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"abstract": "Fractures in patients affected by HIV are more frequent than what is reported in patients with no retroviral diseases. Chronic infection with HIV likely contributes to increased systemic inflammation, which has been associated with increased rates of fracture. We report a case of a 56-year-old male (HIV + in treatment with Atripla) heavy worker, at the beginning affected by intra-articular proximal humerus fracture treated with endoprosthesis replacement and later by periprosthetic fracture treated with plate, screws and cerclages. Follow up was performed with clinical evaluation (ROM, VAS, Quick Dash, ASES, Simple shoulder test, UCLA Score, Constant score) and shoulder radiographs. Bone metabolism disorders in HIV patients lead to low BMD values, changes in bone turnover markers, and histomorphometric abnormalities, especially when HIV is present along with HCV or other hepatopathies. Additional therapy with bisphosphonate and Vitamin D should always be carried out when possible to prevent such types of orthopaedic complications.",
"affiliations": "Universita di Roma \"Sapienza\". angelo.decarli@gmail.com.;Array. EDOARDOGAJ@GMAIL.COM.;. dav.desideri@gmail.com.;. scrivano89@gmail.com.;. gianlucafedeli@gmail.com.;. anto.vada76@gmail.com.",
"authors": "De Carli|Angelo|A|;Gaj|Edoardo|E|;Desideri|Davide|D|;Scrivano|Marco|M|;Fedeli|Gianluca|G|;Vadala|Antonio Pasquale|AP|",
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"country": "Italy",
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"doi": "10.23750/abm.v91i3.9026",
"fulltext": "\n==== Front\nActa Biomed\nActa Biomed\nActa Bio Medica : Atenei Parmensis\n0392-4203 2531-6745 Mattioli 1885 Italy \n\n32921777\nACTA-91-81\n10.23750/abm.v91i3.9026\nCase Report\nBone methabolic disorders in HIV positive patients: a case report\nDe Carli Angelo 1 Gaj Edoardo 1 Desideri Davide 1 Scrivano Marco 1 Fedeli Gianluca 1 Vadalà Antonio Pasquale 1 1 Orthopaedic unit and Kirk Kilgour Sports injury Center, S. Andrea Hospital, University of Rome “Sapienza”, Rome, Italy\nCorrespondence: Edoardo Gaj Orthopaedic unit and Kirk Kilgour Sports injury Center, S. Andrea Hospital, University of Rome “Sapienza”, Via di Grottarossa 1035-1039 - 00189 Rome, Italy edoardogaj@gmail.com Phone: +39 3335475130 FAX +39 0633775887\n2020 \n07 9 2020 \n91 3 e2020081 e2020081\n14 11 2019 25 11 2019 Copyright: © 2020 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA2020This work is licensed under a Creative Commons Attribution 4.0 International LicenseFractures in patients affected by HIV are more frequent than what is reported in patients with no retroviral diseases. Chronic infection with HIV likely contributes to increased systemic inflammation, which has been associated with increased rates of fracture. We report a case of a 56-year-old male (HIV + in treatment with Atripla) heavy worker, at the beginning affected by intra-articular proximal humerus fracture treated with endoprosthesis replacement and later by periprosthetic fracture treated with plate, screws and cerclages. Follow up was performed with clinical evaluation (ROM, VAS, Quick Dash, ASES, Simple shoulder test, UCLA Score, Constant score) and shoulder radiographs. Bone metabolism disorders in HIV patients lead to low BMD values, changes in bone turnover markers, and histomorphometric abnormalities, especially when HIV is present along with HCV or other hepatopathies. Additional therapy with bisphosphonate and Vitamin D should always be carried out when possible to prevent such types of orthopaedic complications. (www.actabiomedica.it)\n\nHIV +HCV +periprosthetic fractureProximal humerus fractureBone disorders\n==== Body\nIntroduction\nFractures in patients affected by HIV, whether spontaneous, after trauma, or after orthopedic procedures are higher than what is reported in patients with no retroviral diseases (1). In Literature, some authors have already shown how the use of antiretroviral drugs might affect bone mineral density (BMD) thus leading to a higher risk of fractures (2).\n\nSo far it has been demonstrated how co-infection of HCV and HIV brings on a significant decrease in BMD, worse than when HCV or HIV are singularly present as infectious disease. Moreover it has been prospected that the longer the diagnosis of HIV, the higher the percentage of risk fracture, setting as a turning point 7 years after the diagnosis, according to what Mondy(3) proposed; still, the majority of case reports and studies published report their experiences with regard to lower limbs and spine fractures, with few experiences reported with regard to upper limb or periprosthetic fractures.\n\nCase Report\nOur case report is on a 56-year-old man involved in heavy-lifting work activities. This man had been diagnosed with HIV infection 6 years earlier: for this reason, he was undergoing medical therapy with antiretroviral drugs (Atripla, 1 tablet per day). In June 2011 he experienced a traumatic fracture of the proximal humerus with significant dislocation of bone fragments (Fig. 1). He was then admitted to our Orthopaedic Department, where he was surgically treated with endoprosthesis replacement. At the time of admission his blood exams did not show significant alterations (AST 64 U/L, ALT 58 U/L, LDH 724 U/L, PCR 0.60 mg/dl, WBC 8.51 103 /uL, HCV and HBV negative). At follow-ups clinical and radiological exams showed satisfactory results in terms of functional recovery and osteointegration of the prosthesis. Fourteen months after surgery, while swimming, the patient started experiencing shoulder pain: admitted to our ER Department he underwent an X-Ray which showed a periprostethic fracture (Fig. 2). For this reason, he underwent a revision of the fracture with a long-stem cuff tear arthropathy (CTA) endoprosthesis and the use of a plate with screws and metallic cerclages (Fig. 3). After revision of the fracture, his antiretroviral treatment was modified in order to avoid a potential decrease of BMD. Atripla was substituted with a new drug which did not contain Tenofovir, since it was thought to be responsible for a potential important alteration of bone mineral metabolism. In addition, he was given a therapy for further prevention of osteoporosis with alendronates and cholecalciferol.\n\nFig. 1 Proximal humerus fracture; AO Classification: 11C3.2\n\nFig. 2 Periprosthetic fracture;\n\nFig. 3 Osteosynthesis of the fracture with plate, screws and cerclages.\n\nAt this time (84-month follow-up), patient reported satisfaction with regard to his functional activity, being able to perform normal daily living and working activities; he had stopped performing heavy-lifting activity since he was made aware of potential negative consequences arising from a re-refracture. Physical examination showed a forward flexion of 80°, an internal rotation of 60° and an external rotation of 30°. Patient was evaluated at the final follow up with the following rating scales: VAS 2 Quick Dash 4,8 ASES 81,6 SST 66,7 UCLA Score 24 Constant score 42; no signs of infection or further periprostethic bone density decrease have been shown on X-Rays, despite his continued use of retroviral therapy.\n\nDiscussion\nInitiation of anti-retroviral treatment (ART) is frequently associated with bone loss of 2–6% in the hip and spine over the first 1–2 years of treatment, with bone mass stabilizing or increasing thereafter (4,5). Available data on the role for antiretroviral drugs in bone loss in HIV patients are conflicting. Some studies suggest a role for antiretroviral drugs, mostly protease inhibitors, whereas other studies do not (6,7,8). It is a matter of debate whether these drugs may influence BMD (9,10): indeed, while antiretroviral drugs may induce bone toxicity, they also improve general health, allowing patients to gain weight and to be physically active. The exact reason for the increased risk of fracture among HIV patients is unknown, although it is likely multifactorial. Patients with HIV may have higher rates of known risk factors for osteoporosis, such as smoking or hepatitis C co-infection (11,12,13).\n\nChronic infection with HIV likely contributes to increased systemic inflammation, which has been associated with increased rates of fracture (14,15,16); in addition, the virus may alter bone regulatory mechanisms leading to further decreases in bone density (17).\n\nLow BMD and fracture were increasingly associated with HIV/HCV coinfection compared to HIV monoinfected and HIV/HCV uninfected or seronegative individuals, suggesting that HCV contributes more of a burden than HIV infection alone. In a large retrospective cohort study, a significant increase in the risk of hip fracture was demonstrated in HCV/HIV co-infected subjects when compared between HCV mono-infected and HIV mono-infected or noninfected individuals (18).\n\nA significantly higher risk of osteoporotic fracture, such as vertebral or hip fracture, in HCV/HIV co-infected versus HIV mono-infected individuals was reported by Maalouf et al. (19).\n\nDual treatment for HIV/hepatitis B co-infection has also been shown to be associated with a higher risk of hip fracture compared to ART treatment in HIV mono-infected and noninfected individuals (20).\n\nIn 2006, HIV-infected men and women from the USA with osteoporosis (defined as a BMD T-score ≤2.5) were associated as having a significantly increased incidence of fracture (21).\n\nSo far authors have basically focused their attention on the coinfection of HIV and HCV thus showing an additional role of hepatitis C (and its correspondent hepatopathy and drug treatment) in determining a decrease in BMD. This factor has been proved to be significant in regard to hip and spine factures.\n\nIn this case we reported the onset of a significant worsening in BMD in a patient with HIV monoinfectious disease; moreover, bone complications occurred in an upper limb bone, with no typical weight-bearing characteristics as with typical bone fracture complications in HIV patients. What’s more, re-fracture of the operated humerus occurred in an atraumatic way, thus suggesting the severe osteoporosis localized in that bone. Despite what has largely been reported by other authors’ experiences, in this case report we describe the onset of a fracture (and most of all of an atraumatic refracture) in a patient with HIV monoinfection whose upper limb was twice subjected to a bone fracture. Thus far, risks of atraumatic bone fractures have usually been reported in patients with HIV and HCV coinfection, in particular with regard to the lower limb and spine, probably because of their mechanical characteristics. In this case, the prolonged antiretroviral therapy with Tenofovir (the active ingredient of the Atripla treatment he was treated with) has probably exposed the patient to an excessive decrease of BMD.\n\nConclusion\nBone metabolism disorders in HIV patients lead to low BMD values, changes in bone turnover markers, and histomorphometric abnormalities, especially when HIV is present along with HCV or other hepatopathies. In this case report we show a case of an HIV monoinfected patient who experienced a significant bone mineral density loss in an upper limb bone, this suggesting that the risk of fractures is not just typical of patients with HIV/HCV coinfection, and it is not just typical of weight-bearing bones, such as femur of vertebra. Additional therapy with bisphosphonate and Vitamin D should always be carried out when possible to prevent such types of orthopaedic complications.\n\nPatient declaration statement:\nThe authors certify that they have obtained all appropriate patient consent form. In the form the patient has given her consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initial will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nConflict of interest:\nEach author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article\n==== Refs\nReferences\n1 Guaraldi G Zona S Brothers TD Aging with HIV vs. HIV seroconversion at older age: a diverse population with distinct comorbidity profiles PLoS ONE 2015 10 e0118531 25874806 \n2 Battalora L Buchacz K Armon C Low bone mineral density and risk of incident fracture in HIV-infected adults Antivir Ther 2016 21 45 54 26194468 \n3 Mondy K Yarasheski K Powderly WG Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virusinfected individuals Clin Infect Dis 2003 36 482 90 12567307 \n4 Cassetti I Madruga JV Suleiman JM Study 903E Team*. