Preservation in Adolescents Treated With Chemotherapy for Cancer.",
"title_normalized": "triptorelin for fertility preservation in adolescents treated with chemotherapy for cancer"
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"companynumb": "IT-ADIENNEP-2018AD000292",
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"abstract": "BACKGROUND\nSymptoms of theophylline toxicity and factors that augment the risk of developing it are well documented in the literature. However these appear to be poorly considered in clinical practice. This case underlines the challenges in recognising and managing theophylline toxicity; moreover the requirement for improved application of knowledge of its pharmacokinetics to our practice.\n\n\nMETHODS\nIn this case we observe how theophylline toxicity can be overlooked due to the presence of non-specific symptoms and lack of a structured system to mitigate error in detection, in both hospital medicine and general practice. Here, the initial theophylline concentration measurement was documented as 59.3 mg/l in a patient taking the medication long-term, with the previous concentration being recorded one year prior. Management consisted of suspension of theophylline along with best supportive care, however in the process other conditions were exacerbated and the patient ultimately died in hospital. Congestive cardiac failure, congestive liver disease and polypharmacy were factors isolated from this case that expedited the patients' development of theophylline toxicity. This was perpetuated by delay in diagnosis due to presentation with generalised symptoms including tachycardia, vomiting and neurological symptoms.\n\n\nCONCLUSIONS\nFindings from this case necessitate a requirement for more stringent monitoring of theophylline when taken chronically in those who demonstrate risk factors for toxicity. This would aim to prevent accumulation of the drug, toxicity onset and subsequent acute presentation to hospital. Intervention, through charcoal haemoperfusion may provide a means of enhanced recovery to reduce sequelae of toxicity.",
"affiliations": "Foundation Year 1 Doctor. Royal United Hospital NHS Foundation Trust, Combe Park, Bath, BA1 3NG, UK. michael.hopkins2@nhs.net.;Consultant Respiratory Physician. Royal United Hospital NHS Foundation Trust, Combe Park, Bath, BA1 3NG, UK. rob.mackenizeross@nhs.net.",
"authors": "Hopkins|Michael E|ME|;MacKenzie-Ross|Robert V|RV|",
"chemical_list": "D001993:Bronchodilator Agents; D013806:Theophylline",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-016-0050-4",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 5010.1186/s40360-016-0050-4Case ReportCase Report: The risks associated with chronic theophylline therapy and measures designed to improve monitoring and management Hopkins Michael E. michael.hopkins2@nhs.net MacKenzie-Ross Robert V. rob.mackenizeross@nhs.net Foundation Year 1 Doctor. Royal United Hospital NHS Foundation Trust, Combe Park, Bath, BA1 3NG UK Consultant Respiratory Physician. Royal United Hospital NHS Foundation Trust, Combe Park, Bath, BA1 3NG UK 5 3 2016 5 3 2016 2016 17 1322 10 2015 12 2 2016 © Hopkins and MacKenzie-Ross. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSymptoms of theophylline toxicity and factors that augment the risk of developing it are well documented in the literature. However these appear to be poorly considered in clinical practice. This case underlines the challenges in recognising and managing theophylline toxicity; moreover the requirement for improved application of knowledge of its pharmacokinetics to our practice.\n\nCase Presentation\nIn this case we observe how theophylline toxicity can be overlooked due to the presence of non-specific symptoms and lack of a structured system to mitigate error in detection, in both hospital medicine and general practice. Here, the initial theophylline concentration measurement was documented as 59.3 mg/l in a patient taking the medication long-term, with the previous concentration being recorded one year prior. Management consisted of suspension of theophylline along with best supportive care, however in the process other conditions were exacerbated and the patient ultimately died in hospital. Congestive cardiac failure, congestive liver disease and polypharmacy were factors isolated from this case that expedited the patients’ development of theophylline toxicity. This was perpetuated by delay in diagnosis due to presentation with generalised symptoms including tachycardia, vomiting and neurological symptoms.\n\nConclusions\nFindings from this case necessitate a requirement for more stringent monitoring of theophylline when taken chronically in those who demonstrate risk factors for toxicity. This would aim to prevent accumulation of the drug, toxicity onset and subsequent acute presentation to hospital. Intervention, through charcoal haemoperfusion may provide a means of enhanced recovery to reduce sequelae of toxicity.\n\nKeywords\nTheophyllineToxicologyPharmacokineticsDrug InteractionsDrug adverse effectsissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nTheophylline is a member of the methylxanthine class of medications and is typically used in the management of patients with airway disorders such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. This is due to its relaxing effect on smooth muscle within the bronchi and pulmonary vasculature, as well as stimulating central respiratory drive [1]. Theophylline is used in the management of reversible airways obstruction or exacerbations of COPD [2], it is typically an adjunct to other, more commonly prescribed medications, such as beta-2 agonists and steroids. The dose is typically started at 225 mg BD and then increased to 450 mg BD after one week. Classically, theophylline is not prescribed as a first-line medication due to its narrow therapeutic index, the British National Formulary (BNF) suggest target plasma concentrations of 10–20 mg/l [2].\n\nThis case outlines an example of the severity of adverse effects demonstrated by theophylline; furthermore we explore the pitfalls in recognising theophylline toxicity, particularly when taking the medication chronically. Many of the typical symptoms of theophylline toxicity are non-specific, which further perpetuates the challenges of recognition in a long-term user. These include nausea, vomiting, fatigue, tachycardia and central nervous system (CNS) effects such as dizziness and seizures [3]. When given in the acute setting, more precautions are taken to monitor serum concentrations. However it appears we are less stringent on monitoring when the medication is taken chronically, as exemplified in this case. The BNF suggests monitoring every 6–12 months for those patients on a stable dose [4]. However significant individual variations in hepatic metabolism of the drug also contribute to a difficulty in maintaining a therapeutic concentration.\n\nThe aim of this report is to provide a case-based example to advocate more stringent theophylline concentration monitoring, particularly in patients considered high risk for toxicity. The intention is to help prevent toxicity occurring in patients taking this medication long-term.\n\nCase Presentation\nMrs. E was a 57-year-old lady with a 12-year history of COPD, with an FEV1 of 30 %. Furthermore, she had a past medical history of carcinoma of the breast, type 2 diabetes mellitus and left ventricular failure (LVF), which was diagnosed on an echocardiogram (ECHO) in July 2014. Despite a diagnosis of COPD she continued to smoke 20–30 cigarettes/day.\n\nShe was prescribed a number of medications to help manage her airways disease including tiotropium, seretide 500, salbutamol, prednisolone and most recently oral theophyline (450 mg twice daily), which was started in April 2013 as an adjunct to her current medications.\n\nShe was admitted in June 2015 following a fall with notable decreased sensation bilaterally in her lower limbs and a tachycardia of 133 beats per minute. Spinal cord compression was an initial concern, however this was excluded with a magnetic resonance imaging (MRI) spine. There was no change to her theophylline prescription on admission to hospital and no new medication was prescribed that would affect theophylline metabolism.\n\nOver several days additional symptoms were noted, including worsening nausea, blurred vision, increasing fatigue (with stable blood sugars) and worsening speech with slurring of words. Development of vomiting resulted in a decision to measure her theophylline concentration and perform a CT head, as no obvious cause for her symptoms had been elicited. The CT head was reported as clear of any ischaemia, haemorrhage or space-occupying lesion.\n\nThe trough theophylline concentration was 59.3 mg/l. The last result obtained in July 2014 during an admission for influenza related infective exacerbation of COPD was reported as 20.2 mg/l, marginally above the 10-20 mg/l recommended reference range. The concentration was then not re-checked either in primary care or in hospital; it therefore became apparent this was a case of chronic theophylline toxicity.\n\nManagement\nThe medical team at The National Poisons Information Service was contacted for advice on management of this patient. The rationale being abnormally high theophylline concentration, furthermore this was a case of chronic, rather than acute toxicity, for which we felt specialist input was required.\n\nThe patient was monitored for significant effects of toxicity; these include seizures (reported at trough concentrations of 50 mg/l [5]), reduced conscious level and tachyarrhythmias. Although Mrs. E suffered a persistent tachycardia, her heart rate remained in sinus rhythm. Cardiac monitoring was started. She was managed conservatively by stopping the theophylline and monitoring symptoms. Due to vomiting, oral activated charcoal was excluded and although charcoal haemoperfusion was discussed, it was not accessible at the RUH and as Mrs. E was haemodynamically stable and not acidotic, it was deemed not to be essential. This point will be discussed further in the conclusion.\n\nMrs. E developed electrolyte imbalances not long after the vomiting started, suffering hypokalaemia (3.2 mmol/l), hypomagnaesemia (0.56 mmol/l) and hypocalcaemia (1.96 mmol/l). This was postulated to be secondary to both vomiting and theophylline accumulation. This subsequently resulted in a pseudo-obstruction, diagnosed on abdominal x-ray. A nasogastric tube was placed and she was supplemented with appropriate electrolytes via intravenous infusion. An arterial blood gas demonstrated a pH 7.398 (7.34-7.44), pO2 (kPa) 9.24 (11–14), pCO2 (kPa) 6.36 (4.7-6.0), HCO3− (mEq/l) 21.7 (22–26), lactate (mmol/l) 1.5 (0.4-2.2). As no signs of acidosis were present and bicarbonate was at the low end of the normal range, we decided not to prescribe bicarbonate for this patient.\n\nAfter stopping her theophylline and without any active intervention her serum concentration fell gradually (Table 1). By the time her theophylline concentration was within therapeutic range, her electrolytes had been corrected and her pseudo-obstruction had resolved. However, she developed signs of fluid overload, her heart rate also remained in persistent sinus tachycardia. Notably, findings of Congestive Cardiac Failure (CCF) were demonstrated on a previous echocardiogram and were substantiated by results of her computed tomography (CT) abdomen/pelvis and ultrasound sonography scan (USS) liver during her current admission; these both showed abnormal appearances of the liver consistent with cardiac dysfunction. It therefore appeared she had developed acute CCF. Ultimately, this resulted in challenging fluid balance management with serial chest x-rays demonstrating worsening bilateral effusions and renal function continuing to decline until the death of the patient.Table 1 Theophylline measurements post stopping of the medication\n\nTime after initial measurement\tTheophylline Level (mg/L)\t\nInitial Measurement\t59.3\t\n12 h\t51.6\t\n24 h\t43.4\t\n48 h\t31.1\t\n3 days\t22.8\t\n4 days\t15.4\t\n5 days\t10.1\t\nSerial theophylline readings recorded after stopping the medication. Initial reading was a trough measurement post stopping the medication. Theophylline reference range 10-20 mg/L\n\n\n\nDiscussion\nThere are a number of key learning points to draw from this case, pertaining to multiple areas of clinical practice. In retrospect, it remains difficult to understand exactly to what extent theophylline toxicity contributed to the death of this patient with multiple co morbidities. However, what is clear from the literature and from this case is that toxic theophylline concentrations can result in significant morbidity with potentially fatal outcomes [6].\n\nAs a medication with a narrow therapeutic index and an inexorable correlation between plasma concentration and therapeutic/toxic effects, there should be an impetus on close monitoring of serum concentration. Theophylline is rapidly and completely absorbed after oral administration and freely distributes throughout fat-free tissues. The drug is primarily metabolised by the cytochrome P450 liver enzyme, CYP1A2, and also eliminated via the hepatic route, with a half life of 9 h [7, 8]. There are a number of medications and conditions that can impact on this, rendering theophylline a difficult drug to manage. One such condition is CCF with hepatic congestion, which has been demonstrated to reduce the clearance by 50 % and double the half life, thereby reducing drug elimination and increasing concentrations [5, 9, 10]. Other recognised factors which can reduce theophylline clearance include increased age and liver enzyme inhibiting medications [11, 12]. A key point that pertains to this case is that smoking is an inducer of CYP1A2. We recognise that Mrs. E continued to smoke until her final hospital admission, which theoretically would confer an increased elimination of theophylline and act as protective mechanism against the development of toxicity. To our knowledge she was receiving no medications that are inhibitors of this enzyme. However it is critical to recognise these (Table 2.) as well as identifying recent smoking cessation; as these could both significantly impact on theophylline concentrations [13].Table 2 Medications that inhibit the liver enzyme CYP1A2\n\nCYP1A2 inhibitors\t\nAtazanavir\t\nCimetidine\t\nCiprofloxacin\t\nEnoxacin\t\nEthinyl Estradiol\t\nFluvoxamine\t\nThiabendazole\t\nList outlining some commonly prescribed medications that are recognised to inhibit CYP1A2\n\n\n\nIndeed, we should approach treating patients with theophylline, who have underlying CCF, with increased caution. With data demonstrating that elimination time of the drug can be doubled [9, 10] with this condition, there should be a greater onus on primary care physicians, as well as hospital clinicians to monitor the serum concentration to avoid chronic intoxication. It is sub-standard practice to neglect to monitor theophylline concentrations for over a year in a patient with established CCF, particularly when they have had a previously high reading [14]. The BNF suggests that serum concentrations should be measured every 6–12 months in patients with a stable dose after 5 days [3]. However it would be reasonable to suggest that those patients who have risk factors for reduced elimination or metabolism of the drug, such as CCF or liver disease, are monitored at least every 6 months to avoid the manifestation of significant intoxication and avoid acute presentation.\n\nWhen discussing with Mrs. E the reasons behind her admission, it was interesting to hear that neither she, nor her full-time carer, knew the name theophylline or its indication. In cases of polypharmacy like this, it can be challenging for patients to remember all medications, their indication and associated adverse effects. This further substantiates the argument for responsibility within healthcare professionals to provide close monitoring and support for these vulnerable patients.\n\nIndeed there were shortcomings in patient management in this case, however it is recognising intoxication that poses one of the key challenges. This difficulty can be attributed to the generalised symptoms displayed by the patient. Neurological symptoms, fatigue, vomiting, blurred vision; these are all symptoms that could be a manifestation of multiple other disorders, especially in a patient with multiple co-morbidities. Other reports have described concomitant findings, outlining the challenges of diagnosing theophylline toxicity in hospital due to the broad array of symptoms at presentation [4]. We postulate that better education around toxicology and an increased awareness of chronic theophylline toxicity, as well as serum concentration screening for all patients who come through the emergency department taking this medication, may help improve outcomes within the hospital setting.\n\nWith regards to intervention, one study demonstrated that in cases of severe theophylline toxicity (trough concentration >48 mg/l) there was a significant reduction in morbidity and mortality to those patients who underwent charcoal haemoperfusion [15]. This increases theophylline clearance from the normal endogenous value of 50 ml/kg/h up to 157 ml/kg/h [16]. In future cases, it would be interesting to observe whether charcoal haemoperfusion would enhance recovery from theophylline toxicity and improve patient outcomes as the literature tenuously suggests [15]? At what serum concentration would you expect to see a consistently significant benefit from this therapy? Further research is required into charcoal haemoperfusion as well as incidence of theophylline toxicity before this intervention can become more widely available across hospitals.\n\nConclusions\nFindings from this case necessitate a requirement for more stringent monitoring of theophylline when taken chronically in those who demonstrate risk factors for toxicity. This would aim to prevent accumulation of the drug, toxicity onset and subsequent acute presentation to hospital. Intervention, through charcoal haemoperfusion may provide a means of enhanced recovery to reduce sequelae of toxicity.\n\nEthics\nConsent to publish\nDue to the unfortunate death of the patient in our case report, consent to publish this report was obtained from her daughter (her next of kin). A written copy of this consent form is available for review from the series editor of this journal.\n\nFormal approval from an ethics committee has not been sought as this is a ‘Case-Report’ and therefore does no require research ethics committee approval.\n\nAvailability of supporting data and materials\nAll relevant data for this case report was collected from the case notes of the patient discussed. Although confidentiality must be maintained, these case notes can be acquired from the medical records department at the Royal United Hospital, Bath.\n\nAbbreviations\nBNFBritish national formulary\n\nCCFcongestive cardiac failure\n\nCNScentral nervous system\n\nCOPDchronic obstructive pulmonary disease\n\nCTcomputed tomography\n\nECHOechocardiogram\n\nLVFleft ventricular failure\n\nMRImagnetic resonance imaging\n\nRUHroyal united hospital\n\nUSSultrasound sonography scan\n\nCompeting interests\n\nThe authors declare they have no competing interests\n\nAuthors’ contributions\n\nMEH–Primary author. Conceptualised the case study, involved in background research, data collation and drafting the manuscript. RVM-R–Involved in critically revising the content of the manuscript. Ensuring the data included was correct and accurate. All read and approved the final manuscript.\n\nAuthors’ information\n\nMEH–Foundation Year 1 Doctor, RUH, Bath. MBChB, BSc (Hons.)\n\nRVM-R–Consultant Respiratory Physician, RUH, Bath. MB BChir, MRCP.\n\nWe thank the National Poisons Information Service (Cardiff) for their help in management of this case.\n==== Refs\nReferences\n1. Ebadi M Alphabetical presentation of drugs–Aminophylline Desk Reference of Clinical Pharmacology. 2nd Ed. CRC Press 2007 62 63 \n2. British National Formulary. Airways Disease, obstructive. 70th Edition. September 2015-March 2016. pp237-238.\n3. Mohamad N Nizam Abd Halim N Ahmad R Baharuddin KA Theophylline toxicity: A case report of the survival of an undiagnosed patient who presented to the emergency department Malays J Med Sci 2009 16 2 33 37 22589656 \n4. Khan S, Jones S, Preston CL. Theophylline Interactions. The Pharmaceutical Journal. 2014;293:7818.\n5. Zwillich CW Sutton FD Jr Neff TA Cohn WM MD Matthay RA Weinberger MM MILESM Theophylline-Induced Seizures in Adults: Correlation with Serum Concentrations Ann Intern Med 1975 82 6 784 787 10.7326/0003-4819-82-6-784 237450 \n6. Shannon M Predictors of Major Toxicity after Theophylline Overdose Ann Intern Med 1993 119 12 1161 1167 10.7326/0003-4819-119-12-199312150-00002 8239246 \n7. Hosenpud JD Greenberg BH Clinical Pharmacokinetics in Congestive Cardiac Failure Congestive Heart Failure 2007 3 Lippincott Williams and Wilkins 431 432 \n8. van der Weide J Steijns LS Van Weelden MJ The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement 2003 13 3 169 172 \n9. Jusko WJ Gardner MJ Mangione A Schentag JJ Koup JR Vance JW Factors affecting theophylline clearances: Age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol J Pharm Sci 2006 68 11 1358 1366 10.1002/jps.2600681106 41932 \n10. Kuntz HD Straub H May B Theophylline elimination in congestive heart failure J Mol Med 1983 61 21 1105 1106 \n11. Jonkman JH Upton RA Pharmacokinetic drug interactions with theophylline Clin Pharmacokinet 1984 9 4 309 334 10.2165/00003088-198409040-00002 6147220 \n12. Mangoni AA Jackson SD Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications Br J Clin Pharmacol 2004 57 1 6 14 10.1046/j.1365-2125.2003.02007.x 14678335 \n13. Kroon LA Drug interactions with smoking Am J Health Syst Pharm 2007 64 1917 1921 10.2146/ajhp060414 17823102 \n14. LeGatt DF Theophylline toxicity--a consequence of congestive heart failure Drug Intell Clin Pharm 1983 17 1 59 60 6825561 \n15. Park GD Spector R Roberts RJ Goldberg MJ Weismann D Stillerman A Flanigan MJ Use of hemoperfusion for treatment of theophylline intoxication Am J Med 1983 74 6 961 966 10.1016/0002-9343(83)90790-8 6859064 \n16. Ehlers SM Zaske DE Sawchuk RJ Massive Theophylline OverdoseRapid Elimination by Charcoal Hemoperfusion JAMA 1978 240 5 474 475 10.1001/jama.1978.03290050064026 96282\n\n",
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"mesh_terms": "D001993:Bronchodilator Agents; D003131:Combined Modality Therapy; D057210:Delayed Diagnosis; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D006333:Heart Failure; D006801:Humans; D007866:Leg; D017093:Liver Failure; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D010523:Peripheral Nervous System Diseases; D019338:Polypharmacy; D029424:Pulmonary Disease, Chronic Obstructive; D012640:Seizures; D013610:Tachycardia; D013806:Theophylline",
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"title": "Case Report: The risks associated with chronic theophylline therapy and measures designed to improve monitoring and management.",
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"abstract": "We report 2 patients with drug-resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies.",
"affiliations": "Division of Pediatric Neurology, Department of Pediatrics and Department of Neurobiology, Duke University School of Medicine, Durham, NC.;Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC.;Division of Cardiology, Department of Pediatrics, Duke University School of Medicine, Durham, NC.;Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC.;Center for Human Genome Variation, Duke University School of Medicine, Durham, NC.;Center for Human Genome Variation, Duke University School of Medicine, Durham, NC.;Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.;Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.;Department of Neurology, Wake Forest University, Winston-Salem, NC.;Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC.;Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.;Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.;Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.;Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC.;Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.;Center for Human Genome Variation, Duke University School of Medicine, Durham, NC.",
"authors": "Mikati|Mohamad A|MA|;Jiang|Yong-Hui|YH|;Carboni|Michael|M|;Shashi|Vandana|V|;Petrovski|Slave|S|;Spillmann|Rebecca|R|;Milligan|Carol J|CJ|;Li|Melody|M|;Grefe|Annette|A|;McConkie|Allyn|A|;Berkovic|Samuel|S|;Scheffer|Ingrid|I|;Mullen|Saul|S|;Bonner|Melanie|M|;Petrou|Steven|S|;Goldstein|David|D|",
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"mesh_terms": "D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D011802:Quinidine",
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"title": "Quinidine in the treatment of KCNT1-positive epilepsies.",
"title_normalized": "quinidine in the treatment of kcnt1 positive epilepsies"
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"abstract": "Although rare cases of prolymphocytic transformation from splenic B-cell lymphomas and follicular lymphoma have been reported, prolymphocytic transformation from lymphoplasmacytic lymphoma has not been previously reported. We report a case of 76-year-old-male patient with a history of Waldenström macroglobulinemia diagnosed in 2010 and treated with infusion chemotherapy. He was in clinical remission for 5 years. In 2016, he presented with diffuse lymphadenopathy, and a head and neck lymph node biopsy showed lymphoplasmacytic lymphoma. MYD88 mutation was detected by polymerase chain reaction. A subsequent bone marrow biopsy showed B-cell lymphoma with increased prolymphocytes. Peripheral blood showed numerous circulating prolymphocytes. MYD88 was detected by polymerase chain reaction in the bone marrow. Cerebrospinal fluid was positive for lymphoma cells with prolymphocytic morphology. An IgM κ paraprotein was noted by immunofixation performed on the patient's serum, urine, and cerebrospinal fluid. The patient was resistant to chemotherapy, developed multiorgan failure, and died shortly thereafter.",
"affiliations": "Department of Pathology and Laboratory Medicine, Hematology/Oncology Division, University of California Irvine (UCI) Medical Center, Orange, CA 92868, USA.;Department of Pathology and Laboratory Medicine, Hematology/Oncology Division, University of California Irvine (UCI) Medical Center, Orange, CA 92868, USA.;Department of Medicine, Hematology/Oncology Division, University of California Irvine (UCI) Medical Center, Orange, CA 92868, USA.;Department of Medicine, Hematology/Oncology Division, University of California Irvine (UCI) Medical Center, Orange, CA 92868, USA.;Department of Pathology and Laboratory Medicine, Hematology/Oncology Division, University of California Irvine (UCI) Medical Center, Orange, CA 92868, USA.;Department of Pathology and Laboratory Medicine, Hematology/Oncology Division, University of California Irvine (UCI) Medical Center, Orange, CA 92868, USA. Electronic address: srezk@uci.edu.",
"authors": "Zhang|Kuixing|K|;Farrell|Daniel|D|;Jeyakumar|Deepa|D|;O'Brien|Susan|S|;Zhao|Xiaohui|X|;Rezk|Sherif A|SA|",
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"issn_linking": "0046-8177",
"issue": "90()",
"journal": "Human pathology",
"keywords": "Cerebrospinal fluid; Lymphoplasmacytic lymphoma; Marginal zone lymphoma; Prolymphocytic leukemia; Waldenström macroglobulinemia",
"medline_ta": "Hum Pathol",
"mesh_terms": "D000368:Aged; D002471:Cell Transformation, Neoplastic; D006801:Humans; D008214:Lymphocytes; D018442:Lymphoma, B-Cell, Marginal Zone; D008224:Lymphoma, Follicular; D008297:Male; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "9421547",
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"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Prolymphocytic transformation of lymphoplasmacytic lymphoma: an extremely unusual event.",
"title_normalized": "prolymphocytic transformation of lymphoplasmacytic lymphoma an extremely unusual event"
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"abstract": "Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.\nAdrenocortical carcinoma is an important differential diagnosis for virilization in young childrenMitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosisMitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completedIn our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.",
"affiliations": "Medical School, University of Oxford, Oxford, UK.;Liggins Institute, University of Auckland, Auckland, New Zealand.;Liggins Institute, University of Auckland, Auckland, New Zealand.;Starship Children's Health, Auckland District Health Board, Auckland, New Zealand.;Starship Children's Health, Auckland District Health Board, Auckland, New Zealand.;Starship Children's Health, Auckland District Health Board, Auckland, New Zealand.",
"authors": "Oddie|Philip D|PD|;Albert|Benjamin B|BB|;Hofman|Paul L|PL|;Jefferies|Craig|C|;Laughton|Stephen|S|;Carter|Philippa J|PJ|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-18-0059EDM180059Unusual Effects of Medical TreatmentMitotane in the treatment of childhood adrenocortical carcinoma: a potent endocrine disruptor P D Oddie and othersMitotane in childhood ACC: endocrine disruptorOddie Philip D 1Albert Benjamin B 2Hofman Paul L 23Jefferies Craig 23Laughton Stephen 3Carter Philippa J 31 Medical School, University of Oxford, Oxford, UK2 Liggins Institute, University of Auckland, Auckland, New Zealand3 Starship Children’s Health, Auckland District Health Board, Auckland, New ZealandCorrespondence should be addressed to P J Carter Email philippac@adhb.govt.nz23 8 2018 2018 2018 18-005915 7 2018 31 7 2018 © 2018 The authors2018The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nAdrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.\n\nLearning points:\nAdrenocortical carcinoma is an important differential diagnosis for virilization in young children\n\nMitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis\n\nMitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.\n\nPatients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed\n\nIn our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.\n==== Body\nBackground\nAdrenocortical carcinoma (ACC) is a rare, malignant tumor of the adrenal glands with a bimodal distribution, affecting young children and adults. In children, it can present with virilization secondary to increased androgen levels. The primary treatment modality is surgery, but adjuvant chemotherapy is important (1), especially where there is evidence of residual disease or adverse histology.\n\nMitotane is an adrenal-selective chemotherapeutic agent derived from the insecticide DDT (2). It causes adrenal necrosis, particularly of cells in the zona glomerulosa and zona fasciculata and is associated with improved prognosis in both adults and children with ACC (2, 3). Despite its utility as an adrenal-selective drug, mitotane has a wide-ranging side effect profile including gastrointestinal disturbance, confusion, ataxia and raised liver enzymes (4). In terms of endocrine complications, adrenal insufficiency is near universal and hypothyroidism and gynecomastia have also been reported in adults (4, 5). There is scant data on the drug’s pediatric side effects and no data concerning frequency.\n\nCase presentation\nA 4-year-old girl was referred to pediatric endocrinology with a 6-week history of clitoromegaly and pubic hair development. She was otherwise well, with no clinical evidence of Cushing’s syndrome or estrogen exposure. No concerns were raised regarding her genitalia at birth. On examination, her clitoris was enlarged (length 2.6 cm), no gonads were palpable in the inguinal region and she had Tanner stage 3 pubic hair and prepubertal Tanner stage 1 breast development.\n\nInvestigation\nInitial investigations showed elevated androgens, with estradiol and gonadotrophins in the prepubertal range. The cortisol response to synthetic ACTH was normal (Table 1a) and a pelvic ultrasound demonstrated a prepubertal uterus and ovaries. An abdominal ultrasound scan showed a right adrenal mass, which was subsequently confirmed with MRI. A laparoscopic transperitoneal right adrenalectomy was performed and tissue was sent for histological review at Boston Children’s Hospital resulting in the diagnosis of ACC. The tumor was classed as stage III due to spillage that occurred during surgery, indicating possible residual disease. Multiple unfavorable histological features were present including a high mitotic and proliferative index, atypical mitoses, anaplasia, vascular invasion, capsular invasion and necrosis.\nTable 1 Hormones before, during and after treatment.\n\n\tBaselinea\tPost Opb\tCycle 7c\tCycle 8d\t1 month post cycle 8e\t2.5 month post cycle 8f\t2 month post M-Rxg\t4.5 month post M-Rxh\tReference range\t\nWeeks since diagnosis\t0\t2\t32\t35\t39\t44\t54\t65\t\t\nThyroxine (µg/day)\t0\t0\t0\t25\t32\t37.5\t37.5\t25\t\t\nTestosterone\t6.7\t<0.4\t<0.4\t\t\t\t\t<0.4\t0.0–0.5 nmol/L\t\nDHEA-S\t17.7\t0.2\t<0.01\t\t\t\t\t<0.01\t0.01–0.7 µmol/L\t\nAndrostenedione \t10.9\t<1.0\t<1.0\t\t\t\t\t<1.0\t<2 nmol/L\t\n17-Hydroxyprogesterone\t6.4\t<1.0\t<1.0\t\t\t\t\t<1.0\t<3.5 nmol/L\t\nACTH\t3\t\t133\t\t\t\t<1\t93\t2–11 pmol/L\t\nCortisol\t151\t255\t\t\t\t\t1630\t24\t170–500 nmol/L\t\nPost-ACTH-cortisol\t430\t517\t\t\t\t\t\t\t>400 nmol/L\t\nEstradiol\t<30\t\t<30\t\t\t\t\t<30\t<80 pmol/L\t\nLH (unstimulated)\t<0.1\t\t<0.1\t\t\t\t\t\t0–2.5 IU/L\t\nFSH (unstimulated)\t0.3\t\t0.3\t\t\t\t\t\t0–6.5 IU/L\t\nLH (stimulated)\t\t\t2.3\t\t\t\t\t9\t0–2.5 IU/L\t\nFSH (stimulated)\t\t\t0.7\t\t\t\t\t15\t0–6.5 IU/L\t\nFree T4\t\t\t7.9\t11\t11.3\t11\t15\t16\t10–20 pmol/L\t\nTSH\t\t\t4\t7.8\t0.91\t2.2\t1.3\t3.8\t0.5–4.5 pmol/L\t\n\naBaseline tests at the time of initial presentation showing elevated androgens and normal response to synthetic ACTH; bTests from after surgery showing normal androgen levels and normal response to synthetic ACTH; cTests following early breast development showing GnRH-independent precocious puberty and central hypothyroidism; d,e,g,fTests showing return to normal thyroid function with increasing doses of thyroxine; g,hCortisol and ACTH results following cessation of M-Rx and continuing supra-physiological hydrocortisone; hElevated gonadotrophins demonstrating central precocious puberty. Androgen and thyroid function results are normal.\n\nM-Rx, mitotane treatment.\n\n\n\n\nTreatment\nGiven the tumor’s stage and histology, the patient was treated with a combination of oral mitotane and intravenous cytotoxic drugs (cisplatin, etoposide and doxorubicin) as per the ARAR0332 protocol [https://www.childrensoncologygroup.org/index.php/arar0332 -accessed 29/01/18]. As mitotane is known to cause adrenal insufficiency, the patient was started on a relatively low physiological replacement hydrocortisone (6 mg/m2/day, oral). The dose of mitotane was gradually increased to 2.5 g/m2/day, which was the maximal dose tolerated due to severe and continuous gastrointestinal side effects. Monitoring of levels was planned but given the low dose that our patient received, it was inferred that levels would be subtherapeutic and specific measurement was not clinically useful. Three months after starting mitotane, during admission for cycle 5, she was found to have hypochloremic hyponatremia in conjunction with hypomagnesemia, normal pH and potassium (Table 2). She was euvolemic and asymptomatic other than subtle periorbital edema. Both mineralocorticoid deficiency and cisplatin-induced renal salt wasting were considered; however, plasma renin was low.\nTable 2 Electrolytes and hormones at presentation of adrenal insufficiency.\n\n\tCycle 5 week 1a\tFebrile neutropeniab\tStress dose hydrocortisonec\tHydrocortisone reducedd\tHydrocortisone restored\tReference range\t\nDays since start of cycle 5\t0\t14\t16\t28\t30\t\t\nSodium\t125\t124\t137\t125\t137\t135–145 mmol/L\t\nPotassium\t4.4\t4.1\t4.4\t4.4\t3.8\t3.5–5.2 mmol/L\t\nChloride\t91\t94\t104\t88\t107\t95–110 mmol/L\t\npH\t7.39\t7.41\t7.38\t\t\t7.36–7.44\t\nMagnesium\t0.57\t0.58\t0.77\t\t\t0.7–1.0 mmol/L\t\nRenin\t\t4\t3\t4\t94\t9–34 U/L\t\nAldosterone\t\t\t74\t\t\t140–2200 pmol/L\t\nACTH\t\t\t\t133\t\t2–11 pmol/L\t\naRoutine blood tests before cycle 5 of chemotherapy show hypochloremic hyponatremia with hypomagnesemia. Cisplatin-induced renal salt wasting was considered; bPatient developed febrile neutropenia and stress dose hydrocortisone was started; cElectrolytes improve following treatment with stress dose hydrocortisone; dPatient was readmitted with fatigue and hyperpigmentation following attempt to reduce the dose of hydrocortisone; eElectrolytes improve following permanent restoration of stress dose hydrocortisone.\n\n\n\n\nThe patient developed febrile neutropenia and was treated with stress doses of hydrocortisone (38.5 mg/m2/day, initially IV then oral). Attempting to reduce this dose over the next month resulted in severe fatigue, hypotension and recurrent hyponatremia. She also had increasing skin pigmentation –particularly on the hands, feet and existing scars (Fig. 1A and B) and ACTH levels were raised (Table 2). As it was likely that this was due to mitotane interfering with steroid metabolism (6), supra-physiological doses of hydrocortisone were continued.\nFigure 1 Increased skin pigmentation in our patient demonstrating adrenal insufficiency after an attempt to reduce the dose of replacement hydrocortisone. (A) Hyperpigmented nailbeds; (B) hyperpigmented existing abdominal scars.\n\n\n\n\nOutcome and follow-up\nThree weeks later (cycle 7), the patient developed additional endocrine problems. After 4 months of treatment, at an age of 5 years and 3 months, she had early breast development with a rapidly advancing bone age (8 years and 10 months vs 5 years and 9 months performed 6 months previously). A GnRH (SA) stimulation test performed at this time confirmed GnRH-independent precocious puberty (Table 1c). Her estradiol and androgen levels were unrecordably low.\n\nShe developed probable central hypothyroidism (Table 1c) with a T4 of 7.9 pmol/L (11.0–22.0 pmol/L) and was started on treatment with oral levothyroxine (25 µg/day). This increased T4 to 10 mol/L over 1 month. Increasing the dose to 37.5 µg/day achieved a T4 of 15 pmol/L.\n\nAfter completing her last cycle of chemotherapy, the patient’s thyroid function tests remained normal (Table 1h) and levothyroxine was discontinued. She continued to require hydrocortisone at supra-physiological doses and attempts to wean hydrocortisone produced increased fatigue. Her pubertal stage continued to advance to Tanner stage 3 breast development. She also had a single episode of vaginal bleeding 2 months after discontinuation of mitotane, which was thought to reflect a withdrawal bleed. An MRI scan showed that the patient’s uterus and ovaries remained prepubertal. Repeat GnRH stimulation testing revealed that she had developed secondary CPP (Table 1h). She was started on leuprolide 11.25 mg IM 3-monthly to suppress puberty.\n\nDiscussion\nWe report the case of a child with ACC who suffered multiple endocrinopathies as a result of mitotane chemotherapy. As a rare treatment for a rare condition, side effects in childhood ACC are poorly documented. Our case demonstrates the challenges of managing adrenal insufficiency and hypothyroidism in patients taking mitotane. Furthermore, we report the first case of mitotane causing PPP which subsequently triggered CPP.\n\nManaging adrenal insufficiency during mitotane treatment is a challenge. Not only does mitotane decrease endogenous levels of glucocorticoid and mineralocorticoid through its cytotoxic effect on the adrenal cortex, it also reduces the efficacy of exogenous steroid replacement by increasing CYP34A-mediated hepatic clearance of glucocorticoids and production of cortisol-binding globulin (6, 7). In our patient, this resulted in symptomatic primary adrenal insufficiency as we did not anticipate the very high dose of hydrocortisone required (32 mg/m2/day). Five months after stopping mitotane, our patient continued to require supra-physiological doses of hydrocortisone to maintain near-normal ACTH levels.\n\nOur patient also developed hypothyroidism. Typical changes in thyroid function during mitotane therapy include a reduced T4, with relatively normal levels of TSH and T3 (8). Explanations for this picture include increased thyroid-binding globulin and altered deiodinase activity (7). A recent study, using data from 10 adult, female patients treated with mitotane, demonstrated numerous changes in keeping with central hypothyroidism, possibly due to destruction of pituitary thyrotroph cells (5, 8). Given our patient’s normal TSH concentration, it appeared that central hypothyroidism was most likely. This was easily managed with levothyroxine, and resolved following cessation of treatment.\n\nAlthough gynecomastia in men is a common side effect of mitotane treatment, PPP in girls appears to be undocumented (4). Our patient presented with virilization without signs of feminization that ceased to progress with excision of her ACC. However, while being treated with mitotane, she showed progressive breast development and a rapid advancement in bone age. Suppressed gonadotrophins during a GnRH stimulation test confirmed a peripheral cause. Mitotane is known to have estrogenic action. This has been demonstrated in cell lines, where mitotane increases SHBG production in an estrogen receptor alpha (ERα)-dependent manner (9). This is not surprising given mitotane’s similarity to DDT, another estrogenic endocrine disruptor. Thus, the development of feminization with advanced bone age can be explained by the estrogenic actions of mitotane.\n\nOur patient’s precocious puberty continued to progress following withdrawal of mitotane. As confirmed by GnRH stimulation testing, this was due to development of CPP, which occurs following prolonged exposure to sex hormones or endocrine disruptors (10).\n\nThis report demonstrates the wide ranging and potentially life-threatening side effects of mitotane in children. In addition to reinforcing the importance of prompt recognition of the complications of adrenal insufficiency and hypothyroidism, we provide the first evidence that the estrogenic effects of mitotane can cause feminization and subsequent development of PPP. Some side effects, such as the development of CPP, may occur after mitotane therapy has been completed and should be taken into account when treating children with ACC.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nSigned, written consent has been obtained from the patient’s guardian, and consent form filed in the patient’s notes.\n\nAuthor contribution statement\nP D Oddie wrote the first draft of the manuscript. B B Albert, P L Hofman, C Jefferies, S Laughton and P J Carter provided clinical care to the patient. P D Oddie, P L Hofman and P J Carter edited and submitted the manuscript. P J Carter was the patient’s named physician and supervised the manuscript. All authors reviewed the final manuscript and approved it for publication.\n==== Refs\nReferences\n1 Ribeiro RC Figueiredo B. \nChildhood adrenocortical tumours . European Journal of Cancer \n2004 \n40 \n1117 –1126 . (10.1016/j.ejca.2004.01.031 )15110875 \n2 Terzolo M Angeli A Fassnacht M Daffara F Tauchmanova L Conton PA Rossetto R Buci L Sperone P Grossrubatscher E \net al\nAdjuvant mitotane treatment for adrenocortical carcinoma . New England Journal of Medicine \n2007 \n356 \n2372 –2380 . (10.1056/NEJMoa063360 )17554118 \n3 Redlich A Boxberger N Strugala D Frühwald MC Leuschner I Kropf S Bucsky P Vorwerk P. \nSystemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial . Klinische Pädiatrie \n2012 \n224 \n366 –371 . (10.1055/s-0032-1327579 )23143764 \n4 Fassnacht M Allolio B. \nClinical management of adrenocortical carcinoma . Best Practice and Research Clinical Endocrinology and Metabolism \n2009 \n23 \n273 –289 . (10.1016/j.beem.2008.10.008 )19500769 \n5 Russo M Scollo C Pellegriti G Cotta OR Squatrito S Gullo D Frasca F Cannavò S. \nMitotane treatment in patients with adrenocortical cancer causes central hypothyroidism . Clinical Endocrinology \n2016 \n84 \n614 –619 . (10.1111/cen.12868 )26221968 \n6 Chortis V Taylor AE Schneider P Tomlinson JW Hughes BA O’Neil DM Libé R Allolio B Bertagna X Beuschlein F , et al\nMitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement . Journal of Clinical Endocrinology and Metabolism \n2013 \n98 \n161 –171 . (10.1210/jc.2012-2851 )23162091 \n7 Van Seters AP Moolenaar AJ. \nMitotane increases the blood levels of hormone-binding proteins . Acta Endocrinologica \n1991 \n124 \n526 –533 .1903011 \n8 Zatelli MC Gentilin E Daffara F Tagliati F Reimondo G Carandina G Ambrosio MR Terzolo M Uberti EC. \nTherapeutic concentrations of mitotane (o,p’-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model . Endocrinology \n2010 \n151 \n2453 –2461 . (10.1210/en.2009-1404 )20392828 \n9 Nader N Raverot G Emptoz-Bonneton A Déchaud H Bonnay M Baudin E Pugeat M. \nMitotane has an estrogenic effect on sex hormone- binding globulin and corticosteroid-binding globulin in humans . Journal of Clinical Endocrinology and Metabolism \n2006 \n91 \n2165 –2170 . (10.1210/jc.2005-2157 )16551731 \n10 Latronico AC Brito VN Carel JC. \nCauses, diagnosis, and treatment of central precocious puberty . Lancet Diabetes and Endocrinology \n2016 \n4 \n265 –274 . (10.1016/S2213-8587(15)00380-0 )26852255\n\n",
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"title": "Mitotane in the treatment of childhood adrenocortical carcinoma: a potent endocrine disruptor.",
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"abstract": "A 66-year-old female with advanced primary open-angle glaucoma and Descemet's stripping endothelial keratoplasty OD with previously noted inferior stromal edema presented with a 1-month history of progressive decreased visual acuity after starting netarsudil twice daily. Her best-corrected visual acuity was 20/80 OD and no light perception OS. The right cornea was notable for inferior small epithelial bullae in a reticular pattern from 2 to 9 o'clock encroaching on the visual axis involving both sides of the graft-host junction. The reticular epithelial edema resolved upon discontinuation of netarsudil and best-corrected visual acuity improved to 20/50 but was limited by persistent stromal edema. We report a patient with a history of a partially decompensated Descemet's stripping endothelial keratoplasty who develops reticular epithelial corneal edema after starting netarsudil. This unique pattern of edema may present in the setting of preexisting endothelial cell dysfunction when netarsudil is used, a complication not noted in the Food and Drug Administration (FDA) trials.",
"affiliations": "School of Medicine, Baylor College of Medicine.;Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX.;Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX.;Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX.",
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"issue": "29(11)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000368:Aged; D001565:Benzoates; D002387:Cataract Extraction; D003316:Corneal Diseases; D015715:Corneal Edema; D057111:Descemet Stripping Endothelial Keratoplasty; D064420:Drug-Related Side Effects and Adverse Reactions; D019573:Epithelium, Corneal; D005260:Female; D020327:Glaucoma Drainage Implants; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D019654:Lens Implantation, Intraocular; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000072776:Slit Lamp Microscopy; D014130:Trabeculectomy; D014792:Visual Acuity; D015091:beta-Alanine; D054460:rho-Associated Kinases",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "e124-e126",
"pmc": null,
"pmid": "32826765",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reticular Epithelial Edema: An Uncommon Side Effect of ROCK/NET Inhibitor Netarsudil.",
"title_normalized": "reticular epithelial edema an uncommon side effect of rock net inhibitor netarsudil"
} | [
{
"companynumb": "US-AERIE-2020-001717",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIn RCT of adults with decompensated cirrhosis, GCSF mobilizes hematopoietic stem cells HSC and improves short-term outcome. An FDA-IND for sequential Kasai-GCSF treatment in biliary atresia BA was approved. This phase 1 study examines GCSF safety in Kasai subjects. Preliminary short-term outcome was evaluated.\n\n\nMETHODS\nGCSF (Neupogen) at 5 or 10 μg/kg (n = 3/group) was given in 3 daily doses starting on day 3 of Kasai surgery (NCT03395028). Serum CD34+ HSC cell counts, and 1-month of GCSF-related adverse events were monitored. The 6-months Phase 1 clinical outcome was compared against 10 subsequent post Phase 1 Kasai patients who did not receive GCSF.\n\n\nRESULTS\nWith GCSF, WBC and platelet count transiently increased, LFT and serum creatinine remained stable. Reversible splenic enlargement (by 8.5-20%) occurred in 5/6 subjects. HSC count increased 12-fold and 17.5-fold for the 5 μg/kg and10 ug/kg dose respectively; with respective median total bilirubin levels for GCSF vs no-GCSF groups of 55 vs 91 μM at 1 month, p = 0.05; 15 vs 37 μM at 3 months, p = 0.24); and the 6-months cholangitis frequency of 40% vs 90%, p = 0.077.\n\n\nCONCLUSIONS\nGCSF safely mobilizes HSC in Kasai infants and may improve short-term biliary drainage and cholangitis. Phase 2 efficacy outcome of GCSF adjunct therapy for sequential Kasai and GCSF is pending.",
"affiliations": "Department of Surgery and Pediatrics, University of Illinois College of Medicine, Chicago, IL, United States. Electronic address: aithanh@uic.edu.;Vietnam National Children Hospital, Hanoi, Vietnam.;Children's National Hospital, Washington, D.C, United States.;University of Rochester School of Medicine and Dentistry, Rochester, NY, United States.;Children's National Hospital, Washington, D.C, United States.;Baylor College of Medicine Department of Surgery, Houston, TX, United States.;Vietnam National Children Hospital, Hanoi, Vietnam.;Vietnam National Children Hospital, Hanoi, Vietnam.;Vietnam National Children Hospital, Hanoi, Vietnam.;Vietnam National Children Hospital, Hanoi, Vietnam.;Vietnam National Children Hospital, Hanoi, Vietnam.",
"authors": "Holterman|AiXuan|A|;Nguyen|Hoa Pham Anh|HPA|;Nadler|Evan|E|;Vu|Giap H|GH|;Mohan|Parvathi|P|;Vu|Megan|M|;Trinh|Thuy Thi|TT|;Bui|Huong Thuy Thi|HTT|;Nguyen|Binh Thanh|BT|;Quynh|Anh Tran|AT|;Pham|Hien Duy|HD|",
"chemical_list": "D003115:Colony-Stimulating Factors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpedsurg.2021.03.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3468",
"issue": "56(7)",
"journal": "Journal of pediatric surgery",
"keywords": "Biliary atresia; Cholangitis; GCSF; Global health; IND; Kasai; Low middle income country; Phase 1 study; Safety",
"medline_ta": "J Pediatr Surg",
"mesh_terms": "D000328:Adult; D001656:Biliary Atresia; D003115:Colony-Stimulating Factors; D006098:Granulocytes; D006412:Hematopoietic Stem Cells; D006801:Humans; D007223:Infant; D011171:Portoenterostomy, Hepatic; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0052631",
"other_id": null,
"pages": "1179-1185",
"pmc": null,
"pmid": "33965236",
"pubdate": "2021-07",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Granulocyte-colony stimulating factor GCSF mobilizes hematopoietic stem cells in Kasai patients with biliary atresia in a phase 1 study and improves short term outcome.",
"title_normalized": "granulocyte colony stimulating factor gcsf mobilizes hematopoietic stem cells in kasai patients with biliary atresia in a phase 1 study and improves short term outcome"
} | [
{
"companynumb": "US-AMGEN-USASP2021078204",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "The incidence of disseminated infection with Scedosporium species is increasing in patients with haematological malignancy. Two fatal cases are reported of patients with acute myeloid leukaemia and neutropenia who presented with Scedosporium endophthalmitis. Diagnosis of fungal infection was delayed as blood and vitreous cultures were positive only after 3 days in patient 1 and blood culture was positive at 7 days in patient 2. Despite antifungal therapy with amphotericin B and additional fluconazole in patient 2, both patients died of overwhelming fungal septicaemia. Post-mortem examination of the right globe in patient 1 showed haemorrhagic necrotizing chorioretinitis with numerous fungal hyphae in choroidal vessels, choroid, retina and vitreous. Scedosporium species are often resistant to conventional antifungal therapy including amphotericin B. Diagnosis is difficult and mortality in disseminated infection is high.",
"affiliations": "Department of Anatomical Pathology, St Vincent's Hospital, Fitzroy, Victoria, Australia. mckelvpa@svhm.org.au",
"authors": "McKelvie|P A|PA|;Wong|E Y|EY|;Chow|L P|LP|;Hall|A J|AJ|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole",
"country": "Australia",
"delete": false,
"doi": "10.1046/j.1442-9071.2001.00444.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1442-6404",
"issue": "29(5)",
"journal": "Clinical & experimental ophthalmology",
"keywords": null,
"medline_ta": "Clin Exp Ophthalmol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D017809:Fatal Outcome; D005260:Female; D015725:Fluconazole; D016469:Fungemia; D006801:Humans; D007951:Leukemia, Myeloid; D008297:Male; D008875:Middle Aged; D008271:Mycetoma; D009503:Neutropenia; D021681:Scedosporium",
"nlm_unique_id": "100896531",
"other_id": null,
"pages": "330-4",
"pmc": null,
"pmid": "11720162",
"pubdate": "2001-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Scedosporium endophthalmitis: two fatal disseminated cases of Scedosporium infection presenting with endophthalmitis.",
"title_normalized": "scedosporium endophthalmitis two fatal disseminated cases of scedosporium infection presenting with endophthalmitis"
} | [
{
"companynumb": "AU-PFIZER INC-2015145867",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Acyclovir-induced neuropsychiatric symptoms (AINSs) may resemble several diseases of the central nervous system. Laboratory testing of acyclovir may be critical in supporting the diagnosis of AINSs when there is doubt. We present a case of suspected herpes encephalitis in which the diagnosis of AINSs was supported by therapeutic drug monitoring of plasma and cerebrospinal fluid concentrations of acyclovir and its main metabolite 9-carboxymethoxymethylguanine.",
"affiliations": "Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.",
"authors": "von Euler|Mia|M|;Axelsson|Gudmundur|G|;Helldén|Anders|A|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1097/FTD.0b013e31828faa35",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4356",
"issue": "35(4)",
"journal": "Therapeutic drug monitoring",
"keywords": null,
"medline_ta": "Ther Drug Monit",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D002490:Central Nervous System; D003937:Diagnosis, Differential; D016903:Drug Monitoring; D020803:Encephalitis, Herpes Simplex; D005260:Female; D006801:Humans; D001523:Mental Disorders; D008875:Middle Aged; D020258:Neurotoxicity Syndromes",
"nlm_unique_id": "7909660",
"other_id": null,
"pages": "417-9",
"pmc": null,
"pmid": "23851913",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Differential diagnosis of central nervous system involvement in a patient treated with acyclovir.",
"title_normalized": "differential diagnosis of central nervous system involvement in a patient treated with acyclovir"
} | [
{
"companynumb": "SE-ACTAVIS-2014-11386",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo follow-up on all available infliximab-treated SLE patients for safety and long-term efficacy in order to extract information that is useful for planning appropriate controlled trials with infliximab in SLE.\n\n\nMETHODS\nWe analysed charts of six patients treated in an open-label safety trial and seven additional patients treated with infliximab on a compassionate care basis for uncontrolled SLE organ inflammation.\n\n\nRESULTS\nOut of nine patients with lupus nephritis, six had a long-term response after four infusions of infliximab in combination with AZA, lasting for up to 5 years. All five patients with lupus arthritis responded, but this response did not last for >2 months after the last infusion. One additional patient had a long-lasting improvement in SLE interstitial lung disease. No symptoms suggestive of infliximab-induced SLE flares occurred in any patients. Short-term treatment appeared relatively safe, but one patient developed deep-vein thrombosis and several infections. Under long-term therapy, two patients had life-threatening or fatal events, namely CNS lymphoma and Legionella pneumonia. Retreatment and treatment without concomitant immunosuppression led to drug reactions.\n\n\nCONCLUSIONS\nShort-term therapy with four infusions of infliximab in combination with AZA was relatively safe, and had remarkable long-term efficacy for lupus nephritis and, potentially, also interstitial lung disease. Long-term therapy with infliximab, however, was associated with severe adverse events in two out of three SLE patients, which may have been provoked by infliximab and/or by their long-standing refractory SLE and previous therapies.",
"affiliations": "Department of Medicine III, Division of Rheumatology, University Clinical Center Carl Gustav Carus at the Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. martin.aringer@uniklinikum-dresden.de",
"authors": "Aringer|Martin|M|;Houssiau|Frederic|F|;Gordon|Caroline|C|;Graninger|Winfried B|WB|;Voll|Reinhard E|RE|;Rath|Eva|E|;Steiner|Guenter|G|;Smolen|Josef S|JS|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/kep270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "48(11)",
"journal": "Rheumatology (Oxford, England)",
"keywords": null,
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001379:Azathioprine; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D017563:Lung Diseases, Interstitial; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "1451-4",
"pmc": null,
"pmid": "19748965",
"pubdate": "2009-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Adverse events and efficacy of TNF-alpha blockade with infliximab in patients with systemic lupus erythematosus: long-term follow-up of 13 patients.",
"title_normalized": "adverse events and efficacy of tnf alpha blockade with infliximab in patients with systemic lupus erythematosus long term follow up of 13 patients"
} | [
{
"companynumb": "AT-JNJFOC-20170426645",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "A case is presented involving a young woman on several illicit drugs (heroin, cocaine and cannabis) as well as two medications and a solvent used for their anesthetic and narcotic properties: thiopental, ketamine and chloroform. This complex drug use was supported by hair analysis over a 10.5 cm segment of the hair taken at autopsy. The average measured concentrations in hair were: thiopental = 5.3 ng/mg, pentobarbital = 10.0 ng/mg, ketamine = 11.3 ng/mg norketamine = 1.0 ng/mg, diazepam = 1.2 ng/mg, nordiazepam = 0.1 ng/mg, 6-acetylmorphine = 4.4 ng/mg, morphine = 3.4 ng/mg, codeine = 1.2 ng/mg, cocaine = 5.5 ng/mg, benzoylecgonine = 1.5 ng/mg and methylecgonine ester = 1.0 ng/mg. While the ketamine/norketamine ratio is consistent with that already reported on drug detection in hair, the thiopental/pentobarbital ratio seems to be inverted.",
"affiliations": "Laboratoired' Expertises TOXLAB, Paris, France.",
"authors": "Gaillard|Y|Y|;Pépin|G|G|",
"chemical_list": "D002186:Cannabinoids; D013287:Illicit Drugs; D007649:Ketamine; D003932:Heroin; D002725:Chloroform; D003042:Cocaine; D013874:Thiopental",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "43(2)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D002186:Cannabinoids; D002725:Chloroform; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine; D017809:Fatal Outcome; D005260:Female; D005554:Forensic Medicine; D008401:Gas Chromatography-Mass Spectrometry; D006197:Hair; D003932:Heroin; D006801:Humans; D013287:Illicit Drugs; D007649:Ketamine; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D013874:Thiopental",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "435-8",
"pmc": null,
"pmid": "9544560",
"pubdate": "1998-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Evidence of polydrug use using hair analysis: a fatal case involving heroin, cocaine, cannabis, chloroform, thiopental and ketamine.",
"title_normalized": "evidence of polydrug use using hair analysis a fatal case involving heroin cocaine cannabis chloroform thiopental and ketamine"
} | [
{
"companynumb": "FR-PFIZER INC-2021893223",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THIOPENTAL SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Eight cases of fetal and infant death related to maternal methamphetamine abuse are presented. The mean fetal blood concentration of methamphetamine was 0.36 microgram/mL (range, 0.03-1.20 micrograms/mL), and the mean concentration of amphetamine was 0.05 microgram/mL (range, 0-0.08 microgram/mL). Both maternal and fetal blood methamphetamine concentrations were obtained in two cases. The maternal and fetal methamphetamine concentrations for these two cases were 0.21 and 0.40 microgram/mL and 0.18 and 1.20 micrograms/mL, respectively. The cause of death for each case, as listed by the pathologist, is also discussed.",
"affiliations": "Institute of Forensic Sciences, Oakland, California 94609, USA.",
"authors": "Stewart|J L|JL|;Meeker|J E|JE|",
"chemical_list": "D002492:Central Nervous System Depressants; D008694:Methamphetamine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/21.6.515",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "21(6)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000022:Abortion, Spontaneous; D002492:Central Nervous System Depressants; D005260:Female; D005313:Fetal Death; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008694:Methamphetamine; D011247:Pregnancy; D012127:Respiratory Distress Syndrome, Newborn; D019966:Substance-Related Disorders",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "515-7",
"pmc": null,
"pmid": "9323536",
"pubdate": "1997-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fetal and infant deaths associated with maternal methamphetamine abuse.",
"title_normalized": "fetal and infant deaths associated with maternal methamphetamine abuse"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES-US-R13005-16-00131",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHAMPHETAMINE"
},
"dru... |
{
"abstract": "The management of heparin-induced thrombocytopenia (HIT) in the perioperative period for patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) can be a challenging clinical scenario. Once a diagnosis of HIT has been established, heparin products typically are avoided and alternative therapies for anticoagulation are started. Alternative anticoagulation strategies for CPB are limited and often have various pharmacokinetic profiles that may lead to increased perioperative bleeding. Historically the use of a GPIIb/IIIa inhibitor, such as tirofiban, followed by unfractionated heparin (UFH) is the typical alternative for surgeries requiring DHCA in patients with HIT at the authors' institution. This article presents a case in which cangrelor followed by UFH was used in a 20-year-old patient with suspected HIT and chronic thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy surgery requiring CPB and DHCA. Due to the frequency of significant postoperative bleeding encountered when using tirofiban and UFH, it was decided to attempt to block platelet aggregation with significantly shorter-acting cangrelor. The authors hypothesized that cangrelor would reduce the risk of significant bleeding compared with tirofiban because of its favorable pharmacokinetics. Specifically, cangrelor has a short elimination half-life of 3 to 6 minutes, and its elimination is not altered by renal and hepatic impairment. This case report discusses the pathophysiology of HIT, the alternative anticoagulants used for HIT type II in pulmonary thromboendarterectomy, and the potential of cangrelor in conjunction with UFH to be a favorable option for patients in similar clinical scenarios.",
"affiliations": "Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA. Electronic address: Scott.seider.2@gmail.com.;Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA.;Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA.;Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA.",
"authors": "Seider|Scott|S|;Ross|Michael|M|;Pretorius|Victor|V|;Maus|Timothy|T|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D000249:Adenosine Monophosphate; C117446:cangrelor; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1053/j.jvca.2018.04.051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0770",
"issue": "33(4)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "cangrelor; cardiopulmonary bypass; deep hypothermic circulatory arrest; heparin-induced thrombocytopenia",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D000249:Adenosine Monophosphate; D000925:Anticoagulants; D001777:Blood Coagulation; D004359:Drug Therapy, Combination; D004691:Endarterectomy; D006493:Heparin; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D013921:Thrombocytopenia; D055815:Young Adult",
"nlm_unique_id": "9110208",
"other_id": null,
"pages": "1050-1053",
"pmc": null,
"pmid": "29853315",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Use of Cangrelor and Heparin for Anticoagulation in a Patient Requiring Pulmonary Thromboendarterectomy Surgery with Suspected Heparin-Induced Thrombocytopenia.",
"title_normalized": "the use of cangrelor and heparin for anticoagulation in a patient requiring pulmonary thromboendarterectomy surgery with suspected heparin induced thrombocytopenia"
} | [
{
"companynumb": "US-TEVA-2019-US-1038464",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "An 82-year-old female presented with multiple oral ulcers and malena for 1 week. Her laboratory tests revealed pancytopenia and acute renal failure. She had history of rheumatoid arthritis for which she was taking 7.5 mg methotrexate weekly and stage 4 chronic kidney disease from diabetic nephropathy. During the hospital stay, she developed pneumonia and septic shock requiring norepinephrine and vasopressin. She underwent continuous venovenous hemodiafiltration. Leucovorin, filgrastim, and multiple packed red blood cell and platelet transfusions were given. She remained hypotensive and pancytopenic despite all interventions. She died on day 6 of hospital stay from acute hypoxic respiratory failure due to septic shock.",
"affiliations": "Department of Internal Medicine, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, USA.;Department of Internal Medicine, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, USA.;Department of Internal Medicine, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, USA.;Department of Internal Medicine, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, USA.",