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviralnaıve HIV-1-infected patients HIV Clin Trials 2007 8 164 72 17621463 \n5 Assoumou L Katlama C Viard JP ANRS Osteovir study group. Changes in bone mineral density over a 2-year period in HIV-1-infected men under combined antiretroviral therapy with osteopenia AIDS 2013 27 2425 30 24029735 \n6 Mondy K Yarasheski K Powderly WG Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virusinfected individuals Clin Infect Dis 2003 36 482 90 12567307 \n7 Nolan D Upton R McKinnon E Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir AIDS 2001 15 1275 80 11426072 \n8 Dolan SE Kanter JR Grinspoon S Longitudinal analysis of bone density in human immunodeficiency virus-infected women J Clin Endocrinol Metab 2006 91 2938 45 16735489 \n9 Fernandez Rivera J Garcia R Lozano F Relationship between low bone mineral density and highly active antiretroviral therapy including protease inhibitors in HIV-infected patients HIV Clin Trials 2003 4 337 46 \n10 Tebas P Yarasheski K Henry K Evaluation of the virological and metabolic effects of switching protease inhibitor combination antiretroviral therapy to nevirapine-based therapy for the treatment of HIV infection AIDS Res Hum Retroviruses 2004 20 589 94 15242534 \n11 Horvath KJ Eastman M Prosser R Goodroad B Worthington L Addressing smoking during medical visits: patientswith human immunodeficiency virus Am J Prev Med 2012 43 5 Suppl 3 S214 S221 23079219 \n12 Tesoriero JM Gieryic SM Carrascal A Lavigne HE Smoking among HIV positive New Yorkers: prevalence, frequency and opportunities for cessation AIDS Behav 2010 14 4 824 835 18777131 \n13 Sherman KE Rouster SD Chung RT Rajicic N Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group Clin Infect Dis 2002 34 6 831 837 11833007 \n14 Lau B Sharrett AR Kingsley LA C-reactive protein is a marker for human immunodeficiency virus disease progression Arch Intern Med 2006 166 1 64 70 16401812 \n15 Deeks SG Tracy R Douek DC Systemic effects of inflammation on health during chronic HIVinfection Immunity 2013 39 4 633 645 24138880 \n16 Schett G Kiechl S Weger S High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study Arch Intern Med 2006 166 22 2495 2501 17159016 \n17 Vikulina T Fan X Yamaguchi M Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats Proc Natl Acad Sci U S A 2010 107 31 13848 13853 20643942 \n18 Lo Re V 3rd Volk J Newcomb CW Risk of hip fracture associated with hepatitis C virus infection and hepatitis C/human immunodeficiency virus coinfection Hepatology 2012 56 1688 98 22619086 \n19 Maalouf NM Zhang S Drechsler H Brown GR Tebas P Bedimo R Hepatitis C co-infection and severity of liver disease as risk factors for osteoporotic fractures among HIV-infected patients J Bone Miner Res 2013 28 2577 83 23677838 \n20 Byrne DD Newcomb CW Carbonari DM Increased risk of hip fracture associated with dually treated HIV/hepatitis B virus coinfection J Viral Hepat 2015 22 936 47 25754215 \n21 Battalora L Buchacz K Armon C Low bone mineral density and risk of incident fracture in HIV-infected adults Antivir Ther 2016 21 45 54 26194468\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0392-4203",
"issue": "91(3)",
"journal": "Acta bio-medica : Atenei Parmensis",
"keywords": null,
"medline_ta": "Acta Biomed",
"mesh_terms": "D001860:Bone Plates; D005593:Fracture Fixation, Internal; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D057068:Periprosthetic Fractures; D012784:Shoulder Fractures; D016896:Treatment Outcome",
"nlm_unique_id": "101295064",
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"pages": "e2020081",
"pmc": null,
"pmid": "32921777",
"pubdate": "2020-09-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24029735;18777131;16401812;25874806;23079219;16735489;12567307;11833007;20643942;15242534;25754215;17159016;26194468;11426072;22619086;23677838;14583850;17621463;24138880",
"title": "Bone methabolic disorders in HIV positive patients: a case report.",
"title_normalized": "bone methabolic disorders in hiv positive patients a case report"
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"abstract": "OBJECTIVE\nTo report a case series, whereby we encountered a transient increase in retinal cotton wool spots (CWS) following anti-vascular endothelial growth factor (anti-VEGF) therapy for the treatment of macular edema secondary to central retinal vein occlusion (CRVO).\n\n\nMETHODS\nEighteen eyes were treated with intravitreal aflibercept (IVA), and 5 were treated with intravitreal ranibizumab (IVR). Fundus photographs obtained 1 month after initial IVA or IVR injections were retrospectively evaluated for the presence of CWS.\n\n\nRESULTS\nTwenty-one (91.3%) patients had the following systemic diseases: hypertension, diabetes mellitus without retinopathy, dyslipidemia, or chronic renal failure requiring dialysis. One month after treatment, reduced macular edema was observed in 21 (91.3%) eyes. Initial injections facilitated complete resolution in 14 eyes, and CWS gradually became fainter with additional injections.\n\n\nCONCLUSIONS\nSome eyes with CRVO-related macular edema can show a transient increase in CWS after initial anti-VEGF therapy; however, macular edema, retinal hemorrhage, and visual acuity were improved in almost every case.",
"affiliations": "Department of Ophthalmology, Osaka Medical College, Takatsuki, Japan.",
"authors": "Kida|Teruyo|T|;Tsujikawa|Akitaka|A|;Muraoka|Yuki|Y|;Harino|Seiyo|S|;Osaka|Rie|R|;Murakami|Tomoaki|T|;Ooto|Sotaro|S|;Suzuma|Kiyoshi|K|;Morishita|Seita|S|;Fukumoto|Masanori|M|;Suzuki|Hiroyuki|H|;Ikeda|Tsunehiko|T|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D042442:Vascular Endothelial Growth Factors; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "Switzerland",
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"doi": "10.1159/000443622",
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"issn_linking": "0030-3755",
"issue": "235(2)",
"journal": "Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde",
"keywords": null,
"medline_ta": "Ophthalmologica",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D007564:Japan; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012170:Retinal Vein Occlusion; D012171:Retinal Vessels; D012189:Retrospective Studies; D042442:Vascular Endothelial Growth Factors; D014792:Visual Acuity",
"nlm_unique_id": "0054655",
"other_id": null,
"pages": "106-13",
"pmc": null,
"pmid": "26800210",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cotton Wool Spots after Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Associated with Central Retinal Vein Occlusion.",
"title_normalized": "cotton wool spots after anti vascular endothelial growth factor therapy for macular edema associated with central retinal vein occlusion"
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"companynumb": "JP-REGENERON PHARMACEUTICALS, INC.-2016-11908",
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"abstract": "BACKGROUND\nCostello syndrome is a rare syndrome of multiple congenital anomalies. The typical clinical traits include dysmorphic craniofacial features, skin hyperpigmentation and excess, feeding difficulties leading to severe postnatal growth retardation, short stature, joint hypermobility, and delayed psychomotor development. Additionally, Costello syndrome may present with an increased incidence of congenital heart disease, hypertrophic cardiomyopathy, and increased risk of both benign and malignant tumors. Furthermore, cases of patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented.\n\n\nMETHODS\nWe present a patient with Costello syndrome who has been successfully treated with recombinant human growth hormone (rhGH) for almost 4 years.\n\n\nCONCLUSIONS\nThe possibility of growth hormone (GH) treatment can be considered in cases of documented GH deficiency in patients with Costello syndrome, but only under close oncologic and cardiologic supervision.",
"affiliations": "Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Ulica Unii Lubelskiej 1, 71-252, Szczecin, Poland. ew.berus@gmail.com.;Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Ulica Unii Lubelskiej 1, 71-252, Szczecin, Poland. petrela1@wp.pl.;Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Ulica Unii Lubelskiej 1, 71-252, Szczecin, Poland. anitajozwa@wp.pl.;Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland. agatkas3@gmail.com.;Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland. m.pelc@czd.pl.;Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland. m.walasek@czd.pl.;Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Ulica Unii Lubelskiej 1, 71-252, Szczecin, Poland. sekr.pediatrii@spsk1.szn.pl.",
"authors": "Blachowska|Ewa|E|;Petriczko|Elżbieta|E|;Horodnicka-Józwa|Anita|A|;Skórka|Agata|A|;Pelc|Magdalena|M|;Krajewska-Walasek|Małgorzata|M|;Walczak|Mieczysław|M|",
"chemical_list": "D011994:Recombinant Proteins; D019382:Human Growth Hormone",
"country": "England",
"delete": false,
"doi": "10.1186/s13052-015-0209-4",
"fulltext": "\n==== Front\nItal J PediatrItal J PediatrItalian Journal of Pediatrics1824-7288BioMed Central London 20910.1186/s13052-015-0209-4Case ReportRecombinant growth hormone therapy in a girl with costello syndrome: a 4-year observation http://orcid.org/0000-0003-3091-077XBlachowska Ewa ew.berus@gmail.com Petriczko Elżbieta petrela1@wp.pl Horodnicka-Józwa Anita anitajozwa@wp.pl Skórka Agata agatkas3@gmail.com Pelc Magdalena m.pelc@czd.pl Krajewska-Walasek Małgorzata m.walasek@czd.pl Walczak Mieczysław sekr.pediatrii@spsk1.szn.pl Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Ulica Unii Lubelskiej 1, 71-252 Szczecin, Poland Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland 26 1 2016 26 1 2016 2016 42 104 8 2015 10 12 2015 © Blachowska et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\n Costello syndrome is a rare syndrome of multiple congenital anomalies. The typical clinical traits include dysmorphic craniofacial features, skin hyperpigmentation and excess, feeding difficulties leading to severe postnatal growth retardation, short stature, joint hypermobility, and delayed psychomotor development. Additionally, Costello syndrome may present with an increased incidence of congenital heart disease, hypertrophic cardiomyopathy, and increased risk of both benign and malignant tumors. Furthermore, cases of patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented.\n\nCase presentation\n We present a patient with Costello syndrome who has been successfully treated with recombinant human growth hormone (rhGH) for almost 4 years.\n\nConclusions\nThe possibility of growth hormone (GH) treatment can be considered in cases of documented GH deficiency in patients with Costello syndrome, but only under close oncologic and cardiologic supervision.\n\nKeywords\nCostello syndromeGrowth hormone deficiencyHypertrophic cardiomyopathyMalignancyHRAS geneissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nCostello syndrome (CS, OMIM #218040) is caused by heterozygous germline mutations in the proto-oncogene HRAS that cause dysfunction of the Ras-MAPK signaling pathway. To date, 15 mutations in HRAS have been identified. The birth prevalence of this disease is estimated at 1:1,230,000 to 1:300,000 [1–4]. Clinically, CS is characterized by polyhydramnios, high birth weight, postnatal growth retardation, relative macrocephaly, coarse facial features, loose skin, especially of the hands and feet, hyperpigmentation, hypertrophic cardiomyopathy, atrial arrhythmias, papillomata, developmental delay or mental retardation, and predisposition to malignancies. In the newborn and neonatal periods, the presence of suggestive facies and severe feeding difficulties leading to failure to thrive and hypoglycemia help make the correct diagnosis [5–7]. Furthermore, cases of Costello syndrome patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented in the literature [8–11]. Due to the complex nature of the discussed syndrome, patients require multidisciplinary care (provided by cardiologists, speech therapists, gastroenterologists, orthopedic surgeons) along with early stimulation and developmental support. Because of the short stature and growth hormone deficiency in this condition, growth hormone therapy is often considered. For decades there has been great debate on the anticipated risk of carcinogenesis and cardiomyopathy weighted against the potential benefits resulting from recombinant human growth hormone (rhGH) therapy. To date, there are no conclusive data showing a negative role of rhGH therapy in the development of these diseases.\n\nHere we report a six-year-old patient with Costello syndrome, who has been successfully treated with rhGH for 42 months.\n\nCase presentation\nAM, was born at 40 weeks gestation by caesarean section (due to large fetal mass) as the first baby of healthy and nonconsanguineous parents with a birth weight of 4270 g (>97 c), length of 55 cm (50 c) and head circumference of 38 cm (>97c). Her Apgar score was 7/7/8 points. The pregnancy was complicated by polyhydramnios and impaired glucose tolerance in the mother.\n\nIn the neonatal period, generalized edema, hypoglycemia, and hypocalcaemia were observed. Transthoracic echocardiography revealed thickened muscles of both ventricles and septum, although follow-up cardiac examinations revealed no evidence of cardiomyopathy.\n\nDuring the first two years of life the child was repeatedly hospitalized due to a number of problems (the clinical symptoms observed in the patient are presented in Table 1). At the age of 8 weeks the girl was evaluated due to failure to thrive. Physical examination revealed: poorly developed subcutaneous tissue with excess skin (this was attributed to resolution of edema), reduced muscle tone, and enlarged liver. Laboratory tests did not find evidence of hypothyroidism or inborn errors of metabolism. Ultrasonography followed by gastric scintiscan and upper GI series revealed hiatal hernia and gastric endoscopy, the latter being the base for a diagnosis of gastroesophageal reflux. Additionally, the 24-h esophageal pH study was conducted, to further help with diagnosis, yielding inconsistent results that were borderline normal. At the age of four months the patient manifested psychomotor delay, joint laxity, variable muscle tone, and hyperactive knee reflexes. Follow-up cardiac examinations revealed no signs of cardiomyopathy, but complex premature ventricular and supraventricular contractions and sinus arrest were present. She required treatment with amiodarone, which was withdrawn after one month. No cardiac arrhythmias were shown in subsequent 24-h-Holter monitoring.Table 1 Symptoms in consecutive months of life\n\nChild’s age\tClinical symptoms\t\n\tLack of appetite\tVomiting, spitting up\tDysphagia\tEsophagitis\tUnderweight\tHepatomegaly\tNeurological abnormalities\tDelayed speech development\tLoose skin\tCoarse facial features\tArrhythmias\tHypertrophic cardiomyopathy\tExcessive joint laxity\tAchilles tendon contractures\tShort stature\t\n1 month\t\t\t\t\t\t\t\t\t\na\n\t\t\t+b\n\t\t\t\t\n2−3 months\t+\t+\t+\t+\t\t+\t\t\t+\t\t\t\t\t\t\t\n4−6 months\t+\t+\t+\t+\t+\t\t+d\n\t\t+\t\t+c\n\t\t+\t\t\t\n7−9 months\t+\t+\t+\t+\t+\t\t+d\n\t+\t+\t\t\t\t+\t\t\t\n11−24 months\t+\t+\t+\t+\t+\t\t\t+\t+\t+\t\t\t+\t\t+\t\n24−36 months\t\t\t\t\t+\t\t\t+\t+\t+\t\t\t+\t\t+\t\n>3 years of life\t\t\t\t\t\t\t\t+\t+\t+\t\t\t+\t+\t+\t\nKey\n\n\naEdema\n\n\nbSuspicion, later studies did not confirm hypertrophic cardiomyopathy\n\n\ncTransient\n\n\ndReduced muscle tone, periodic spasticity of the lower limbs\n\n\n\nThe treatment of gastroesophageal reflux, which involved proton pump inhibitors and prokinetic agents, was ineffective. During eight months, her weight gain had been only 1000 g. At the age of nine months the patient weighed 5300 g (SD: −4.92). Due to persistent feeding difficulties she was referred for surgical treatment and Nissen fundoplication was performed at the age of 11 months. The improvement after abovementioned procedure was very brief, with feeding difficulties quickly reoccurring. Due to lack of improvement after pharmacological treatment, and persistent signs of gastroesophageal reflux in performed endoscopy our patient was qualified for second operation. Finally the decision about surgical treatment was abandoned due to slow spontaneous improvement in feeding and apetite after the patient was 3 years old.\n\nAt the age of 2 years and 9 months Costello syndrome was suspected on the basis of phenotypic traits (large mouth, wide lips, short nasal bridge, loose skin deeply fissured on the palms and soles of the feet, joint laxity, and abnormal feet position, Fig. 1) and case history. The diagnosis was confirmed by molecular tests, which identified c.35G > C (p.G12A) substitution in the HRAS gene, the second most common mutation responsible for Costello syndrome. Molecular studies in both parents revealed that this mutation occurred de novo [3, 4].Fig. 1 The presented 6-year-old girl with Costello syndrome after 30 months of treatment with rhGH. The pictures show typical phenotypic features of the syndrome: loose skin with deep palmar creases (a); abnormal feet position as a result of excessive joint laxity (b)\n\n\n\nThe investigation of delayed growth was performed at the age of 3 years and 2 months. Physical examination noted significantly short stature, i.e., a height of 84 cm (SD: −4.33), and underweight, 10.7 kg (SD: −2.86). Routine laboratory tests did not show any abnormalities. Electrocardiographic examination and abdominal ultrasound were normal. Hormone analysis revealed normal thyroid function, normal daily cortisol profile and rhythm. Reduced levels of insulin-like growth factor 1 in relation to chronological age were detected (26,3 ng/ml, normal level range at this age 49–289 ng/ml). Bone age was found to be consistent with the chronological age. Growth hormone levels did not reach normal values in the nocturnal secretion test or in L-Dopa and clonidine stimulation tests (maximum secretion: 8 ng/ml), see Table 2 for details. Based on the above findings and clinical observations, partial endogenous growth hormone deficiency was established.Table 2 Growth hormone secretion in nocturnal and stimulation tests\n\n\t0’\t30’\t60’\t90’\t120’\t150’\t\nNocturnal GH excretion [ng/ml]\t4,4\t2,1\t0,8\t1,7\t2,0\t1,9\t\nGH after L-dopa [ng/ml]\t0,94\t0,99\t1,1\t1,3\t1,2\t0,88\t\nGH after clonidine [ng/ml]\t0,91\t0,96\t5,2\t8,0\t4,0\t2,5\t\n\n\nAt the age of 3 years and 9 months the girl was qualified for growth hormone therapy, following careful considerations of the risks and benefits and discussion of the issue with the child’s parents.\n\nGrowth hormone was administered by subcutaneous injection once daily, in the evening, at a dose of 0.031 mg/kg/day. Initially, the check-up visits in the Department were held every three months, and then every six months. The following issues were evaluated: response to treatment, tolerability, and laboratory test results, with particular emphasis on carbohydrate metabolism and bone age progression (Table 3).Table 3 Selected auxological parameters of the patient during rhGH treatment\n\nAge [years and months]\tBody height [cm]\tBody height SDS\tGrowth rate [cm/year]\tBody weight [kg]\tBody weight SDS\tBMI [kg/m2]\tBMI SDS\tBone age [years and months]\t\n3 years and 2 months\t84\t−4.94\t2.10\t10.7\t−2.86\t15.2\t−0.504\t\t\n3 years 9 months (start of rhGH treatment)\t84.7\t−4.92\t0.80\t12.1\t−2.60\t16.9\t1.005\t3 years\t\n4 years\t88.9\t−3.48\t16.80\t12.1\t−2.58\t15.3\t0.02\t\t\n4 years 5 months\t92\t−3.29\t7.44\t13.3\t−2.41\t15.7\t0.496\t\t\n4 years 8 months\t93.3\t−3.31\t7.40\t14\t−2.28\t16.1\t0.508\t4 years 2 months\t\n5 years 2 months\t97.8\t−2.84\t5.20\t15.4\t−1.80\t16.1\t0.507\t\t\n5 years 6 months\t103\t−2.02\t9.00\t16\t−1.77\t15.1\t0.475\t5 years – 5 years 9 months\t\n6 years 1 month\t107.5\t−1.67\t13.00\t19\t−0.92\t16.4\t0.511\t\t\n6 years 8 months\t109\t−1.78\t2.57 a\n\t18.4\t−1.46\t15.5\t0.480\t7 years 10 months\t\n7 years 2 months\t115\t−1.61\t12.00\t20.3\t−1.28\t15.3\t0.466\t\t\n\naInterruptions in rhGH administration caused by orthopedic treatment\n\n\n\nDuring the initial check-ups, significant acceleration of growth was recorded. Throughout the first year of treatment, her growth rate was 9.49 cm/year, and in the next two years it was 12.36 cm/year and 7.71 cm/year, respectively, while during the pretreatment period her average growth rate was 4.28 cm/year. The curves of the patient's body weight and height gain before and during rhGH treatment are shown in Fig. 2a and b.Fig. 2 The course of growth (a) and weight gain (b) in the patient before and during rhGH treatment\n\n\n\nDuring the treatment, progression of the abnormalities within the ligaments of the ankles and hip joints (right club foot, left plano-valgus foot, shortening of the Achilles tendon, dislocation of the right hip) was observed. At the age of 5 years and 6 months, surgical correction of both feet was necessary due to further progression of mobility impairment, and plasty of the hip joint was performed in the following year. At present, the patient is recovering after the last intervention.\n\nCurrently, after 42 months of rhGH treatment, the girl has grown 30.3 cm, reaching a body height above the 3rd percentile (115 cm; SD: −1.61), her weight gain has been 10.4 kg. Her current weight is 20.3 kg (10–25 percentile; SD: −1.28). So far, no serious adverse events have been observed. The patient tolerates daily injections of growth hormone well, she receives comprehensive speech therapy and rehabilitation, and attends kindergarten. Her parents have observed a significant improvement in her psychomotor development, especially with respect to speech.\n\nDiscussion\nCostello syndrome was first described in 1977 by Jack Costello, a New Zealand pediatrician, in two unrelated children who presented similar phenotypic characteristics. The molecular etiology of this syndrome (germline mutations in the HRAS gene) was identified in 2005 [2]. Among many dysfunctions associated with this condition, impaired growth is one of the most challenging clinical problems [8, 12, 13]. The average final height in Costello syndrome patients, without growth-stimulating therapy, reaches about 138 cm (118–148 cm) [7]. The pathogenesis of short stature associated with this condition has been studied in recent decades. The first cases diagnosed with partial/total endogenous growth hormone deficiency and treated with rhGH were described in the 1990s [9–11]. To date, there are few studies in the scientific literature that assess the safety and efficacy of rhGH therapy in individual patients [14, 15]. As the syndrome is extremely rare, evaluating a larger group of patients iseems to be a very difficult task. Increased incidence of cancer and increased risk of development of hypertrophic cardiomyopathy are serious clinical problems that should be taken into account when considering treatment with rhGH [1, 7, 8, 15]. Gripp et al. [5] estimated that the risk of developing tumors in patients with Costello syndrome reaches 17 %, most of which are rhabdomyosarcoma, neuroblastoma, papilloma, and bladder cancer. Interestingly, the p.G12A mutation detected in our patient is the main mutation associated with the higher risk of cancer in CS, which correlates with an up to 57 % risk in affected patients (2, 3). However, no occurrence of malignancy has been noted in the patient so far. Growth hormones promote cell divisions, which may generate a potential hazard. However, existing research in this area has given inconclusive results [14, 15]. Stein et al. [13] presented long-term observations involving three patients with endogenous growth hormone deficiency successfully treated with rhGH with no severe adverse events. On the other hand, cases of patients with unsatisfactory response to rhGH therapy [9] and complications during the treatment have also been documented. There are reports describing a case of a 16-year-old girl diagnosed with bladder cancer after 7 years of rhGH therapy [16], a 26-month-old boy diagnosed with rhabdomyosarcoma after one year of treatment [14], and progression of hypertrophic cardiomyopathy in a 6-year-old boy treated with rhGH [17]. However, in all of these cases it is difficult to assess whether the administration of growth hormone actually influenced the development of these diseases and to what extent.\n\nDuring 3.5 years of follow-up, we have observed accelerated growth in our rhGH-treated patient, and no serious health complications have yet occurred. In infancy the girl was diagnosed with supraventricular arrhythmias and hypertrophic cardiomyopathy, which was not confirmed in subsequent echocardiography. However, because of the risk of recurrence she remains under the systematic control of a cardiologist. The observed motor-system problems, resulting from the excessive ligamentous laxity associated with Costello syndrome, were already present before the initiation of growth hormone therapy. It seems that their progression was associated with significant growth acceleration resulting from GH supply, but the impact of rhGH therapy alone is difficult to assess.\n\nConclusions\nThe available data, based on a small number of reported cases of Costello syndrome treated with recombinant growth hormone, do not allow drawing general conclusions. The very good response to the treatment, demonstrated in our case, improved her body height prognosis and eliminated the disability related to extreme short stature. The 3.5-year observation revealed no serious side effects. However, reports of the otherauthors regarding the development and progression of cancer and hypertrophic cardiomyopathy in children with Costello syndrome treated with rhGH indicate that these patients require special oncologic and cardiologic supervision.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nGHGrowth hormone\n\nHRASHarvey rat sarcoma viral oncogene homolog\n\nMAPKMitogen-activated protein kinases\n\nrhGHRecombinant human growth hormone\n\nSDStandard deviation\n\nGIGastrointestinal\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nEP and EB conceived the study, participated in its design and coordination, and helped to draft the manuscript. MKW and AS diagnosed the patient with Costello syndrome and MP carried out the molecular genetic studies, additionally, all three of them helped to draft the manuscript. MW participated in the sequence alignment. EP and EB participated in the design of the study and performed the statistical analysis. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe research was partially supported by the National Science Center Project UMO-2011/03/N/NZ2/00516 and MNiSW Project PB 0056/B/P01/2008/35.\n\nThe technical and language assistance was provided by Proper Medical Writing Sp. z o.o., Warsaw, Poland.\n==== Refs\nReferences\n1. Gripp KW, Lin AE. Costello Syndrome. GeneReviews® University of Washington, Initial Posting: August 29, 2006; Last Update: January 12, 2012.\n2. Aoki Y Niihori T Kawame H Kurosawa K Ohashi H Tanaka Y Germline mutations in HRAS proto-oncogen cause Costello syndrome Nat Genet 2005 37 1038 40 10.1038/ng1641 16170316 \n3. Kerr B Delrue M-A Sigaudy S Perveen R Marche M Burgelin I Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases J Med Genet 2006 43 401 5 10.1136/jmg.2005.040352 16443854 \n4. Pelc M Ciara E Krajewska-Walasek M Zespół Costello jako przykład rzadkich zaburzeń funkcji szlaku sygnalnego Ras-MAPK: obraz kliniczny i diagnostyka molekularna choroby Pediatr Pol 2012 87 19 32 10.1016/S0031-3939(12)70590-5 \n5. Gripp KW Scott CI Nicholson L McDonald-McGinn DM Ozeran JD Jones MC Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol Am J Med Genet 2002 108 80 7 10.1002/ajmg.10241 11857556 \n6. Kerr B Eden B Dandamudi R Shannon N Quarrell O Emmerson A Ladusans E Gerrard M Donnai D Costello syndrome: two cases with embryonal rhabdomyosarcoma J Med Genet 1998 35 1036 1039 10.1136/jmg.35.12.1036 9863604 \n7. van Eeghen AM van Gelderen I Hennekam RCM Costello syndrome: report and review Am J Med Genet 1999 82 187 93 10.1002/(SICI)1096-8628(19990115)82:2<187::AID-AJMG17>3.0.CO;2-2 9934987 \n8. Gregersen N Viljoen D Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations Am J Med Genet Part A 2004 129A 171 5 10.1002/ajmg.a.30189 15316966 \n9. Okamoto N Chiyo H Imai K Otani K Futagi Y A Japanese patient with the Costello syndrome Hum Genet 1994 93 605 6 10.1007/BF00202834 8168845 \n10. Schimke RN Donaldson D Moore W Growth hormone deficiency in Costello syndrome Proc Greenwood Genet Ctr 1996 15 195 \n11. Yetkin I Ayvaz G Arslan M Yilmaz M Cakir N A case of Costello syndrome with endocrine features Ann Genet 1998 41 157 60 9833070 \n12. Legault L Gagnon C Lapointe N Growth hormone deficiency in Costello syndrome: a possible explanation for the short stature J Pediatr 2001 138 151 2 10.1067/mpd.2001.110115 11148542 \n13. Stein RI Legault L Daneman D Weksberg R Hamilton J Growth Hormone Deficiency in Costello Syndrome Am J Med Genet Part A 2004 129A 166 70 10.1002/ajmg.a.30187 15316968 \n14. Kerr B Einaudi MA Clayton P Gladman G Eden T Saunier P Is growth hormone treatment beneficial or harmful in Costello syndrome? J Med Genet 2003 40 10.1136/jmg.40.6.e74 12807973 \n15. Rauen KA Hefner E Carrillo K Taylor J Messier L Aoki Y Molecular Aspects, Clinical Aspects and Possible Treatment Modalities for Costello Syndrome: Proceedings From the 1st International Costello Syndrome Research Symposium 2007 Am J Med Genet Part A 2008 146A 1205 17 10.1002/ajmg.a.32276 18412122 \n16. Gripp KW Scott CI Nicholson L Figueroa TE Second case of bladder carcinoma in a patient with Costello syndrome Am J Med Genet 2000 90 256 9 10.1002/(SICI)1096-8628(20000131)90:3<256::AID-AJMG16>3.0.CO;2-D 10678668 \n17. Kobayashi D Cook AL Williams DA Progressively worsening hypertrophic cardiomyopathy in a child with newly diagnosed Costello syndrome while receiving growth hormone therapy Cardiol Young 2010 20 459 61 10.1017/S1047951110000260 20307337\n\n",