"authors": "Shaikh|Nasreen|N|0000-0002-3092-4664;Sardar|Muhammad|M|;Raj|Rishi|R|0000-0002-4151-3246;Jariwala|Punit|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/9056086",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/9056086Case ReportA Rapidly Fatal Case of Low-Dose Methotrexate Toxicity http://orcid.org/0000-0002-3092-4664Shaikh Nasreen shaikh.drn@gmail.comSardar Muhammad http://orcid.org/0000-0002-4151-3246Raj Rishi Jariwala Punit Department of Internal Medicine, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, USAAcademic Editor: Fabrizio Conti\n\n2018 13 6 2018 2018 905608626 2 2018 24 4 2018 Copyright © 2018 Nasreen Shaikh et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.An 82-year-old female presented with multiple oral ulcers and malena for 1 week. Her laboratory tests revealed pancytopenia and acute renal failure. She had history of rheumatoid arthritis for which she was taking 7.5 mg methotrexate weekly and stage 4 chronic kidney disease from diabetic nephropathy. During the hospital stay, she developed pneumonia and septic shock requiring norepinephrine and vasopressin. She underwent continuous venovenous hemodiafiltration. Leucovorin, filgrastim, and multiple packed red blood cell and platelet transfusions were given. She remained hypotensive and pancytopenic despite all interventions. She died on day 6 of hospital stay from acute hypoxic respiratory failure due to septic shock.\n==== Body\n1. Introduction\nWe wanted to report this case to create awareness that methotrexate toxicity can be fatal. Although a low-dose regimen is used in the treatment of rheumatoid arthritis, it can be potentially toxic in the presence of chronic kidney disease especially in the elderly with multiple comorbidities. The American College of Rheumatology guidelines have given recommendations regarding monitoring complete blood count (CBC), liver transaminases, and creatinine and mention that in the presence of comorbidities more frequent monitoring is warranted; however; specific guidelines in the presence of chronic kidney disease are lacking. Methotrexate should be used with utmost caution in the presence of chronic kidney disease.\n\n2. Presentation\nAn 82-year-old female presented to the emergency room with complaints of bleeding oral ulcers and black tarry stools for 1 week. Her past medical history was significant for paroxysmal atrial fibrillation for which she was taking apixaban, rheumatoid arthritis for which she was taking 7.5 mg methotrexate once a week for 6 years, coronary artery disease with left circumflex and right coronary artery stent placement 6 years ago, congestive heart failure with reduced ejection fraction for which she was taking digoxin and furosemide, diabetes mellitus type 2 on repaglinide, hypertension, and stage 4 chronic kidney disease secondary to diabetes and hypertension. At the time of presentation, her vitals were stable. She had multiple bleeding oral ulcers, and digital rectal exam did not show fresh blood but occult blood was positive.\n\nHer complete blood count revealed a hemoglobin of 8.1 g/dL with MCV of 106.8 fL consistent with macrocytic anemia, platelet count of 73 × 103/µL, WBC count of 4.0 × 103/µL with absolute neutrophil count of 500, sodium 147 mEq/L, potassium 6.0 mEq/L, bicarbonate 14 mEq/L, creatinine 7.75 mg/dL, BUN 125 mg/dL, eGFR 5 ml/min/1.73 m2, ALT 30 U/L, AST 26 U/L, alkaline phosphatase 56 U/L, digoxin level of 1.3 ng/mL, and methotrexate level of 0.27 µmol/L. 12-lead EKG revealed the first degree AV block, and telemetry showed frequent pauses of 2.5 seconds and escalation to type 2 block at times. Chest X-ray on admission showed cardiomegaly but no pulmonary disease. Patient's advanced directives indicated that she did not want resuscitation.\n\nHer previous lab results were reviewed, and it was noted that the decline in renal function occurred over a span of two weeks. She had renal function tests done 2 weeks prior to the present admission which showed the beginning of worsening renal function as compared to her baseline with a creatinine of 3.58 mg/dL and eGFR of 12 ml/min/1.73 m2. She however continued to take Methotrexate.\n\nDuring day 1 of hospital stay, she had 2 episodes of hematemesis after which hemoglobin and platelets dropped to 7.4 g/dL and 29 × 103/µL, respectively. Her WBC count was 500/mm3 and absolute neutrophil count dropped to zero. The patient was given intravenous leucovorin 100 mg every 6 hours and filgrastim 480 mcg subcutaneously once daily, as she was neutropenic. She was given 2 units of packed red blood cell and 1 unit of platelet transfusion. Hemoglobin and platelet levels came up to 8.1 g/dL and 30 × 103/µL, respectively. Darbepoetin 60 mcg subcutaneous was also administered. Intravenous normal saline with 40 mEq bicarbonate was given at 50 cc/hr. Hemodialysis was initiated; however, patient became hypotensive with her MAP ranging from 55 to 60 mmHg. Continuous venovenous hemodiafiltration (CVVHFD) was then started.\n\nOn day 2 of hospital stay, she spiked fevers of 101.2F. Chest X-ray was repeated and showed left mid and lower lung field opacity suggestive of consolidation. Blood cultures were immediately sent and IV meropenem 1 g every 12 hours, IV vancomycin 1 gram dosed daily according to trough levels, and IV caspofungin 50 mg every 24 hours were initiated empirically. Blood cultures grew Klebsiella pneumoniae. Broad spectrum antibiotics were continued. MTX levels trended down to 0.18 µmol/L. Absolute neutrophil count only came up to 100/mm3. Her oxygen saturation was maintained over 90% with the help of high-flow nasal cannula at 40 L/min.\n\nOn day 3, she became increasingly hypotensive due to septic shock requiring norepinephrine at 14 mcg/min. Vasopressin was also added at 0.03 units/min. Leucovorin rescue was discontinued as MTX levels were now 0.02 µmol/L. Platelets dropped to 13 × 103/µL, hence 1 unit of platelets were transfused. Despite administering filgrastim, the absolute neutrophil count again dropped to zero with a WBC count of 300/mm3. Intravenous hydrocortisone 100 mg every 8 hours was also initiated for septic shock. On day 4, the patient continued to require high-doses of norepinephrine and vasopressin. Repeat blood cultures were negative.\n\nShe remained hypotensive requiring increasing amount of norepinephrine. Neutropenia, anemia, and thrombocytopenia persisted. Goals of care were discussed with the family on day 5, and it was decided to stop CVVHFD and withdraw care while initiating comfort measures. The patient expired on day 6 of hospital stay from acute hypoxic respiratory failure due to septic shock.\n\n3. Discussion\nThis is a case of an elderly woman with multiple comorbidities who experienced a fatal decline in her health that was triggered by continuation of low-dose methotrexate therapy for rheumatoid arthritis, which generally is an excellent drug for inflammatory arthritis with a good safety profile, despite worsening renal function. Renal dysfunction led to accumulation of toxic levels of methotrexate resulting in pancytopenia and making the patient susceptible to infections and severe sepsis ultimately causing her demise.\n\nMethotrexate is currently considered the first-line disease-modifying antirheumatic drugs (DMARDs) [1, 2]. It is an antimetabolite that competitively inhibits the conversion of dihydrofolate to tetrahydrofolate by binding to dihydrofolate reductase. Tetrahydrofolate is essential for the synthesis of thymidine and purines required for DNA synthesis. High-dose methotrexate treatment is defined as a dose greater than 500 mg/m2 given intravenously and is mostly used in the treatment of various malignancies [3]. Low-dose regimen (5 mg to 25 mg once weekly) has been widely and safely used in the treatment of rheumatoid arthritis, psoriasis, and many other rheumatologic diseases.\n\nThe prevalence of rheumatoid arthritis in elderly is increasing over last two decades, and in many countries, the prevalence can be as high as 40% in the elderly patient (older than 65 years) [4]. Many studies have proved its safety in this group of patients. In 1995, Felson et al. did analyses on pooled data from 11 clinical trials comprising of 496 patients, which showed neither age nor renal impairment had any effect on the efficacy of methotrexate; however, its toxicity remained unchanged in elderly but significantly increased in the patient with reduced renal function [5]. In 1996, Bologna et al. studied effects of low-dose methotrexate treatment in 469 patients and concluded that age at initiation of methotrexate treatment did not influence its efficacy or toxicity [6]. This led to the conclusion that reduced renal function in our patient might be responsible for severe toxicity.\n\nAs over 90% of methotrexate is excreted and unchanged renally by the mechanism of glomerular filtration, tubular secretion, and tubular reabsorption, its elimination half-life increases and the clearance decreases with the degree of renal impairment [7]. Medication causing decreased renal elimination (aminoglycosides, cyclosporine, nonsteroidal anti-inflammatory agents, sulfonamides, probenecid, salicylates, penicillin, colchicine, cisplatin, and other nephrotoxic drugs) and drugs causing displacement of methotrexate from its protein-binding sites (salicylates, probenecid, sulfonamides, barbiturates, phenytoin, retinoids, sulfonylureas, and tetracyclines) significantly increase its toxicity.\n\nThe MATRIX study (Methotrexate and Renal Insufficiency study) conducted in 2004 concluded that serum creatinine alone is not enough to evaluate renal failure in patients taking methotrexate and suggested to follow creatinine clearance measurement [8]. Since then, many guidelines have been published regarding dose adjustments of methotrexate based on renal impairment. University College London Hospital compiled together many references and suggested that methotrexate dosing should be reduced to 65% for creatinine clearance below 60 ml/min and to 50% for creatinine clearance below 45 ml/min. Holding methotrexate all together was suggested if creatinine clearance is under 30 ml/min. The concomitant use of other nephrotoxic drugs as mentioned above is also an important factor in dose adjustment of methotrexate in patients with kidney dysfunction. It is unclear why our patient continued to take methotrexate despite worsening renal function. She was an elderly lady on multiple medications who lived by herself, and it can be speculated that she was not able to care for herself adequately.\n\nNeedless to say, patients on methotrexate need regular laboratory tests to monitor their kidney function, liver function, and blood counts. The American College of Rheumatology has guidelines for following patients on methotrexate with routine blood tests consisting of a complete blood count, liver function test, and creatinine. If the patient has been on the medication for more than 6 months, blood tests are required to be done every 12 weeks. However, in the presence of comorbidities or abnormal lab results, more frequent monitoring is warranted [9].\n\nIf not adjusted renally, it can lead to adverse events most commonly manifesting in the form of mucositis, hepatotoxicity, nephrotoxicity, and myelosuppression. Most of the toxicity profile has been studied in patients taking high-dose methotrexate for cancers. Few studies have been done on the toxicity of low-dose methotrexate. In a study by Kivity et al. clinical characteristics and risk factors for low-dose methotrexate toxicity were studied in 28 patients. Pancytopenia was the most common manifestation of low-dose methotrexate toxicity seen in 78.5% of the cohort while hepatoxicity in the form of mild elevation of liver enzymes was seen in only 28%. This is in accordance with our patient who presented with pancytopenia with normal liver function tests. They also found that drug level monitoring did not correlate with the degree of pancytopenia and the serum drug levels did not differ in patients who died from toxicity from those who recovered from it [10]. Nonetheless, there are recommendations to trend methotrexate levels until the level is <0.1 µM [11]. In another case study by Calvo-Romero et al., it was found that pancytopenia due to low-dose methotrexate therapy is more likely to occur in the presence of renal impairment [12]. Mori et al. retrospectively analyzed 40 cases of low-dose methotrexate-induced myelosuppression and concluded that myelosuppression can occur abruptly at any time during treatment. They also mentioned that serum albumin levels and folic acid supplementation were the most important risk factors affecting the severity of pancytopenia. Our patient was not taking folic acid supplements and was found to have severe pancytopenia [13]. Table 1 summarizes studies, case series, and case reports regarding low-dose methotrexate toxicity.\n\nManagement of methotrexate toxicity is aimed towards giving folinic acid rescue and enhancing methotrexate elimination. Folinic acid replenishes intracellular stores of reduced folic acid by competitively inhibiting cellular uptake of methotrexate. Methotrexate excretion can be enhanced by hydration with >3 L/m2 per day to maximize urine output [3]. Methotrexate can precipitate in the acidic urine causing crystalluria, hence alkalinizing the urine with oral or parenteral sodium bicarbonate can help prevent this and improve methotrexate excretion [18]. Another way to enhance elimination is via extracorporeal methods such as hemodialysis, high-flux hemodialysis, plasma exchange, and continuous renal replacement therapy [19]. In 2012, the US FDA approved glucarpidase for intravenous use in methotrexate toxicity in renal impairment. It is a recombinant form of carboxypeptidase G2 which is a bacterial enzyme that cleaves methotrexate into two catabolites. These catabolites are much less toxic than the parent compound and are excreted hepatically [20]. At present, data regarding the use of glucarpidase in low-dose methotrexate toxicity is lacking.\n\n4. Conclusion\nTo conclude, it cannot be emphasized enough that methotrexate, although a very useful drug in the treatment of inflammatory arthritis, even when used in the lowest dose, may prove to be fatal in the presence of renal insufficiency. Routine CBC, liver, and renal function tests for patients on methotrexate should be performed at more frequent intervals in presence of chronic kidney disease. Myelosuppression from methotrexate can occur abruptly at any time during treatment. Methotrexate drug levels may not correspond with the severity of toxicity.\n\nConsent\nAll authors declare that written informed consent was obtained from the patient (or other approved parties) for publication of this case report and accompanying images.\n\nConflicts of Interest\nAuthors have declared that no conflicts of interest exist.\n\nAuthors' Contributions\nNasreen Shaikh was the primary resident taking care of the patient and wrote the case report. The case report was edited and finalized with the help of the senior resident Rishi Raj. Muhammad Sardar was the resident from hem-oncology who helped manage the methotrexate toxicity and provide valuable input for the case report. Punit Jariwala was the primary attending of the patient and helped in gathering crucial information.\n\nTable 1 Studies, case series, and case reports regarding low-dose methotrexate toxicity.\n\nAuthor\tYear\tStudy type\tResults\t\nNisar et al. [14]\t1995\tRetrospective study\nN=85\t1 patient developed pancytopenia and died\t\nOhosone et al. [15]\t1997\tProspective study\nN=284\tLiver dysfunction: 3.2%\nPancytopenia: 1.4%\nNo fatality\t\nCalvo-Romero et al. [12]\t2001\tCase series\nN=2\tPancytopenia and renal impairment in both cases with 1 death\t\nKivity et al. [10]\t2014\tRetrospective study\nN=28\tPancytopenia: 78.5%\nHepatic dysfunction: 28%\t\nJariwala et al. [16]\t2014\tCase series\nN=2\tPancytopenia, renal dysfunction, and fatality in both cases\t\nMori et al. [13]\t2016\tRetrospective study\nN=40 (only patients with myelosuppression were included)\tMyelosuppression can occur abruptly at any time during therapy\t\nMameli et al. [17]\t2017\tCase report\tPancytopenia, renal dysfunction, and death\n==== Refs\n1 Weinblatt M. E. Efficacy of methotrexate in rheumatoid arthritis British Journal of Rheumatology 1995 34 2 43 48 8535649 \n2 Buchbinder R. Hall S. Sambrook P. N. Methotrexate therapy in rheumatoid arthritis: a life table review of 587 patients treated in community practice Journal of Rheumatology 1993 20 4 639 644 8496857 \n3 Howard S. C. McCormick J. Pui C. H. Buddington R. K. Harvey R. D. Preventing and managing toxicities of high-dose methotrexate Oncologist 2016 21 12 1471 1482 10.1634/theoncologist.2015-0164 2-s2.0-85006725824 27496039 \n4 Laiho K. Tuomilehto J. Tilvis R. Prevalence of rheumatoid arthritis and musculoskeletal diseases in the elderly population Rheumatology International 2001 20 3 85 87 10.1007/s002960000087 2-s2.0-0035089721 11354562 \n5 Rheumatoid Arthritis Clinical Trial Archive Group The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis Journal of Rheumatology 1995 22 218 223 7738941 \n6 Bologna C. Viu P. Jorgensen C. Effect of age on the efficacy and tolerance of methotrexate in rheumatoid arthritis British Journal of Rheumatology 1996 35 5 453 457 8646436 \n7 Bressolle F. Bologna C. Kinowski J. M. Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients Annals of the Rheumatic Diseases 1998 57 2 110 113 10.1136/ard.57.2.110 2-s2.0-0031977519 9613341 \n8 Karie S. Gandjbakhch F. Janus N. Kidney disease in RA patients: prevalence and implicationon RA-related drugs management: the MATRIX study Rheumatology 2008 47 3 350 354 10.1093/rheumatology/kem370 2-s2.0-39449125915 18238787 \n9 Singh J. A. Saag K. G. Bridges S. L. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis Arthritis Care and Research 2016 68 1 1 25 10.1002/acr.22783 2-s2.0-84956767541 26545825 \n10 Kivity S. Zafrir Y. Loebstein R. Pauzner R. Mouallem M. Mayan H. Clinicalcharacteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients Autoimmunity Reviews 2014 13 11 1109 1113 10.1016/j.autrev.2014.08.027 2-s2.0-84908499715 25172240 \n11 Al-Quteimat O. M. Al-Badaineh M. A. Practical issues with high dose methotrexate therapy Saudi Pharmaceutical Journal 2014 22 4 385 387 10.1016/j.jsps.2014.03.002 2-s2.0-84906259036 25161385 \n12 Calvo-Romero J. M. Severe pancytopenia associated with low-dose methotrexate therapy for rheumatoid arthritis Annals of Pharmacotherapy 2001 35 12 1575 1577 10.1345/aph.1a052 2-s2.0-0035665953 11793624 \n13 Mori S. Hidaka M. Kawakita T. Factors associated with myelosuppression related to low-dose methotrexatetherapy for inflammatory rheumatic diseases PLoS One 2016 11 4 e0154744 10.1371/journal.pone.0154744 2-s2.0-84966350062 \n14 Nisar M. Carlisle L. Amos R. Experience with low-dose methotrexate: toxicity, tolerability and effect on conventional patterns of drug therapy for inflammatory arthritis Clinical Rheumatology 1995 14 5 544 550 10.1007/bf02208152 2-s2.0-0029125876 8549093 \n15 Ohosone Y. Okano Y. Kameda H. Toxicity of low-dose methotrexate in rheumatoid arthritis—clinical characteristics in patients with MTX-induced pancytopenia and interstitial pneumonitis Ryumachi 1997 37 1 16 23 9128419 \n16 Jariwala P. Kumar V. Kothari K. Thakkar S. Umrigar D. D. Acute methotrexate toxicity: a fatal condition in two cases of psoriasis Case Reports in Dermatological Medicine 2014 2014 3 946716 10.1155/2014/946716 \n17 Mameli A. Barcellona D. Marongiu F. Fatal cytopenia induced by low-dose methotrexate in elderly with rheumatoid arthritis. identification of risk factors American Journal of Therapeutics 2017 24 1 e106 e107 10.1097/mjt.0000000000000486 2-s2.0-84984677288 27574942 \n18 Rouch J. A. Burton B. Dabb A. Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate Journal of Oncology Pharmacy Practice 2017 23 1 3 9 10.1177/1078155215610914 2-s2.0-85006399788 26467268 \n19 Vilay A. M. Mueller B. A. Haines H. Alten J. A. Askenazi D. J. Treatment ofmethotrexate intoxication with various modalities of continuous extracorporealtherapy and glucarpidase Pharmacotherapy 2010 30 1 p. 111 10.1592/phco.30.1.111 \n20 Green J. M. Glucarpidase to combat toxic levels of methotrexate in patients Therapeutics and Clinical Risk Management 2012 8 403 413 10.2147/tcrm.S30135 2-s2.0-84875359514 23209370\n\n",
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"title": "A Rapidly Fatal Case of Low-Dose Methotrexate Toxicity.",
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"abstract": "Chloroquine and hydroxy chloroquine are widely use in Africa and all over the world as anti-malarial drugs but also in the treatment of chronic inflammatory diseases. Since the outbreak of COVID-19 pandemic, Morocco have included this medication in the COVID-19 treatment guidelines in association with azithromycine. Besides dermatologic problems, ocular impairments and gastro-intestinal effects, quinolines may also cause rarely described psychiatric adverse effects. To our knowledge, there has been no reports of psychiatric side effects of chloroquine or hydroxy chloroquine in the actual context of COVID-19 pandemic. Here, we present the description of two COVID-19 patients who showed psychiatric side effects after chloroquine treatment. One patient expressed psychotic symptoms and the other one experienced acute and intense anxiety. In both cases, and according to Naranjo score, the association between chloroquine and psychiatric side effects was probable.",
"affiliations": "Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco.;Faculty of Medicine and pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco.;Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco.",
"authors": "Benjelloun|Roukaya|R|;Otheman|Yassine|Y|;El Kettani|Chafik|C|",
"chemical_list": "D000962:Antimalarials; D002738:Chloroquine",
"country": "Uganda",
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"doi": "10.11604/pamj.supp.2020.35.24064",
"fulltext": "\n==== Front\nPan Afr Med J\nPan Afr Med J\nPAMJ\nThe Pan African Medical Journal\n1937-8688 The African Field Epidemiology Network \n\nPAMJ-SUPP-35-2-83\n10.11604/pamj.supp.2020.35.24064\nCase Report\nPsychiatric side effects of chloroquine in COVID-19 patients: two case reports\nBenjelloun Roukaya 1& Otheman Yassine 2 EL Kettani Chafik 1 1 Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco\n2 Faculty of Medicine and pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco\n& Corresponding author: Roukaya Benjelloun, Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco, benjelloun@um6ss.ma\n20 6 2020 \n2020 \n35 Suppl 2 8305 6 2020 09 6 2020 © Roukaya Benjelloun et al.2020The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Chloroquine and hydroxy chloroquine are widely use in Africa and all over the world as anti-malarial drugs but also in the treatment of chronic inflammatory diseases. Since the outbreak of COVID-19 pandemic, Morocco have included this medication in the COVID-19 treatment guidelines in association with azithromycine. Besides dermatologic problems, ocular impairments and gastro-intestinal effects, quinolines may also cause rarely described psychiatric adverse effects. To our knowledge, there has been no reports of psychiatric side effects of chloroquine or hydroxy chloroquine in the actual context of COVID-19 pandemic. Here, we present the description of two COVID-19 patients who showed psychiatric side effects after chloroquine treatment. One patient expressed psychotic symptoms and the other one experienced acute and intense anxiety. In both cases, and according to Naranjo score, the association between chloroquine and psychiatric side effects was probable.\n\nChloroquineCOVID-19psychiatryanxietyhallucinationside effect\n==== Body\nIntroducton\nAntimalarial drugs are widely indicated for different medical conditions and may cause rare but still described psychiatric adverse effects [1]. Behavioral and mood disturbances such as psychosis, anxiety and irritability have been described for decades as possible side effects of quinolines, either they are indicated as curative treatment or as malaria chemo prophylaxy [2,3] There is a renewed interest in antimalarial drugs since they have been used in the treatment of COVID-19 [4], with still ongoing debates on this medication´s efficiency and safety for infected patients [5]. In Morocco, and since the onset of the outbreak, confirmed cases of COVID-19 are systematically put under association of hydroxychloroquine or chloroquine and azithromycine as first line treatment [6]. To the best of our knowledge, psychiatric adverse side effects induced by chloroquine or hydroxhychloroquine in the actual context of COVID-19 outbreak have been until now poorly documented. Here we report two cases of COVID-19 in patients treated with chloroquine associated with azithromycine and who presented with acute onset psychiatric symptoms.\n\nPatient and observation\nCase 1: on March 31st, a 46 years old male patient, with a previous history of mild depressive episode treated with vortioxetine since November 2019, and diagnosed with COVID-19 after he presented with dry cough, fever, sore throat and fatigue. The patient had positive result on reverse transcription polymerase chain reaction (PCR) analysis of nose swab specimen. He was admitted into isolated COVID-19 ward and received chloroquine- azithromycine association. He had an electrocardiogram every two days. QT interval was normal to prolonged (corrected QT max: 490ms). On the ninth day of treatment, the patient showed symptoms of distress and insomnia. On the evening of the same day, he showed abrupt onset of psychotic symptoms such as visual hallucinations and incoherent speech, with the outburst of odd behavior and repeated attempts to run away from hospital. The patient´s insight was preserved. The cerebral CT scan was normal. We performed laboratory tests: ionogram, blood count, differential coagulation times, serum glucose, creatinine, sodium, potassium, liver enzymes, HIV, VHB, VHC and Syphilis serologies, who turned out to be normal. We made the decision to interrupt COVID-19 medication protocol as well as vortioxetine, and we initiate amilsulpride at the dose of 100 mg per day. Psychotic symptoms disappeared totally after 48 hours. We tapered off and then stopped amilsulpride within a week. The patient remained asymptomatic, and we evaluated him once in two weeks. On the latest psychiatric assessment (May 20), the patient showed no psychotic symptoms.\n\nCase 2: a 35 years old female patient, without any personal or family history of mental illness was diagnosed with non-severe form of COVID-19. The patient was admitted into isolated ward and put under azithomycin/chloroquine association. Three days after the treatment initiation, she expressed symptoms of insomnia, recurrent panic attacks with palpitations, sensation of imminent death, feeling of not being able to control her thoughts, depersonalization and derealization. She also expressed persistent sadness with permanent negative thoughts, and fear of dying, herself and her loved ones. The patient received 2.5 mg of lorazepam spread over 24 hours, with moderate improvement of anxiety symptoms. Five days after the azithomycin-chloroquine initiation, and two days after the onset of anxiety symptoms, the patient interrupted azithtromycin-chloroquine association on her own initiative. Anxiety symptoms disappeared rapidly. We indicated to switch to hydroxychloroquine associated with azithromycin. The patient went under this treatment for six days, and remained asymptomatic. After she left hospital, we followed her up by phone. She did not express any distress, anxiety or other psychiatric symptom.\n\nDiscussion\nMoroccan health authorities have set up guidelines for the management of COVID-19 patients including the association of azithromycine and hydroxychloroquine or chloroquine as a first line treatment. According to Moroccan guidelines, chloroquine dosing is 1000mg per day, and hydroxychloroquine dosing is 600mg per day. Both have to be maintained for ten days. Chloroquine and hydroxychloroquine are antimalarial drugs that are also used in the treatment of dermatological, rheumatological and infectious diseases [7]. Various side effects may occur; most of them are gastro-intestinal discomfort, visual disturbance, skin rashes and extrapyramidal symptoms. Rare psychiatric side effects are also described [8]. For both patients, Use of the Naranjo adverse drug reaction scale yielded a score of 7 for chloroquine, which indicates a probable relationship between chloroquine and psychiatric adverse side effects. Regarding Azithromycine, the Naranjo score was 2 for the first patient and 1 for the second patient. Thus, the relationship between psychiatric adversive effects and azithromycine is possible. For the first patient, the Naranjo score for vortioxetine, was 0, which indicates that the relationship with psychiatric side effects is doubtful [9,10].\n\nMost frequent psychiatric side effects expressed by patients under chloroquine or hydroxychloroquine are mania, visual hallucinations, derealization, anxiety, agitation and violent behaviors [11]. Other side effects may also be described. In 1988, Bhatia et al. reported a Capgras syndrome induced by chloroquine in a 9 years old patient [12]. More recently, Collins et al. reported a case of a 15 years old female patient with a catatonic state induced by chloroquine [13]. In the latter case, psychiatric symptoms occurred after hydroxychloroquine usual treatment was replaced by chloroquine. Similarly, our second patient we presented showed intense anxiety under chloroquine and remained asymptomatic after we switched to hydroxychloroquine. Indeed, compared to hydroxychloroquine, chloroquine has a narrower therapeutic index, with higher toxicity and increased risk of side effects [14] The first patient we presented had a previous history of mild depressive episode treated with vortioxetine. Psychiatric history has been identified as a possible risk factor for psychiatric side effects induced by chloroquine/hydroxychloroquine that occur independently of treatment duration and dosing [15]. When patients have undergoing psychiatric condition, antimalarial medication put them at risk of worsening their psychiatric symptoms [16].\n\nMechanisms of psychiatric side effects of antimalarials remain unclear [17]. In addition to the hypothesis of chloroquine effect on muscarinic and dopaminergic pathways, it was found to be antagonist to both 5-HT3A and 5-HT3B receptors [18]. Since chloroquine belongs to quinolone group, it may also, as well as fluoroqouinolones, act as an angonist to N-methyl-d-aspartate (NMDA) and as an antagonist to gamma-aminobutyric acid (GABA ) receptors [19]. Dopamine, serotonin, acetylcholine glutamate and gamma-aminobutyric acid are all known as neurotransmitters that play a key role in cognition, perception and mood pathways. Thus, chloroquine and hydroxychloroquine can provoke and/or enhance symptoms of anxiety, hallucinations, delusional thoughts or depression [20]. Beyond clinical features of these two case reports, their common thread is the COVID-19 outbreak context. Using hydroxychloroquine or chloroquine as a first line treatment for COVID-19 patients is still controversial. Since these medications are still used in many countries, patients have to be informed of psychiatric potential adverse effects and physicians need to set up preliminary psychiatric screening and careful monitoring in order to detect and manage rapidly potential mood and/or behavior disturbances.\n\nConclusion Up Down\n\nIn Africa, and all over the world, quinolines are widely used in the treatment of various medical conditions. Since the beginning of COVID-19 outbreak, many countries decided to include hydroxy chloroquine and chloroquine to medical treatment guidelines of COVID-19 patients. What is important to keep in mind is: Psychiatric adverse effects due to chloroquine may occur and should be monitored even if they are described as rare. Beside psychotic symptoms, patients may experiment intense anxiety with derealisation and the feeling of imminent death due to chloroquine. Regarding psychiatric adverse effects, hydroxy chloroquine appears to be less at risk than chloroquine. In the specific context of COVID-19 outbreak, potential psychiatric side effects due to chloroquine or hydroxy chloroquine have to been monitored and this dimension has to be included in the global assessment of COVID-19 patients.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nDr Benjelloun collected data. Dr Benjelloun and Pr Otheman elaborated and developed the manuscript. Pr El Kettani corrected the manuscript. All authors read and agreed on the final manuscript.\n==== Refs\nReferences\n1 Telgt DS van der Ven AJ Schimmer B Droogleever-Fortuyn HA Sauerwein RW Serious psychiatric symptoms after chloroquine treatment following experimental malaria infection Ann Pharmacother 2005 39 3 551 554 15728331 \n2 Akhtar S Mukherjee S Chloroquine Induced Mania Int J Psychiatry Med 1993 23 4 349 356 8175247 \n3 Tran TM Browning J Dell ML Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report Malar J 2006 5 74 16925829 \n4 Devaux CA Rolain JM Colson P Raoult D New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19 Int J Antimicrob Agents 2020 55 5 105938 32171740 \n5 Molina JM Delaugerre C Le Goff J Mela-Lima B Ponscarme D Goldwirt L No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection Med Mal Infect 2020 6 50 4 384 32240719 \n6 du Maroc Royaume Répartition des cas par Région. 18-06-2020 Accessed June 3, 2020 \n7 Sahoo S Kumar M Sinha VK Chloroquine-induced recurrent psychosis Am J Ther 2007 14 4 406 407 17667217 \n8 Garg P Mody P Lall KB Toxic psychosis due to chloroquine--not uncommon in children Clin Pediatr (Phila) 1990 29 8 448 450 2208904 \n9 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 7249508 \n10 Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury LiverTox: Clinical and Research Information on Drug-Induced Liver Injury 2012 Bethesda (MD) National Institute of Diabetes and Digestive and Kidney Diseases \n11 Bhatia MS Malik SC Psychiatric complications of chloroquine Indian J Psychiatry 1994 36 2 85 87 21743675 \n12 Bhatia MS Singhal PK Agrawal P Malik SC Capgras syndrome in chloroquine induced psychosis Indian J Psychiatry 1988 30 3 311 313 21927327 \n13 Collins Gregory B McAllister Mark S Chloroquine Psychosis Masquerading as PCP: A Case Report J Psychoactive Drugs 2008 6 40 2 211 4 18720672 \n14 Browning DJ Pharmacology of Chloroquine and Hydroxychloroquine Hydroxychloroquine and Chloroquine Retinopathy 2014 35 63 \n15 Biswas PS Sen D Majumdar R Psychosis following chloroquine ingestion: a 10-year comparative study from a malaria-hyperendemic district of India Gen Hosp Psychiatry 2014 36 2 181 186 24290896 \n16 Juurlink DN Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection CMAJ 2020 192 17 E450 E453 32269021 \n17 Das P Rai A Chopra A Philbrick K Psychosis likely induced by hydroxychloroquine in a patient with chronic Q fever: a case report and clinically relevant review of pharmacology Psychosomatics 2014 55 4 409 413 24268495 \n18 Bogaczewicz A Sobow T Psychiatric adverse effects of chloroquine Psychiatria i Psychologia Kliniczna 2017 17 111 114 \n19 Sarro A Sarro G Adverse Reactions to Fluoroquinolones. An Overview on Mechanistic Aspects Curr Med Chem 2001 8 371 84 11172695 \n20 Kehr J Yoshitake T Ichinose F Yoshitake S Kiss B Gyertyán I Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity Psychopharmacology (Berl) 2018 5 235 5 1593 1607 29637288\n\n",
"fulltext_license": "CC BY",
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"issue": "35(Suppl 2)",
"journal": "The Pan African medical journal",
"keywords": "COVID-19; Chloroquine; anxiety; hallucination; psychiatry; side effect",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000328:Adult; D000962:Antimalarials; D001007:Anxiety; D000086382:COVID-19; D002738:Chloroquine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009018:Morocco; D011605:Psychoses, Substance-Induced",
"nlm_unique_id": "101517926",
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"pages": "83",
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"pmid": "33623607",
"pubdate": "2020",
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"references": "15728331;32269021;2208904;7249508;32171740;24268495;16925829;32240719;29637288;17667217;11172695;18720672;8175247;24290896;21743675;21927327",
"title": "Psychiatric side effects of chloroquine in COVID-19 patients: two case reports.",
"title_normalized": "psychiatric side effects of chloroquine in covid 19 patients two case reports"
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"abstract": "Statins are widely used and are currently the state-of-the-art treatment for primary and secondary prevention of cardiovascular disease. Although statins are generally well tolerated and present an excellent safety profile, adverse effects from muscle toxicity may occur in some patients. Statin-induced dermatomyositis (DM) is a rare adverse event associated with its use and very few fatal cases have been reported. We present the case of a 69-year-old man with early onset DM precipitated by a small dose of simvastatin. Despite immediate cessation of the agent and the use of systemic corticosteroids, the case took a very aggressive and fatal course. Such progression is extremely unusual for statin-induced DM. Despite the safety of statins, we highlight the importance of identifying potential side effects associated with this class of medications. We also emphasize the importance of correct diagnosis and close follow-up of patients with statin side effects.",
"affiliations": "Universidade Federal de Santa Maria, Department of Clinical Medicine, Santa Maria, RS, Brazil.;Hospital Universitário de Santa Maria, Dermatology Service, Santa Maria, RS, Brazil.;Hospital Universitário de Santa Maria, Dermatology Service, Santa Maria, RS, Brazil.;Universidade Federal de Santa Maria, Department of Clinical Medicine, Santa Maria, RS, Brazil.",
"authors": "Chemello|Raíssa Massaia Londero|RML|;Benvegnú|Ana Maria|AM|;Dallazem|Lia Natália Diehl|LND|;Chemello|Diego|D|",