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"journal": "Italian journal of pediatrics",
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"medline_ta": "Ital J Pediatr",
"mesh_terms": "D002675:Child, Preschool; D056685:Costello Syndrome; D003937:Diagnosis, Differential; D005260:Female; D019382:Human Growth Hormone; D006801:Humans; D011994:Recombinant Proteins",
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"title": "Recombinant growth hormone therapy in a girl with Costello syndrome: a 4-year observation.",
"title_normalized": "recombinant growth hormone therapy in a girl with costello syndrome a 4 year observation"
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"abstract": "BACKGROUND\nHigh-dose vitamin C is increasingly used for sepsis and more recently for coronavirus disease 2019 (COVID-19) infections. Proponents argue that the low cost and near perfect safety profile of vitamin C support its early adoption. Yet, adverse events might be underreported and underappreciated.\n\n\nMETHODS\nWe report a 73-year-old non-diabetic white man with end-stage renal disease on peritoneal dialysis admitted to the intensive care unit with septic shock that was suspected to be due to peritonitis. The patient was enrolled in LOVIT (Lessening Organ Dysfunction with VITamin C; ClinicalTrials.gov identifier: NCT03680274), a randomized placebo-controlled trial of high-dose intravenous vitamin C. He developed factitious hyperglycemia, as measured with a point-of-care glucometer, that persisted for 6 days after discontinuation of the study drug, confirmed to be vitamin C after unblinding. He also had short-lived iatrogenic coma because of hypoglycemia secondary to insulin administration. These events triggered a protocol amendment.\n\n\nCONCLUSIONS\nAlthough factitious hyperglycemia has been reported before using certain glucometers in patients treated with high-dose vitamin C, the persistence of this phenomenon for 6 days after the discontinuation of the therapy is a distinguishing feature. This case highlights the importance of monitoring glucose with a core laboratory assay for up to a week in specific populations, such as patients on peritoneal dialysis.",
"affiliations": "Department of Critical Care Medicine, Université de Montréal, 5400 Boul Gouin Ouest, Montreal, QC, H4J 1C5, Canada. olivier.lachance.2@umontreal.ca.;Department of Medical Biochemistry, Université de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC, J1H 5H3, Canada.;Department of Critical Care Medicine, Sunnybrook Health Sciences Centre and Interdepartmental Division of Critical Care Medicine, University of Toronto, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.;Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC, J1H 5H3, Canada.;Department of Medicine, Université de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC, J1H 5H3, Canada.;Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC, J1H 5H3, Canada.;Department of Medicine, Université de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC, J1H 5H3, Canada.",
"authors": "Lachance|Olivier|O|http://orcid.org/0000-0002-2738-0029;Goyer|François|F|;Adhikari|Neill K J|NKJ|;Masse|Marie-Hélène|MH|;Bilodeau|Jean-François|JF|;Lamontagne|François|F|;Leclair|Marc-André|MA|",
"chemical_list": "D014815:Vitamins",
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"doi": "10.1186/s13256-021-02869-4",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2869\n10.1186/s13256-021-02869-4\nCase Report\nHigh-dose vitamin-C induced prolonged factitious hyperglycemia in a peritoneal dialysis patient: a case report\nhttp://orcid.org/0000-0002-2738-0029\nLachance Olivier olivier.lachance.2@umontreal.ca\n\n1\nGoyer François Francois.Goyer@USherbrooke.ca\n\n2\nAdhikari Neill K. J. neill.adhikari@utoronto.ca\n\n3\nMasse Marie-Hélène marie-helene.masse.ciussse-chus@ssss.gouv.qc.ca\n\n4\nBilodeau Jean-François jean.francois.bilodeau@usherbrooke.ca\n\n5\nLamontagne François Francois.Lamontagne@USherbrooke.ca\n\n45\nLeclair Marc-André Marc-Andre.Leclair@USherbrooke.ca\n\n5\n1 grid.14848.31 0000 0001 2292 3357 Department of Critical Care Medicine, Université de Montréal, 5400 Boul Gouin Ouest, Montreal, QC H4J 1C5 Canada\n2 grid.86715.3d 0000 0000 9064 6198 Department of Medical Biochemistry, Université de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC J1H 5H3 Canada\n3 grid.17063.33 0000 0001 2157 2938 Department of Critical Care Medicine, Sunnybrook Health Sciences Centre and Interdepartmental Division of Critical Care Medicine, University of Toronto, 2075 Bayview Ave, Toronto, ON M4N 3M5 Canada\n4 grid.411172.0 0000 0001 0081 2808 Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC J1H 5H3 Canada\n5 grid.86715.3d 0000 0000 9064 6198 Department of Medicine, Université de Sherbrooke, 3001 12e Avenue N, Sherbrooke, QC J1H 5H3 Canada\n21 5 2021\n21 5 2021\n2021\n15 2977 8 2020\n16 4 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\nHigh-dose vitamin C is increasingly used for sepsis and more recently for coronavirus disease 2019 (COVID-19) infections. Proponents argue that the low cost and near perfect safety profile of vitamin C support its early adoption. Yet, adverse events might be underreported and underappreciated.\n\nCase presentation\n\nWe report a 73-year-old non-diabetic white man with end-stage renal disease on peritoneal dialysis admitted to the intensive care unit with septic shock that was suspected to be due to peritonitis. The patient was enrolled in LOVIT (Lessening Organ Dysfunction with VITamin C; ClinicalTrials.gov identifier: NCT03680274), a randomized placebo-controlled trial of high-dose intravenous vitamin C. He developed factitious hyperglycemia, as measured with a point-of-care glucometer, that persisted for 6 days after discontinuation of the study drug, confirmed to be vitamin C after unblinding. He also had short-lived iatrogenic coma because of hypoglycemia secondary to insulin administration. These events triggered a protocol amendment.\n\nConclusions\n\nAlthough factitious hyperglycemia has been reported before using certain glucometers in patients treated with high-dose vitamin C, the persistence of this phenomenon for 6 days after the discontinuation of the therapy is a distinguishing feature. This case highlights the importance of monitoring glucose with a core laboratory assay for up to a week in specific populations, such as patients on peritoneal dialysis.\n\nKeywords\n\nAscorbic acid\nVitamin C\nIntensive care\nSeptic shock\nSepsis\nPeritoneal dialysis\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nHigh-dose vitamin C therapy for sepsis is being actively debated in the critical care community. A single-center before–after study suggested that high-dose intravenous vitamin C combined with thiamine and hydrocortisone dramatically decreases mortality, organ failure, and vasopressor requirements in septic shock [1], which was contradicted by a recent multicenter open-label randomized clinical trial [2]. Another trial found that high-dose intravenous vitamin C reduced 28-day mortality in patients with sepsis and acute respiratory distress syndrome [3].\n\nSkeptics have criticized early reports of efficacy, while enthusiasts argue that the high burden of sepsis and low cost and remarkable safety of vitamin C justify early adoption. Yet, vitamin C therapy has already been associated with factitious hyperglycemia and harmful iatrogenic hypoglycemia [4, 5], causing death in at least one report [6]. LOVIT (Lessening Organ Dysfunction with VITamin C) is a multicenter randomized controlled trial (ClinicalTrials.gov identifier: NCT03680274) examining the effects of intravenous vitamin C (50 mg/kg every 6 hours for 96 hours) in septic patients in the intensive care unit (ICU). A patient in this trial had factitious hyperglycemia leading to insulin administration and hypoglycemic coma, which triggered a protocol amendment, highlighting the hazards of such therapy.\n\nCase presentation\n\nA 73-year-old non-diabetic (HbA1c 5.7%) white man with end-stage renal disease on peritoneal dialysis was admitted with diarrhea, fever, and hypotension. At home, the patient was on automated nocturnal peritoneal dialysis (6 × 2 L × 2.5% over 8 hours) with 2 L of icodextrin as a daytime dwell. Physical examination was unremarkable except for abdominal distension. Sepsis due to peritonitis was suspected, and he received intravenous fluids, vasopressors, and broad-spectrum antibiotics. Blood cultures grew Salmonella spp. The patient continued to receive peritoneal dialysis, with three daytime exchanges of 2.5% or 4.25% dextrose and one night exchange of icodextrin. The patient had some urine output at baseline but became anuric following hospital admission.\n\nThe patient consented to participation in the LOVIT trial 18 hours after admission to the ICU. Before the first dose of study drug, he received subcutaneous insulin due to sepsis-associated hyperglycemia. Capillary blood glucose was monitored with the Accu-Chek Inform II glucometer (F. Hoffmann-La Roche Ltd.). On hospital day 5, he received intravenous insulin for worsening hyperglycemia, after which he became unconscious. A blood sample sent to the core laboratory and tested using a hexokinase assay showed severe hypoglycemia (1.7 mmol/L; normal > 4 mmol/L). Insulin was discontinued, 50% dextrose was administered, and his cognitive status normalized.\n\nAfter unblinding, research staff confirmed that he had been receiving vitamin C. He was discharged to the ward on hospital day 10. An ascorbic acid level of 568 μmol/L (normal range: 30–114 μmol/L) was measured using a spectrophotometric dinitrophenylhydrazine assay 5 days after discontinuing vitamin C therapy, on hospital day 11, and important differences between blood glucose measured by the core laboratory and point-of-care glucometers persisted until hospital day 12 (Fig. 1). Following this event, the LOVIT trial protocol was amended to mitigate the risk of factitious hyperglycemia. The patient was discharged home without any apparent sustained harm.Fig. 1 Glucose values from glucometer and core laboratory assay before, during, and after vitamin C administration. Note that core laboratory measurements were not available between day 2 and day 5\n\nDiscussion\n\nHigh-dose vitamin C treatments is increasingly used outside of trials for various conditions such as sepsis and more recently for coronavirus disease 2019 (COVID-19) infections [7]. This case highlights that the adverse effects of high-dose vitamin C treatment may not be fully appreciated and that claims of vitamin C’s absolute safety are likely unfounded. Although factitious hyperglycemia on point-of-care glucometers in the presence of elevated plasma ascorbic acid is documented [4, 8], the persistence of factitious hyperglycemia for 6 days after discontinuing vitamin C therapy is a distinguishing feature of this case. An earlier study in patients with burn injury suggested that measuring glucose with a core laboratory method for 24 hours after discontinuation of high-dose vitamin C was a safe approach [4]. The severity and the persistence of this episode suggests that a longer period of monitoring of blood glucose, up to 1 week, might be necessary, perhaps particularly in patients with reduced renal function and those receiving peritoneal dialysis. During this extended period, glucose should be monitored with a core laboratory assay, or other device whose glucose levels are documented to be reliable in the presence of high plasma ascorbic acid concentrations, until no discrepancy with point-of-care glucometers can be demonstrated.