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"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omx063omx063Case ReportAggressive and fatal statin-induced dermatomyositis: a case report Chemello Raíssa Massaia Londero Benvegnú Ana Maria Dallazem Lia Natália Diehl Chemello Diego \nUniversidade Federal de Santa Maria, Department of Clinical Medicine, Santa Maria, RS, Brazil\nHospital Universitário de Santa Maria, Dermatology Service, Santa Maria, RS, BrazilCorrespondence address. Centro de Ciências da Saúde, Prédio 26A, Faixa de Camobi, Km 09, Santa Maria, RS, Brazil. Tel: +55-55-3220-8508; Fax: +55-55-3220-8000; E-mail: chemello.diego@gmail.com12 2017 11 12 2017 11 12 2017 2017 12 omx06305 4 2017 06 7 2017 13 8 2017 © The Author 2017. Published by Oxford University Press.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nStatins are widely used and are currently the state-of-the-art treatment for primary and secondary prevention of cardiovascular disease. Although statins are generally well tolerated and present an excellent safety profile, adverse effects from muscle toxicity may occur in some patients. Statin-induced dermatomyositis (DM) is a rare adverse event associated with its use and very few fatal cases have been reported. We present the case of a 69-year-old man with early onset DM precipitated by a small dose of simvastatin. Despite immediate cessation of the agent and the use of systemic corticosteroids, the case took a very aggressive and fatal course. Such progression is extremely unusual for statin-induced DM. Despite the safety of statins, we highlight the importance of identifying potential side effects associated with this class of medications. We also emphasize the importance of correct diagnosis and close follow-up of patients with statin side effects.\n==== Body\nINTRODUCTION\nStatins are currently the state-of-the-art in pharmaceutical intervention for reducing the probability of cardiovascular disease (CVD) events in patients with moderate or high risk. Substantial evidence indicates the safety of statins, with myalgia as the most commonly reported side effect. Severe muscular side effects are rare and fatal events are unusual. We present the case of a 69-year-old man with early onset dermatomyositis (DM) precipitated by a small dose of simvastatin. Despite immediate cessation of the agent and early institution of immunosuppressive therapy, the outcome was unfavorable.\n\nCASE REPORT\nA 69-year-old man presented with a 1-week history of erythroderma, which began 3 days after the prescription of simvastatin (20 mg/day) for primary prevention of CVD (Fig. 1). His comorbidities included hypertension, Type 2 diabetes-mellitus, and chronic obstructive pulmonary disease due to a history of smoking. Statin therapy was immediately discontinued and he was treated with systemic corticosteroids (prednisone 1 mg/kg/day) with initial improvement.\n\n\nFigure 1: Erythrodermia in front (A) and back (B) of thorax and abdomen.\n\nAfter a 2-month period on a progressively reduced steroid dosage, the patient was admitted to the hospital due to muscle weakness and ulcer formation at the site of his previous rash. Physical examination also revealed heliotrope rash, Gottron’s papules and periungual telangiectasias (Fig. 2). Muscle testing found evidence of proximal muscle weakness affecting the hip and shoulder girdles. There was no fever, calcinosis, Raynaud’s phenomenon, dyspnea or sclerodactyly.\n\n\nFigure 2: Right hand picture showing scaly erythematous lesions on the extensor surfaces of the proximal and distal interphalangeal joints (Gottron papules) and periungual telangeictasias.\n\nLaboratory evaluation showed elevated levels of creatine kinase (CK) (617 mg/dl) and CK-MB enzymes (50 mg/dl). The anti-histidyl-tRNA synthetase (anti-Jo-1) and anti-Mi-2 auto-antibodies were negative. There was no evidence of cardiologic, rheumatologic or infectious disease. Malignancy work-up was performed with contrast-enhanced chest and abdomen computed tomography. He also underwent upper and lower gastrointestinal endoscopy showing no signs of malignancy. Additionally, levels of available tumor markers (CA19-9, carcinoembryonic antigen, lactate dehydrogenase, prostate-specific antigen, thyroglobulin) were all non-suggestive of neoplasm. An ulcer biopsy revealed basal layer vasculopathic degeneration of keratinocytes with eosinophilic infiltrate and leukocytoclastic vasculitis. A deltoid muscle biopsy was performed, showing nonspecific findings. However, a muscle MRI revealed areas of fatty infiltration and muscle edema (Fig. 3).\n\n\nFigure 3: Magnetic resonance imaging of shoulders (A and B) and hip (C and D) showing areas of fatty infiltration, corresponding to hyperintensity within muscles on T1-weighted images (A and C, arrows) and muscle edema, corresponding to areas of hyperintensity on short-tau-inversion-recovery sequences (B and D, arrowhead).\n\nStatin-induced DM was diagnosed. Despite high-dose methylprednisolone therapy, only mild clinical improvement was observed over the next two weeks. The patient developed dysphagia and rapidly progressed to aspiration pneumonia and sepsis. Additional treatment with high-dose corticosteroids or other immunosuppressive drugs was not possible. The patient died several days later.\n\nDISCUSSION\nStatins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are currently the preferred pharmaceutical intervention for reducing the probability of CVD events and mortality by at least a moderate amount in adults aged 40–75 years who have one or more CVD risk factors and a calculated 10-year CVD event risk of at least 10%.\n\nSubstantial evidence indicates the safety of statins, with myalgia as the most commonly reported side effect [1]. However, statin-associated auto-immune myopathy has also been observed. The recommended classification is to break down this spectrum of diseases into inflammatory myopathies (polymyositis and DM) and necrotizing myopathy [2–4]. Although its incidence is not known with certainty, data suggest that it occurs in ~2–3 of every 100 000 patients treated with statins. Fatal cases are extremely rare, occurring in only 0.2 or fewer instances per million statin prescriptions [5–7].\n\nThe present report highlights a rare case of fatal DM precipitated by small dose of simvastatin. Statin-induced DM is believed to be an auto-immune skeletal muscle disorder. It usually manifests from 2 months up to 5 years after initiation of statin therapy, although there are case reports showing earlier symptom onset [8]. Typical features of DM include muscle pain, weakness and tenderness, which are proximal and symmetrical. Unique dermatological features usually accompany muscle weakness and are pathognomonic of the disease. These include scaly erythematous lesions found on the extensor surfaces of the metacarpophalangeal, proximal interphalangeal and distal interphalangeal joints known as Gottron’s papules. Moreover, patients may develop a violaceous eruption on the upper eyelids, sometimes associated with periorbital edema, known as heliotrope rash [9].\n\nIn typical cases of DM, elevated levels of CK and other muscle enzymes are common. As expected in auto-immune diseases, patients have unique auto-antibodies that are associated with different clinical features, which can be present in up to 70% of cases [9]. Muscle damage can be evaluated through muscle biopsy or MRI. The last, shows fatty infiltration (corresponding to areas of hyperintensity within muscles on T1-weighted images) and muscle edema (corresponding to areas of hyperintensity on short-tau-inversion-recovery sequences). DM muscle biopsy analysis shows perifascicular atrophy and perivascular inflammation, characterized by macrophages, B cells, and plasmacytoid dendritic cell infiltration. In the present case, the two measured auto-antibodies were negative, although other specific laboratory tests could not be performed due to limited resources. The muscle biopsy also was inconclusive, which is reported in up to 20% of inflammatory myopathies [10]. Nevertheless, the typical clinical features and MRI findings strongly support a diagnosis of statin-induced DM. Despite attempts to a definitive diagnosis, an autopsy studied was deferred by the patient's family.\n\nThe present case also highlights the potential role of statins as triggers of immune system disease. It also emphasizes the need for more aggressive treatment and closer follow-up of cases without complete initial recovery. Contrary to the majority of cases reported so far, our report is characterized by very early development after initiating simvastatin therapy. Moreover, a malignant course ensued even after discontinuation of the offending agent and treatment with corticosteroids. Among the reasons for this could be the type of statin used. Lipophilic statins are more likely to enter non-hepatic cells such as myocytes and therefore may theoretically be more myotoxic. This may explain the large number of case reports of myopathies induced by simvastatin and atorvastatin [11]. Although the exact mechanism of statins-induced DM is not completely known, genetic predisposition could also be involved. For example, several studies have demonstrated the disease is frequently related to variants in SLCO1B1, a gene regulating hepatic statin uptake. Because, the disease does not develop in the great majority of subjects with genetic predisposition, environmental triggers or additional genetic factors are also likely to have a casual role [12].\n\nCONCLUSION\nAlthough statins are currently the preferred pharmaceutical intervention for reducing the probability of CVD, statin-associated auto-immune myopathy exists as a rare side effect. When such diagnosis is suspected, immediate cessation of the agent and early institution of immunosuppressive therapy are critical. Nevertheless, rare cases can take a lethal course.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nFUNDING\nNo funding requirement.\n\nETHICAL APPROVAL\nNo ethical approval required.\n\nCONSENT\nWritten consent was provided by the patient’s relative.\n\nGUARANTOR\nCorresponding author (Dr D. Chemello).\n==== Refs\nREFERENCES\n1 \nBibbins-Domingo K , Grossman DC , Curry SJ , Davidson KW , Epling JW , García FA , et al \nStatin use for the primary prevention of cardiovascular disease in adults: US preventive services task force recommendation statement . JAMA 2016 ;316 :1997 –2007 .27838723 \n2 \nSathasivam S \nStatin induced myotoxicity . Eur J Intern Med 2012 ;23 :317 –24 .22560377 \n3 \nPasternak RC , Smith SC , Bairey-Merz CN , Grundy SM , Cleeman JI , Lenfant C , et al \nACC/AHA/NHLBI clinical advisory on the use and safety of statins . Circulation 2002 ;106 :1024 –8 .12186811 \n4 \nVasconcelos OM , Campbell WW \nDermatomyositis-like syndrome and HMG-CoA reductase inhibitor (statin) intake . Muscle Nerve 2004 ;30 :803 –7 .15389654 \n5 \nGroup HPSC \nMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial . Lancet 2002 ;360 :7 –22 .12114036 \n6 \nStaffa JA , Chang J , Green L \nCerivastatin and reports of fatal rhabdomyolysis . N Engl J Med 2002 ;346 :539 –40 .\n7 \nMammen AL \nStatin-associated autoimmune myopathy . N Engl J Med 2016 ;374 :664 –9 .26886523 \n8 \nZaraa IR , Labbène I , Mrabet D , Zribi H , Chelly I , Zitouna M , et al \nSimvastatin-induced dermatomyositis in a 50-year-old man . BMJ Case Rep 2011 ;2011:bcr0220113832. doi:10.1136/bcr.02.2011.3832.\n9 \nMammen AL \nAutoimmune myopathies . Continuum (Minneap Minn) 2016 ;22 :1852 –70 . (6, Muscle and Neuromuscular Junction Disorders).27922497 \n10 \nVan De Vlekkert J , Maas M , Hoogendijk JE , De Visser M , Van Schaik IN \nCombining MRI and muscle biopsy improves diagnostic accuracy in subacute-onset idiopathic inflammatory myopathy . Muscle Nerve 2015 ;51 :253 –8 .24895239 \n11 \nOztas M , Ugurlu S , Aydin O \nAtorvastatin-induced dermatomyositis . Rheumatol Int 2017 ;37 :1217 –9 .28238074 \n12 \nGhatak A , Faheem O , Thompson PD \nThe genetics of statin-induced myopathy . Atherosclerosis 2010 ;210 :337 –43 .20042189\n\n",
"fulltext_license": "CC BY-NC",
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"journal": "Oxford medical case reports",
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"nlm_unique_id": "101642070",
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"pages": "omx063",
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"title": "Aggressive and fatal statin-induced dermatomyositis: a case report.",
"title_normalized": "aggressive and fatal statin induced dermatomyositis a case report"
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"abstract": "Herpes simplex encephalitis (HSE) is a rare disease, but it is the most common form of sporadic encephalitis. HSE is transmitted through direct contact and developing nosocomial HSE is rarely reported in the literature. Nosocomial HSE is difficult to diagnose due to its non-specific clinical features. In this article, we present a case of nosocomial HSE that was responsible for grave consequence. We also explore its causes, outcome, and give recommendations to avoid such fatal occurrence. We stress on strict adherence to the standard precautions and preventive control measures.",
"affiliations": "King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, P.O. Box: 12723, Jeddah 21483, Saudi Arabia. Electronic address: halgahtani@hotmail.com.;King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.",
"authors": "Algahtani|Hussein|H|;Shirah|Bader|B|;Hmoud|Mohammed|M|;Subahi|Ahmad|A|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
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"journal": "Journal of infection and public health",
"keywords": "Encephalitis; Herpes simplex virus; Hospital-acquired infection; Nosocomial infection",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D003428:Cross Infection; D020803:Encephalitis, Herpes Simplex; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "343-347",
"pmc": null,
"pmid": "27686257",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nosocomial herpes simplex encephalitis: A challenging diagnosis.",
"title_normalized": "nosocomial herpes simplex encephalitis a challenging diagnosis"
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"activesubstancename": "LACOSAMIDE"
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"abstract": "Donor cell leukemia (DCL) is a rare complication of hematopoietic stem cell transplantation (HSCT) which occurs in ~5% of all leukemic relapses. In the English literature, >60 cases of DCL have been reported, however, only two cases of DCL following HSCT for the treatment of severe aplastic anemia (SAA) have been described to date. In the present study, the case of a 25 year-old male patient diagnosed with SAA, who underwent a peripheral blood stem cell transplantation (PBSCT) using cells obtained from a sibling with an identical human leukocyte antigen, is presented. The patient developed acute myeloid leukemia with an (8;21)(q22;q22) translocation and an extra copy of the chromosome 8 in donor cells 2.5 years following PBSCT, which was preceded by the development of Graves' disease 1 year following PBSCT. The leukemia achieved complete remission following 1 cycle of priming therapy, 2 cycles of consolidation chemotherapy with daunorubicin and cytarabine and maintenance therapy with interleukin-2 (IL-2). At present, the patient has discontinued IL-2 therapy, and the DCL has been in molecular remission for >3 years. The present case indicates that chemotherapy and IL-2 maintenance therapy are an effective treatment for DCL; hyperthyroidism was relieved following treatment, although hypothyroidism subsequently developed.",
"affiliations": "Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.;Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.",
"authors": "Ma|Hongbing|H|;Liu|Ting|T|",
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"country": "Greece",
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"doi": "10.3892/ol.2016.4452",
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"issn_linking": "1792-1074",
"issue": "11(6)",
"journal": "Oncology letters",
"keywords": "donor cell leukemia; severe aplastic anemia; stem cell leukemia",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "3858-3862",
"pmc": null,
"pmid": "27313707",
"pubdate": "2016-06",
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"title": "Development of donor cell leukemia following peripheral blood stem cell transplantation for severe aplastic anemia: A case report.",
"title_normalized": "development of donor cell leukemia following peripheral blood stem cell transplantation for severe aplastic anemia a case report"
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"abstract": "Deep abdominal vein thrombosis is extremely rare among thrombotic events secondary to the use of contraceptives. A case to illustrate the clinical utility of ethno-specific pharmacogenetic testing in warfarin management of a Hispanic patient is reported. A 37-year-old Hispanic Puerto Rican, non-gravid female with past medical history of abnormal uterine bleeding on hormonal contraceptive therapy was evaluated for abdominal pain. Physical exam was remarkable for unspecific diffuse abdominal tenderness, and general initial laboratory results-including coagulation parameters-were unremarkable. A contrast-enhanced computed tomography showed a massive thrombosis of the main portal, splenic, and superior mesenteric veins. On admission the patient was started on oral anticoagulation therapy with warfarin at 5 mg/day and low-molecular-weight heparin. The prediction of an effective warfarin dose of 7.5 mg/day, estimated by using a recently developed pharmacogenetic-guided algorithm for Caribbean Hispanics, coincided with the actual patient's warfarin dose to reach the international normalized ratio target. We speculate that the slow rise in patient's international normalized ratio observed on the initiation of warfarin therapy, the resulting high risk for thromboembolic events, and the required warfarin dose of 7.5 mg/day are attributable in some part to the presence of the NQO1*2 (g.559C>T, p.P187S) polymorphism, which seems to be significantly associated with resistance to warfarin in Hispanics. By adding genotyping results of this novel variant, the predictive model can inform clinicians better about the optimal warfarin dose in Caribbean Hispanics. The results highlight the potential for pharmacogenetic testing of warfarin to improve patient care.",
"affiliations": "University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA.;University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA.;University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA.;University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA; University of Puerto Rico Humacao Campus, Humacao, PR, USA.;University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA.;University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA.;University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA.",
"authors": "Hernandez-Suarez|Dagmar F|DF|;Claudio-Campos|Karla|K|;Mirabal-Arroyo|Javier E|JE|;Torres-Hernández|Bianca A|BA|;López-Candales|Angel|A|;Melin|Kyle|K|;Duconge|Jorge|J|",
"chemical_list": null,
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961668204910.1177_2324709616682049Case ReportPotential of a Pharmacogenetic-Guided Algorithm to Predict Optimal Warfarin Dosing in a High-Risk Hispanic Patient Role of a Novel NQO1*2 PolymorphismHernandez-Suarez Dagmar F. MD1Claudio-Campos Karla BSc1Mirabal-Arroyo Javier E. MD1Torres-Hernández Bianca A. PhD12López-Candales Angel MD, FACC, FASE1Melin Kyle PharmD1Duconge Jorge PhD, BScPharm11 University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA2 University of Puerto Rico Humacao Campus, Humacao, PR, USADagmar F. Hernandez-Suarez, MD, University of Puerto Rico School of Medicine, Medical Sciences Building, PO Box 365067, San Juan, PR 00936-5067, USA. Email: dagmar.hernandez@upr.edu01 12 2016 Oct-Dec 2016 4 4 232470961668204930 9 2016 5 11 2016 8 11 2016 © 2016 American Federation for Medical Research2016American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Deep abdominal vein thrombosis is extremely rare among thrombotic events secondary to the use of contraceptives. A case to illustrate the clinical utility of ethno-specific pharmacogenetic testing in warfarin management of a Hispanic patient is reported. A 37-year-old Hispanic Puerto Rican, non-gravid female with past medical history of abnormal uterine bleeding on hormonal contraceptive therapy was evaluated for abdominal pain. Physical exam was remarkable for unspecific diffuse abdominal tenderness, and general initial laboratory results—including coagulation parameters—were unremarkable. A contrast-enhanced computed tomography showed a massive thrombosis of the main portal, splenic, and superior mesenteric veins. On admission the patient was started on oral anticoagulation therapy with warfarin at 5 mg/day and low-molecular-weight heparin. The prediction of an effective warfarin dose of 7.5 mg/day, estimated by using a recently developed pharmacogenetic-guided algorithm for Caribbean Hispanics, coincided with the actual patient’s warfarin dose to reach the international normalized ratio target. We speculate that the slow rise in patient’s international normalized ratio observed on the initiation of warfarin therapy, the resulting high risk for thromboembolic events, and the required warfarin dose of 7.5 mg/day are attributable in some part to the presence of the NQO1*2 (g.559C>T, p.P187S) polymorphism, which seems to be significantly associated with resistance to warfarin in Hispanics. By adding genotyping results of this novel variant, the predictive model can inform clinicians better about the optimal warfarin dose in Caribbean Hispanics. The results highlight the potential for pharmacogenetic testing of warfarin to improve patient care.\n\nwarfarinCaribbean HispanicspharmacogeneticsNQO1thrombosisdosing algorithmcover-dateOctober-December 2016\n==== Body\nIntroduction\nWarfarin (Coumadin) is an oral anticoagulant drug that inhibits the vitamin K–dependent clothing factors. To date, it has demonstrated to be highly effective in the treatment and prevention of several thromboembolic disorders, including atrial fibrillation, artificial heart valves, pulmonary embolism, antiphospholipid syndrome, and deep vein thrombosis.1,2 Despite the advent of the new direct oral anticoagulants,3 warfarin continues to be the mainstay in oral anticoagulation for many patients. According to IMS Health, about 20 million of warfarin prescriptions were dispensed annually in recent years within the Unites States.4,5 However, warfarin ranks as one of the top 10 prescription drugs by reports of adverse episodes in outpatients.6,7 In spite of its proven clinical utility and the fact that this drug has been on the market for a long time, optimal warfarin dosing continues to be a challenge due to the wide variability among patients, narrow therapeutic index, high potential for drug interactions, high potential for food-based interactions (vitamin K–containing products), and variability in pharmacogenomics.1,8\n\nPharmacogenetic algorithms to predict effective warfarin dose have been developed in several populations worldwide.1 Nonetheless, individuals of Hispanic heritage have been largely excluded from derivation cohorts.9-11 This seems to exacerbate existing health care disparities due to the omission of certain ethno-specific genetic polymorphisms on relevant pharmacogenes (eg, NQO1*2, CYP4F2*3, CYP2C9*8) of clinical significance among individuals from this minority group.\n\nTo our knowledge, there are no reported data regarding the application of pharmacogenetic-guided algorithm in Hispanics with massive abdominal vein thrombosis to determine the optimal warfarin dose. In this report, a recently developed admixture-adjusted pharmacogenetic algorithm for Caribbean Hispanics is applied to a patient carrying a loss of function NQO1*2 (g.559C>T, p.P187S) polymorphism, which seems to be significantly associated with resistance to warfarin in this population.\n\nCase Presentation\nA case is described of a 37-year-old white Hispanic Puerto Rican non-gravid female (147 lbs) with past medical history of abnormal uterine bleeding for 4 months who visited the emergency room due to abdominal pain. The patient mentioned having been evaluated by gynecology service a month ago, and she was started on medroxyprogesterone acetate (Provera, Pfizer, New York, NY), although she just used the medication for 10 days. Moreover, she underwent endometrial curettage procedure and biopsy with no further complications a week before starting with symptoms. She had no history of tobacco, alcohol, or illegal drugs use. On initial evaluation, the patient stated having started with abdominal bloating and upper mild abdominal pain, constant, no radiating, dull, not related with meals or bowel movements, about 2 weeks prior to her visit. She denied nausea, vomiting, fever, anorexia, diarrhea, and constipation. Due to no improvement of symptoms—despite being treated with antacid medications for a suspected gastritis—she went to seek medical attention to the emergency room. Physical examination was just remarkable for unspecific diffuse abdominal tenderness. Additionally, general initial laboratory results were unremarkable with a prothrombin time and partial thromboplastin time of 10.0 and 26.6 seconds, respectively, and international normalized ratio (INR) of 0.9. No electrolyte abnormalities or anemia were observed. As part of an initial imaging workup, a contrast-enhanced abdominal computed tomography was ordered and an acute on chronic massive thrombosis of the main portal, splenic, and superior mesenteric veins was diagnosed (Figure 1). The patient was then admitted under oral anticoagulation therapy with warfarin at 5 mg/day and low-molecular-weight heparin (ie, Lovenox [enoxaparin] injections) 70 mg every 12 hours, the second discontinued at day 7 of therapy. The need to use a short course of low-molecular-weight heparin was due to the initial temporal effect of Coumadin in promoting clot formation as a consequence to the secondary increase of protein C and protein S factors, also dependent of vitamin K. Follow-up laboratories showed normal results in antithrombin III, protein C and protein S activity, antiphospholipid antibodies, factor V Leiden mutation, JAK2 mutation, prothrombin gene mutation, flow cytometry for CD55 and CD59, and direct Coombs test.\n\nFigure 1. Contrast-enhanced computed tomography of the abdomen and pelvis showing a massive thrombosis of the main portal, splenic, and superior mesenteric veins.\n\nOn initial evaluation, the patient was approached by our team and agreed to participate as a volunteer in an Institutional Review Board–approved research study aiming to investigate the clinical utility of a recently developed pharmacogenetic-guided algorithm for Caribbean Hispanics.12 Consequently, we collected a buccal swap sample and genotype testing was performed after obtaining her written consent. The sample was interrogated for 6 relevant genetic variants on 4 candidate pharmacogenes (ie, CYP2C9, CYP4F2, NQO1, and VKORC1) using the corresponding probes from TaqMan SNP assay technology (Applied Biosystems, Foster City, CA). Consequently, she was found to be single carrier of the NQO1*2 (g.559C>T, p.P187S) polymorphism and noncarrier of the the remaining analyzed variants.\n\nBased on the diagnosis of deep vein thrombosis, the recommended INR therapeutic range is between 2.0 and 3.0. The patient was initiated on oral warfarin at 5 mg/day following dose recommendations in clinical charts (nomograms) and current American College of Chest Physicians guidelines.13,14 The baseline INR value on admission was 0.9 (Table 1). Consecutive INR value of 1.1 was measured on day 3 of therapy and the warfarin dose was increased to 10 mg/day (the highest dose given). Following the pharmacogenetic-driven algorithm recommendations, the patient was prescribed warfarin at the dose of 7.5 mg/day for further prevention of thrombus formation. She was kept on this dose until discharge when she reported 2 continue INR values on therapeutic range. Notably, the dose prescribed at the time of achieving the first target INR was 7.5 mg/day (Figure 2). It is important to mention that during the follow-up period, warfarin dosing was stopped on 2 occasions. First, on day 7 due to an INR value of 4.0 (patient was on 10 mg/day) and on day 17 after a reported INR of 5.09.\n\nTable 1. Consecutive International Normalized Ratio (INR) Measurements and Daily Warfarin Dose Over the Entire Follow-up Period (ie, 12 weeks). Therapeutic Range Was Set at 2.0 to 3.0.\n\nNo.\tDay/Week\tTest Date\tINR Value\tDosing (mg/day)\t\n1\tBaseline\tMarch 26, 2016\t0.9a\t5 mg/day\t\n2\tDay 3/week 1\tMarch 28, 2016\t1.1a\tRise to 10 mg/day\t\n3\tDay 7/week 1\tApril 1, 2016\t4.0b\t10 mg/day and then stop warfarin\t\n4\tDay 8/week 1\tApril 2, 2016\t4.7b\tOne day off\t\n5\tDay 9/week 2\tApril 3, 2016\t2.8c\tResume warfarin at 7.5 mg/day\t\n6\tDay 10/week 2\tApril 4, 2016\t1.3a\t7.5 mg/day\t\n7\tDay 11/week 2\tApril 5, 2016\t1.6a\t7.5 mg/day\t\n8\tDay 12/week 2\tApril 6, 2016\t2.2c\t7.5 mg/day\t\n9\tDay 13/week 2\tApril 7, 2016\t2.6c\t7.5 mg/day and discharged\t\n10\tDay 17/week 3\tApril 11, 2016\t5.09b\tStop warfarin for 1 day\t\n11\tDay 18/week 3\tApril 12, 2016\t3.86b\tResume warfarin at 5 mg/day\t\n12\tDay 21/week 3\tApril 15, 2016\t2.93c\t5 mg Monday to Friday; 7.5 mg Saturday and Sunday\t\n13\tDay 26/week 4\tApril 20, 2016\t3.30b\t5 mg Monday to Friday; 7.5 mg Saturday and Sunday\t\n14\tWeek 7\tMay 8, 2016\t3.35b\t5 mg Monday to Friday; 7.5 mg Saturday and Sunday\t\n15\tWeek 9\tMay 26, 2016\t3.17b\t5 mg Monday to Friday; 7.5 mg Saturday and Sunday\t\n16\tWeek 11\tJune 4, 2016\t2.15c\t5 mg Monday to Friday; 7.5 mg Saturday and Sunday\t\n17\tWeek 11\tJune 8, 2016\t2.07c\t7.5 mg/day\t\n18\tWeek 12\tJune 11, 2016\t2.18c\t7.5 mg/day\t\n19\tWeek 12\tJune 16, 2016\t1.81a\t5 mg Monday to Friday; 7.5 mg Saturday and Sunday\t\na Below therapeutic range.\n\nb Above therapeutic range.\n\nc INR levels on target.\n\nFigure 2. Serial INR values and daily warfarin doses over the follow-up period. The optimal warfarin dose of 7.5 mg/day was predicted (green line) by a pharmacogenetic-guided algorithm. Therapeutic range (2.0-3.0) is represented as a gray shaded area. Routinely prescribed “standard” average daily dose of warfarin (ie, 5 mg/day) is depicted as a dashed line in red.\n\nAs per protocol, a 3-month follow-up period was undertaken for identifying warfarin-related adverse episodes as well as other relevant on-treatment events in the patient. Warfarin dosing was changed 6 times in this patient during the course of 90 days. There were 19 INR assessments, with 4 tests made before the patient reached first INR on target (Table 1). Thirty-seven percent of these INRs exceeded target range, peaking at 5.09. Last INR measured on week 12 was 1.81, suggesting a mild subtherapeutic level of warfarin dosage, and re-exposing her to a slightly higher risk of thrombosis. Previous reports suggest a 17-fold increase in stroke as INR fell below 2.0, whereas the risk for major and life-threatening bleeding events increases 42% for each unit of INR increment above therapeutic range.15 Fortunately, in this case neither strokes nor thromboembolic events or major life-threatening bleeding episodes were reported. Over the follow-up period, the patient reported 2 bruises (one in the calves and the other in the thighs) on weeks 2 to 4, moderate palpitations and dark stools on week 3, chest pain on weeks 3 and 4 and weeks 11 and 12, as well as recurrent fatigue, weakness, anxiety, and discomfort.\n\nDiscussion\nDeep abdominal vein thrombosis is extremely rare among thrombotic events secondary to the use of contraceptives.16 Patients with this condition are at high risk of mortality due to the resulting extensive intestinal ischemia secondary to the blood flow obstruction. Thus, it represents a medical emergency that needs to be treated immediately and yet the mortality rate remains significant.17 Furthermore, the unspecific abdominal symptoms—often referred as the main complaint—and findings on physical examination make difficult the diagnosis, which results in frequent delays in therapy. To date, prompt anticoagulation represents the mainstay therapy. Nevertheless, bowel surgical resection might become the most appropriate choice when associated surgical complications are present. In the present case, we introduced for the first time genetic information to guide the anticoagulation therapy in a Hispanic female with an atypical thrombosis.\n\nPharmacogenetic Analysis\nAn admixture-adjusted pharmacogenetic algorithm that explained more than two thirds of the observed variance in stable warfarin dose within Caribbean Hispanics was recently developed by our team.12 Among predictors of warfarin dose variability in this model, the effect on dose of all CYP2C9 polymorphisms combined was −18%, whereas the effect of both VKORC1-AA and VKORC1-GA status combined was −13%. CYP4F2*3 18000G>A (V433M, rs2108622) and NQO1*2 c.559C>T (P187S, rs1800566) variants were independently associated with a 17% and 10% increase of the dose per variant allele, respectively, whereas the admixture index decreases the dose by 7%. In the proposed model, the effect (%) on the estimates of the effective dose is calculated per number of variant alleles (ie, CYP2C9, CYP4F2, NQO1, and VKORC1), per decades (Age) and per 0.25-unit increase in the dose-adjusted INR response at the third day.\n\nThe observed frequency of the NQO1*2 (g.559C>T, p.P187S, rs1800566) “resistant” polymorphism among the cardiovascular patients from the Puerto Rican population used as the “derivation cohort” was 0.10 (95% confidence interval [CI] = 0.07-0.13).12 There are 15.7% carriers of the C/T heterozygous genotype for the NQO1*2 SNP (95% CI 0.12-0.21) and 2% were double carriers (T/T) of this variant (95% CI = 0.007-0.05).12 The NAD(P)H dehydrogenase, quinone 1 (NQO1) gene encodes for a FAD-binding cytoplasmic 2-electron reductase enzyme that catalyzes the reduction of vitamin K to its active hydroquinone form, and it is therefore involved in the vitamin K–dependent prothrombin synthesis.18,19 Notably, the combination of CYP4F2*3 and NQO1*2 “resistant” variants, identified in as many as 20.4% and 17.7% of individuals from the Puerto Rican study cohort, respectively, had only been previously described to be associated with higher warfarin dose requirements in another US Hispanic population of Mexican descents.10\n\nThe prediction of 7.5 mg/day of maintenance warfarin by the developed pharmacogenetic-guided algorithm coincided with the patient’s actual effective warfarin dose to reach the INR therapeutic target. The delayed increase in the INR levels of this patient during the initial phase of therapy—in addition to the life cycle of existing clotting factors—may be, in part, a consequence of the NQO1*2 (g.559C>T, p.P187S) polymorphism found in this subject. Interestingly, this genetic variant seems to be significantly associated in Hispanics with resistance to warfarin.10,12\n\nAlthough American College of Chest Physicians guidelines recommends against routine use of pharmacogenetic testing for guiding doses of warfarin in patients initiating therapy (Grade 1B),14 the new and revised 2014 American Heart Association/American Stroke Association guidelines for the primary prevention of stroke recommend that pharmacogenetic dosing of vitamin K antagonists may be considered when therapy is initiated (level of evidence C).20 According to the Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines for warfarin maintenance dosing, the recommendations based on genetic information are rated as level A or strong, and are derived from numerous observational studies and some prospective trials that suggest the ability to more accurately identify stable therapeutic warfarin dose requirements through the use of both individual genotypes and clinically relevant information.1 The CPIC guideline also indicates that the use of pharmacogenetic algorithm-based dosing is a better predictive tool and, therefore, is recommended over other methods as long as clinical decision support systems or electronic means are available. This CPIC guideline is currently under revision to update recommendations and incorporate new evidences. Nevertheless, at the moment, there should be some level of consideration for the feasibility of pharmacogenetic testing in the context of warfarin treatment across various health care settings, as widespread pharmacogenetic testing in the outpatient setting may not be feasible or cost-effective.