\n\nIn people with normal kidney function, ascorbic acid is mostly excreted renally [9]. Peritoneal dialysis may have contributed to this patient’s course, since pharmacokinetic studies have shown that peritoneal dialysis does not reliably clear plasma oxalic acid, which is a major end product of ascorbic acid oxidation [10]. In addition, icodextrin has been associated with factitious hyperglycemia due to an accumulation of its metabolites, notably maltose [11], although modern glucometers (including the Accu-Chek Inform II) are reportedly impervious to this interference. However, in vitro studies have confirmed significant positive interference on the Accu-Chek Inform II for high plasma concentrations of vitamin C (850–1700 μmol/L) [8]. The mechanism is related to the electrochemical method of measuring glucose and oxidation of vitamin C at the electrode surface, which creates a current yielding a false signal of hyperglycemia. While some evidence suggests that certain glucometers (for example, StatStrip [Nova Biomedical]) are more reliable than others in the context of high-dose vitamin C therapy, clinical experience with such devices remains extremely limited [12]. Since glucometers are ubiquitous on medical wards, the cost of acquiring, calibrating, and regularly testing point-of-care devices impervious to ascorbic acid interference will need to be considered as an additional cost of high-dose vitamin C treatment, which may not be justified unless a clear benefit of this treatment can be demonstrated.\n\nThis event reinforces the importance of rigorously evaluating novel interventions, even if they are relatively inexpensive and routinely available. The dose of vitamin C required to improve outcomes in sepsis may exceed that required to normalize plasma levels [13], since scavenging of oxygen radicals and other mechanisms of action may require high intracellular ascorbic acid concentrations. Adverse events are underappreciated and underreported. To mitigate these effects, research should address vitamin C’s optimal dosing and pharmacokinetics in critically ill septic patients, including those with renal failure.\n\nConclusion\n\nBefore the widespread adoption of high-dose vitamin C for the treatment of septic shock, additional randomized trials should assess its safety and potential side effects, which might otherwise be underreported. In certain populations, such as patients undergoing peritoneal dialysis, the risk of persistent factitious hyperglycemia while using point-of-care glucometers is of particular importance. In this population, measurement of blood glucose should be done with core laboratory assay for up to a week after vitamin C discontinuation.\n\nAbbreviation\n\nLOVIT Lessening Organ Dysfunction with VITamin C\n\nAcknowledgements\n\nWe thank Christian Audet for the infographic.\n\nAuthors’ contributions\n\nOL contributed to the clinical management of the patient, literature review and manuscript writing. FG contributed to the literature review of the interference between point-of-care glucose monitors and ascorbic acid and contributed to manuscript writing. M-HM contributed to manuscript writing. J-FB contributed with clinical expertise on the case and manuscript revision. NKJA, M-AL and FL contributed to the interpretation of the case, manuscript writing and revisions. All authors read and approved the final manuscript.\n\nFunding\n\nLOVIT is funded by a grant from the Lotte and John Hecht Memorial Foundation. The funder had no role in the writing of this case report.\n\nAvailability of data and materials\n\nAll data generated or analyzed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe LOVIT trial has been approved by the Comité d’éthique de la recherche du Centre intégré universitaire de santé et de services sociaux de l’Estrie - Centre hospitalier universitaire de Sherbrooke (Reference MP-31-2019-2945). The patient provided verbal and written consent for his participation in the LOVIT trial.\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\nDrs. Adhikari and Lamontagne are co-principal investigators of the LOVIT trial.\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. Marik PE Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study Chest 2017 151 6 1229 1238 10.1016/j.chest.2016.11.036 27940189\n2. Fujii T Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial JAMA 2020 323 423 10.1001/jama.2019.22176 31950979\n3. Fowler AA 3rd Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial JAMA 2019 322 13 1261 1270 10.1001/jama.2019.11825 31573637\n4. Kahn SA Lentz CW Fictitious hyperglycemia: point-of-care glucose measurement is inaccurate during high-dose vitamin C infusion for burn shock resuscitation J Burn Care Res 2015 36 2 e67 71 10.1097/BCR.0000000000000141 25162951\n5. Kim SK Spurious elevation of glucose concentration during administration of high dose of ascorbic acid in a patient with type 2 diabetes on hemodialysis Yonsei Med J 2013 54 5 1289 1292 10.3349/ymj.2013.54.5.1289 23918584\n6. MAUDE Adverse Event Report: ROCHE DIAGNOSTICS ACCU-CHEK ® INFORM II TEST STRIPS BLOOD GLUCOSE MONITORING TEST STRIPS. 2017. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/detail.cfm?mdrfoi__id=6767309&pc=LFR.\n7. Peng, Z. Vitamin C infusion for the treatment of severe 2019-nCoV Infected Pneumonia. 2020. NCT04264533. https://clinicaltrials.gov/ct2/show/NCT04264533?id=NCT04264533&draw=2&rank=1&load=cart.\n8. Cho J Influence of vitamin C and maltose on the accuracy of three models of glucose meters Ann Lab Med 2016 36 3 271 274 10.3343/alm.2016.36.3.271 26915620\n9. Morgan SH Oxalate metabolism in end-stage renal disease: the effect of ascorbic acid and pyridoxine Nephrol Dial Transplant 1988 3 1 28 32 3132636\n10. Mydlik M Derzsiova K Renal replacement therapy and secondary hyperoxalemia in chronic renal failure Kidney Int Suppl 2001 78 S304 S307 10.1046/j.1523-1755.2001.59780304.x 11169031\n11. Riley SG Spurious hyperglycaemia and icodextrin in peritoneal dialysis fluid BMJ 2003 327 7415 608 609 10.1136/bmj.327.7415.608 12969932\n12. Ceriotti F Comparative performance assessment of point-of-care testing devices for measuring glucose and ketones at the patient bedside J Diabetes Sci Technol 2015 9 2 268 277 10.1177/1932296814563351 25519295\n13. Oudemans-van Straaten HM Spoelstra-de Man AM de Waard MC Vitamin C revisited Crit Care 2014 18 4 460 10.1186/s13054-014-0460-x 25185110\n\n",
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"mesh_terms": "D000368:Aged; D000086382:COVID-19; D006801:Humans; D006943:Hyperglycemia; D008297:Male; D010530:Peritoneal Dialysis; D000086402:SARS-CoV-2; D014815:Vitamins",
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"title": "High-dose vitamin-C induced prolonged factitious hyperglycemia in a peritoneal dialysis patient: a case report.",
"title_normalized": "high dose vitamin c induced prolonged factitious hyperglycemia in a peritoneal dialysis patient a case report"
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"abstract": "Adverse effects of amiodarone are rarely seen in pediatric patients, but may occur if amiodarone is applied for long-term treatment. Two rather rare phenomena are blue-gray skin pigmentation and pulmonary mass. They represent important differential diagnoses from more common clinical complications like pneumonia and drug-induced toxic skin lesions.",
"affiliations": "Department for Pediatric Cardiology University of Leipzig - Heart Center Strümpellstr. 39 04289 Leipzig Germany.;Department for Pediatric Cardiology University of Leipzig - Heart Center Strümpellstr. 39 04289 Leipzig Germany.;Department for Pediatric Cardiology German Heart Center St. Augustin St. Augustin Germany.;Department for Pediatric Cardiology University of Leipzig - Heart Center Strümpellstr. 39 04289 Leipzig Germany.",
"authors": "Paech|Christian|C|;Wagner|Franziska|F|;Suchowerskyj|Philipp|P|;Weidenbach|Michael|M|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.483CCR3483Case ReportCase ReportsThe blue child – amiodarone‐induced blue‐gray skin syndrome and pulmonary mass in a child C. Paech et al.Paech Christian \n1\nWagner Franziska \n1\nSuchowerskyj Philipp \n2\nWeidenbach Michael \n1\n1 Department for Pediatric CardiologyUniversity of Leipzig ‐ Heart CenterStrümpellstr. 3904289LeipzigGermany2 Department for Pediatric CardiologyGerman Heart Center St. AugustinSt. AugustinGermany* Correspondence\n\nChristian Paech, Department for Pediatric Cardiology, University of Leipzig – Heart Center, Strümpellstr. 39, 04289 Leipzig, Germany. Tel: +49 341 / 8651036; Fax: +00493418651143; E‐mail: christian.paech@uni-leipzig.de\n08 2 2016 3 2016 4 3 10.1111/ccr3.2016.4.issue-3276 278 04 9 2015 10 12 2015 14 12 2015 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key clinical message\nAdverse effects of amiodarone are rarely seen in pediatric patients, but may occur if amiodarone is applied for long‐term treatment. Two rather rare phenomena are blue‐gray skin pigmentation and pulmonary mass. They represent important differential diagnoses from more common clinical complications like pneumonia and drug‐induced toxic skin lesions.\n\nAmiodaronearrhythmiachildpulmonary massskin pigmentationGerman Research Foundation (DFG)Universität Leipzig source-schema-version-number2.0component-idccr3483cover-dateMarch 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.7.6 mode:remove_FC converted:01.03.2016\n\nClinical Case Reports \n2016 ; 4 (3 ): 276 –278 \n\n\n\nThe authors confirm that informed consent was obtained from the patient and parents.\n==== Body\nIntroduction\nAmiodarone is a widely used and highly effective drug in the treatment of various atrial and ventricular arrhythmias. Severe adverse effects are well known especially in the long‐term treatment. Atrial arrhythmias are a frequently encountered clinical challenge in patients with congenital heart disease. Currently, some of these patients may undergo electrophysiologic study with radiofrequency ablation. Yet, drug treatment is still an important treatment option in this group of patients. Actual guidelines provide the clinician with several treatment options of which amiodarone is one of the most effective, although with the cost of a wide range of adverse effects 1. To the authors knowledge this is the first description reporting an amiodarone‐induced blue‐gray skin pigmentation and pulmonary mass in a child. CASE: A 13‐year‐old male patient, weighing 31.7 kg, with congenital Ebstein's anomaly was referred to our center for cardiac surgery. The patient's history included a primary univentricular approach with Glenn anastomosis at the age of 10 months, tricuspid valve reconstruction and implantation of a transvenous pacemaker for sick sinus syndrome at the age of 6 years. Due to atrial flutter he was treated with amiodarone (6 mg/kg/day) since the age of 7 years. At the time of admission the patient was in NYHA class III due to congestive heart failure without any pulmonary symptoms. Most strikingly he presented with a blue‐gray facial skin pigmentation (Fig. 1). In addition, preoperative X‐ray revealed several ominous pulmonary nodules. A computed tomography was performed (Fig. 2) and the suspicion of an abscess forming pneumonia aroused. Yet, blood chemistry was unremarkable and the patient showed no signs of an infection. Reviewing literature these findings were associated with chronic amiodarone intake. Bronchoscopy was performed which showed numerous marcrophages with foamy cytoplasm, presumably in the context of lipid sediment, and confirmed the diagnosis. Remarkably, no risk factors were identified in the child that could have predisposed to his condition. Amiodarone was discontinued after successful cardiac surgery with tricuspid valve reconstruction, right atrial reduction plastic, MAZE procedure, removal of the transvenous pacemaker system and implantation of an epimyocardial pacing system. Postoperative course was uneventful. Follow‐up after 1 year showed a thorough disappearance of the blue‐gray skin pigmentation and absence of atrial arrhythmia. Noteworthy, the pulmonary nodules showed only incomplete regression after 2 years follow‐up.\n\nFigure 1 Demonstrating the patient's blue‐gray skin pigmentation.\n\nFigure 2 A: Chest X‐ ray showing nodular pulmonary infiltration. B: Computer tomography showing the nodular lesions with the aspect of abscess forming pneumonia.\n\nDiscussion\nAmiodarone is one of the most effective and commonly used drugs available for treatment of cardiac arrhythmias in the adult and pediatric population. It prolongs the cardiac repolarization through the sodium and calcium channel block and nonselective β‐adrenergic inhibition. It has a long plasma half‐life of about 57 days and is hepatically metabolized 2. Many adverse effects are reported, especially in the long‐term treatment. Apart from frequent adverse effects like corneal microdeposits, reported in up to 90% of patients, and photosensitivity (25–75%), blue‐gray skin discoloration (4–9%), and pulmonary toxicity (1–17%) are rather rare 3. The incidence of blue‐gray skin discoloration in children is estimated <2% 4.\n\nAmiodarone‐induced blue‐gray skin pigmentation is most often reported to occur following long‐term treatment in elderly patients with a predominance of male patients. The exact pathomechanism of blue‐gray skin syndrome is still controversial. Several different theories are discussed in literature. These include drug‐induced lipidosis, photosensitivity reaction to ultraviolet light, or leukocytoclastic vasculitis 5. The typical feature of the blue‐gray skin syndrome is the strictly facial skin pigmentation. It is speculated that ultraviolet light induces amiodarone and its metabolites to attach to the blood vessel walls and the perivascular tissue. This is associated with local vasodilatation and increased diffusion of amiodarone and its metabolites, resulting in chronic tissue accumulation. Therefore, only sun exposed regions are affected 6. Molecular mechanisms have been described by Morissette et al. 7 who analyzed skin biopsies of patients with blue‐gray skin syndrome and concluded that the vacuolar sequestration of amiodarone occurs at concentrations close to therapeutic levels. It is mediated by V‐ATPase and evolves toward persistent macroautophagy and phospholipidosis. In case of discontinuation of amiodarone complete relief of symptoms can be expected.