\n\nMost of the currently available pharmacogenetic-driven warfarin dosing algorithms overlook the effect of polymorphisms occurring on pharmacogenetic loci not found to be strongly associated with warfarin dose requirements among White Europeans,21-25 as opposed to the common CYP2C9*2, CYP2C9*3, and VKORC1-1639G>A variants that are indeed systematically incorporated into the developed models. It is becoming increasingly clear that the utility of existing models is limited in patients with mixed ancestry like Caribbean Hispanics or African Americans. A previously reported clinical trial (COAG, NCT00839657) raised concerns about real benefits from genotyping patients on warfarin to optimal dose predictions.25 Nonetheless, we strongly believe the COAG trial failed to account for certain ethno-specific genetic polymorphisms of clinical relevance, which led to significant errors in dosing predictions among individuals of African heritage. Accordingly, it is fairly reasonable to expect the same poor predictability by ignoring admixture and novel pharmacogenetic markers (eg, NQO1*2) of potential clinical interest in patients from underrepresented populations like Caribbean Hispanics.\n\nConclusions\nThe case reported supports our perception about the predictability of our pharmacogenetic model, after adding the genotyping result of this novel variant, in order to better inform clinicians on optimal warfarin dosing in the Hispanic population. Additionally, it highlights the potential for pharmacogenetic testing of warfarin to improve patient care and reduced health care costs. Further studies are warranted to determine whether the applied algorithm in this case could decrease adverse outcomes, hospital stay, and contribute as an important decision support tool on initiation of warfarin therapy.\n\nThe material presented herein is the result of work supported with resources from and the use of facilities at the UPR-MSC RCMI Center for Genomics in Health Disparities and Rare Disorders for performing genetic assays. The authors also want to thank the patient for her participation in this study.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This investigation was supported in part by grants from the National Heart, Lung, and Blood Institute (Grant Number SC1 HL123911); the Research Center in Minority Institutions from the National Institute on Minority Health and Health Disparities (Award Number 8G12 MD007600); and the Minority Biomedical Research Support-Research Initiative for Scientific Enhancement at the University of Puerto Rico Medical Sciences Campus (Grant Number R25 GM061838).\n==== Refs\nReferences\n1 \nJohnson JA Gong L Whirl-Carrillo M \nClinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing . J Clin Pharmacol Ther . 2011 ;90 :625 -629 .\n2 \nBristol-Myers Squibb . Coumadin (warfarin sodium) [Package insert] . Princeton, NJ : Bristol-Myers Squibb \nhttp://packageinserts.bms.com/pi/pi_coumadin.pdf. Accessed November 21, 2016 .\n3 \nRuff CT Giugliano RP Braunwald E \nComparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials . Lancet . 2014 ;383 :955 -962 .24315724 \n4 \nBartholow M \nTop 200 drugs of 2012 . Pharmacy Times . 2013 ;79 (7 ):42 -44 .\n5 \nIMS Institute for Healthcare Informatics . Declining medicine use and costs: for better or worse? A review of the use of medicines in the United States in 2012 \nhttp://www.imshealth.com/en/thought-leadership/webinar-library/declining-medicine-use-and-costs-for-better-or-worse-u.s-2012. Accessed November 21, 2016 .\n6 \nWysowski DK Nourjah P Swartz L \nBleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action . Arch Intern Med . 2007 ;167 :1414 -1419 .17620536 \n7 \nBudnitz DS Pollock DA Weidenbach KN Mendelsohn AB Schroeder TJ Annest JL \nNational surveillance of emergency department visits for outpatient adverse drug events . JAMA . 2006 ;296 :1858 -1866 .17047216 \n8 \nGulseth MP Grice GR Dager WE \nPharmacogenomics of warfarin: uncovering a piece of the warfarin mystery . Am J Health Syst Pharm . 2009 ;66 :123 -133 .19139476 \n9 \nDuconge J Cadilla CL Seip RL Ruaño G \nWhy admixture matters in genetically-guided therapy: missed targets in the COAG and EU-PACT trials . PR Health Sci J . 2015 ;34 :175 -177 .\n10 \nBress A Patel SR Perera MA Campbell RT Kittles RA Cavallari LH \nEffect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans . Pharmacogenomics . 2012 ;13 :1925 -1935 .23215885 \n11 \nDuconge J \nPopulation heterogeneity and genomic admixture: relevance for global pharmacogenetics . Pharmaco-genomics Pharmacoproteomics . 2014 ;5 :5 . doi:10.4172/2153-0645.1000e141 .\n12 \nDuconge J Ramos AS Claudio-Campos K \nA novel admixture-based pharmacogenetic approach to refine warfarin dosing in Caribbean Hispanics . PLoS One . 2016 ;11 :e0145480 .26745506 \n13 \nAgeno W Gallus AS Wittkowsky A Crowther M Hylek EM Palareti G \nOral Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines . Chest . 2012 ;141 (2 suppl ):e44S -e88S .22315269 \n14 \nHolbrook A Schulman S Witt DM ; American College of Chest Physicians . Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines . Chest . 2012 ;141 (2 suppl ):e152S -e184S .22315259 \n15 \nAnsell JE \nOptimizing the efficacy and safety of oral anticoagulant therapy: high-quality dose management, anticoagulation clinics, and patient self-management . Semin Vasc Med . 2003 ;3 :261 -270 .15199459 \n16 \nLidegaard Ø Løkkegaard E Svendsen AL Agger C \nHormonal contraception and risk of venous thromboembolism: national follow-up study . BMJ . 2009 ;339 :b2890 .19679613 \n17 \nBrunaud L Antunes L Collinet-Adler S \nAcute mesenteric venous thrombosis: case for nonoperative management . J Vasc Surg . 2001 ;34 :673 -679 .11668323 \n18 \nJaiswal AK \nHuman NAD(P)H: quinone oxidoreductase2 . Gene structure, activity, and tissue-specific expression . J Biol Chem . 1994 ;269 :14502 -14508 .8182056 \n19 \nJaiswal AK Bell DW Radjendirane V Testa JR \nLocalization of human NQO1 gene to chromosome 16q22 and NQO2-6p25 and associated polymorphisms . Pharmacogenetics . 1999 ;9 :413 -418 .10471077 \n20 \nMeschia JF Bushnell C Boden-Albala B ; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; Council on Hypertension . Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association . Stroke . 2014 ;45 :3754 -3832 .25355838 \n21 \nHigashi MK Veenstra DL Kondo LM \nAssociation between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy \nJAMA . 2002 ;287 :1690 -1698 .11926893 \n22 \nSanderson S Emery J Higgins J \nCYP2C9 gene variants, drug dose, and bleeding risk in warfarin treated patients: a HuGEnet systemic review and meta-analysis . Genet Med . 2005 ;7 :97 -104 .15714076 \n23 \nTakahashi H Wilkinson GR Nutescu EA \nDifferent contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance doses of warfarin in Japanese, Caucasians and African Americans . Pharmacogenet Genomics . 2006 ;16 :101 -110 .16424822 \n24 \nCaldwell MD Berg RL Zhang KQ \nEvaluation of genetic factors for warfarin dose prediction . Clin Med Res . 2007 ;5 :8 -16 .17456829 \n25 \nKimmel SE French B Kasner SE \nA pharmacogenetic versus a clinical algorithm for warfarin dosing . N Engl J Med . 2013 ;369 :2283 -2293 .24251361\n\n",
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"keywords": "Caribbean Hispanics; NQO1; dosing algorithm; pharmacogenetics; thrombosis; warfarin",
"medline_ta": "J Investig Med High Impact Case Rep",
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"title": "Potential of a Pharmacogenetic-Guided Algorithm to Predict Optimal Warfarin Dosing in a High-Risk Hispanic Patient: Role of a Novel NQO1*2 Polymorphism.",
"title_normalized": "potential of a pharmacogenetic guided algorithm to predict optimal warfarin dosing in a high risk hispanic patient role of a novel nqo1 2 polymorphism"
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"abstract": "OBJECTIVE\nTo report a case of olanzapine-induced hyperglycemia leading to a hyperosmolar, hyperglycemic, nonketonic coma.\n\n\nMETHODS\nA 51-year-old, 85.5-kg (ideal body weight 79.9 kg), white man presented to a Veterans Affairs hospital with a serum glucose concentration of 1596 mg/dL. Soon thereafter, he went into a hyperosmolar, hyperglycemic, nonketonic coma. Olanzapine therapy had been instituted less than six months prior to this event; approximately two months before this event, his blood glucose was 108 mg/dL. Eight days after stopping olanzapine, the glucose concentration returned to normal, and the patient no longer required insulin nor any other glucose-lowering agents.\n\n\nCONCLUSIONS\nThe insulin resistance caused by olanzapine is normally attributed to the weight gain associated with the drug. In this patient, it appears that olanzapine caused hyperglycemia by a mechanism other than weight gain.\n\n\nCONCLUSIONS\nThis case report and others from the literature suggest that olanzapine therapy may induce hyperglycemia in some patients.",
"affiliations": "Veterans Affairs Boston Healthcare System, MA 02130-4817, USA. roefaro.john@boston.va.gov",
"authors": "Roefaro|J|J|;Mukherjee|S M|SM|",
"chemical_list": "D014150:Antipsychotic Agents; D001786:Blood Glucose; D001569:Benzodiazepines; D010890:Pirenzepine; D000077152:Olanzapine",
"country": "United States",
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"doi": "10.1345/aph.10178",
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"issn_linking": "1060-0280",
"issue": "35(3)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001714:Bipolar Disorder; D001786:Blood Glucose; D006801:Humans; D006944:Hyperglycemic Hyperosmolar Nonketotic Coma; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010890:Pirenzepine; D013313:Stress Disorders, Post-Traumatic",
"nlm_unique_id": "9203131",
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"pages": "300-2",
"pmc": null,
"pmid": "11261526",
"pubdate": "2001-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Olanzapine-lnduced hyperglycemic nonketonic coma.",
"title_normalized": "olanzapine lnduced hyperglycemic nonketonic coma"
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"abstract": "BACKGROUND\nPlasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma.\n\n\nMETHODS\nA 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant. Morphological and immunohistochemical characterization of the extramedullary disease demonstrated that the tumor cells were derived from the monocyte-macrophage lineage. Next generation sequencing (NGS) studies detected similar clonal aberrations in the diagnostic plasma cell population and post-therapy neoplastic cells, including IGH-MAF rearrangement, multiple genetic mutations in RAS signaling pathway proteins, and loss of tumor suppressor genes. Molecular genetic analysis also revealed unique genomic alterations in the transformed tumor cells, including gain of NF1 and loss of TRAF3.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case of myeloid sarcoma transdifferentiated from plasma cell neoplasm. Our findings in this unique case suggest clonal evolution of plasma cell myeloma to myeloma neoplasm and the potential roles of abnormal RAS/RAF signaling pathway in lineage switch or transdifferentiation.",
"affiliations": "Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205-7199, USA.;Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205-7199, USA.;Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205-7199, USA. yyuan@uams.edu.",
"authors": "Gralewski|Jonathon H|JH|;Post|Ginell R|GR|;van Rhee|Frits|F|;Yuan|Youzhong|Y|http://orcid.org/0000-0003-4087-3466",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13000-018-0692-1",
"fulltext": "\n==== Front\nDiagn PatholDiagn PatholDiagnostic Pathology1746-1596BioMed Central London 69210.1186/s13000-018-0692-1Case ReportMyeloid transformation of plasma cell myeloma: molecular evidence of clonal evolution revealed by next generation sequencing Gralewski Jonathon H. jhgralewski@uams.edu 1Post Ginell R. gpost@uams.edu 1van Rhee Frits vanrheefrits@uams.edu 2http://orcid.org/0000-0003-4087-3466Yuan Youzhong 501-526-5072yyuan@uams.edu 11 0000 0004 4687 1637grid.241054.6Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199 USA 2 0000 0004 4687 1637grid.241054.6Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR USA 20 2 2018 20 2 2018 2018 13 1530 10 2017 12 2 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPlasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma.\n\nCase presentation\nA 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant. Morphological and immunohistochemical characterization of the extramedullary disease demonstrated that the tumor cells were derived from the monocyte-macrophage lineage. Next generation sequencing (NGS) studies detected similar clonal aberrations in the diagnostic plasma cell population and post-therapy neoplastic cells, including IGH-MAF rearrangement, multiple genetic mutations in RAS signaling pathway proteins, and loss of tumor suppressor genes. Molecular genetic analysis also revealed unique genomic alterations in the transformed tumor cells, including gain of NF1 and loss of TRAF3.\n\nConclusion\nTo our knowledge, this is the first case of myeloid sarcoma transdifferentiated from plasma cell neoplasm. Our findings in this unique case suggest clonal evolution of plasma cell myeloma to myeloma neoplasm and the potential roles of abnormal RAS/RAF signaling pathway in lineage switch or transdifferentiation.\n\nKeywords\nClonal evolutionMyeloid sarcomaMolecular profilingNext generation sequencingTransdifferentiationPlasma cell myelomaRAS/RAF signaling pathwayissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPlasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes and most often involves the bone marrow. Malignant plasma cells are defined immunophenotypically by diminished or increased expression of at least two antigens not present on non-neoplastic plasma cells. For example, malignant plasma cells show decreased or loss of CD45 and/or CD19 expression and may aberrantly express CD56, CD117, and/or CD20 [1]. Immunohistochemical stains performed on diagnostic biopsies demonstrate retained expression of non-neoplastic plasma cell antigens (e.g. CD138 and MUM-1) and cytoplasmic light chain restriction. PCM is characterized by molecular heterogeneity, including balanced translocations involving the immunoglobulin heavy chain locus, complex karyotypes, and mutations in the RAS signaling cascade [2–4]. For example, KRAS, NRAS and BRAF mutations are detected in approximately 33% of newly diagnosed PCM patients [3, 4].\n\nDisease progression in PCM can be associated with disease at extramedullary sites, high grade plasma cell morphology, acquisition of additional genetic mutations or possibly reactivation of Epstein Barr virus infection [3, 5–7]. Although plasma cells may resemble blasts and express aberrant myeloid antigens [5, 8], malignant plasma cells retain expression of a subset of plasma cell markers and demonstrate light chain restriction, allowing immunohistochemical classification of the tumor as PCM. A subset of patients with PCM develop secondary malignancies following high dose chemotherapy. Therapy-related myeloid neoplasms are the most common secondary malignancy in PCM [9]. We recently described the rapid onset of therapy-related acute leukemia in patients in complete remission for PCM. In this series, the immunophenotype and karyotype of the leukemic cells was distinctly different than that seen in the original PCM [10].\n\nHere we report a rare case of multiple soft tissue sarcomas arising in a patient in complete remission for high-risk PCM. Immunohistochemical stains and flow cytometry showed that the tumor cells expressed monocyte-macrophage (CD163, CD68 and lysozyme) and myeloid antigens (myeloperoxidase and CD13) without plasma cell markers. Fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) studies demonstrated a clonal relationship between the diagnostic PCM and transformed tumor cells, including loss of tumor suppressor genes and multiple, clonal/subclonal mutations in the RAS pathway. To our knowledge, this is the first reported case of myeloid transformation in PCM.\n\nCase presentation\nA sixty-year-old Caucasian male presented to our institution with chest pain. A complete blood count showed anemia (hemoglobin of 8.0 g/dL; reference range 13–17 g/dL) and thrombocytopenia (platelet count of 69,000/μL; reference range 150,000–450,000/μL). Review of the peripheral blood smear revealed 12% circulating plasma cells. Additional laboratory evaluation demonstrated an elevated total serum protein of 11.3 g/dL (reference range: 6.4–8.3 g/dL) and serum M-component (6.8 g/dL) with increased IgG (9010 mg/dL; reference range: 700–1600 mg/dL) and free lambda light chain (120 mg/dL; reference range 0.57–2.63 mg/dL). The diagnostic bone marrow biopsy demonstrated a hypercellular bone marrow for age extensively involved by lambda light chain-restricted plasma cells (Fig. 1). Concurrent flow cytometric analysis showed that the neoplastic plasma cells were positive for CD38, CD138, and CD20 (heterogeneous) and negative for CD45, CD27, CD81, CD56, and CD19. Cytogenetic analysis of the bone marrow aspirate cells revealed a complex karyotype: 43,XY,del(1)(p13p32),+ 3,der(3;6)(q10;p10),del(5)(q15q33),? t(9;15)(p24;q24),-10,add(13)(p11.2),del(14)(q24),-20,-22,inc[3]/46,XY[17]. Myeloma FISH studies were uninformative due to paucity of analyzable plasma cells. Gene array studies were consistent with high-risk c-MAF subgroup [2]. Foundation One™ NGS studies revealed IGH-MAF gene rearrangement and several genomic alterations, including BRAF G469V and G466A, KRAS A146V, MAP3K6 Q943, CDKN2A/B loss, TRAF3 R505 and PTPRO E379K (Table 1). Magnetic-resonance imaging (MRI) and positron-emitted topography (PET) scans highlighted multiple focal lesions in the cervical spine, rib cage, tibia, and fibula, but no extramedullary disease.Fig. 1 Morphologic examination (top) and immunohistochemical stains (bottom) performed on the diagnostic bone marrow core biopsy. The H&E stained sections of the bone marrow biopsy revealed a diffuse infiltrate of plasma cells (× 20) with nuclear pleomorphism; a subset of plasma cells showed prominent nucleoli (× 500). The plasma cells expressed CD138, MUM-1 with lambda light chain restriction (× 200)\n\nTable 1 Next-generation sequencing of the diagnostic bone marrow aspirate and left gingival lesion\n\nBone marrow aspirate\tSoft tissue\t\nBRAF1 G466A subclonal, G469 subclonal\tBRAF G469A\t\nKRAS A146V\tKRAS A146V\t\nIGH IGH-MAF rearrangement\tIGH IGH-MAF rearrangement\t\nCDKN2A/B loss\tCDKN2A/B loss\t\nMAP3K6 Q943, truncation exon 22\tMAP3K6 Q943, truncation exon 22\t\nTRAF3 R505\tNF1 R2450\t\nPTPRO E379K – subclonal\tCCT6B splice site 615-2A > G TNFAIP3 W85\t\n\n\nThe patient received induction chemotherapy (Velcade, Dexamethasone, Thalidomide-Cisplatin, Doxorubicin, Cyclophosphamide and Etoposide; VDT-PACE) followed by cytoreduction (Cytoxan, Etoposide, Mesna, Cisplatin, Dexamethasone and Cytarabine; PACMED) and bridging therapy with carfilzomib and daratumumab. An autologous stem cell transplant was performed 10 months after initial diagnosis. Two months after stem cell transplant, bone marrow evaluation was morphologically negative for PCM with no minimal residual disease detected by 8-color flow cytometry; however, PET-CT imaging showed multiple focal lesions in the bilateral femoral shafts, humeri and a 1.8 × 1.2 cm mass in the right perineal region (Fig. 2). A PET-CT imaging study showed that the lesion in the perineal region had increased in size to approximately 3.1 × 2.1 cm with new extramedullary lesions noted in the left mandibular soft tissue, lungs/mediastinal lymph nodes and liver (Fig. 2). The differential diagnosis included multifocal myelomatous disease progression versus infectious etiology. The patient underwent fine needle aspiration of mediastinal lymph nodes and punch biopsy of the gingival lesion.Fig. 2 PET-CT image (left) showing the lesions in the proximal right tibia, right proximal femur and perineum. PET-CT image (right) demonstrate increased size of the previous lesions and new lesions in the left mandibular soft tissue, liver, lungs and mediastinum three months after first time PET-CT\n\n\n\nThe Diff-Quik™ stained sections prepared from the mediastinal lymph node FNA showed large atypical cells with abundant cytoplasm with immature chromatin (Fig. 3). The H&E stained sections prepared from the cell block demonstrated similar morphologic features including an infiltrate of immature monocytic cells with rare mature granulocytes (Fig. 3). Immunohistochemical stains showed that the neoplastic cells expressed myeloperoxidase (MPO; subset), CD163, lysozyme, and were negative for CD138 (Fig. 3). Additional immunohistochemical studies revealed positivity for CD68 and lack of MUM-1, PAX-5, CD56, S-100, and P53 expression (not shown). Concurrent flow cytometric analysis revealed atypical cell populations with distinct CD45 expression and forward and side scatter properties comprising 80% of total analyzed events. One population with increased side and forward scatter comprised 40% of total events. These cells expressed CD45 (bright), CD33, HLA-DR, CD14 (bright), CD11b (bright) and CD36 (variable) (Fig. 4; red), consistent with monocytic lineage. A second population of cells with decreased forward and side scatter showed a similar immunophenotype with variable expression of CD33 and dimmer expression of CD45, CD11b and CD14 (Fig. 4; blue). Both populations were negative for CD34 and CD117. The H&E stained sections of the gingival biopsy showed similar morphologic features, including a dermal infiltrate of large, immature cells with irregular nuclear contours and ample cytoplasm (not shown). Immunohistochemical stains of the gingival biopsy showed an immunophenotype similar to the mediastinal lymph node, including CD68, CD163, lysozyme, MPO (subset) expression and lack of CD138, MUM-1, PAX-5, CD34, and CD56 expression (not shown). FISH studies performed on the mediastinal lymph node and gingival biopsies revealed a translocation between chromosomes 14 and 16 [IGH and MAF genes; t(14;16)(q32;q23)] in approximately 76% and 73% of interphase nuclei examined (Fig. 5), respectively. FISH probes for t(11q23) and del(17p13.1) showed normal signal patterns. Cytogenetic studies performed on the mediastinal lymph node were unsuccessful due to no cell growth. The gingival lesion showed a normal karyotype (46,XY[4]/45,Y,-X[1]) with a low mitotic index. NGS studies performed on the gingival lesion demonstrated IGH-MAF rearrangement, BRAF and KRAS mutations, CDKN2A/B loss, TNFAIP3 and NF1 mutations (Table 1).Fig. 3 Morphologic examination and immunohistochemical stains performed on the fine needle aspirate of the mediastinal lymph node. The Diff-Quik™ stained slides show large monocytoid cells with ample blue-grey cytoplasm, round to irregular nuclear contours and immature chromatin (× 500, top-left). The H&E stained sections prepared from the cell block shows a diffuse infiltrate of monocytoid cells with ample cytoplasm and round to irregular nuclear contours (× 200 and × 400, top-right). The tumor cells were negative for CD138 and positive for myeloperoxidase (MPO), CD163 and lysozyme (× 200)\n\nFig. 4 Flow cytometric analysis of mediastinal lymph node revealed two cell populations with distinct forward and side scatter and CD45 expression intensity. One population with increased side and forward scatter comprised 40% of total events (red). This population expressed CD33, HLA-DR, CD36 (variable), CD14 (bright) and CD11b (bright) and were negative for CD34 and CD117. A second population of cells with decreased forward and side scatter showed a similar immunophenotype with variable expression of CD33 and dimmer CD11b and CD14 (blue). These cells were also negative for CD34 and CD117\n\nFig. 5 Fluorescence in-situ hybridization studies demonstrating t(14;16)(q32;q23) in both mediastinal lymph node (a) and gingival biopsy (b). The abnormal signaling patterns are 2R1G1F (a) and 2R1G1F (b) by dual color, dual fusion probes\n\n\n\nThe patient received induction chemotherapy (7 + 3 regimen of cytarabine and idarubicin). At follow up, the patient developed neutropenic fever with persistent pancytopenia despite receiving recombinant granulocytic colony stimulating factor. He was re-admitted one week later for possible sepsis/bacteremia. As the patient’s health continued to deteriorate and the soft tissue masses continued to grow, he decided to stop treatments and medical interventions. The patient went into palliative care approximately two months after the diagnosis of multifocal myeloid sarcoma and died shortly thereafter.\n\nDiscussion\nWe report a case of multiple soft tissue sarcomas in a patient in complete remission for high-risk PCM. The neoplastic cells at the extramedullary sites were large with immature chromatin and expressed the monocyte-macrophage antigen CD163 [11], CD14 and CD68 as well as myeloid antigens MPO and CD13. The tumor cells were negative for S-100 and CD138, consistent with absence of dendritic cell differentiation [12, 13] or relapsed PCM, respectively. The immature nuclear features and expression of the myeloid antigens MPO and CD13 was most consistent with the diagnosis of myeloid sarcoma with monocytic differentiation. Furthermore, FISH studies showed IGH-MAF translocation in the transformed cells and PCR identified an IGH gene rearrangement. NGS- based assays revealed similar genomic alterations suggesting a clonal relationship between the original PCM and secondary myeloid sarcoma.\n\nHematopoiesis, once viewed as a unidirectional maturation of pluripotent hematopoietic stem cells into specific lineages (such as lymphoid and myeloid), shows considerable plasticity in both normal and malignant hematopoietic cells. Lineage switching has been described in histiocytic sarcoma (HS), Langerhans cell sarcoma or dendritic cell tumor that occur secondary to or synchronous with mediastinal germ cell tumors [14], lymphoid [12, 13, 15–22], and myeloid malignancies [23, 24]. Histiocytic sarcoma cells are derived from bone marrow monocyte precursors [25], expresses monocyte-macrophage antigens (CD163, CD68, and lysozyme) and lack expression of myeloid antigens such as CD33, CD13 and MPO [11, 25, 26]. The identification of clonal associations between HS and antecedent malignancies suggests that HS or myeloid sarcoma can differentiate from other cell lineages or develop from a common progenitor cell [12–20, 23, 27].\n\nSeveral studies indicate that commitment to specific lineage and lineage conversion depends on the activity of lineage-specific transcription factors [28–30]. For example, PAX-5 is required for B cell differentiation and commitment to B cell lineage [31–33]. B cells that lack PAX-5 expression can differentiate into macrophages, dendritic cells, osteoclasts, granulocytes and natural killer cells [32]. Similarly, the activity of the transcription factors PU.1 and CCAAT/enhancer binding protein alpha (C/EBPα) are important for myeloid progenitor cells to commit to the granulocyte-monocyte lineage [34]. Xie et al. showed overexpression of C/EBPα and C/EBPβ converted mature murine B cells into macrophages by suppressing PAX-5 expression [29]. Furthermore, studies using C/EBPα transgenic mice suggest that B cells are directly converted to other lineages through a biphenotypic intermediate cells rather than a two-step process of dedifferentiation and redifferentiation [34]. In support of a mechanism involving direct transdifferentiation, Feldman et al. showed loss of PAX-5 expression and up regulation of PU.1 and CEBPβ in eight cases of histiocytic-dendritic cell sarcomas derived from antecedent follicular lymphoma [12]. Since we do not know the expression pattern of PU.1, C/EBPα or C/EBPβ in these soft tissue tumors, their role in lineage transformation is unclear. However, PAX-5 was not expressed in the original PCM, therefore down regulation of PAX-5 cannot explain the development of monocytic-macrophage lineage. MUM-1, a transcription factor required for plasma cell differentiation [35], was expressed in the original plasma cell tumor but was not detected in the myeloid sarcomas (Figs. 1 and 3). Whether down-regulation of MUM-1 contributes to monocyte-macrophage transformation in plasma cell myeloma is unknown.\n\nLimited data exist regarding the molecular genetics of transformed myeloid sarcoma; however several reports evaluating secondary HS suggest molecular complexity and heterogeneity. Similar to our case showing loss of CDKN2A/B, loss of CDKN2A has been reported in HS subsequent to B-lymphoblastic leukemia [15, 36]. BRAF V600E mutation has been reported in de novo HS [37] and HS following splenic marginal zone lymphoma [13] and hairy cell leukemia [38]. NGS analysis of the myeloid sarcoma in this case showed a clonal, non V600E activating mutation in BRAF. The BRAF mutation (G469A) is distinct from other variants identified in de novo HS, including BRAF F595 L, BRAF (G466R), BRAF (G464 V) and BRAF (N581S); however, as in this case, these BRAF variants are not mutually exclusive with activating RAS mutations [39, 40].\n\nLike other cases of secondary HS [23], a clonal relationship between the primary PCM and secondary tumor in current case was confirmed by FISH and NGS analyses showing IGH-MAF gene rearrangement, and similar genomic alterations in KRAS, BRAF and MAK3K6. IGH-MAF translocation is present in 3–6% of PCM cases [41] and this molecular subtype often shows concurrent activating mutations in RAS-RAF and NF-kB signaling pathways [42]. In human cell lines, c-MAF promotes monocyte-macrophage differentiation through downreguation of CEBPα [43], suggesting a possible role of c-MAF in PCM phenotypic transformation.\n\nIn addition to shared clonal abnormalities, additional aberrancies were detected in the sarcoma tumor cells, including deletion of a subclone of BRAF (G466A), loss of TRAF3 R505 and new clonal mutations in NF1 and TNFAIP3 (Table 1). TRAF3 is a critical determinant of B cell survival and loss of function mutations in TRAF3 and TNFAIP3 are associated with B cell malignancies and PCM [44, 45]. NF1 mutation, a negative regulator of RAS signaling, has been reported in rare cases of plasma cell myeloma [4] and approximately 4% of acute myeloid leukemia [46], but not reported in HS.\n\nIt is uncertain whether the molecular switch from PCM to a myeloid lineage tumor involves direct transdifferentiation via transcription factor dysregulation as suggested for B cell lymphomas, or whether the myeloid lineage tumors arose from a distinct, neoplastic clone that expanded following chemotherapy [12, 15–18]. Regardless of the mechanism, NGS findings suggest a clonal relationship with clonal evolution and a possible role of NF1, TNFAIP3 and TRAF3 in myeloid transformation of plasma cell myeloma.\n\nConclusion\nTo our knowledge, this is the first reported case of PCM transformation to a secondary tumor with monocyte-macrophage lineage. As in other reports, the response to chemotherapy and prognosis is poor with patients dying from progressive disease [18, 19, 23, 25, 26]. This study highlights the importance of molecular analysis to establish a clonal relationship in metachronous or synchronous tumors, as addressed by other reports [47, 48]. The findings of an additional mutation in RAS-BRAF signaling (NF1 mutation) and NF-kB activation (TNFAIP3) suggests multiple mechanisms contribute to lineage transformation.\n\nAbbreviations\nFISHFluorescence in situ hybridization\n\nHSHistiocytic sarcoma\n\nMPOMyeloperoxidase\n\nMSMyeloid sarcoma\n\nNGSNext generation sequencing\n\nPCMPlasma cell myeloma\n\nAcknowledgements\nWe thank the University of Arkansas for Medical Sciences Department of Pathology for providing funds to perform IGH gene rearrangement studies and the molecular laboratory staff who performed this assay (Stacie Delaune and Molly Robbins).\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nJG, GRP, FVR and YY collected case information. JG, GRP and YY wrote the manuscript. JG, GRP, FVR and YY edited the manuscript. All authors have read and approve the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Rawstron AC Orfao A Beksac M Bezdickova L Brooimans RA Bumbea H Dalva K Fuhler G Gratama J Hose D Report of the European myeloma network on multiparametric flow cytometry in multiple myeloma and related disorders Haematologica 2008 93 3 431 438 10.3324/haematol.11080 18268286 \n2. 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Amato T Abate F Piccaluga P Iacono M Fallerini C Renieri A De Falco G Ambrosio MR Mourmouras V Ogwang M Clonality analysis of immunoglobulin gene rearrangement by next-generation sequencing in endemic Burkitt lymphoma suggests antigen drive activation of BCR as opposed to sporadic Burkitt lymphoma Am J Clin Pathol 2016 145 1 116 127 10.1093/ajcp/aqv011 26712879 \n48. Ambrosio MR Rocca BJ Ginori A Mourmouras V Amato T Vindigni C Lazzi S Leoncini L A look into the evolution of Epstein-Barr virus-induced lymphoproliferative disorders: a case study Am J Clin Pathol 2015 144 5 817 822 10.1309/AJCP2G0VKTKPNPRR 26486748\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1746-1596",
"issue": "13(1)",
"journal": "Diagnostic pathology",
"keywords": "Clonal evolution; Molecular profiling; Myeloid sarcoma; Next generation sequencing; Plasma cell myeloma; RAS/RAF signaling pathway; Transdifferentiation",
"medline_ta": "Diagn Pathol",
"mesh_terms": "D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D060965:Clonal Evolution; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D057089:Pathology, Molecular; D010950:Plasma Cells",
"nlm_unique_id": "101251558",
"other_id": null,
"pages": "15",
"pmc": null,
"pmid": "29463311",
"pubdate": "2018-02-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26990812;16858416;22648549;24076551;26286813;12098702;23721279;22033491;26486748;28427158;25856582;15832085;27259537;19926586;10477683;23801128;24429703;23460398;2158625;11869895;24434212;20962323;18272816;15163413;12874768;25833113;16728703;21795746;26712879;23759932;20973102;26582644;2137556;21720200;28376906;25228298;28359033;16923394;15050956;26187047;10524622;18268286;27856472;25193957;24567436;25838910;24720374",
"title": "Myeloid transformation of plasma cell myeloma: molecular evidence of clonal evolution revealed by next generation sequencing.",
"title_normalized": "myeloid transformation of plasma cell myeloma molecular evidence of clonal evolution revealed by next generation sequencing"
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"abstract": "We report a case of 30-year-old female who presented initially with hair loss, photosensitive malar rash, morning stiffness and synovitis. She was diagnosed with Rhupus syndrome based on clinical and laboratory findings. Few months after starting hydroxychloroquine, esomeprazole and azathioprine, and failing methotrexate (because of erosive pill-induced esophagitis), she presented with generalized maculopapular dusky reddish rash in her body, back and extremities. Her anti-double stranded-DNA, anti-nuclear antibody, anti-Ro/SSA and anti-La/SSB were positive. Anti-cyclic citrullinated peptide antibody was moderately positive. She had low complements: C3 and C4. Herpes simplex IgM and mycoplasma tested negative. Skin biopsy from right arm showed evidence of erythema multiform. She met the criteria for the diagnosis of Rowell syndrome. We managed her with hydroxychloroquine, prednisolone, mycophenolate mofetil and topical agents and discontinued esomeprazole. We also review the management of Rowell syndrome in the literature.",
"affiliations": "Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard - Health Affairs, Jeddah, Saudi Arabia.;Division of Rheumatology, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard - Health Affairs, Jeddah, Saudi Arabia.",
"authors": "Almansouri|Abdulrahman Y|AY|0000-0001-9486-3082;Alzahrani|Zeyad A|ZA|0000-0001-8696-7930",
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"doi": "10.2147/OARRR.S255790",
"fulltext": "\n==== Front\nOpen Access Rheumatol\nOpen Access Rheumatol\nOARRR\nrheu\nOpen Access Rheumatology : Research and Reviews\n1179-156X Dove \n\n255790\n10.2147/OARRR.S255790\nCase Report\nA Case of Rhupus with Rowell Syndrome\nAlmansouri and AlzahraniAlmansouri and Alzahranihttp://orcid.org/0000-0001-9486-3082Almansouri Abdulrahman Y 1 http://orcid.org/0000-0001-8696-7930Alzahrani Zeyad A 2 1 Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard - Health Affairs, Jeddah, Saudi Arabia\n2 Division of Rheumatology, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard - Health Affairs, Jeddah, Saudi Arabia\nCorrespondence: Abdulrahman Y Almansouri P.O. Box 7194, Jeddah21462, Saudi ArabiaTel +966 565656486 Email red.amlor@gmail.com\n09 6 2020 \n2020 \n12 91 96\n08 4 2020 21 5 2020 © 2020 Almansouri and Alzahrani.2020Almansouri and Alzahrani.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\nWe report a case of 30-year-old female who presented initially with hair loss, photosensitive malar rash, morning stiffness and synovitis. She was diagnosed with Rhupus syndrome based on clinical and laboratory findings. Few months after starting hydroxychloroquine, esomeprazole and azathioprine, and failing methotrexate (because of erosive pill-induced esophagitis), she presented with generalized maculopapular dusky reddish rash in her body, back and extremities. Her anti-double stranded-DNA, anti-nuclear antibody, anti-Ro/SSA and anti-La/SSB were positive. Anti-cyclic citrullinated peptide antibody was moderately positive. She had low complements: C3 and C4. Herpes simplex IgM and mycoplasma tested negative. Skin biopsy from right arm showed evidence of erythema multiform. She met the criteria for the diagnosis of Rowell syndrome. We managed her with hydroxychloroquine, prednisolone, mycophenolate mofetil and topical agents and discontinued esomeprazole. We also review the management of Rowell syndrome in the literature.\n\nKeywords\nRowell syndromesystemic lupus erythematosuserythema multiformcutaneous lupus erythematosusrheumatoid arthritis\n==== Body\nIntroduction\nRowell syndrome is a diagnosis of erythema multiform (EM) that is rarely associated with systemic lupus erythematosus (SLE). It was first described in 1963 by Rowell et al.1 It occurs mostly in middle-aged women. To reach a diagnosis, all major criteria plus one minor criterion must be met.2 Major criteria include the presence of systemic or cutaneous lupus erythematosus (CLE), erythema multiform-like lesions and antinuclear antibodies (ANA). Minor criteria include the presence of chilblains, anti-Ro or anti-La antibodies or rheumatoid factor (RF). While Rhupus was defined by meeting the clinical and laboratory criteria of both SLE, as per 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE,3 and that of rheumatoid arthritis (RA), as per the 2010 ACR/EULAR classification criteria of RA.4\n\nCase Report\nA 30-year-old lady who lives in Taif in Saudi Arabia presented to our hospital in Jeddah with maculopapular reddish dusky rash around tips of fingers and toes, spreading to involve both upper and lower limbs and back.\n\nShe first presented to our clinic in late August 2019 with history of hair loss, oral ulcers, photosensitivity and bilateral symmetrical elbow, wrist, metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint pain with swelling in the wrists. She also suffered from morning stiffness (lasted for 20 mins), fatigue and weight loss. No history of abortion, miscarriage, venous thromboembolism or other features of antiphospholipid syndrome was reported previously. She has some features suggestive of Raynaud’s phenomenon in form of whitish to bluish and reddish discoloration of her fingers with cold weather, especially in the winter. She is married with three children. No joint deformity was observed. She had a positive ANA, anti-double-stranded DNA (Anti-dsDNA), anti-ribonucleoprotein (anti-RNP), anti-smith and anti-Ro/SSA and anti-La/SSB antibodies. She also had a moderately positive anti-cyclic citrullinated peptide antibody (anti-CCP), normal creatinine and negative RF, lupus anticoagulant, anticardiolipin antibodies and beta-2-glycoprotein-1 antibodies. Additionally, she had minimal proteinuria (Table 1). The possibility of having Rhupus syndrome was entertained and we started her on prednisolone 15mg once daily and hydroxychloroquine (HCQ) 200mg twice a day. She was seen in clinic in two months’ time and showed improvement. Few weeks later, her joint pain got worse and she sought help in another hospital in Taif. She was thought to have RA mainly and was started on methotrexate (MTX) 12.5mg once weekly orally, with discontinuation of HCQ. Two weeks later, she suffered from nausea, severe heart burn and reflux symptoms. She was admitted and gastroscopy was done and showed erosive esophagitis. The erosive esophagitis was thought to be caused by MTX, so it was discontinued. Azathioprine, prednisolone, and esomeprazole were initiated. We planned to treat her with rituximab therapy, due to unavailability of belimumab.Table 1 Laboratory Results of the Patient Initial and Follow-Up Serology\n\nInvestigation\tInitial Result\tFollow-Up\tReference Range\tUnit\t\nAnti-CCP IgG\t58.20\t–\t<20 is negative\n20–39 is weak positive\n40–59 is mod. positive\n≥ 60 is strong positive\tUnit\t\nAnti-RNP\t652.7\t–\t<20 is negative\n>80 is strong positive\tUnit\t\nAnti-Ro/SSA\t118.68\t–\t<20 is negative\n>80 is strong positive\tUnit\t\nAnti-La/SSB\t124.29\t–\t<20 is negative\n>80 is positive\tUnit\t\nAMA\t<1:20\t–\t<1:20 is negative\tTiter\t\nAnti-Smith\t150\t–\t<20 is negative\n>80 is strong positive\tUnit\t\nAnti-dsDNA\t1722.53\t305\t0–200 negative\n201–300 equivocal\n301–800 mod. Positive\n>800 strong positive\tIU/mL\t\nRF\t<10.7\t–\t<10.7\tIU/mL\t\nANA IFA\tPositive\t–\tNegative\t-\t\nC3\t0.38\t0.96\t0.9–1.8\tg/L\t\nC4\t<0.06\t0.11\t0.1–0.4\tg/L\t\nAnti-Jo\t2.54\t–\t<20 is negative\tUnit\t\nHCV antibody\tNegative\t–\tNegative\t–\t\nAnti-HBc\tNegative\t–\tNegative\t–\t\nHBsAg\tNegative\t–\tNegative\t–\t\nHSV1/2 IgM\tNegative\t–\tNegative\t–\t\nHSV 1/2IgG\tPositive\t–\tNegative\t–\t\nMycoplasma IgG\t<10\t–\t<10\tAU/mL\t\nMycoplasma IgM\t<10\t–\t<10\tIndex\t\nMycoplasma IgA\t<8.5\t–\t<8.5\tAU\t\nAnticardiolipin IgG\t3.58\t–\t<15 is negative\tGPL Unit\t\nAnticardiolipin IgM\t8.85\t–\t<12.5 is negative\tMPL Unit\t\nAnticardiolipin IgA\t2.42\t–\t<12 is negative\tAPL Unit\t\nBeta-2-glycoprotein −1 IGA\t7.16\t–\t<20 is negative\tSAU\t\nBeta-2-glycoprotein −1 IgG\t15.38\t–\t<20 is negative\tSGU\t\nBeta-2-glycoprotein −1 IgM\t1.87\t–\t<20 is negative\tSMU\t\nLupus anticoagulant\tUndetected\t–\tUndetected\tLA1\t\nSerum creatinine\t59\t62\t50–74\tumol/L\t\nUrine protein\t166\t<68\t<68\tmg/L\t\nUrine protein-creatinine ratio\t37.22\tCC\t≤20\tmg/mmol\t\nAbbreviations: Anti-CCP IgG, anti-cyclic citrullinated peptide antibody; anti-RNP, anti-ribonucleoprotein antibody; AMA, anti-mitochondrial antibody; anti-dsDNA, anti-double stranded DNA; RF, rheumatoid factor; ANA, anti-nuclear antibody; C3, complement 3; C4, complement 4; HCV antibody, hepatitis C virus antibody; anti-HBc, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HSV1/2 IgM, herpes simplex virus 1 and 2 IgM; HSV 1/2 IgG, herpes simplex virus 1 and 2 IgG; CC, cannot calculate urine protein creatinine ratio due to low urine protein.\n\n\n\n\nFew weeks after this admission, in early February 2020, she presented to the ER with new rash that started around the tips of her fingers and toes. Azathioprine was escalated to 150mg and she was discharged on 10mg prednisolone. Her rash progressed further to involve both hands, forearms, her back, lower leg and soles of her feet with ulcerations on the toes’ tips. There were bullae formation in both soles of feet; more on the left foot. The rash was maculopapular, blanchable, dusky, red in color and non-itchy (Figure 1). Her face was also involved with the rash spreading on both of her cheeks. The patient also had oral ulcerations in her mouth, with evidence of mucositis, that were painful and located beneath the lips and on the hard palate. Her laboratory investigations showed improving anti-dsDNA, low C3 and C4, and negative mycoplasma IgG, IgM and IgA, negative herpes simplex IgM; however, the IgG antibody was positive. The patient was admitted and started on prednisolone 40mg along with azathioprine 150 mg and HCQ. Topical agents including betamethasone and fusidic acid were used. Dermatology performed a skin biopsy from the lesion and the patient was scheduled to receive rituximab. While the patient was waiting to receive rituximab, she spiked fever and rituximab infusion was delayed. Examination showed cheeks redness with honey crusting. The possibility of infectious cause, disease flare or medication related side effect was entertained. She was started on piperacillin/tazobactam and vancomycin for treatment with an increase in the dose of prednisolone to 60mg once daily. Superficial cultures grew Staphylococcus aureus that was methicillin sensitive and Acinetobacter baumanni. Skin biopsy later on that day showed interface dermatitis consistent with EM or Steven Johnson syndrome. After meeting the criteria, a diagnosis of Rowell syndrome was made. Esomeprazole, azathioprine and HCQ were held. The patient overall condition and rash continued to improve with this dose of prednisolone. Nail shedding was observed at the end of second week of admission. HCQ 200mg twice daily was re-introduced along with mycophenolate mofetil (MMF) 500mg BID before discharge and was tolerated well. During her stay, no evidence of venous thromboembolism was observed. In the follow-up visit, her symptoms generally improved, with resolution of skin rash in her extremities (Figures 2 and 3), body and face. Complements level raised to near normal and anti-dsDNA improved significantly (Table 1). MMF was escalated to 1 g BID and tapering of prednisolone continued. For glucocorticoid-induced osteoporosis prevention, we started the patient on alendronate 70mg once weekly, along with vitamin D and calcium. However, she suffered from heart burn so it was discontinued. We will start her on denosumab next visit.Figure 1 Picture taken during flare of erythema multiform: showing maculopapular, blanchable, dusky and red in color that was non-itchy rash and involved both hands, forearms, body and lower limbs.\n\nFigure 2 Picture of left forearm two months after discharge: resolution of erythema multiform rash with residual skin hyperpigmentation.\n\nFigure 3 Picture of right forearm two months after discharge from the hospital: again, resolution of erythema multiform rash can be appreciated.\n\n\n\nDiscussion\nErythema multiform is (an acute immune-mediated skin condition characterized by appearance of target-like lesions on the skin5). It has multiple well-known causes in the literature including infectious (as herpes simplex virus infection and mycoplasma pneumonia infection), drug related (as non-steroidal anti-inflammatory drugs (NSAIDs), antiepileptics and antibiotics), malignancy and autoimmune diseases.5 A typical course includes resolution within 2 weeks, with possible recurrence in some patients.\n\nIn the rare presence of both EM and SLE, when meeting the criteria,2 a diagnosis of Rowell syndrome is reached. Rowell syndrome has been described in the literature to be part of CLE spectrum.6 Nevertheless, it is also found to be triggered after starting certain medications. For example, proton pump inhibitors, terbinafine and valproic acid.7\n\nLooking back to our patient we can note that her lesions started 3 months after initiating esomeprazole, for her MTX-related erosive esophagitis, and azathioprine. Her symptoms worsened with the increase in the dose of azathioprine to 150 mg despite being on low dose steroids. Azathioprine has been described in the literature to be associated with Rowell syndrome, but this was not a very strong association.8 Proton pump inhibitors were also described in the literature after similar period of time.7 Never the less her symptoms started to improve when both medications were discontinued and while receiving higher doses of steroids. To our knowledge this is the first case report of overlap syndrome (Rhupus syndrome) presenting with Rowell syndrome. Therefore, the clinical and therapeutic response of the patient to various therapies represents an interesting addition to the literature.\n\nFurthermore, when managing EM and the possibility of herpes simplex virus is entertained, usually an antiviral is used. Occasionally prednisolone and other immune suppressant agents, such as azathioprine or MMF, are introduced.5 In CLE and Rowell syndrome, HCQ in addition to other immune suppressant agents has been used. Table 2 shows summary of different agents used in 46 open access case reports of Rowell syndrome found in Google scholar and PubMed for the treatment of Rowell syndrome and their frequencies. Mean age for patients in these papers was 39 years old and 68% of patients were female. Most authors used prednisolone to induce remission, in addition to HCQ as a backbone therapy. Other immunosuppressant agents, such as azathioprine and MMF, have also been used. These are in concordance with EULAR recommendations of management of CLE.9,10Table 2 Summary of 46 Open Access Case Reports of 48 Patients with Rowell Syndrome7,11–55\n\nAgent Name\tNumber of Patients Treated Successfully\tPercentage of Success in Treated Patients\tPercentage of Patients Treated Out of 48 Patients\t\nSteroids\t42/45\t93%\t93%\t\nHCQ/chloroquine\t25/27\t92%\t55%\t\nTopical agents\t13/13\t100%\t28%\t\nAzathioprine\t7/8\t87%\t16%\t\nMMF\t5/5\t100%\t1%\t\nCyclosporine\t2/3\t66%\t0.6%\t\nAntibiotics\t4/4\t100%\t0.8%\t\nDapsone\t0/1\t0%\t0.02%\t\nThalidomide\t0/1\t0%\t0.02%\t\nNSAIDs\t1/1\t100%\t0.02\t\nCyclophosphamide\t1/2\t50%\t0.04%\t\nIVIG\t1/1\t100%\t0.02%\t\nAbbreviations: HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; NSAIDs, non-steroidal anti-inflammatory drugs; IVIG, intravenous immunoglobulin.\n\n\n\n\nWe conclude that Rowell syndrome can be treated according to the skin section of 2019 update of the EULAR recommendations for the management of SLE.\n\nInstitutional Approval\nNo institutional approval was required for the publication of this manuscript.\n\nConsent\nA written informed consent was obtained from the patient for publication of her case details with image of her cutaneous lesions.\n\nDisclosure\nAll authors declare no conflict of interest.\n==== Refs\nReferences\n1. Rowell \nNR , Beck \nJS , Anderson \nJR . Lupus erythematosus and erythema multiforme-like lesions: a syndrome with characteristic immunological abnormalities\n. Arch Dermatol . 1963 ;88 (2 ):176 –180\n. doi:10.1001/archderm.1963.01590200064012 14043605 \n2. Zeitouni \nN , Funaro \nD , Cloutier \nR , Gagné \nE , Claveau \nJ . Redefining rowell’s syndrome\n. Br J Dermatol . 2000 ;142 (2 ):343 –346\n. doi:10.1046/j.1365-2133.2000.03306.x 10730772 \n3. Aringer \nM , Costenbader \nK , Daikh \nD , et al. 2019 European league against rheumatism/American college of rheumatology classification criteria for systemic lupus erythematosus\n. Arthritis Rheum . 2019 ;71 :1400 –1412\n. doi:10.1002/art.40930 \n4. Aletaha \nD , Neogi \nT , Silman \nAJ , et al. 2010 Rheumatoid arthritis classification criteria: an American college of rheumatology/European league Against rheumatism collaborative initiative\n. Arthritis Rheum . 2010 ;62 :2569 –2581\n. doi:10.1002/art.27584 20872595 \n5. Wetter DA. Erythema multiforme: pathogenesis, clinical features, and diagnosis. In: UpToDate, Post, TW, editor. Waltham, MA: UpToDate; 2020. Available from: https://www.uptodate.com/contents/erythema-multiforme-pathogenesis-clinical-features-and-diagnosis. Accessed \n6 \n3 , 2020 .\n6. Torchia \nD , Romanelli \nP , Kerdel \nF . Erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis associated with lupus erythematosus\n. J Am Acad Dermatol . 2012 ;67 (3 ):417 –421\n. doi:10.1016/j.jaad.2011.10.012 22101216 \n7. Pozharashka \nJ , Dourmishev \nL , Balabanova \nM , Vassileva \nS , Miteva \nL . Rowell’s syndrome triggered by omeprazole\n. Acta Dermatovener Cr . 2019 ;27 (2 ):124 –126\n.\n8. Vaida-Voevod \nDA , Felea \nI , Damian \nL , Pamfil \nC , Rednic \nS . lAB0564 the controversial rowell syndrome: to be or not to be?\n\nAnn Rheum Dis . 2019 ;78 :1743 –1744\n.\n9. Fanouriakis \nA , Kostopoulou \nM , Alunno \nA , et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus\n. Ann Rheum Dis . 2019 ;78 :736 –745\n. doi:10.1136/annrheumdis-2019-215089 30926722 \n10. Kuhn \nA , Aberer \nE , Bata‐Csörgő \nZ , et al. S2k guideline for treatment of cutaneous lupus erythematosus – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV)\n. J Eur Acad Dermatol Venereol . 2017 ;31 :389 –404\n. doi:10.1111/jdv.14053 27859683 \n11. Müller \nCS , Hinterberger \nL , Vogt \nT , Pföhler \nC . Rowell syndrome–case report with discussion of significance of diagnostic accuracy\n. BMJ Case Rep . 2011 ;2011 . doi:10.1136/bcr.09.2011.4755 \n12. Lahiri \nD , Agarwal \nR , Mondal \nD , Hajra \nA , Sarkar \nN , Mukhopadhyay \nJ . Rowell’s syndrome: a case report and review of literature\n. J Case Rep . 2015 ;5 (1 ):163 –165\n. doi:10.17659/01.2015.0041 \n13. Schissler \nC , Banea \nS , Tortel \nM-C , Mahé \nA . Un nouveau cas de syndrome de Rowell\n. Ann Dermatol Venereol . 2017 ;144 (Issue 4 ):263 –267\n. doi:10.1016/j.annder.2017.02.005 28325515 \n14. Bhat \nRY , Varma \nC , Bhatt \nS , Balachandran \nC . Rowell syndrome\n. Indian Dermatol Online J . 2014 ;5 (Suppl 1 ):S33 –S35\n. doi:10.4103/2229-5178.144526 25506561 \n15. Green \nM , Roy \nD . Rowell syndrome: targeting a true definition\n. CUTIS . 2017 ;100 (1 ):E8 –E11\n.\n16. Alkul \nS , Behrens \nE , Stetson \nC . Rowell syndrome with recurrence from photoexacerbation: a case report\n. SAGE Open Med Case Rep . 2019 ;7 :2050313X1984733 . doi:10.1177/2050313x19847337 \n17. Ward \nJORDANM , Hess \nJN , Davis \nLS . Targetoid-like lesions in the setting of systemic lupus erythematosus: a case of rowell syndrome\n. J Rheumatol . 2020 ;47 (2 ):298 –299\n. doi:10.3899/jrheum.181021 32007943 \n18. Brănișteanu \nD , Ianoşi \nS , Dimitriu \nA , Stoleriu \nG , Oanţǎ \nA , Daniel \nB . Drug-induced rowell syndrome, a rare and difficult to manage disease: a case report\n. Exp Ther Med . 2017 . doi:10.3892/etm.2017.5557 \n19. Roustan \nG , Salas \nC , Barbadillo \nC , Sánchez Yus \nE , Mulero \nJ , Simón \nA . Lupus erythematosus with an erythema multiforme-like eruption\n. Eur J Dermatol . 2000 ;10 (6 ):459 –462\n.10980468 \n20. Shahid \nS , Khan \nM , Qadar \nL , et al. the first case of rowell syndrome with lupus nephritis and lobar pneumonia in a male child reported in Pakistan\n. Cureus . 2019 ;11 (5 ):e4604 . doi:10.7759/cureus.4604 31309027 \n21. Akintayo \nRO , Olarinoye \nGM , Akintayo \nFC , Ilesanmi \nON . Rowell syndrome in Nigeria: systemic lupus erythematosus presenting as recurrent erythema multiforme in a young woman\n. Acta Dermatovenerol Croat . n.d. ;27 (3 ):200 –201\n.31542069 \n22. Kantardjiev \nV , Stoikova \nE , Broshtilova \nV . Drug-induced rowell syndrome in a male patient\n. Scr Sci Med . 2018 ;50 (4 ):36 . doi:10.14748/ssm.v50i4.5810 \n23. Lee \nA , Batra \nP , Furer \nV , Cheung \nW , Wang \nN , Franks \nJA \nJr. Rowell syndrome (systemic lupus erythematosus + erythema multiforme)\n. Dermatol Online J . 2009 ;15 (8 ). Retrieved from : https://escholarship.org/uc/item/5pf8k3r2.\n24. Solanki \nLS , Dhingra \nM , Thami \nGP . Rowell syndrome\n. Indian Pediatr . 2012 ;49 :854 –855\n. doi:10.1007/s13312-012-0183-5 23144117 \n25. Marini \nA , Draege \nH , Schneider \nM , et al. Rowell syndrome with palmoplantar involvement and suspected epitope spreading\n. Adv Dermatol VENEREOL . 2006 ;87 (3 ). doi:10.2340/00015555-0242 \n26. Tiwary \nAK , Mishra \nDK . ANA-negative systemic lupus erythematosus with targetoid lesions: rowell syndrome or just a rare presentation of lupus erythematosus\n. J Pak Assoc Dermatol . 2016 ;26 (3 ):269 –272\n.\n27. Madke \nB , Khopkar \nU . Rowells syndrome in an Indian male and review of the literature\n. Indian Dermatol Online J . 2015 ;6 (7 ):12 . doi:10.4103/2229-5178.171058 \n28. Modi \nGM , Shen \nA , Mazloom \nA , et al. Lupus erythematosus masquerading as erythema multiforme: does rowell syndrome really exist?\n\nDermatol Online J . 2009 ;15 (2 ). Retrieved from : https://escholarship.org/uc/item/9q89x24r.\n29. Bhobe \nMR , Tambe \nS , Jindal \nS , Jerajani \nHR . Rowell’s syndrome to ds-DNA negative lupus nephritis: a yet unreported progression\n. Indian J Dermatol . 2015 ;60 :215 .\n30. Sharma \nA , Sharma \nR . Rowell syndrome: a case report and review of literature\n. Internet J Rheumatol Clin Immunol . 2016 ;4 (1 ). doi:10.15305/ijrci/v4i1/202 \n31. Müller \nCSL , Hinterberger \nL , Vogt \nT , et al. Rowell syndrome – case report with discussion of significance of diagnostic accuracy\n. Case Rep . 2011 ;2011 :bcr0920114755 .\n32. Siddhavatam \nC , Kekathi \nV , Saifullah \nQS , Kakarla \nS . An interesting case of systemic lupus erythematosus – rowell’s syndrome\n. J NTR Univ Health Sci . 2017 ;6 :60 –63\n.\n33. Anjay \nB , Hemachandar \nR . Systemic lupus with erythema multiforme–so called rowell’s syndrome\n. Int j Multidiscip Curr Res . 2016 ;4 :n .\n34. Fiallo \nP , Tagliaimetra \nAG , Santoro \nG , Venturino \nE . Rowell’s syndrome\n. Int J Dermatol . 1995 ;34 (9 ):635 –636\n. doi:10.1111/j.1365-4362.1995.tb01093.x 7591463 \n35. Baroni \nA , Piccolo \nV , Russo \nT , et al. Norfloxacin-induced subacute cutaneous lupus with erythema multiforme-like lesions: the enigma of the rowell syndrome\n. J Dtsch Dermatol Ges . 2014 ;12 (11 ):1039 –1042\n. doi:10.1111/ddg.12392 25382568 \n36. Solanki \nD , Dalal \nE , Darji \nN . Case report of a rowell?S Syndrome\n. Int J Sci Res . 2014 ;3 (Issue 1 ):7 –8\n.\n37. Aydin \nF , Senturk \nN , Yuksel \nEP , Yildiz \nL , Canturk \nT , Turanli \nAY . Systemic lupus erythematosus with an erythema multiforme-like lesions\n. Indian J Dermatol . 2007 ;52 :56 –58\n. doi:10.4103/0019-5154.31928 \n38. Sharma \nYK , Chauhan \nS . Overlap syndrome with rowell’s syndrome, antiphospholipid syndrome, primary sterility, and sensorineural hearing loss: a case report, brief review, and analysis of cases of rowell’s syndrome reported from India and Abroad\n. Indian J Dermatol . 2018 ;63 :418 –423\n. doi:10.4103/ijd.IJD_437_17 30210166 \n39. Reed \nK , Oberlender \nS , Purcell \nS (2014 , March 14 ). Subacute cutaneous lupus erythematosus with erythema multiforme-like lesions: consideration for rowell syndrome\n. Poster presented at: The Philadelphia Dermatological Society Conference ; Philadelphia, PA .\n40. Murad \nA , Shudell \nE , Mulligan \nN . Rowell’s syndrome induced by terbinafine\n. Case Rep . 2015 ;2015 :bcr2015210360 .\n41. Champagne \nC , Ratnavel \nR , Wong \nT . Severe rowell syndrome associated with oral terbinafine\n. Clin Exp Dermatol . 2012 ;37 (7 ):822 –823\n. doi:10.1111/j.1365-2230.2012.04363.x 22998546 \n42. Yachoui \nR , Cronin \nPM . Systemic lupus erythematosus associated with erythema multiforme-like lesions\n. Case Rep Rheumatol . 2013 ;2013 :1 –3\n. doi:10.1155/2013/212145 \n43. Gerlicz-Kowalczuk \nZA , Krzysiek \nJ , Dominiak \nM , Kaszuba \nA . Rowell’s syndrome – case report and review of the literature\n. Dermatol Rev . 2016 ;103 (3 ):214 –217\n. doi:10.5114/dr.2016.60625 \n44. Katerina \nD , Nora \nP , Gorgi \nG , Filip \nG , Bashkim \nO . Erythema multiforme-like skin lesions in a patient with systemic lupus erythematosus\n. Glob Dermatol . 2014 ;1 (1 ):13 –16\n. doi:10.15761/GOD.1000105 \n45. Ahn \nJW , Kim \nJH , Jeon \nJH , Oh \nCH , Song \nHJ . P171: a case of Rowell's syndrome\n. 프로그램북 (구 초록집 . 2014 ;66 (1 ):357 .\n46. Kim \nYU , Lee \nSW , Kim \nKJ , EP \nH . P155: a case of Rowell's syndrome\n. 프로그램북 (구 초록집 . 2014 ;66 (1 ):351 –352\n.\n47. Basu \nA , Ray \nY , Bhowmik \nP , Rahman \nM , Goswami \nRP . SLE in a male patient presented initially as rowell’s syndrome\n. J Assoc Physic Ind . 2018 ;66 (1 ):98 –99\n.\n48. Altomare \nG , Capella \nGL , Frigerio \nE , Fracchiolla \nC . La posizione nosografica della sindrome di Rowell: a proposito di un caso\n. Ann Ital Dermatol Clin Sper . 1997 ;51 (2 ):59 –62\n.\n49. Kacalak‐Rzepka \nA , Kiedrowicz \nM , Bielecka‐Grzela \nS , Ratajczak‐Stefanska \nV , Maleszka \nR , Mikulska \nD . Rowell’s syndrome in the course of treatment with sodium valproate: a case report and review of the literature data\n. Clin Exp Dermatol . 2009 ;34 (6 ):702 –704\n. doi:10.1111/j.1365-2230.2008.02972.x 19040509 \n50. Caleya \nJ , López \nF , Martín Rodrigo \nL , Gonzalvo Rodriguez \nP , Hidalgo García \nY . Rowell’s syndrome: the two sides of the truth\n. Rheumatol Clín . 2016 ;12 (6 ):354 –355\n. doi:10.1016/j.reumae.2015.11.016 \n51. Kartal Durmazlar \nSP , Oktay \nB , Eren \nC , Eskioğlu \nF . So-called rowell’s syndrome: report of a case\n. J Turk Acad Dermatol . 2009 ;3 :93201c .\n52. Roy \nS , Majumdar \nSD , Chakrabartty \nS , Chakravarti \nS . Rowell syndrome in a nine year old child\n. Sri Lanka J Child Health . 2020 ;49 (1 ):87 –89\n. doi:10.4038/sljch.v49i1.8909 \n53. Amatya \nB , Maharjan \nL . Rowell syndrome secondary to anti-tubercular therapy: a case report and literature review\n. Our Dermatol Online . 2017 ;8 (2 ):200 –203\n. doi:10.7241/ourd.20172.54 \n54. Miglino \nB , Tiberio \nR , Graziola \nF , Annali \nG , Giacalone \nA , Colombo \nE , Savoia \nP. \nA case report of rowell syndrome\n. J Am Acad Dermatol . 2018 ;79 (3 ). doi:10.1016/j.jaad.2018.05.087 \n55. Nastałek \nM , Wojas-Pelc \nA . Erythema exudativum multiforme as a skin manifestation of acute systemic lupus erythematosus. Rowell’s syndrome\n. Dermatol Rev . 2010 ;97 (1 ):21 –28\n.\n\n",
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"keywords": "Rowell syndrome; cutaneous lupus erythematosus; erythema multiform; rheumatoid arthritis; systemic lupus erythematosus",
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"title": "A Case of Rhupus with Rowell Syndrome.",
"title_normalized": "a case of rhupus with rowell syndrome"
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"abstract": "Bile acid nephropathy, also known as cholemic nephrosis or nephropathy, is an entity that can be seen in patients with severe cholestatic liver disease. It typically is associated with acute kidney injury (AKI) with various forms of hepatic disease. Most often, patients with severe obstructive jaundice develop this lesion, which is thought to occur due to direct bile acid injury to tubular cells, as well as obstructing bile acid casts. Patients with end-stage liver disease also can develop AKI, in which case a more heterogeneous lesion occurs that includes hepatorenal syndrome and acute tubular injury/necrosis. In this circumstance, acute tubular injury develops from a combination of hemodynamic changes with some contribution from direct bile acid-related tubular toxicity and obstructive bile casts. We present a case of AKI due to bile acid nephropathy in a bodybuilder who developed severe cholestatic liver disease in the setting of anabolic androgenic steroid use.",
"affiliations": "Section of Nephrology, Yale University School of Medicine, New Haven, CT.;Department of Pathology, Yale University School of Medicine, New Haven, CT.;Department of Pathology, Yale University School of Medicine, New Haven, CT.;Section of Nephrology, Yale University School of Medicine, New Haven, CT. Electronic address: mark.perazella@yale.edu.",
"authors": "Luciano|Randy L|RL|;Castano|Ekaterina|E|;Moeckel|Gilbert|G|;Perazella|Mark A|MA|",
"chemical_list": "D045930:Anabolic Agents; D000728:Androgens; D001647:Bile Acids and Salts; D013256:Steroids; D013739:Testosterone; D009277:Nandrolone; D008696:Methandrostenolone",
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"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Bile acid nephropathy; acute kidney injury; cholestatic jaundice",
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"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D045930:Anabolic Agents; D000728:Androgens; D001647:Bile Acids and Salts; D006801:Humans; D008297:Male; D008696:Methandrostenolone; D009277:Nandrolone; D013177:Sports; D013256:Steroids; D019966:Substance-Related Disorders; D013739:Testosterone",
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"title": "Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid.",
"title_normalized": "bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid"
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"abstract": "This phase Ib, dose-escalation study investigated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and preliminary efficacy of the pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) inhibitor voxtalisib [30 or 50 mg twice daily (BID)], in combination with rituximab (voxtalisib+rituximab) or rituximab plus bendamustine (voxtalisib+rituximab+bendamustine), in relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma and chronic lymphocytic leukaemia (CLL). MTD and RP2D of voxtalisib were determined using a 3 + 3 dose-escalation design. Adverse events (AEs), plasma PK and disease response were recorded. Thirty-seven patients were enrolled. The RP2D of voxtalisib in combination with rituximab or rituximab+bendamustine was 50 mg BID. Four patients experienced a total of five dose-limiting toxicities. The most frequent AEs were nausea (45·9%), fatigue (37·8%) headache (32·4%) and pyrexia (32·4%). The most frequent grade ≥3 AEs were neutropenia (27·0%), thrombocytopenia (24·3%), anaemia (16·2%) and febrile neutropenia (10·8%). Voxtalisib PK parameters were not affected by co-administration with rituximab or rituximab+bendamustine. Of 35 efficacy-evaluable patients, four (11·4%) achieved complete response and 13 (37·1%) achieved partial response. Voxtalisib, in combination with rituximab or rituximab+bendamustine, demonstrated an acceptable safety profile and encouraging anti-tumour activity in relapsed or refractory B-cell malignancies.",
"affiliations": "The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. farrukh.awan@osumc.edu.;Developmental Therapeutics Program, University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.;Sanofi, Cambridge, MA, USA.;Sanofi, Bridgewater, NJ, USA.;Sanofi, Cambridge, MA, USA.;University of Alabama, Birmingham, AL, USA.",
"authors": "Awan|Farrukh T|FT|;Gore|Lia|L|;Gao|Lei|L|;Sharma|Jyoti|J|;Lager|Joanne|J|;Costa|Luciano J|LJ|",
"chemical_list": "D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; D058570:TOR Serine-Threonine Kinases",
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"journal": "British journal of haematology",
"keywords": "PI3K/mTOR; chronic lymphocytic leukaemia; non-Hodgkin lymphoma; pharmacokinetics; rituximab",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015448:Leukemia, B-Cell; D016393:Lymphoma, B-Cell; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D012008:Recurrence; D019233:Retreatment; D000069283:Rituximab; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome",
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"title": "Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies.",
"title_normalized": "phase ib trial of the pi3k mtor inhibitor voxtalisib sar245409 in combination with chemoimmunotherapy in patients with relapsed or refractory b cell malignancies"
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"abstract": "Spontaneous spinal epidural abscess (SEA) is a rare diagnosis; only eight cases have been reported during pregnancy. Diagnosis of SEA can be difficult, especially when the classic triad of fever, back pain, and neurologic deficits are not present. Early diagnosis and treatment are necessary to reduce potential morbidity and mortality.\n\n\n\nWe report two separate cases of SEA in pregnancy and summarize the existing literature. Case 1: A 20-year-old G1P0 presented at 35-week gestation with low back pain and lower extremity (LE) weakness. Magnetic resonance imaging (MRI) revealed thoracic SEA. The patient underwent cesarian delivery followed by posterior thoracic laminectomy and fusion (T9-11), abscess decompression, and antibiotic therapy. Unfortunately, there was a recurrence of her infection requiring a second irrigation and debridement 1 month after index procedure. At final follow-up, the patient had complete neurologic recovery. Case 2: A 38-year-old G10P0 presented at 36-week gestation in labor with LE weakness and difficulty ambulating. After delivery, she had significant LE neurologic deficits. MRI demonstrated thoracic osteodiscitis with associated epidural abscess. She underwent thoracic laminectomy and fusion (T7-12), abscess decompression, and antibiotic therapy. Unfortunately, despite aggressive treatment, she has persistent LE neurologic deficits.\n\n\n\nPregnancy complicates the diagnosis and treatment strategies of SEA: back pain is very commonly underestimated, especially in the absence of fever and gross neurologic deficits. Prompt diagnosis and treatment are paramount to prevent neurologic decline and facilitate recovery. It is important to perform a focused physical exam noting motor strength, sensation, and reflexes. Coordinated management between the Emergency Department, OB-GYN, and spinal surgery team is required for best possible patient outcomes. Typically, management consists of aggressive surgical decompression and antibiotic therapy.",
"affiliations": "Department of Orthopaedics, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Daniel.Robinson@unchealth.unc.edu.;Department of Orthopaedics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.;WakeMed Orthopaedics, Raleigh, NC, USA.",
"authors": "Robinson|Daniel L|DL|0000-0002-2931-579X;Lewis|Scott|S|;Regan|Conor|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41394-021-00437-y",
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"issn_linking": "2058-6124",
"issue": "7(1)",
"journal": "Spinal cord series and cases",
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"medline_ta": "Spinal Cord Ser Cases",
"mesh_terms": "D000328:Adult; D001416:Back Pain; D019299:Decompression, Surgical; D020802:Epidural Abscess; D005260:Female; D006801:Humans; D007796:Laminectomy; D008279:Magnetic Resonance Imaging; D011247:Pregnancy; D055815:Young Adult",
"nlm_unique_id": "101680856",
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"pmid": "34446695",
"pubdate": "2021-08-26",
"publication_types": "D016428:Journal Article",
"references": "27046967;29992066;20664432;17566949;16269087;1921486;2385334;25060090;17443503;17093252;27424376;10447289;24845921;15028325;28017192;273412;19935037;25230605",
"title": "Spontaneous spinal epidural abscess in pregnancy: a case series.",
"title_normalized": "spontaneous spinal epidural abscess in pregnancy a case series"
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "Background: Fluoropyrimidines are mainstay chemotherapeutics in the treatment of gastrointestinal cancers and are also used to treat breast cancer and head and neck cancers. However, 5-flourouracil (5-FU) and capecitabine may induce cardiotoxicity that mostly presents as acute coronary syndromes. We compared the incidence of cardiotoxicity induced by 5-FU and capecitabine in patients with colorectal cancer and sought to identify risk markers for cardiotoxicity.Methods: We reviewed all consecutive patients with colorectal cancer who received 5-FU or capecitabine at one institution in the neoadjuvant (2007-2016), adjuvant (2000-2016) or metastatic setting (2007-2016).Results: Totally, 995 patients received 5-FU and 1241 received capecitabine. The incidence of cardiotoxicity induced by 5-FU was 5.2% [95% confidence interval (CI): 3.8-6.6%] and 4.1% (95% CI: 3.0-5.2%) induced by capecitabine (p = .21). The most common events were angina without ischemia (5-FU: 1.6%, capecitabine: 1.3%, p = .53), angina with ischemia on ECG (5-FU: 0.9%, capecitabine: 0.8%, p = .53), unspecified chest pain (5-FU: 0.9%, capecitabine: 0.6%, p = .34), ST-elevation myocardial infarction (5-FU: 0.5%; capecitabine: 0.4%, p = .76) and non-ST-elevation myocardial infarction (5-FU: 0.7%, capecitabine: 0.5%, p = .50). Cardiac arrest or sudden death occurred in 0.5 and 0.4%, respectively (p = 1). No risk markers for cardiotoxicity induced by 5-FU were identified. In the capecitabine group, ischemic heart disease was a risk marker (odds ratio: 2.9, 95% CI: 1.2-7.0, p = .016).Conclusions: Five percent of patients treated with 5-FU developed cardiotoxicity and 4% treated with capecitabine. Ischemic heart disease was a risk marker for cardiotoxicity induced by capecitabine.",