\n\nAmiodarone‐induced pulmonary mass is very rarely reported in adults and according to Labombarda F et al. 8, is extremely rare in children. Basically it is thought to represent a subtype of the rather common phenomenon of amiodarone‐induced pulmonary toxicity (AIPT). Facchini and colleagues reported that amiodarone can damage the lung via an indirect immune reaction or direct cytotoxic damage 9. The different mechanisms of injury contribute to the variability of symptoms onset, ranging from 1 to 6 months. Typically AIPT presents as infiltration of the pulmonary interstitium with inflammatory cells, interstitial fibrosis, and hyperplasia of type II pneumocytes. On biopsy, the presence of foamy macrophages confirms exposure to amiodarone. While AIPT mostly appears as diffuse parenchymal infiltration, the occurrence of amiodarone‐induced pulmonary mass is thought to be due to a selective accumulation of the drug in a prior lung lesion 10. As reported in literature, patients with amiodarone‐induced pulmonary mass typically present with dyspnea, cough, and fever, which can easily be mistaken as symptoms of pneumonia. Most patients respond well to withdrawal of amiodarone and prednisolone can be added to promote healing.\n\nAfter all, the adverse effects of amiodarone are rarely seen in pediatric patients. This may be due to the fact that amiodarone is mainly used for the acute treatment of arrhythmias, for example in the postoperative setting. But even if amiodarone is used in the outpatient setting to treat for example supraventricular arrhythmias in infants, there is a substantial number of patients who expect spontaneous disappearance of their arrhythmia and treatment is only needed for a time period of months in contrast to the long‐term treatment of atrial fibrillation or ventricular arrhythmias in adults that often require treatment for several years. Nevertheless, adverse effects similar to those reported in adults can be seen in children if amiodarone is applied for long‐term treatment. Consequently, close monitoring of possible adverse effects, early dose reduction in amiodarone and effective sun protection of exposed regions are of particular importance to prevent adverse effects of long‐term amiodarone treatment in children. As there currently exists a wide range of effective antiarrhythmic drugs for children available on the market, alternative substances should always be considered if a long‐term treatment is expected 1.\n\nConclusion\nLong‐term administration of amiodarone can cause severe side effects in children even if an approved dosage is prescribed. Close monitoring of possible adverse effects, early dose reduction of amiodarone and effective sun protection of exposed regions may prevent adverse effects of long‐term amiodarone treatment. The use of alternative substances should be considered.\n\nConflict of interest\nNone.\n\nAcknowledgments\n“We acknowledge support from the German Research Foundation (DFG) and Universität Leipzig within the program of Open Access Publishing”.\n==== Refs\nReferences\n1 \n\nBrugada , J. \n, \nN. \nBlom \n, \nG. \nSarquella‐Brugada \n, \nC. \nBlomstrom‐Lundqvist \n, \nJ. \nDeanfield \n, \nJ. \nJanousek \n, et al. 2013 \nPharmacological and non‐pharmacological therapy for arrhythmias in the pediatric population: EHRA and AEPC Arrhythmia Working group joint consensus statement . Europace \n15 :1337 –1382 .23851511 \n2 \n\nGonzalez‐Arriagada , W. A. \n, \nA. R. \nSantos Silva \n, \nP. A. \nVargas \n, \nO. P. \nde Almeida \n, and \nM. A. \nLopes \n. 2013 \nFacial pigmentation associated with amiodarone . Gen. Dent. \n61 :e15 –e17 .23823354 \n3 \n\nVassallo , P. \n, and \nR. G. \nTrohman \n. 2007 \nPrescribing amiodarone an evidence‐based review of clinical indications . JAMA \n298 :1312 –1322 .17878423 \n4 \n\nCoumel , P. L. \n, and \nJ. \nFidelle \n. 1980 \nAmiodarone in the treatment of cardiac arrhythmias in children: one hundred thirty‐five cases . Am. Heart. J. \n100 :1063 –1069 .7446409 \n5 \n\nWiper , A. \n, \nD. H. \nRoberts \n, and \nM. \nSchmitt \n. 2007 \nAmiodarone‐induced skin pigmentation: Q‐switched laser therapy, an effective treatment option . Heart \n93 :15 – Highlighted 07.06.201517170336 \n6 \n\nBahadir , S. \n, \nR. \nApaydin \n, \nU. \nCobanoilu \n, \nZ. \nKapicioilu \n, \nY. \nOzora \n, \nM. \nGökçe \n, et al. 2000 \nAmiodarone pigmentation, eye and thyroid alterations . J. Eur. Acad. Dermatol. Venereol. \n14 :194 –195 .11032064 \n7 \n\nMorissette , G. \n, \nA. \nAmmoury \n, \nD. \nRusu \n, \nM. C. \nMarguery \n, \nR. \nLodge \n, \nP. E. \nPoubelle \n, et al. 2009 \nIntracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology . Br. J. Pharmacol. \n157 :1531 –1540 .19594752 \n8 \n\nLabombarda , F. \n, \nP. \nOu \n, \nB. \nStos \n, \nJ. \nde Blic \n, \nE. \nVillain \n, and \nD. \nSidi \n. 2008 \nAcute amiodarone‐induced pulmonary toxicity: an association of risk factors in a child operated by arterial switch operation . Congenit. Heart. Dis. \n3 :365 –367 .18837818 \n9 \n\nFacchini , G. \n, \nS. \nForte \n, \nP. \nPodda \n, \nF. \nPiro \n, and \nS. \nCarlone \n. 2008 \nPulmonary masses in a patient with blue‐gray cutaneous hyperpigmentation . Eur. Rev. Med. Pharmacol. Sci. \n12 :113 –116 .18575161 \n10 \n\nRodriguez‐Garcia , J. L. \n, \nJ. C. \nGarcia‐Nietob \n, \nF. \nBallestab \n, \nE. \nPrietoa \n, \nM. A. \nVillanuevaa \n, and \nJ. \nGallardoa \n. 2001 \nPulmonary mass and multiple lung nodules mimicking a lung neoplasm as amiodarone‐induced pulmonary toxicity . Eur. J. Intern. Med. \n12 :372 –276 .11395302\n\n",
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"keywords": "Amiodarone; arrhythmia; child; pulmonary mass; skin pigmentation",
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"title": "The blue child - amiodarone-induced blue-gray skin syndrome and pulmonary mass in a child.",
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"abstract": "Eltrombopag is approved for the treatment of chronic immune thrombocytopenia purpura (ITP) in pediatric patients 1 year and older who have demonstrated an insufficient response to corticosteroids and intravenous immunoglobulin. We present the case of a 2-year-old boy with chronic immune thrombocytopenia purpura who developed life-threatening adverse effects of acute liver failure, metabolic acidosis and encephalopathy with standard drug dosing. To our knowledge, this is the first case of eltrombopag-induced hepatic encephalopathy highlighting the critical need for prescribers to exercise caution when prescribing eltrombopag in the pediatric setting.",
"affiliations": "Caylor School of Nursing, Lincoln Memorial University, Knoxville, TN Division of Pediatric Hematology and Oncology, University of Minnesota, Minneapolis, MN.",
"authors": "Hermann|Erin|E|;Ferdjallah|Asmaa|A|",
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"title": "Eltrombopag-Induced Metabolic Acidosis and Hepatic Encephalopathy in Pediatric ITP.",
"title_normalized": "eltrombopag induced metabolic acidosis and hepatic encephalopathy in pediatric itp"
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"abstract": "OBJECTIVE\nWe analyzed incidence and profile of infections in children with acute lymphoblastic leukemia (ALL) treated with hematopoietic stem cell transplantation (HSCT) in Polish pediatric HSCT departments, over a 2-year period.\n\n\nMETHODS\nHospital records of 67 patients, who underwent allogeneic HSCT for ALL, were analyzed retrospectively for microbiologically documented infection: bacterial infection (BI), viral infection (VI), and fungal infection (FI). The majority of patients (40/67; 59.7%) underwent HSCT from matched unrelated donors (MUD).\n\n\nRESULTS\nIn total, 84 BI in 31 patients, 93 VI in 50 patients, and 27 FI in 22 patients were diagnosed. No differences were found in the frequency of occurrence of BI according to the type of transplant (P = .16); the occurrence of VI was statistically more frequent in MUD transplant recipients as compared with matched sibling donors (MSD) and mismatched related donors (MMFD; P = .001) and there was a trend in MUD patients for the higher occurrence of FI in comparison with MSD and MMFD transplants (P = .08). Regarding disease status, the occurrence of BI, VI, and FI was statistically more frequent in children who underwent transplantation in their first complete remission (CR1), rather than those who underwent transplantation in ≥CR2 (P < .05). In conclusion, infectious complications are an important cause of morbidity in children with ALL treated with allogeneic HSCT and the incidence of infections is high in this group of patients.",
"affiliations": "Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, University Children Hospital, Lublin, Poland. Electronic address: a.prazmo@umlub.pl.;Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, University Children Hospital, Lublin, Poland.;Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, University Children Hospital, Lublin, Poland.;Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.;Clinical Immunology and Transplantation Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Department of Transplantation, Children's University Hospital, Krakow, Poland.;Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Poznań, Poland.;Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Poznań, Poland.;Department of Pediatric Transplantology, Hematology and Oncology, Medical University, Wrocław, Wrocław, Poland.;Department of Pediatric Transplantology, Hematology and Oncology, Medical University, Wrocław, Wrocław, Poland.;Department of Pediatric Transplantology, Hematology and Oncology, Medical University, Wrocław, Wrocław, Poland.;Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.",
"authors": "Zaucha-Prażmo|A|A|;Kowalczyk|J R|JR|;Drabko|K|K|;Czyżewski|K|K|;Goździk|J|J|;Zając-Spychała|O|O|;Wachowiak|J|J|;Frączkiewicz|J|J|;Gorczyńska|E|E|;Kałwak|K|K|;Styczyński|J|J|",
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"doi": "10.1016/j.transproceed.2017.09.027",
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"medline_ta": "Transplant Proc",
"mesh_terms": "D000293:Adolescent; D001424:Bacterial Infections; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D008297:Male; D009181:Mycoses; D011044:Poland; D011183:Postoperative Complications; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D035781:Siblings; D013997:Time Factors; D014019:Tissue Donors; D014777:Virus Diseases; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2183-2187",
"pmc": null,
"pmid": "29149980",
"pubdate": "2017-11",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Incidence of Infectious Complications in Children With Acute Lymphoblastic Leukemia Treated With Hematopoietic Stem Cell Transplantation.",
"title_normalized": "incidence of infectious complications in children with acute lymphoblastic leukemia treated with hematopoietic stem cell transplantation"
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"abstract": "Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolytic anemia and thrombosis and is notoriously associated with aplastic anemia and myelodysplastic syndromes. Rarer associations include myeloproliferative neoplasms (MPNs), which are also burdened by increased thrombotic tendency. The therapeutic management of this rare combination has not been defined so far. Here, we describe a 62-year-old man who developed a highly hemolytic PNH more than 10 years after the diagnosis of MPN. The patient started eculizumab, obtaining good control of intravascular hemolysis but without amelioration of transfusion-dependent anemia. Moreover, we performed a review of the literature regarding the clinical and pathogenetic significance of the association of PNH and MPN. The prevalence of PNH clones in MPN patients is about 10%, mostly in association with JAK2V617F-positive myelofibrosis. Thrombotic events were a common clinical presentation (35% of subjects), sometimes refractory to combined treatment with cytoreductive agents, anticoagulants, and complement inhibitors. The latter showed only partial effectiveness in controlling hemolytic anemia and, due to the paucity of data, should be taken in consideration after a careful risk/benefit evaluation in this peculiar setting.",
"affiliations": "Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.",
"authors": "Giannotta|Juri Alessandro|JA|;Fattizzo|Bruno|B|;Barcellini|Wilma|W|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3389/fonc.2021.756589",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.756589\nOncology\nCase Report\nParoxysmal Nocturnal Hemoglobinuria in the Context of a Myeloproliferative Neoplasm: A Case Report and Review of the Literature\nGiannotta Juri Alessandro 1 *\n\nFattizzo Bruno 1 2\n\nBarcellini Wilma 1\n\n1 Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy\n2 Department of Oncology and Oncohematology, University of Milan, Milan, Italy\nEdited by: Abbas Ghaderi, Shiraz University of Medical Sciences, Iran\n\nReviewed by: Francesca Schieppati, Papa Giovanni XXIII Hospital, Italy; Marco Santoro, Università degli Studi di Palermo, Italy\n\n*Correspondence: Juri Alessandro Giannotta, jurigiann@gmail.com\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n11 11 2021\n2021\n11 75658910 8 2021\n15 10 2021\nCopyright © 2021 Giannotta, Fattizzo and Barcellini\n2021\nGiannotta, Fattizzo and Barcellini\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.\nParoxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolytic anemia and thrombosis and is notoriously associated with aplastic anemia and myelodysplastic syndromes. Rarer associations include myeloproliferative neoplasms (MPNs), which are also burdened by increased thrombotic tendency. The therapeutic management of this rare combination has not been defined so far. Here, we describe a 62-year-old man who developed a highly hemolytic PNH more than 10 years after the diagnosis of MPN. The patient started eculizumab, obtaining good control of intravascular hemolysis but without amelioration of transfusion-dependent anemia. Moreover, we performed a review of the literature regarding the clinical and pathogenetic significance of the association of PNH and MPN. The prevalence of PNH clones in MPN patients is about 10%, mostly in association with JAK2V617F-positive myelofibrosis. Thrombotic events were a common clinical presentation (35% of subjects), sometimes refractory to combined treatment with cytoreductive agents, anticoagulants, and complement inhibitors. The latter showed only partial effectiveness in controlling hemolytic anemia and, due to the paucity of data, should be taken in consideration after a careful risk/benefit evaluation in this peculiar setting.\n\nparoxysmal nocturnal hemoglobinuria\nmyeloproliferative neoplasm\ncomplement inhibitors\nthrombosis\nbone marrow failure\ncase report\n==== Body\npmcIntroduction\n\nParoxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder caused by the somatic mutations of phosphatidylinositol glycan A (PIGA). The consequent defect of glycosyl phosphatidylinositol (GPI)-anchored proteins on red blood cell (RBC) surface increases the susceptibility of PNH cells to complement-mediated destruction, leading to intravascular hemolytic anemia, which is the main clinical feature of the disease (1, 2). The natural history of PNH was burdened by high morbidity due to chronic anemia and considerably increased mortality, mainly related to fatal thrombotic events (3). With the advent of complement inhibitors, PNH patients significantly ameliorated their quality of life and survival (4). PNH has been described in the context of bone marrow failure (BMF) syndromes, namely, aplastic anemia (AA) and myelodysplastic syndrome (MDS) (4). However, with the development of more sensitive cytofluorimetric techniques (5), PNH clones of various sizes are increasingly being detected in various onco-hematologic and autoimmune disorders (6–9). The coexistence of PNH and myeloproliferative neoplasms (MPNs) has been reported, but its clinical/prognostic significance and therapeutic management are still poorly known. Moreover, these two conditions share an overlapping clinical presentation, represented by thrombotic events at usual and unusual sites (3, 10–13). Here, we provide the description of a patient with MPN who was subsequently diagnosed with PNH and required specific treatment for hemolytic anemia. In addition, we searched for the available evidence in literature about the association of PNH and MPN, collecting data over the last 40 years in MEDLINE via PubMed and the National Library of Medicine. In detail, we reviewed data about the coexistence of clinically overt PNH and MPN, the prevalence of PNH clones in MPN patients, and the prevalence of MPN driver mutations in PNH subjects.\n\nCase Description\n\nA 62-year-old Caucasian male was diagnosed with Janus kinase (JAK)2-negative essential thrombocythemia (ET) in May 2007 due to isolated asymptomatic thrombocytosis ( Table 1 ). His medical history was unremarkable, except for moderate arterial hypertension on regular treatment; no previous thrombotic events were registered. Bone marrow (BM) evaluation showed normocellularity (40%), increased mature megakaryocytes, slight increase of reticulin fibers (MF-1), and normal karyotype. Once-daily acetylsalicylic acid (ASA) and low-dose hydroxyurea (HU) were started with adequate control of platelet count. From March 2016, a trend to increased lactate dehydrogenase (LDH) levels was noticed, and from February 2019, a mild macrocytic anemia [hemoglobin (Hb) 10.2 g/dL, mean corpuscular volume (MCV) 103 fL; normal iron and vitamin status] developed ( Figure 1 ). Direct antiglobulin test (DAT) was negative, with mild elevation of unconjugated bilirubin (UB, 1.3 mg/dL), consumption of haptoglobin, and increased reticulocytes. HU dose was decreased, but anemia worsened (Hb nadir 7 g/dL), LDH rose to 4× upper limit of normal (ULN), and peripheral CD34-positive cells increased. The patient became strongly symptomatic for anemia, requiring about 1–2 RBC units/month. His physical examination was unremarkable. In October 2019, BM reevaluation showed increased cellularity (>95%) with dystrophic megakaryocytes and increased fibrosis (MF-2) and was therefore interpreted as fibrotic evolution of ET. Molecular tests on peripheral blood revealed the presence of a type-2 calreticulin (CALR) mutation at exon 9. Abdomen ultrasonography displayed normal spleen and liver size. HU and ASA were stopped, and an attempt with steroids (oral prednisone 50 mg/day) was made with a transient response and reappearance of transfusion dependency during tapering (2–3 packed RBC units/month). In February 2020, danazol was administered, again without anemia improvement. In November 2020, due to persistent intravascular hemolytic anemia and referred dark-colored urines, a flow cytometry for PNH was made and turned positive with a clone size of 95%/94% on neutrophils/monocytes. Low-molecular weight heparin (LMWH) prophylaxis (enoxaparin 4,000 units/day) was started, and the patient was referred to our center for treatment indications. No major PNH-related symptoms were registered. In December 2020, the patient started eculizumab after recommended vaccinations. In the subsequent months, Hb stabilized at 7.5–8 g/dL, LDH progressively lowered to 1.1×–1.2× ULN, and transfusion need returned to 1–2 units/month, with subjective amelioration of the quality of life and disappearance of hemoglobinuria. LMWH was stopped. In June 2021, due to a minor response to eculizumab, a re-evaluation was performed: DAT result turned positive for complement without evidence of cryoagglutinins (as frequently observed under eculizumab treatment), and UB levels slightly increased, indicative of extravascular hemolysis (EVH) during terminal complement inhibitor treatment. BM biopsy confirmed increased age-adjusted cellularity, granulocytic hyperplasia, and numerous megakaryocytes in loose and dense clusters, including both mature and atypical, dystrophic cells; fibrosis was stable with diffuse increase in reticulin and focal bundles of thick collagen fibers (MF-2); of note, hyperplasia of the erythroid lineage in the absence of dysplastic features was described. Karyotype analysis was normal. Analyzed by an expert hemopathologist, the BM trephine was consistent with MPN unclassifiable (MPN-U). A targeted next-generation sequencing (NGS) myeloid panel confirmed the presence of type-2 CALR mutation [variant allele frequency (VAF), 45%] and showed an additional somatic mutation in ten-eleven translocation 2 (TET2) gene (VAF, 9.7%). The patient is continuing regular fortnightly eculizumab infusions, with subjective benefit, although with persistent transfusion dependence.\n\nTable 1 Laboratory parameters at different time points of the clinical history of the patient.\n\n\tET diagnosis (May 2007)\tPost-ET MF (Oct 2019)\tPNH diagnosis (Nov 2020)\tMonth +6 after ECU start (June 2021)\tNormal ranges\t\nHb (g/dL)\t13.5\t7*\t7.3*\t8*\t13.5–17.5\t\nPLT (×103/μL)\t830\t396\t450\t540\t130–400\t\nWBC (×103/μL)\t7.5\t4.5\t6.0\t8.5\t4.8–10.8\t\nLDH (× ULN)\t0.8\t4\t4\t1.1\t-\t\nUB (mg/dL)\t0.5\t1.3\t1.3\t2.0\t0–0.8\t\nRetics (×109/L)\t40\t140\t200\t155\t20–100\t\nHaptoglobin (mg/dL)\t70\t<10\t<10\t<10\t30–200\t\nCD34+ cells (n/μL)\t7\t56\t56\t60\t-\t\nET, essential thrombocythemia; MF, myelofibrosis; PNH, paroxysmal nocturnal hemoglobinuria; ECU, eculizumab; Hb, hemoglobin; PLT, platelet; WBC, white blood cell; LDH, lactate dehydrogenase; ULN, upper limit of normal; UB, unconjugated bilirubin; Retics, reticulocytes. *Pre-transfusion Hb levels.\n\nFigure 1 Trend of hemoglobin (Hb; dotted black line) and lactate dehydrogenase (LDH; dashed-dotted black line) levels along the patient’s clinical journey. ULN, upper limit of normal; HU, hydroxyurea; ASA, acetylsalicylic acid; LMWH, low-molecular weight heparin; ET, essential thrombocythemia; PNH, paroxysmal nocturnal hemoglobinuria. Red drops represent red blood cell transfusions.\n\nReview of the Literature\n\nClinical Association of Paroxysmal Nocturnal Hemoglobinuria and Myeloproliferative Neoplasm\n\nSince the 1970s, several case reports about the coexistence of PNH and MPN have been described ( Table 2 ). A total of 23 cases have been reported so far, mainly in association with myelofibrosis (MF; n = 12), followed by polycythemia vera (PV; n = 3), MPN-U (n = 2), and only one case each of ET (20) and chronic myeloid leukemia (CML) (19). Nine cases were JAK2-positive, while only two CALR- and one MPL-mutated (24). In 12 cases, the diagnosis of MPN preceded that of PNH, and the clinical suspicion for the latter (when indicated) was the development of hemolytic or iron-deficient anemia (15, 17, 20). The diagnoses were concomitant in seven patients, whose main clinical presentation included atypical thromboses or the coexistence of hemolytic anemia and thrombocytosis (18, 21, 24, 25). In the remaining four subjects, the diagnosis of MPN followed that of PNH and derived from recurrent thrombosis or development of thrombocytosis/leukocytosis (14, 18, 19). Ten patients harbored PNH clones >10% (8/10 were >50%), while in four cases, it was <10%. PNH clone size showed a complessively wide distribution, as reported by Richards et al. (23) in a recent large retrospective study analyzing the clinical presentation of 1,081 PNH patients. The five patients with a previous MPN diagnosis had a PNH clone from 0.7% to 96.3%, while cytopenic/myelodysplastic patients generally harbored smaller clones, and hemolytic/thrombotic subjects harbored larger ones (23). With regard to treatments, eculizumab was administered in four patients (notably, all with JAK2V617F-positive MPN). In one patient, eculizumab monotherapy was able to resolve anemia (18); in another, the concomitant administration of eculizumab with acenocumarol and HU resolved a severe case of visceral thrombosis (25). In the remaining two cases, hemolytic anemia was refractory, and one experienced visceral thrombosis recurrence notwithstanding eculizumab plus HU and anticoagulation (18). A retrospective series of 55 PNH patients undergoing hematopoietic stem cell transplantation (HSCT) included two cases associated with MF. The reported overall survival at 5 years was 70%, although the outcome of these two patients is not specified (22). Regarding outcome, four out of the total 23 patients reported (17.4%) died due to acute lymphoblastic/myeloid leukemia progression (16, 17), infections, or liver failure secondary to refractory Budd–Chiari syndrome (18).\n\nTable 2 Association of MPNs and PNH.\n\nType of study, year\tN. of patients (sex, age)\tTiming of PNH and MPN presentation (delay)\tPNH clone size\tMPN diagnosis (driver mutation)\tThrombosis\tTreatment\tOutcome\tNotes\tRef.\t\nCase report, 1979\t1 (M, 60)\tPNH first\t-\tNot specified\tNo\tOxymetholone for hypoplastic PNH\t-\t-\t(14)\t\nRetrospective, 1992\t47 PNH patients, four of whom with MPN\tMPN first\t-\tPMF\t-\t-\t-\tPNH succeeded the development of PMF, while it preceded the diagnosis of MDS.\t(15)\t\nCase report, 1993\t1 (M, 58)\tConcomitant\t-\tPMF\tNo\tHU, splenic irradiation\tDied for AML progression 6 years after diagnosis\tAML blasts were PNH+.\t(16)\t\nCase report, 2005\t1 (M, 53)\tMPN first (2 years before PNH)\t-\tPMF\t3 AMI\tIFN, HU\tDied 6 months after PNH diagnosis due to BCP-ALL progression\tPNH diagnosed for iron-deficient anemia.\t(17)\t\nCase series, 2012\t#1 M, 51\n#2 M, 65\n#3 M, 78\t#1 Concomitant\n#2 PNH first (2 years before MPN)\n#3 PNH first (1 year before MPN)\t#1 99% G, 13% R\n#2 40% R\n#3 73% G, 53% R\t#1 and #2 MPN-U (JAK2)\n#3 PMF (JAK2)\t#1 Multiple thromboses (stroke, BCS)\n#2 splenic infarction under anticoagulation; BCS under HU and ecu\n#3 No\t#1 Ecu\n#2 added HU and ecu to anticoagulation\n#3 ecu, danazol, steroid\t#1 Transfusion-free with ecu, but variceal bleeding due to BCS\n#2 died in 10 months for liver failure and iron overload\n#3 died for clostridiosis 1 year after\t#1 and #2: JAK2V617F detected in PNH+ granulocytes, but not in those PNH- → the JAK2V617F mutation coexists within the PNH clone\n#3: PMF diagnosed for thrombocytosis; anemia refractory to all treatments.\t(18)\t\nCase report, 2015\t1 (M, 52)\tPNH first (11 years before MPN)\t12% CD55-, 24% CD59- G\tCML\tNo\tCyclosporin A, prednisolone, erythropoietin, and Andriol\tPNH responsive to IST, CML responsive to imatinib\tDisappearance of PNH clones at the time of CML diagnosis.