"affiliations": "Department of Oncology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.;Department of Cardiology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.;Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.;Department of Oncology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.;Department of Medicine, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.;Department of Cardiology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.;Department of Cardiology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.;Department of Oncology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.",
"authors": "Dyhl-Polk|Anne|A|;Vaage-Nilsen|Merete|M|;Schou|Morten|M|;Vistisen|Kirsten Kjeldgaard|KK|;Lund|Cecilia Margareta|CM|;Kümler|Thomas|T|;Appel|Jon Michael|JM|;Nielsen|Dorte Lisbet|DL|",
"chemical_list": "D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1080/0284186X.2019.1711164",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0284-186X",
"issue": "59(4)",
"journal": "Acta oncologica (Stockholm, Sweden)",
"keywords": null,
"medline_ta": "Acta Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D066126:Cardiotoxicity; D015179:Colorectal Neoplasms; D003718:Denmark; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005472:Fluorouracil; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "8709065",
"other_id": null,
"pages": "475-483",
"pmc": null,
"pmid": "31931649",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer.",
"title_normalized": "incidence and risk markers of 5 fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer"
} | [
{
"companynumb": "DK-ROCHE-2590871",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "A case of progressive multifocal leukoencephalopathy (PML) occurring on low dose immunosuppression for systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) is presented. Neurologic changes in patients with SLE or SS should not be assumed to be a disease manifestation. Importantly, serious opportunistic infections such as PML can occur in minimally immunosuppressed rheumatic patients. Early diagnosis, facilitated by scrutiny of MRI findings, should trigger measures to reconstitute immunity in an otherwise fatal disease.",
"affiliations": "Neuroimmunology Clinic, Concord Hospital, University of Sydney, NSW, Australia.;Radiology, Concord Hospital, University of Sydney, NSW, Australia.;The Hermitage Medical Centre Suite, NSW, Australia.;Neuroimmunology Clinic, Concord Hospital, University of Sydney, NSW, Australia.;Neuroimmunology Clinic, Concord Hospital, University of Sydney, NSW, Australia; Brain and Mind Centre, University of Sydney, NSW, Australia. Electronic address: swreddel@sydneyneurology.com.au.",
"authors": "Law|Lai Yin|LY|;Tan|Irene|I|;Prowse|Michael|M|;Sean Riminton|D|D|;Reddel|Stephen W|SW|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2019.06.030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "67()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Cystic encephalomalacia; Diagnosis; MRI; Prognosis; Progressive multifocal leukoencephalopathy; Systemic lupus erythematosus",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008180:Lupus Erythematosus, Systemic; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D012859:Sjogren's Syndrome",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "261-263",
"pmc": null,
"pmid": "31278051",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus: Clues to early diagnosis.",
"title_normalized": "progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus clues to early diagnosis"
} | [
{
"companynumb": "AU-BAUSCH-BL-2019-025512",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Gemcitabine and nab-paclitaxel (GnP) combination therapy is a standard regimen for advanced pancreatic ductal adenocarcinoma (PDAC) worldwide; however, concerns regarding the unexpectedly high incidence of interstitial lung disease (ILD) have emerged. We investigated the incidence and predictive factors of ILD in PDAC patients who were treated with GnP combination therapy.\n\n\n\nThirty-seven patients treated with GnP therapy as either 1st or 2nd line treatment were included, among whom seven developed ILD (18.9%). The clinical characteristics (age, etc.) were compared between patients with and without ILD. The diagnostic yield of the markers to predict the presence of ILD was calculated. The clinical course of the seven patients with ILD was summarized. Survival analysis was performed using the Kaplan-Meier method and log-rank test.\n\n\n\nThe median age was higher in patients with ILD (73.0 vs. 65.0 years old, p = 0.03), while no differences were observed in the other clinical characteristics. Among the three investigated markers, SP-D showed the best diagnostic yield (AUC = 0.94) for diagnosing ILD. Though one patient required steroid therapy and the discontinuation of GnP therapy, all patients could undergo subsequent treatment. In the survival analysis, the median survival time of PDAC patients with ILD was comparable to that of patients without ILD (25.1 vs. 24.5 months, p = 0.98).\n\n\n\nILD was observed in 18.9% of PDAC patients treated with GnP therapy. With appropriate management, no prognostic influence was observed.",
"affiliations": "Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan. subaru@fmu.ac.jp.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.;Department of Endoscopy, Fukushima Medical University Hospital, Fukushima, Japan.;Department of Endoscopy, Fukushima Medical University Hospital, Fukushima, Japan.;Department of Endoscopy, Fukushima Medical University Hospital, Fukushima, Japan.;Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan.",
"authors": "Irie|Hiroki|H|;Suzuki|Rei|R|http://orcid.org/0000-0002-4049-0484;Takagi|Tadayuki|T|;Sugimoto|Mitsuru|M|;Konno|Naoki|N|;Sato|Yuki|Y|;Hikichi|Takuto|T|;Nakamura|Jun|J|;Hashimoto|Minami|M|;Ohira|Hiromasa|H|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-019-03983-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "85(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Chemotherapy; Gemcitabine; Interstitial lung disease; Nab-paclitaxel; Pancreatic ductal adenocarcinoma",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D021441:Carcinoma, Pancreatic Ductal; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "517-523",
"pmc": null,
"pmid": "31691078",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Interstitial lung disease in advanced pancreatic ductal adenocarcinoma patients treated with gemcitabine and nab-paclitaxel combination therapy: a retrospective analysis.",
"title_normalized": "interstitial lung disease in advanced pancreatic ductal adenocarcinoma patients treated with gemcitabine and nab paclitaxel combination therapy a retrospective analysis"
} | [
{
"companynumb": "JP-ACCORD-161288",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "1",
"druga... |
{
"abstract": "Adenosine deaminase (ADA) in cerebrospinal fluid (CSF) is considered to be a useful biomarker in differentiating tuberculous meningitis (TBM) from other meningitis in non-HIV patients. However, its specificity decreases in patients with HIV, and other diseases such as cytomegalovirus encephalitis, toxoplasmosis or meningeal lymphomatosis can also elevate ADA in CSF. We here report a rare case of retroviral rebound syndrome in a HIV patient, whose ADA in CSF was elevated.",
"affiliations": "Department of Infectious Diseases, Kobe City Medical Center General Hospital, Japan; Department of General Internal Medicine, Kobe City Medical Center General Hospital, Japan. Electronic address: asakodoi@gmail.com.;Department of Infectious Diseases, Kobe City Medical Center General Hospital, Japan; Department of General Internal Medicine, Kobe City Medical Center General Hospital, Japan.;Department of General Internal Medicine, Kobe City Medical Center General Hospital, Japan.;Department of Infectious Diseases, Kobe City Medical Center General Hospital, Japan; Department of General Internal Medicine, Kobe City Medical Center General Hospital, Japan.",
"authors": "Doi|Asako|A|;Hasuike|Toshikazu|T|;Shindo|Tatsuya|T|;Nishioka|Hiroaki|H|",
"chemical_list": "D015415:Biomarkers; D000243:Adenosine Deaminase",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2020.06.050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "98()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Adenosine deaminase; Cerebrospinal fluid; Human immunodeficiency virus; Meningitis; Retroviral rebound syndrome",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000243:Adenosine Deaminase; D000328:Adult; D015415:Biomarkers; D015658:HIV Infections; D006801:Humans; D008297:Male; D014390:Tuberculosis, Meningeal",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "297-298",
"pmc": null,
"pmid": "32562847",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Elevation of CSF adenosine deaminase in HIV patient with meningitis from retroviral rebound syndrome, a case report.",
"title_normalized": "elevation of csf adenosine deaminase in hiv patient with meningitis from retroviral rebound syndrome a case report"
} | [
{
"companynumb": "JP-GILEAD-2020-0492497",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
},
... |
{
"abstract": "OBJECTIVE\nThe purpose of the study was to evaluate prognostic factors for survival outcomes following embolotherapy for neuroendocrine tumor (NET) liver metastases.\n\n\nMETHODS\nThis was a multicenter retrospective study of 155 patients (60 years mean age, 57 % male) with NET liver metastases from pancreas (n = 71), gut (n = 68), lung (n = 8), or other/unknown (n = 8) primary sites treated with conventional transarterial chemoembolization (TACE, n = 50), transarterial radioembolization (TARE, n = 64), or transarterial embolization (TAE, n = 41) between 2004 and 2015. Patient-, tumor-, and treatment-related factors were evaluated for prognostic effect on hepatic progression-free survival (HPFS) and overall survival (OS) using unadjusted and propensity score-weighted univariate and multivariate Cox proportional hazards models.\n\n\nRESULTS\nMedian HPFS and OS were 18.5 and 125.1 months for G1 (n = 75), 12.2 and 33.9 months for G2 (n = 60), and 4.9 and 9.3 months for G3 tumors (n = 20), respectively (p < 0.05). Tumor burden >50 % hepatic volume demonstrated 5.5- and 26.8-month shorter median HPFS and OS, respectively, versus burden ≤50 % (p < 0.05). There were no significant differences in HPFS or OS between gut or pancreas primaries. In multivariate HPFS analysis, there were no significant differences among embolotherapy modalities. In multivariate OS analysis, TARE had a higher hazard ratio than TACE (unadjusted Cox model: HR 2.1, p = 0.02; propensity score adjusted model: HR 1.8, p = 0.11), while TAE did not differ significantly from TACE.\n\n\nCONCLUSIONS\nHigher tumor grade and tumor burden prognosticated shorter HPFS and OS. TARE had a higher hazard ratio for OS than TACE. There were no significant differences in HPFS among embolotherapy modalities.",
"affiliations": "Division of Interventional Radiology, Department of Radiology, Hospital of the University of Pennsylvania, 1 Silverstein, 3400 Spruce St, Philadelphia, PA, 19104, USA.;Division of Interventional Radiology, Department of Radiology, University of San Diego Medical Center, 200 W Arbor Dr, San Diego, CA, 92103, USA.;Division of Interventional Radiology, Department of Radiology, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI, 53226, USA.;Division of Interventional Radiology, Department of Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.;Division of Interventional Radiology, Department of Radiology, University of San Francisco Medical Center, 505 Parnassus Ave, San Francisco, CA, 94143, USA.;Division of Interventional Radiology, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.;Division of Interventional Radiology, Department of Radiology, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA, 94305, USA.;Division of Interventional Radiology, Department of Radiology, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA, 94305, USA.;Division of Interventional Radiology, Department of Radiology, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA, 94305, USA.;Department of Pathology, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA, 19104, USA.;Department of Biostatistics and Epidemiology, University of Pennsylvania, 432 Guardian Ave, Philadelphia, PA, 19104, USA.;Division of Interventional Radiology, Department of Radiology, Northwestern Memorial Hospital, 251 East Huron, Chicago, IL, 60611, USA.;Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.;Division of Interventional Radiology, Department of Radiology, Hospital of the University of Pennsylvania, 1 Silverstein, 3400 Spruce St, Philadelphia, PA, 19104, USA. michael.soulen@uphs.upenn.edu.",
"authors": "Chen|James X|JX|;Rose|Steven|S|;White|Sarah B|SB|;El-Haddad|Ghassan|G|;Fidelman|Nicholas|N|;Yarmohammadi|Hooman|H|;Hwang|Winifred|W|;Sze|Daniel Y|DY|;Kothary|Nishita|N|;Stashek|Kristen|K|;Wileyto|E Paul|EP|;Salem|Riad|R|;Metz|David C|DC|;Soulen|Michael C|MC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s00270-016-1478-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0174-1551",
"issue": "40(1)",
"journal": "Cardiovascular and interventional radiology",
"keywords": "Embolization; Liver metastases; Neuroendocrine tumor",
"medline_ta": "Cardiovasc Intervent Radiol",
"mesh_terms": "D016461:Chemoembolization, Therapeutic; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018358:Neuroendocrine Tumors; D011379:Prognosis; D057216:Propensity Score; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8003538",
"other_id": null,
"pages": "69-80",
"pmc": null,
"pmid": "27738818",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Embolotherapy for Neuroendocrine Tumor Liver Metastases: Prognostic Factors for Hepatic Progression-Free Survival and Overall Survival.",
"title_normalized": "embolotherapy for neuroendocrine tumor liver metastases prognostic factors for hepatic progression free survival and overall survival"
} | [
{
"companynumb": "US-JNJFOC-20170116805",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"d... |
{
"abstract": "BACKGROUND\nWe hypothesized that the combination of bevacizumab, carboplatin, and pemetrexed will be an effective first-line regimen in fit, elderly patients with nonsquamous non-small-cell lung cancer.\n\n\nMETHODS\nTreatment-naïve, stage IIIB/IV nonsquamous non-small-cell lung cancer patients more than 70 years old with good performance status (Eastern Cooperative Oncology Group performance status 0-1) and adequate organ function were eligible. Carboplatin area under the curve 6, pemetrexed 500 mg/m, and bevacizumab 15 mg/kg were administered on day 1 of each 21-day cycle (up to six cycles) followed by maintenance pemetrexed and bevacizumab. The primary end point of 6-month progression-free survival rate of at least 70% was assessed using a one-stage binomial design. Quality of life (QOL) questionnaires were administered. Polymorphisms in genes encoding relevant proteins (drug targets, transport, and metabolism proteins) were correlated with treatment outcome.\n\n\nRESULTS\nFifty-seven eligible patients were enrolled. Median age was 74.5 years. Median treatment cycles received was 6. The most common grade 3 or higher non-hematologic adverse events were fatigue (26%) and hypertension (11%); 16% had grade 4 neutropenia and 6.5% had grade 4 thrombocytopenia. Three patients experienced grade 3/4 hemorrhagic events (one pulmonary, two gastrointestinal). Primary end point of PFS6 was 60% (95% confidence interval [CI]: 45.9-73%). Median PFS was 7.0 months (95% CI: 5.9-10.1), median overall survival was 13.7 months (95% CI: 9.4-16.8). Polymorphic KDR and VEGFA variants correlated with survival and toxicity, respectively. There was no significant change in overall QOL scores over time.\n\n\nCONCLUSIONS\nThis regimen is feasible and did not decrease the QOL in this study population. However, it did not meet the primary efficacy end point.",
"affiliations": "*Roswell Park Cancer Institute, Buffalo, NY; †Mayo Clinic Rochester, MN 55905; ‡Michiana Hematology Oncology, South Bend, IN; §Illinois CancerCare, Ottawa, IL; ‖Mayo Clinic Scottsdale, AZ; ¶Missouri Valley Cancer Consortium, Omaha, NE; and #Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, MN.",
"authors": "Dy|Grace K|GK|;Molina|Julian R|JR|;Qi|Yingwei|Y|;Ansari|Rafat|R|;Thomas|Sachdev|S|;Ross|Helen J|HJ|;Soori|Gamini|G|;Anderson|Daniel|D|;Aubry|Marie Christine|MC|;Meyers|Jeffrey|J|;Adjei|Araba A|AA|;Mandrekar|Sumithra|S|;Adjei|Alex A|AA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005971:Glutamates; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D042461:Vascular Endothelial Growth Factor A; D000068437:Pemetrexed; D000068258:Bevacizumab; D006147:Guanine; D016190:Carboplatin; D013940:Thymidylate Synthase; D040301:Vascular Endothelial Growth Factor Receptor-2",
"country": "United States",
"delete": false,
"doi": "10.1097/JTO.0000000000000217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-0864",
"issue": "9(8)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": null,
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D005221:Fatigue; D005260:Female; D005838:Genotype; D005971:Glutamates; D006147:Guanine; D006470:Hemorrhage; D006801:Humans; D006973:Hypertension; D008175:Lung Neoplasms; D008297:Male; D009503:Neutropenia; D062072:Patient Acuity; D000068437:Pemetrexed; D020641:Polymorphism, Single Nucleotide; D011788:Quality of Life; D058978:Reduced Folate Carrier Protein; D015996:Survival Rate; D013921:Thrombocytopenia; D013940:Thymidylate Synthase; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2",
"nlm_unique_id": "101274235",
"other_id": null,
"pages": "1146-53",
"pmc": null,
"pmid": "25157767",
"pubdate": "2014-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "15701857;17167137;23835707;24145346;19841321;23226765;18506025;22005471;19594543;23136232;21669012;19307503;21102260;18165641;15027501;20651609;20630084;22608783;19433684;22320189;21900836;22015057;18281657;19339911;19875757;17473654;18824714;16258975;19767093;22129133;23434351;22889494;24852395",
"title": "NCCTG N0821 (Alliance): a phase II first-line study of pemetrexed, carboplatin, and bevacizumab in elderly patients with advanced nonsquamous non-small-cell lung cancer with good performance status.",
"title_normalized": "ncctg n0821 alliance a phase ii first line study of pemetrexed carboplatin and bevacizumab in elderly patients with advanced nonsquamous non small cell lung cancer with good performance status"
} | [
{
"companynumb": "US-ROCHE-1073698",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Necrotising fasciitis (NF) is a soft tissue bacterial-derived infection characterised clinically by fulminant tissue destruction of the poorly blood-supplied muscle fascia and overlying subcutaneous fat. Although these infections first appear as minor superficial manifestations, they are capricious in nature and often lead to sepsis, organ failure and high mortality. We report a case of type II necrotising fasciitis in a 39-year-old Caucasian female patient who presented to the emergency department with cellulitis of her right foot and lower leg that rapidly developed into tissue necrosis. The patient course is of unique interest due to progressive history over a 104 days time frame with complications following surgical treatments and outpatient follow-up. We highlight the importance of early detection and pertinent clinical awareness from a wide range of medical specialties that were involved in this case, and how this process is critical, in order to properly diagnose and treat NF-derived tissue infections.",
"affiliations": "Universidad Autonoma De Guadalajara Medical School, Guadalajara, Mexico.;Universidad Autonoma De Guadalajara Medical School, Guadalajara, Mexico.;University of Medicine and Pharmacy Iuliu, Cluj-Napoca, Romania.;Department of Internal Medicine, Scottsdale Healthcare Shea Medical Center, Scottsdale, Arizona, USA.",
"authors": "Sabre|Alexander|A|;Robles|Carlos G|CG|;Krisar-White|Patricia|P|;Farricielli|Laurie|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D002481:Cellulitis; D019115:Fasciitis, Necrotizing; D005260:Female; D006801:Humans; D035002:Lower Extremity; D009336:Necrosis; D018461:Soft Tissue Infections; D017695:Soft Tissue Injuries",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24973350",
"pubdate": "2014-06-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20304249;8532002;16703512;17060762;15943495;7494032;14758212;2659990",
"title": "Soft tissue injury of the lower extremity complicated by type II necrotising fasciitis highlighting the need for astute clinical practices and proper treatment.",
"title_normalized": "soft tissue injury of the lower extremity complicated by type ii necrotising fasciitis highlighting the need for astute clinical practices and proper treatment"
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"abstract": "Multimodal computed tomography (CT) guides decision-making regarding use of thrombolytic agents in acute ischemic stroke patients. However, postcontrast acute kidney injury (PC-AKI) is a potential adverse effect of the contrast media used, which may require hemodialysis and cause a longer hospital stay. The incidence and risk factors of PC-AKI in acute ischemic stroke patients, particularly in Thailand, remain unclear. Goal. We aimed at determining the incidence and risk factors of PC-AKI in patients with acute ischemic stroke undergoing multimodal CT.\nWe conducted a retrospective review of Thai acute ischemic stroke patients admitted to the King Chulalongkorn Memorial Hospital between January 2014 and December 2017 who received multimodal CT and thrombolytic treatment with alteplase.\nOverall, 109 patients were included for analysis; eight patients (7.3%) developed PC-AKI. Estimated glomerular filtration rate (eGFR) ≤ 30 mL/min and mechanical thrombectomy were risk factors significantly associated with PC-AKI.\nThe incidence of PC-AKI in a real practice setting did not differ from previous reports. Two factors were associated with PC-AKI, eGFR ≤ 30 mL/min and mechanical thrombectomy. Patients without these risk factors may not need to wait for the results of renal function testing prior to multimodal CT.",
"affiliations": "Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.;Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.",
"authors": "Chusiri|Sirichai|S|;Chutinet|Aurauma|A|;Suwanwela|Nijasri Charnnarong|NC|;Puttilerpong|Chankit|C|https://orcid.org/0000-0002-7654-1845",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/7182826",
"fulltext": "\n==== Front\nStroke Res Treat\nStroke Res Treat\nSRT\nStroke Research and Treatment\n2090-8105 2042-0056 Hindawi \n\n10.1155/2020/7182826\nResearch Article\nIncidence and Risk Factors of Postcontrast Acute Kidney Injury in Patients with Acute Ischemic Stroke\nChusiri Sirichai \n1\n Chutinet Aurauma \n2\n\n3\n Suwanwela Nijasri Charnnarong \n2\n\n3\n https://orcid.org/0000-0002-7654-1845Puttilerpong Chankit chankit.p@pharm.chula.ac.th\n1\n \n1Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand\n\n2Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand\n\n3Chulalongkorn Stroke Center, Chula Neuroscience Center, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand\nAcademic Editor: Francisco Campos\n\n\n2020 \n1 4 2020 \n2020 718282628 11 2019 26 1 2020 19 2 2020 Copyright © 2020 Sirichai Chusiri et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Multimodal computed tomography (CT) guides decision-making regarding use of thrombolytic agents in acute ischemic stroke patients. However, postcontrast acute kidney injury (PC-AKI) is a potential adverse effect of the contrast media used, which may require hemodialysis and cause a longer hospital stay. The incidence and risk factors of PC-AKI in acute ischemic stroke patients, particularly in Thailand, remain unclear. Goal. We aimed at determining the incidence and risk factors of PC-AKI in patients with acute ischemic stroke undergoing multimodal CT. \n\nMethods\n We conducted a retrospective review of Thai acute ischemic stroke patients admitted to the King Chulalongkorn Memorial Hospital between January 2014 and December 2017 who received multimodal CT and thrombolytic treatment with alteplase. \n\nResult\n Overall, 109 patients were included for analysis; eight patients (7.3%) developed PC-AKI. Estimated glomerular filtration rate (eGFR) ≤ 30 mL/min and mechanical thrombectomy were risk factors significantly associated with PC-AKI. \n\nConclusion\n The incidence of PC-AKI in a real practice setting did not differ from previous reports. Two factors were associated with PC-AKI, eGFR ≤ 30 mL/min and mechanical thrombectomy. Patients without these risk factors may not need to wait for the results of renal function testing prior to multimodal CT.\n==== Body\n1. Introduction\nStroke is the second leading cause of mortality worldwide and the leading cause of morbidity in the elderly. In 2018, approximately 6.45 million people died from stroke; 40% of these deaths occurred in developing countries [1, 2]. Stroke impacts not only affected patients but also their families, who provide care for them at home. The estimated lifetime cost of stroke care is estimated to range between 59,800 and 230,000 USD per patient [3]. There are 2 types of stroke, ischemic and hemorrhagic, and each has different treatment. Prompt and accurate diagnosis of ischemic stroke is crucial for appropriate management with administration of thrombolytic drug therapy, which can restore cerebral blood flow and prevent morbidity and mortality [4].\n\nMultimodal computed tomography is the recommended imaging investigation in acute ischemic stroke. It is faster and less costly than magnetic resonance imaging [5] and consists of noncontrast computed tomography (NCCT), computed tomography angiography (CTA), and computed tomography perfusion (CTP). NCCT is first used to differentiate between hemorrhagic and ischemic stroke. Then, CTA and CTP evaluate cerebral ischemia and arterial occlusion to guide treatment decision-making regarding thrombolytic drug administration or mechanical thrombolysis procedures. A potential adverse effect of CTA and CTP is postcontrast acute kidney injury (PC-AKI), which may result in prolonged hospitalization and require additional treatment, including hemodialysis [6]. Therefore, kidney function is evaluated prior to multimodal CT. However, this may cause a delay in treatment, which could seriously affect disease prognosis. A wide range of PC-AKI incidence rates has been reported in ischemic stroke patients. This might be due to variable criteria and definitions of PC-AKI among the studies as well as different study designs. In Europe and the US, the incidence of PC-AKI after CTA or CTP reportedly ranges from 1.5% to 14.8% [7–12]. The risk of PC-AKI may be elevated in patients with older age, long-term and uncontrolled diabetes, renal insufficiency, and concurrent use of nephrotoxic drugs [13]. Therefore, we aimed at identifying risk factors for PC-AKI among these patients to help guide proper management.\n\n2. Materials and Methods\nThis study was approved by the Institutional Review Board of the Faculty of Medicine at Chulalongkorn University. We retrospectively reviewed the medical records of Thai acute ischemic stroke patients who were admitted to the King Chulalongkorn Memorial Hospital between January 2014 and December 2017. Patients without serum creatinine data within 7 days after receiving contrast media were excluded. The primary outcome was incidence of PC-AKI. Secondary outcomes were hemodialysis requirement, length of hospital stay, and mortality.\n\nAccording to the stroke protocol of our hospital, patients with suspected acute ischemic stroke receive clinical assessment, intravenous access, and blood sample collection prior to multimodal CT. Imaging studies are obtained without waiting for laboratory results. Blood samples are evaluated for various laboratory parameters including serum urea nitrogen, serum creatinine, and estimated glomerular filtration rate (eGFR) before and within 72 hours after multimodal CT. The eGFR is calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The first patient's serum creatinine was defined as the baseline serum creatinine. All patients in this study were given standard dose alteplase and evaluated for hemorrhagic transformation with NCCT 24 h later. The diagnosis of PC-AKI was defined as a >0.3 mg/dL increase in serum creatinine or ≥1.5–1.9 times increase from baseline within 72 hours [14].\n\nDemographic data, vital signs, laboratory data, total fluid volume administered in the first 24 and 48 h, past medical history (hypertension, anemia, diabetes mellitus, chronic kidney disease (eGFR baseline ≤ 60 mL/min), atrial fibrillation, dyslipidemia, myocardial infarction, congestive heart failure, and current use of metformin), and ischemic stroke complications in the first 7 days (hemorrhagic infarction type I (HI-1), hemorrhagic infarction type II (HI-II), parenchymal hematoma type I (PH1), and parenchymal hematoma type II (PH2)), brain edema, urinary tract infection, and progressive stroke) were recorded. In addition, stroke-relevant data, such as signs and symptoms, time from admission to treatment, the National Institute of Health Stroke Scale (NIHSS) score, and the modified Rankin scale score were recorded. The contrast media used in this study was iopromide (Ultravist®, Bayer HealthCare LLC, Whippany, NJ, USA). Each patient received 50 mL of contrast media for brain CTA and 30 mL for neck CTA. For CTP, each patient received 50 mL of contrast media via intra-arterial injection. Therefore, the total amount of contrast media per patient did not exceed 130 mL.\n\n2.1. Statistical Analysis\nStatistical analysis was performed using the SPSS software, version 22 (IBM Corp., Armonk, NY, USA). Quantitative data are reported as means and standard deviation; qualitative data are shown as numbers and percentage. Incidence was defined as the number of cases divided by the total number of patients included in the study during the specified time period. To determine risk factors associated with PC-AKI, bivariate analyses and multivariate logistic regression were conducted. All variables with a P value of < 0.20 in the bivariate analysis were included in the initial logistic regression model. Variables were then removed in a stepwise fashion from the model based on the highest P value. Goodness of fit for each stepwise model was compared with the likelihood-ratio test. A P value of < 0.05 was considered significant.\n\n3. Results\nDuring the study period, 191 stroke patients received contrast media for multimodal CT. Eighty-two patients were excluded due to lack of serum creatinine data within 7 days after imaging. Finally, 109 patients (57%) were included for analysis.\n\nFifty-nine patients (54.1%) were female. The average patient age was 67.38 ± 14.13 years. PC-AKI occurred in 8 patients (7.3%). Characteristics of the control group (patients without PC-AKI) and the case group (patients with PC-AKI) are shown in Table 1. Significant differences between the control and case groups were found with respect to baseline hematocrit (39.56 ± 5.39 vs. 33.60 ± 7.00, P = 0.013) and baseline hemoglobin (13.12 ± 1.85 vs. 11.10 ± 2.71 g/dL, P = 0.015). Other characteristics, including the NIHSS and modified Rankin scores, stroke complications, and volume of contrast media administered did not differ between the groups. The average time from admission to alteplase administration was 52.3 minutes. Six patients (5.5%) received mechanical thrombectomy.\n\nEight patients developed PC-AKI. The characteristics of each are shown in Table 2. Seven were graded as severe acute renal failure and only 1 required hemodialysis. Fifteen patients died overall; 6 of these were patients who developed PC-AKI (3 died from hemorrhagic transformation, 2 died from infection, and 1 died from large infarction). Although the average length of hospital stay was longer for patients with PC-AKI than those without PC-AKI, the difference was not significant (22 d vs. 16 d, P = 0.309).\n\nFor the initial logistic regression model, the following variables were included: (1) age 60–75 years, (2) SBP of ≥160 mmHg on admission, (3) total fluids administered within 24 hours of admission, (4) baseline eGFR of ≤30 mL/min, (5) anemia, and (6) mechanical thrombectomy. Though SBP on admission, baseline serum creatinine, baseline hemoglobin, baseline hematocrit, and hypertension had P values of < 0.20, we did not include them in the model, but those that overlap with the above variables were selected. After stepwise removal of variables, two significant variables for the development of PC-AKI were found: mechanical thrombectomy and eGFR 30 mL/min (Table 3).\n\n4. Discussion\nThis is the first study to examine PC-AKI in acute stroke patients in Thailand who underwent multimodal CT and received alteplase. All patients underwent imaging without waiting for serum creatinine results, which differs from previous case-control studies. In general, PC-AKI describes a decrease in renal function that follows intravascular administration of contrast media. The decrease in renal function is usually mild and peaks 2–3 days after contrast is administered; therefore, we used the 2018 European Society of Urogenital Radiology criteria to define PC-AKI [14].\n\nA previous study reported a 2.6% incidence of PC-AKI after multimodal CT in acute stroke [10]; however, our rate was higher (7.3%). We excluded 82 (43%) of the eligible patients from analysis because they did not have kidney function testing within 72 hours after receiving contrast media. However, data from these excluded patients showed no evidence of renal dysfunction 7–14 days after contrast administration, so we assume that no patient in this group developed PC-AKI. If we recalculate the incidence of PC-AKI by including them, the incidence of PC-AKI in this study was 4.2%, similar to the previous one. Most of the patients with PC-AKI (7 of 8) developed severe renal failure which required hemodialysis in one. Severe renal failure may be the result of direct kidney damage, not a temporary change in kidney function during hospital admission [15]. However, the length of hospital stay did not significantly differ between patients who developed PC-AKI and those who did not.\n\nWe did not include the variables of hemorrhagic transformation in the analysis for risk factors for developing PC-AKI because hemorrhagic transformation was assessed 24 h after receiving alteplase. Patients may develop PC-AKI before hemorrhage is evaluated; therefore, it is difficult to conclude that it is a true risk factor for PC-AKI. In addition, impaired renal function might be a risk factor for cerebral hemorrhage because renal insufficiency causes platelet dysfunction and induces platelet-vessel wall interaction [16].\n\nLogistic regression analysis found two significant risk factors for developing PC-AKI. One was eGFR of ≤30 mL/min that is a known risk factor for PC-AKI in patients receiving low osmolar contrast media (LOCM), the same type of contrast media used in this study [15]. However, only three of our patients had eGFR of ≤30 mL/min; the number of patients may be too small to definitively conclude that it is a risk factor for PC-AKI. In addition, this group of patients is often excluded from general PC-AKI studies. The second risk factor was mechanical thrombectomy. In patients receiving thrombectomy, an additional 50 mL of contrast media was needed for intra-arterial injection. The total contrast media volume received was therefore 180 mL in these patients. Previous studies have noted that contrast media doses of 30–125 mL have a relatively low risk of kidney toxicity [17, 18]; however, higher doses increase the risk. Another consideration is that intra-arterial injection of contrast media may have a higher risk of causing PC-AKI than intravenous injection, but the evidence is conflicting [19, 20]. In this study, only six patients received thrombectomy; the number of patients is too small to definitively consider it as a risk factor for PC-AKI. Future studies with a larger number of patients are required. Nonetheless, this study demonstrates that multimodal CT treatment is safe and associated with low PC-AKI incidence. There is no need to delay imaging and alteplase treatment in ischemic stroke patients while waiting for kidney function testing results, as delay could result in worse patient outcome.\n\nLimitations of this study include its retrospective design, incomplete clinical data in a considerable proportion of otherwise eligible patients, and small sample size. Further prospective studies are needed to more precisely determine PC-AKI risk factors in acute stroke patients and develop guidelines.\n\n5. Conclusions\nMultimodal CT during acute stroke evaluation is safe with respect to renal function and does not delay evaluation or appropriate treatment. The incidence of PC-AKI in this real practice setting was not significantly different from previous reports. Baseline renal function is an important marker to identify patients at risk. Patients with elevated serum creatinine and those undergoing thrombectomy require intensive monitoring to prevent PC-AKI. Further studies to validate PC-AKI risk factors are warranted to increase the safety of contrast media use in acute stroke patients.\n\nData Availability\nThe patient's data used to support the findings of this study were supplied by the Ethics Committee of Chulalongkorn Hospital (IRB No.665/60) under license and so cannot be made freely available. Requests for access to these data should be made to Sirichai Chusiri, sirichai.chusiri@gmail.com.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nTable 1 Patient characteristics.\n\nBaseline characteristic\tNumber of patients (%)\t\nP value\t\nControl (n = 101)\tCase (n = 8)\t\nAge (years), mean ± SD\t67.30 ± 14.57\t68.38 ± 6.99\t0.835\t\n (i) <60\t29 (28.7)\t0 (0)\t—\t\n (ii) 60–75\t39 (38.6)\t7 (87.5)\t0.027∗\t\n (iii) >75\t33 (32.7)\t1 (12.5)\t0.262\t\nSex\t\t\t\t\n (i) Male\t48 (47.5)\t2 (25)\t0.234\t\nSystolic blood pressure (SBP), mean ± SD\t155.01 ± 29.15\t173.00 ± 30.97\t0.106\t\n (i) SBP ≥ 160 mmHg\t38 (37.6)\t5 (62.5)\t0.180\t\n Body weight (kg), mean ± SD\t61.31 ± 13.24\t59.23 ± 9.54\t0.662\t\nPatient volume status\t\t\t\t\n Total fluids within 24 h (mL), mean ± SD\t2173 ± 846\t2723 ± 1937\t0.129\t\n Total fluids within 48 h (mL), mean ± SD\t4564 ± 1542 \t5281 ± 2484\t0.230\t\nLaboratory data\t\t\t\t\n Baseline serum creatinine (mg/dL), mean ± SD\t1.09 ± 0.56\t1.79 ± 2.47\t0.078\t\n (i) ≥1.5\t9 (8.9)\t2 (25)\t0.167\t\nBaseline eGFR (mL/min), mean ± SD\t70.81 ± 25.09\t61.92 ± 23.47\t0.323\t\n (i) ≤30\t2 (1.98)\t1 (12.5)\t0.128\t\nBaseline hematocrit, mean ± SD\t39.56 ± 5.39\t33.60 ± 7.00\t0.013∗\t\nBaseline hemoglobin (g/dL), mean ± SD\t13.12 ± 1.85\t11.10 ± 2.71\t0.015∗\t\nStroke severity score\t\t\t\t\n NIHSS on admission, mean ± SD\t13.85 ± 6.83\t12.38 ± 7.71\t0.559\t\n Modified Rankin scale on admission, mean ± SD\t4.04 ± 1.25\t4.00 ± 1.23\t0.940\t\nPast medical history\t\t\t\t\n Diabetic mellitus\t25 (24.8)\t1 (12.5)\t0.446\t\n Chronic kidney disease\t36 (35.6)\t3 (37.5)\t0.916\t\n DM and chronic kidney disease\t14 (13.9)\t1 (12.5)\t0.914\t\n Hypertension\t63 (62.4)\t7 (87.5)\t0.186\t\n Congestive heart failure\t6 (5.9)\t0 (0)\t—\t\n Anemia\t32 (31.7)\t4 (50)\t0.202\t\n Myocardial infarction\t12 (11.9)\t1 (12.5)\t0.416\t\n Dyslipidemia\t43 (42.6)\t3 (37.5)\t0.780\t\n Atrial fibrillation\t25 (24.8)\t2 (25)\t0.988\t\n Current metformin use\t9 (8.9)\t0 (0)\t—\t\nStroke complication\t\t\t\t\n Brain edema\t9 (8.9)\t1 (12.5)\t0.736\t\n Progressive stroke\t6 (5.9)\t0 (0)\t—\t\n Urinary tract infection\t11 (10.9)\t2 (25)\t0.350\t\nProcedure and volume of contrast administered\t\t\t\t\n Volume of contrast media, mean ± SD\t127.82 ± 16.47\t130 ± 0\t0.705\t\n Volume/body weight ratio (V/B), mean ± SD\t2.21 ± 0.52\t2.24 ± 0.33\t0.857\t\n Mechanical thrombectomy\t4 (3.9)\t2 (25)\t0.030∗\t\n\n∗\nP < 0.05.\n\nTable 2 Characteristics of the eight patients with PC-AKI.\n\nPt.\tAge (year)\tNIHSS score\tSBP (mmHg)\tInitial serum Cr (mg/dL)\tInitial eGFR (mL/min)\tContrast volume (mL)\tHemorrhagic transformation\tSymptom PC-AKI\tHemodialysis\tDeath\t\n1\t75\t19\t155\t0.55\t92.20\t180\t—\tSevere acute renal failure\t—\t✓\t\n2\t62\t2\t160\t0.80\t71.92\t180\t—\tSevere acute renal failure\t—\t✓\t\n3\t70\t17\t127\t7.86\t13.92\t130\t—\tSevere acute renal failure\t✓\t—\t\n4\t67\t22\t187\t0.9\t63.28\t130\t—\tSevere acute renal failure\t—\t✓\t\n5\t62\t13\t183\t0.83\t69.70\t130\tPH2\tSevere acute renal failure\t—\t✓\t\n6\t80\t6\t197\t1.50\t56.40\t130\tPH2\tSevere acute renal failure\t—\t✓\t\n7\t60\t3\t150\t0.73\t78.66\t180\tPH2\tNo symptom\t—\t—\t\n8\t71\t17\t225\t1.18\t49.24\t130\tPH2\tSevere acute renal failure\t—\t✓\t\nTable 3 Variables associated with development of PC-AKI.\n\nVariables\t\nB\n\tAdjusted OR\t95% CI\t\nP value\t\nAge 60–75 years\t2.464\t11.749\t1.049–131.622\t0.056\t\nTotal fluids within 24 hours\t0.000\t1.000\t0.999–1.001\t0.924\t\nMechanical thrombectomy\t3.530\t34.127\t1.383–842.022\t0.031∗\t\nAnemia\t0.738\t2.092\t0.250–17.489\t0.496\t\nSBP ≥ 160 mmHg on admission\t2.007\t7.438\t0.706–78.380\t0.095\t\neGFR ≤ 30 mL/min\t4.149\t63.363\t0.980–4097.673\t0.048∗\t\n\n∗\nP < 0.05.\n==== Refs\n1 Katan M. 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Incidence of contrast-induced nephropathy a prospective study Journal of Renal Injury Prevention 2017 6 3 192 198 10.15171/jrip.2017.37 2-s2.0-85039968992 \n13 Moos S. I. van Vemde D. N. H. Stoker J. Bipat S. Contrast induced nephropathy in patients undergoing intravenous (IV) contrast enhanced computed tomography (CECT) and the relationship with risk factors: A meta-analysis European Journal of Radiology 2013 82 9 e387 e399 10.1016/j.ejrad.2013.04.029 2-s2.0-84881170561 23711425 \n14 van der Molen A. J. Reimer P. Dekkers I. A. Post-contrast acute kidney injury – part 1: definition, clinical features, incidence, role of contrast medium and risk factors European Radiology 2018 28 7 2845 2855 10.1007/s00330-017-5246-5 2-s2.0-85041836870 29426991 \n15 Davenport M. S. Khalatbari S. Dillman J. R. Cohan R. H. Caoili E. M. Ellis J. H. Contrast material-induced nephrotoxicity and Intravenous Low-Osmolality iodinated contrast material Radiology 2013 267 1 94 105 10.1148/radiol.12121394 2-s2.0-84875441671 23360737 \n16 Liu M. S. Liao Y. Li G. Q. Glomerular filtration rate is associated with hemorrhagic transformation in acute ischemic stroke patients without thrombolytictherapy Chinese Medical Journal 2018 131 14 1639 1644 10.4103/0366-6999.235873 2-s2.0-85049867992 29998881 \n17 Manske C. L. Sprafka J. M. Strony J. T. Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography The American Journal of Medicine 1990 89 5 615 620 10.1016/0002-9343(90)90180-l 2-s2.0-0024990320 2239981 \n18 Cigarroa R. G. Lange R. A. Williams R. H. Hillis D. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease The American Journal of Medicine 1989 86 6 649 652 10.1016/0002-9343(89)90437-3 2-s2.0-0024392252 2729314 \n19 From A. M. Bartholmai B. J. Williams A. W. Cha S. S. McDonald F. S. Mortality associated with nephropathy after radiographic contrast exposure Mayo Clinic Proceedings 2008 83 10 1095 1100 10.4065/83.10.1095 2-s2.0-54049151190 18828968 \n20 Nyman U. Almén T. Jacobsson B. Aspelin P. Are intravenous injections of contrast media really less nephrotoxic than intra-arterial injections? European Radiology 2012 22 6 1366 1371 10.1007/s00330-011-2371-4 2-s2.0-84861526852 22307815\n\n",
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"abstract": "A 68-year-old man with a metastatic neuroendocrine tumor with unknown primary was found to have partially dedifferentiated metastases according to F-FDG uptake. He received 3 cycles of radiopeptide therapy using [Lu]Lutetium-DOTATATE combined with temozolomide. Before this treatment, the patient had already undergone a series of therapies, including biotherapy, everolimus, 5 cycles of radiopeptide therapies, radiotherapy, and bone-protecting therapy with bisphosphonate and receptor activator of NF-κB ligand, each of which temporarily stalled the progress of the disease. After combined treatment with radiopeptide therapy and temozolomide, the patient showed a very good response in all tumor lesions, including the FDG-positive ones.",
"affiliations": "Marien Gesellschaft, Siegen, Germany.",
"authors": "Wei|Xiao|X|;Hain|Susanne|S|;Hartmann|Lynn|L|;Hirzebruch|Stefan|S|;Ahmadzadehfar|Hojjat|H|",
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"abstract": "Incidence and predictors of antitubercular therapy (ATT)-related hepatitis in abdominal tuberculosis are not known. The aim of the study was to identify the incidence and predictors of ATT-induced hepatitis in abdominal tuberculosis.\nA retrospective analysis of patients who received ATT for suspected abdominal tuberculosis with complete follow-up was done. We excluded patients with underlying chronic or acute liver disease necessitating an alteration in the usual ATT at start. We recorded the occurrence of ATT-induced hepatitis and compared patients with and without ATT hepatitis for any predictors of ATT-induced hepatitis.\nOf 163 patients, 22 were excluded (17 missing information, 5 chronic liver disease). One hundred and forty-one patients (mean age: 34.33 ±15.18 years, males: 72) were included. The Mantoux test was positive in 78; 1 had HIV and 32 had an abnormal chest X-ray. Six patients had an alternative diagnosis and 11 needed surgery. Forty-nine (34.8%) had extra-abdominal involvement. Ten patients (7.1%) developed ATT-induced hepatitis. Patients with extra-abdominal tubercular involvement had a greater risk of developing ATT-induced hepatitis (p-value 0.003). None of the other parameters including hematological tests, liver function tests and biochemical parameters were different between the two groups.\nSeven percent of patients treated for abdominal tuberculosis developed ATT hepatitis. Presence of extra-abdominal involvement was associated with ATT hepatitis.",
"affiliations": "Department of Gastroenterology and General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Gastroenterology and General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Gastroenterology and General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Gastroenterology and General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Gastroenterology and General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Gastroenterology and General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Dawra|Saurabh|S|;Mandavdhare|Harshal S|HS|;Singh|Harjeet|H|;Prasad|Kaushal K|KK|;Dutta|Usha|U|;Sharma|Vishal|V|",
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"fulltext": "\n==== Front\nClin Exp HepatolClin Exp HepatolCEHClinical and Experimental Hepatology2392-10992449-8238Termedia Publishing House 8315810.5114/ceh.2019.83158Original PaperExtra-abdominal involvement is associated with antitubercular therapy-related hepatitis in patients treated for abdominal tuberculosis Dawra Saurabh Mandavdhare Harshal S Singh Harjeet Prasad Kaushal K Dutta Usha Sharma Vishal Department of Gastroenterology and General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IndiaAddress for correspondence Vishal Sharma, Assist. Prof., Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India-160012. phone: +917087008099. e-mail: docvishalsharma@gmail.com20 2 2019 3 2019 5 1 60 64 06 8 2018 07 10 2018 Copyright: © 2019 Clinical and Experimental Hepatology2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Aim of the study\nIncidence and predictors of antitubercular therapy (ATT)-related hepatitis in abdominal tuberculosis are not known. The aim of the study was to identify the incidence and predictors of ATT-induced hepatitis in abdominal tuberculosis.\n\nMaterial and methods\nA retrospective analysis of patients who received ATT for suspected abdominal tuberculosis with complete follow-up was done. We excluded patients with underlying chronic or acute liver disease necessitating an alteration in the usual ATT at start. We recorded the occurrence of ATT-induced hepatitis and compared patients with and without ATT hepatitis for any predictors of ATT-induced hepatitis.\n\nResults\nOf 163 patients, 22 were excluded (17 missing information, 5 chronic liver disease). One hundred and forty-one patients (mean age: 34.33 ±15.18 years, males: 72) were included. The Mantoux test was positive in 78; 1 had HIV and 32 had an abnormal chest X-ray. Six patients had an alternative diagnosis and 11 needed surgery. Forty-nine (34.8%) had extra-abdominal involvement. Ten patients (7.1%) developed ATT-induced hepatitis. Patients with extra-abdominal tubercular involvement had a greater risk of developing ATT-induced hepatitis (p-value 0.003). None of the other parameters including hematological tests, liver function tests and biochemical parameters were different between the two groups.\n\nConclusions\nSeven percent of patients treated for abdominal tuberculosis developed ATT hepatitis. Presence of extra-abdominal involvement was associated with ATT hepatitis.\n\ntuberculosisdrug-induced liver injuryperitoneal tuberculosisintestinal tuberculosishepatitis\n==== Body\nIntroduction\nTuberculosis is an important global health concern and has afflicted humans since time immemorial. In India, tuberculosis is a major public health problem with the country harboring one fourth of the world’s tuberculosis burden. The advent of the directly observed treatment strategy has increased the cure rates in these patients with improvement in the outcomes [1]. The current antitubercular therapy (ATT) usually consists of four drugs – rifampin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E) – used in the initiation phase for 2 months followed by three drugs (HRE) in the continuation phase for four months [2]. At least three of these four drugs are recognized to be hepatotoxic and the use of these drugs in combination enhances the risk of hepatotoxicity [3]. Abundant literature is available regarding the incidence, risk factors and outcomes of ATT-related hepatitis in pulmonary tuberculosis [4, 5]. ATT-induced liver injury can have protean manifestations ranging from asymptomatic liver enzyme elevation to acute liver failure. While ATT-induced hepatitis in patients with pulmonary tuberculosis has been well studied in the literature, similar studies in patients presenting primarily with abdominal tuberculosis are limited.\n\nExtrapulmonary tuberculosis represents 15-20% of all newly diagnosed tuberculosis cases in human immunodeficiency virus (HIV) negative patients and 40-50% of patients with HIV coinfection [6]. Abdominal tuberculosis, as per a recent report, constitutes 11% of all cases of extrapulmonary tuberculosis and six months of therapy is recommended for abdominal tuberculosis [2, 7]. Since the incidence of ATT-induced hepatitis in abdominal tuberculosis is less well studied, we did an analysis of our database of patients treated for abdominal tuberculosis to define the incidence of ATT hepatitis and analyze possible factors which could predispose to occurrence of ATT hepatitis.\n\nMaterial and methods\nThe present report is a retrospective analysis of a prospectively recorded database of patients with abdominal tuberculosis treated at a gastroenterology unit of a large tertiary care hospital in North India. We routinely collect data of patients who are initiated on antitubercular therapy for confirmed or probable abdominal tuberculosis. All patients who were treated for possible diagnosis of abdominal tuberculosis (including intestinal, peritoneal, abdominal lymph-nodal) were considered for inclusion. We excluded patients where complete details of follow-up were not available, or those with evidence of underlying chronic liver disease at presentation. The study was approved by the institute ethics committee and the need for informed consent was waived in view of the retrospective nature of the study.\n\nThe type of case of abdominal tuberculosis was defined as either confirmed tuberculosis (acid fast bacilli positivity on stain, culture or polymerase chain reaction based tests or presence of caseating granulomas on tissue fine needle aspiration or biopsy) or probable abdominal tuberculosis (granulomas without caseation, elevated adenosine deaminase (> 32 U/l) in ascitic fluid or clinic-radiological picture consistent with tuberculosis and with demonstration of response to therapy, i.e. mucosal healing or ascites resolution) [8, 9]. Some of the patients who received ATT for a presumed diagnosis of abdominal tuberculosis had eventually been found to have an alternative diagnosis and were included in the analysis as ‘alternative diagnosis’.\n\nClinical history of all patients presenting with a presumptive diagnosis of abdominal tuberculosis was taken and they underwent clinical examination, baseline investigations including complete blood count, biochemical evaluation (liver and kidney function tests), inflammatory markers (C-reactive protein), Mantoux test, serum electrolytes and chest roentgenogram. Abdominal ultrasound (USG) or computed tomography and ascitic fluid evaluation (for peritoneal tuberculosis), colonoscopy and biopsy (intestinal tuberculosis) and USG-guided fine needle aspiration for abdominal lymph-adenopathy were done as indicated. Any invasive procedure was done only after obtaining informed consent. All patients diagnosed with abdominal tuberculosis were started on standard first line ATT (HRZE). The patients were initially followed up fortnightly for the first month and then monthly.\n\nWe defined ATT hepatitis as per previous definitions including any of the following features and exclusion of other differential diagnoses such as acute viral hepatitis (using viral markers IgM anti-HAV, IgM anti-HEV and IgM anti-HBc, HBsAg and anti-HCV) [10]:\n\nfive-fold elevation in alanine aminotransferase (ALT) level in absence of symptoms of ATT hepatitis such as abdominal pain, vomiting, jaundice, etc.,\n\nthree-fold elevation in aspartate aminotransferase (AST) or ALT level in presence of symptoms of ATT hepatitis,\n\na rise in the level of serum total bilirubin to 2 mg/dl or more.\n\nWe calculated the incidence of ATT hepatitis and noted the follow-up strategy in these patients, which was based on the clinician’s discretion. We also compared the baseline parameters such as clinical presentation, laboratory parameters and extent of disease, underlying alternate diagnosis, etc., and also the outcomes amongst patients with and without ATT hepatitis.\n\nStatistical analysis\nThe data were analyzed using SPSS software (version 23.0, IBM). Data were explored for any outliers, errors and missing values. Quantitative or numerical variable were represented with measures of central location, i.e. the mean or median (if non-parametric), with measures of dispersion, i.e. standard deviation or interquartile range. Categorical variables were compared between groups using the chi-square test. Comparison of means between the groups was done with Student’s t test or the Mann-Whitney test depending on the normality of distribution of data. The normality of data was assessed with the Kolmogorov-Smirnov test. We planned to do a multivariate analysis of variables which were significant in univariate analysis to predict the occurrence of ATT hepatitis. The p value of less than 0.05 was statistically significant.\n\nResults\nOf the total of 163 patients with abdominal tuberculosis who were seen, complete information and follow-up were available for 141 patients. Twenty-two patients were excluded because of either incomplete information (17 patients) or underlying chronic liver disease (5 patients) which required modification of the ATT at the time of initiation.\n\nA total of 141 patients presenting with a clinical and/or radiological picture consistent with abdominal tuberculosis and who received ATT were eventually included in the analysis. Of these, 34 cases (24.1%) had confirmed diagnosis, while 107 cases (75.9%) were treated empirically with probable diagnosis of abdominal tuberculosis. Of these, 101 patients had probable tuberculosis, while 6 (4.3%) patients had an alternative diagnosis (5 had Crohn’s disease and 1 had NSAID enteropathy). The mean age of the study group was 34.3 ±15.1 years (13-80 years). Overall 72 (51%) patients were male. Forty-nine (34.8%) patients had associated extra-abdominal tuberculosis. This included 29 cases of pulmonary involvement on chest roentgenogram/ computed tomography, 15 cases of pleural effusion, 5 cases with mediastinal lymphadenopathy, 2 cases each of genitourinary and neurological involvement and 1 case with pericardial involvement. Only 1 patient had HIV infection while 36 patients had other comorbidities. The other comorbidities were diabetes mellitus (7 patients), thyroid disorder (6), hypertension (6), neurological diseases (5), gallstones (4), coronary artery disease (3), chronic obstructive lung disease (4), kidney diseases in 3 (chronic kidney disease and nephrotic syndrome), and chronic pancreatitis, prostatic hypertrophy and extra-hepatic portal venous obstruction in 1 patient each. The clinical presentation of the patients was due to abdominal pain or discomfort (129, 91.5%), intestinal obstruction (45, 31.9%), loss of weight (114, 80.9%), loss of appetite (103, 79%), fever (78, 55.3%), diarrhea (19, 13.5%), abdominal lump/mass (15, 7.8%) and bleeding per rectum (6, 4.3%).\n\nOverall, 6 patients underwent endoscopic dilatation for relief of obstructive symptoms and the sites were ileocecal area (3), ascending colon (2), and multifocal (1). Eleven patients (7.8%) underwent surgery during the course of treatment. The reasons for surgery were recurrent subacute intestinal obstruction in 10 patients (strictures – 7, mass forming lesion – 2, abdominal cocoon – 1) and gastrointestinal bleeding during the initial week in 1 patient. A total of 10 patients (7.1%) developed ATT-induced hepatitis. We then compared the group of patients developing ATT hepatitis with those who did not develop ATT hepatitis (Tables 1 and 2). Table 1 shows the comparison of the baseline characteristics in the two groups. Various hematological and biochemical investigations and also the clinical presentations were similar in the two groups. However, the patients who had a higher frequency of extensive disease with evidence of extra-abdominal involvement had a significantly higher risk of developing ATT-induced hepatitis (p value 0.003). Clinical outcomes including the need for surgery, dilatation and occurrence of mortality were not different between the two groups. Only 1 patient died and the death was in the ATT-induced hepatitis group.\n\nTable 1 Differences between the two groups in baseline characteristics\n\nFactor\tATT-induced hepatitis (10)\tNo hepatitis (131)\tp value\t\nMale gender\t4\t68\t0.527\t\nType of cases\t\t\t0.061\t\n Confirmed\t5\t29\t\n Probable\t5\t86\t\n Alternative\t0\t6\t\nComorbid illness\t4\t32\t0.277\t\nExtra-abdominal tuberculosis\t8\t41\t0.003\t\nPain\t8\t121\t0.203\t\nDiarrhea\t1\t18\t1.000\t\nIntestinal obstruction\t2\t43\t0.502\t\nFever\t5\t73\t0.752\t\nLoss of weight\t6\t108\t0.099\t\nLoss of appetite\t6\t97\t0.459\t\nHematochezia\t0\t6\t1.000\t\nLump abdomen\t0\t15\t0.600\t\nComorbidity\t4\t32\t0.277\t\nHIV positive\t0\t1\t1.000\t\nAge (years)\t33 (4.3)\t29.5 (25.8)\t0.585*\t\nHemoglobin (gm/dl)\t11.1 ±2.0\t10.8 ±2.1\t0.636\t\nTotal leucocyte count (/mm3)\t8850 (8825)\t6750 (4350)\t0.910*\t\nPlatelet count (× 105/mm3)\t4.54 (2.25)\t2.90 (1.76)\t0.346*\t\nSerum bilirubin (mg/dl)\t0.5 (0.5)\t0.6 (0.52)\t0.425*\t\nAlanine aminotransferase (U/l)\t66 (90.5)\t23.5 (11.5)\t0.092*\t\nAspartate aminotransferase (U/l)\t67.5 (98)\t17 (13.3)\t0.068*\t\nAlkaline phosphatase (IU/l)\t111 (130.5)\t90.5 (40)\t0.337*\t\nSerum albumin (gm/dl)\t3.675 (3.15)\t3.7 (2.07)\t0.752*\t\nSerum globulin (gm/dl)\t3.8 (0.52)\t3.45 (0.9)\t0.779*\t\nSerum calcium (mg/dl)\t8.95 (2.42)\t8.725 (1.45)\t0.656*\t\nSerum phosphorous (mg/dl)\t2.81 ±0.9\t3.30 ±0.8\t0.210\t\nInitial weight (kg)\t55 (39)\t49 (17)\t0.387*\t\n* Non-parametric distribution Mann-Whitney U test; in cases where non-parametric test is used the value is for median (interquartile range); otherwise it is provided as mean ± standard deviation.\n\nTable 2 Differences in outcomes of the two groups\n\n\tATT-induced hepatitis (10)\tNo hepatitis (131)\tp value\t\nSurgery\t1\t10\t0.569\t\nDilatation\t0\t6\t1.000\t\nMortality\t1\t0\t0.071\t\nOf the 10 patients who developed ATT-induced hepatitis, 1 died of associated sepsis and another had acute liver failure (ALF) but improved. The median time to onset of ATT hepatitis was 13 days (range: 5-56 days). This patient with ALF was reintroduced with rifampin and isoniazid without further worsening but pyrazinamide was not reintroduced. In rest of the patients reintroduction was done in a phased manner with rifampin followed by isoniazid and pyrazinamide. Only 2 patients developed ATT hepatitis on re-challenge and the drugs implicated were rifampin and isoniazid in 1 case each. These were replaced with oral levofloxacin.\n\nDiscussion\nDrug-induced liver injury (DILI) is one of the most important side effects of tuberculosis treatment. A plethora of reports have been published about the frequency and risk factors of ATT-induced hepatitis in patients with pulmonary tuberculosis. In pulmonary tuberculosis the reported frequency of ATT hepatitis varies across different countries from 1 to 3.3% in Western countries to 8 to 10% in developing countries [6, 11]. This increased incidence in the developing world has been attributed to a number of factors: higher prevalence of viral hepatitis, poor hygienic conditions causing intestinal parasitism, indiscriminate use of drugs, and poor health infrastructure, among others [12]. Studies from India have reported extrapulmonary tuberculosis to be an independent risk factor for developing druginduced hepatitis [13]. Abdominal tuberculosis with its protean manifestations accounts for around 11% of all cases of extrapulmonary tuberculosis [7]. Studies highlighting the specific risk factors associated with ATT-induced hepatitis in this subset have not been reported in the medical literature. This subgroup is important because the yield of microbiological and histological tests is low and often the therapy has to be initiated empirically. Indeed a small subset of patients started on therapy on the basis of ‘probable abdominal tuberculosis’ in the present study had an alternative diagnosis.\n\nThe previous reports regarding predictors of ATT-induced hepatitis have suggested that older age, lower body mass index, hypoalbuminemia, female gender, extensive disease (extrapulmonary disease), and viral hepatitis may predispose to occurrence of DILI [14-16]. While a few earlier studies have reported increased incidence of ATT-induced hepatitis in the age group over 50 years, we did not find any such correlation [16, 17]. Studies from developing countries have indicated low nutritional status to be one of the contributing factors to high incidence of ATT-induced hepatitis [14-16]. No such correlation has been found in our study and the two groups were similar in the initial weight and baseline serum albumin levels. However, the subgroup of patients having extra-abdominal involvement were found to have a significantly higher risk of development of hepatitis in our study. The presence of extrapulmonary tuberculosis itself has been found to be an important risk factor for drug-induced hepatitis in other studies. The presence of an alternative diagnosis did not seem to impact the occurrence of ATT hepatitis. This is important because possibly this subgroup of patients did not warrant ATT. However, since discrimination of intestinal tuberculosis and Crohn’s disease is often difficult, clinicians often have to resort to empirical ATT in such cases [9]. The frequency of ATT hepatitis in our subgroup of patients with abdominal tuberculosis was at least similar to some of the studies on pulmonary tuberculosis. The inferences of our paper are limited by the retrospective study design, lack of evaluation of genetic factors and polymorphisms. However, the present series is a fairly large series of patients with abdominal tuberculosis and the data have been recorded in a prospective database.\n\nTo conclude, the frequency of ATT hepatitis in patients with abdominal tuberculosis is around 7% and presence of extra-abdominal disease may increase the risk of occurrence of ATT-induced hepatotoxicity.\n\nDisclosure\nAuthors report no conflict of interest.\n==== Refs\nReferences\n1 Chetty S Ramesh M Singh-Pillay A Soliman ME Recent advancements in the development of anti-tuberculosis drugs Bioorg Med Chem Lett 2017 27 370 386 28017531 \n2 Sharma SK Ryan H Khaparde S Index-TB guidelines: Guidelines on extra pulmonary tuberculosis for India Indian J Med Res 2017 145 448 463 28862176 \n3 Ramappa V Aithal GP Hepatotoxicity related to anti-tuberculosis drugs: mechanisms and management J Clin Exp Hepatol 2013 3 37 49 25755470 \n4 Abbara A Chitty S Roe JK Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK BMC Infect Dis 2017 17 231. 28340562 \n5 Kar P Karna R Ruttala R Clinical and molecular risk factors of anti-tubercular therapy induced hepatitis J Clin Exp hepatol 10.1016/j.jceh.2018.06.012 \n6 Sharma SK Mohan A Extrapulmonary tuberculosis Indian J Med Res 2004 120 316 353 15520485 \n7 Cherian JJ Lobo I Sukhlecha A Treatment outcome of extrapulmonary tuberculosis under Revised National Tuberculosis Control Programme Indian J Tuberc 2017 64 104 108 28410692 \n8 Sharma V Mandavdhare HS Lamoria S Serial C-reactive protein measurements in patients treated for suspected abdominal tuberculosis Dig Liver Dis 2018 50 559 562 29301734 \n9 Sharma V Mandavdhare HS Dutta U Letter: mucosal response in discriminating intestinal tuberculosis from Crohn’s disease-when to look for it? Aliment Pharmacol Ther 2018 47 859 860 29446132 \n10 Saukkonen JJ Cohn DL Jasmer RM ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee An official ATS statement: hepatotoxicity of antituberculosis therapy Am J Respir Crit Care Med 2006 174 935 952 17021358 \n11 Rathi P Gambhire P Abdominal tuberculosis J Assoc Physicians India 2016 64 38 47 \n12 Gangadharam PR Isoniazid, rifampin, and hepatotoxicity Am Rev Respir Dis 1986 133 963 965 3013057 \n13 Parthasarathy R Sarma GR Janardhanam B Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide Tubercle 1986 67 99 108 3775870 \n14 Singh J Arora A Garg PK Antituberculosistreatment-induced hepatotoxicity: role of predictive factors Postgrad Med J 1995 71 359 362 7644398 \n15 Sharma SK Balamurugan A Saha PK Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment Am J Respir Crit Care Med 2002 166 916 919 12359646 \n16 Tostmann A Boeree MJ Aarnoutse RE Antituberculosis drug-induced hepatotoxicity: concise up-to-date review Gastroenterol Hepatol 2008 23 192 202 \n17 Dhiman RK Saraswat VA Rajekar H A guide to the management of tuberculosis in patients with chronic liver disease J Clin Exp Hepatol 2012 2 260 270 25755442\n\n",
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"title": "Extra-abdominal involvement is associated with antitubercular therapy-related hepatitis in patients treated for abdominal tuberculosis.",
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... |
{
"abstract": "BACKGROUND\nPatients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population.\n\n\nMETHODS\nWe did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2-6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented.\n\n\nRESULTS\n224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7-47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related.\n\n\nCONCLUSIONS\nThe addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients.\n\n\nBACKGROUND\nTG Therapeutics.",
"affiliations": "Willamette Valley Cancer Institute, US Oncology Research, Eugene, OR, USA. Electronic address: jeff.sharman@usoncology.com.;Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Health System, Durham, NC, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.;Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.;Sarah Cannon Cancer Center at Research Medical Center, Kansas City, MO, USA.;Rocky Mountain Cancer Centers, US Oncology Research, Aurora, CO, USA.;Hematology/Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.;Clearview Cancer Institute, Huntsville, AL, USA.;Florida Cancer Specialists, Sarasota, FL, USA.;Cancer Care Centers of South Texas, US Oncology Research, New Braunfels, TX, USA.;Ironwood Cancer and Research Center, Chandler, AZ, USA.;Highlands Oncology Group, Fayetteville, AR, USA.;West Cancer Center, Memphis, TN, USA.;Compass Oncology, US Oncology Research, Vancouver, WA, USA.;TG Therapeutics, New York, NY, USA.;TG Therapeutics, New York, NY, USA.;TG Therapeutics, New York, NY, USA.;Sarah Cannon Research Institute, Nashville, TN, USA.",
"authors": "Sharman|Jeff P|JP|;Brander|Danielle M|DM|;Mato|Anthony R|AR|;Ghosh|Nilanjan|N|;Schuster|Stephen J|SJ|;Kambhampati|Suman|S|;Burke|John M|JM|;Lansigan|Frederick|F|;Schreeder|Marshall T|MT|;Lunin|Scott D|SD|;Zweibach|Alexander|A|;Shtivelband|Mikhail|M|;Travis|Patrick M|PM|;Chandler|Jason C|JC|;Kolibaba|Kathryn S|KS|;Sportelli|Peter|P|;Miskin|Hari P|HP|;Weiss|Michael S|MS|;Flinn|Ian W|IW|",
"chemical_list": "D000911:Antibodies, Monoclonal; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C551803:ibrutinib; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine; C000619007:ublituximab",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(20)30433-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "8(4)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000225:Adenine; D061605:Administration, Intravenous; D000284:Administration, Oral; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D007557:Israel; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D000077982:Progression-Free Survival; D047428:Protein Kinase Inhibitors; D012449:Safety; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e254-e266",
"pmc": null,
"pmid": "33631112",
"pubdate": "2021-04",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D065007:Pragmatic Clinical Trial",
"references": null,
"title": "Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial.",
"title_normalized": "ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high risk chronic lymphocytic leukaemia genuine a phase 3 multicentre open label randomised trial"
} | [
{
"companynumb": "US-ABBVIE-17K-163-3080943-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "3",
... |
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