\t(19)\t\nCase report, 2016\t1\tMPN first (6 years before PNH)\t73% M, 60% G, 14% R\tET (CALR)\tNo\tNo\tAlive\tDiagnosis of PNH because of hemolytic anemia\t(20)\t\nCase report, 2017\t#1 F, 72\n#2 M, 75\t#1 Concomitant\n#2 MPN first (24 years before PNH)\t#1 88.6% G, 86.9% M, 71% R\n#2 <1%\t#1 Post-ET MF (JAK2)\n#2 PV (JAK2V617F)\t#1 Portal vein thrombosis\n#2 multiple arterial and venous thromboses\t#1 HU, anticoagulation\n#2 anticoagulation, anti-platelets\t#1 Recanalization within 2 months\n#2 Alive\tIn #1, cell sorting showed that JAK2+ subclone arose within the PNH population.\t(21)\t\nRetrospective, 2019\t55 PNH patients, two of whom with MPN\tConcomitant\t-\tPMF\t-\tHSCT\t-\tIndication for HSCT was association with MF. Complessive 5-year-OS in the cohort: 70%.\t(22)\t\nRetrospective, 2020\t1081 PNH patients, five of whom with MPN (71, M; 65, F; 55, M; 71, F; 74, M)\tMPN first\t#1 0.7%\n#2 93.3%\n#3 1.2%\n#4 3.4%\n#5 96.3%\t#1 MF (CALR)\n#2 not specified (JAK2)\n#3 PV (JAK2)\n#4 not specified (JAK2)\n#5 not specified (JAK2)\t#1 DVT/PE\n#2 BCS\t-\t-\tSevere hemolysis was evident only in Pt #5\t(23)\t\nCase report, 2020\t1 (M, 49)\tConcomitant\t99%\tPMF (MPL)\tNo\t-\t-\tThe patient presented with anemia, thrombocytosis, elevated LDH, dark-colored urine.\t(24)\t\nCase report, 2021\t1 (F, 51)\tConcomitant\t>90%\tMasked PV (JAK2V617F)\tVenous (hepatic, splenic, kidney)\tAnticoagulation, HU, ecu\tClinical resolution of ascites in 2 months\tNo signs of hemolysis\t(25)\t\nMPN, myeloproliferative neoplasm; PNH, paroxysmal nocturnal hemoglobinuria; PMF, primary myelofibrosis; MDS, myelodysplastic syndrome; HU, hydroxyurea; AML, acute myeloid leukemia; AMI, acute myocardial infarction; IFN, interferon; B-ALL, B-acute lymphoblastic leukemia; G, granulocyte; R, red blood cell; MPN-U, MPN unclassifiable; BCS, Budd–Chiari syndrome; ecu, eculizumab; CML, chronic myeloid leukemia; IST, immunosuppressive treatment; M, monocyte; ET, essential thrombocythemia; HSCT, hematopoietic stem cell transplantation; PV, polycythemia vera; DVT, deep vein thrombosis; PE, pulmonary embolism; LDH, lactate dehydrogenase.\n\nPrevalence of Paroxysmal Nocturnal Hemoglobinuria Clones in Myeloproliferative Neoplasm Patients\n\nSome cross-sectional studies on MPN patients evaluated the association with PNH clones. Tanasi et al. (26) tested 32 patients with MPN and concomitant hemolysis or unexplained anemia and found a PNH clone in three (9.3%) with MF (two JAK2- and one CALR-mutated). Two of them harbored a PNH clone >90% but did not require specific PNH therapy (26). In a recent large monocentric study, more than 3,000 patients were tested for PNH because of unexplained cytopenia/thrombosis, including 92 patients diagnosed with MPN (27). A PNH clone was found in 16 patients (17.4%), mainly MF, and was generally smaller than 1% (except for one patient with a clone of 5%). It was associated with increased frequency of thrombosis without impact on overall survival (28). In a large cross-sectional study including 197 MPN, 14.2% of subjects had CD55/CD59-negative red cells; this prevalence rose to 21.3% in the subgroup of ET patients (29). At variance, in a series of 98 MPN subjects, PNH clones greater than 1% were detected in only two patients (2%) (30), one of whom with recurrent thrombotic complications. Finally, two studies failed to detect PNH clones in MPN patients. In detail, Nazha et al. (31) tested 62 MF patients with significant anemia (Hb <10 g/dL) and elevated LDH, but none of them harbored a PNH clone. Likewise, a study on 136 patients with myeloid disease, including five MF and 15 MDS/MPN overlap, found GPI-negative cells in 8% of low-risk MDS, but none in MPN subjects (32).\n\nPrevalence of Myeloproliferative Neoplasm Driver Mutations in Paroxysmal Nocturnal Hemoglobinuria Patients\n\nThere are isolated reports of PNH patients harboring mutations in MPN-related driver genes, namely, JAK2. Shen et al. (33) performed targeted NGS in a cohort of 36 PNH patients and found JAK2V617F homozygous mutations in two patients (5.5%). Langabeer et al. (34) reported a case of AA-PNH with a concomitant JAK2V617F mutation at low allele ratio (1.8%) without any clinical feature of MPN; intriguingly, the JAK2-positive clone disappeared after cyclosporin therapy, while the PNH clone remained stable. More recently, Santagostino et al. (35) described a case of hemolytic PNH occurring 10 years after HSCT for acute myeloid leukemia (AML); concomitantly, somatic mutation analysis revealed the presence of JAK2 mutation with an allele ratio of 44% and TET2 with a VAF of 34%. Soon after, the patient relapsed for AML.\n\nDiscussion\n\nOur patient, along with the others described, allows several clinical and pathogenic considerations about the rare coexistence of PNH and MPN. Besides AA and MDS, PNH clones have been detected also in the context of lymphoid disorders, such as acute lymphoblastic leukemia and lymphomas (9, 36), and in autoimmune/idiopathic cytopenias (6–8, 37). The review of the literature highlighted that about 10% of MPN patients harbor a PNH clone (26, 29, 30), and this frequency rises up to 17% if clones smaller than 1% are considered (27). More importantly, the disregarded association of these two conditions may cause a significant delay in PNH diagnosis, as observed in our case. Additionally, in the MPN setting, the differential diagnosis of hemolytic anemia may be hampered by several confounders: haptoglobin can be decreased in more than 30% of MF (38), LDH is often elevated as a consequence of disease burden (31), and reticulocytosis can be observed in case of myeloid metaplasia (39). Furthermore, the appearance of anemia in MPN should prompt the exclusion of fibrotic evolution, which was in fact observed in our patient, who met the diagnostic criteria for post-ET MF (40). However, at variance with post-ET MF, BM trephine revealed erythroid hyperplasia, which may be attributed to the concomitant peripheral hemolytic process and indicative of bone marrow compensation. Consultation with an expert hemopathologist may be thus advised when morphological findings are not fully consistent with a clear diagnosis and confounding factors coexist.\n\nAn important clinical issue is the thrombotic risk in MPN-PNH patients and its management. In our literature review, 35% of MPN-PNH subjects had a severe thrombotic presentation, often refractory to combined anticoagulant, cytoreductive, and anti-complement treatments. This frequency appears higher than that reported for isolated untreated PNH (18.8%) (41) and for MPN (complessively 20%, higher in PV vs. ET/MF and JAK2-mutated patients) (12, 13, 42, 43), possibly due to the association of two thrombophilic conditions. With regard to therapy, it is well established that cytoreductive and anti-coagulant/platelet therapies are the cornerstones of thrombosis treatment in MPN, although recurrencies interest about 20% of treated patients (44, 45). In PNH, complement inhibition (Ci) has proven to significantly reduce the thrombotic risk, while anticoagulation alone is poorly effective (4, 46). Whether primary thromboprophylaxis is indicated in untreated PNH is still debated. Given the higher risk observed in patients with a larger clone size (i.e., >50%), they are generally candidates to primary prophylaxis if there are no contraindications. Prophylaxis may be then discontinued once complement inhibitors are started, as in the case described (47). With regard to secondary prophylaxis in patients on complement inhibitors, some experts discontinue anticoagulants when Intravascular hemolysis (IVH) is well controlled by anti-complement therapy (4, 48, 49). Finally, anti-platelet prophylaxis had been stopped in our patient when CALR-positive post-ET MF diagnosis was made. In fact, JAK2-negative ET is apparently associated with lower rates of thrombosis (50, 51); additionally, the indication to anti-thrombotic primary prophylaxis in MF is not clear-cut (52).\n\nAnother relevant clinical issue in MPN-PNH patients may be the infectious risk due to the treatment with anti-complement therapy and the known infectious diathesis observed in MPN (53). Despite the known risk of capsulated bacterial infections under Ci (54), no infectious complications occurred in our patient and in only one out of 23 patients (4%) in the literature (18).\n\nWith regard to therapy, in our patient, eculizumab showed effectiveness in controlling IVH but was not able to resolve transfusion-dependent anemia. Accordingly, the review of the literature showed that only a fraction of MPN-PNH patients responded to eculizumab ( Table 2 ) (18, 25). In classic PNH, persistent anemia under Ci treatment can be caused by residual IVH, concomitant BMF, and EVH. The management of the latter still remains an unmet need, but promising results are coming from clinical trials with proximal complement inhibitors that avoid deposition of C3 on RBC surface (55).\n\nMany speculations can be made regarding the pathogenic significance of the association of MPN and PNH clones. The evidence of MPN driver mutations, particularly JAK2, selectively in GPI-deficient cells (18, 21) has raised the hypothesis that they may confer an intrinsic growth advantage to PNH cells. This cooperative effect has also been proposed for other somatic mutations, such as TET2 (33, 35, 56, 57), also present in our patient. This view would provide a different explanation to the more common notion that PNH cells have an extrinsic growth advantage secondary to an autoimmune, GPI-selective process against bone marrow precursors (58, 59). Interestingly, MPN diagnosis preceded that of PNH in more than half of cases, and Shen et al. (33) demonstrated that PIGA mutation was subclonal to JAK2-mutated clone in their report. It is tempting to speculate that the MPN-associated inflammatory microenvironment (60–63) can impair normal hematopoiesis, exerting an “immune pressure” that favors PNH clone expansion, similarly to what happens in AA.\n\nIn conclusion, the association of MPN and PNH deserves attention because of the unpredictable clinical course often affected by dramatic thrombotic complications. Since PNH diagnosis is based on highly sensitive and cost-effective techniques, testing for PNH clones should be prompted in any MPN patient showing unexplained anemia with/without frank hemolysis, recurrent thrombosis, and/or atypical BM morphologic findings. Anti-complement treatment in the setting of MPN relies on a careful case-by-case evaluation, weighing the contribution of intravascular hemolysis to anemia and the thrombotic risk.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary files. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Comitato Etico Milano Area 2. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nJG, BF, and WB followed the patient, described his clinical history, and revised the literature and the paper for intellectual content. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nWB received consultancy honoraria from Agios, Alexion, Novartis, Annexon, Sanofi, and Sobi. BF received consultancy honoraria from Amgen, Alexion, Novartis, Momenta, Annexon, and Apellis.\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==== Refs\nReferences\n\n1 Brodsky RA . Paroxysmal Nocturnal Hemoglobinuria. Blood (2014) 124 :2804–11. doi: 10.1182/blood-2014-02-522128\n2 Parker CJ . Update on the Diagnosis and Management of Paroxysmal Nocturnal Hemoglobinuria. 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"keywords": "bone marrow failure; case report; complement inhibitors; myeloproliferative neoplasm; paroxysmal nocturnal hemoglobinuria; thrombosis",
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"title": "Paroxysmal Nocturnal Hemoglobinuria in the Context of a Myeloproliferative Neoplasm: A Case Report and Review of the Literature.",
"title_normalized": "paroxysmal nocturnal hemoglobinuria in the context of a myeloproliferative neoplasm a case report and review of the literature"
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"abstract": "Iatrogenic agranulocytosis (IA), by nonchemotherapeutic drugs, is a rare adverse event, resulting in a neutrophil count under 0.5 × 109 cells/L with fever or other suggestive signs of infection.\nThis paper discusses the possible mechanisms responsible for agranulocytosis induced by nonchemotherapeutic drugs. It also describes three cases as well as potential ways to handle such iatrogenic situations.\nNeutropenia under 0.1 × 109 cells/L predispose patients to potentially fatal infections. Empiric broad-spectrum antibiotic and hematopoietic growth factors may be helpful in shortening hospitalization and prevent further infectious complications. Not all drugs associated with IA require frequent hematological monitoring, except medications such as clozapine, ticlopidine, and antithyroids.",
"affiliations": "Hospital Central Do Funchal, Madeira Island, Funchal, Portugal.;Hospital Central Do Funchal, Madeira Island, Funchal, Portugal.;Hospital Central Do Funchal, Madeira Island, Funchal, Portugal.;Hospital Central Do Funchal, Madeira Island, Funchal, Portugal.;Hospital Central Do Funchal, Madeira Island, Funchal, Portugal.;Hospital Central Do Funchal, Madeira Island, Funchal, Portugal.",
"authors": "André|Diogo|D|https://orcid.org/0000-0002-9868-9736;Caldeira|Mónica|M|;Gouveia|Fabiana|F|;Nascimento|Rafael|R|;Chaves|António|A|;Braza O|Maria|M|",
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"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/6125626\nCase Report\nAcute Iatrogenic Agranulocytosis: A Rare and Dire Case of an Adverse Drug Reaction to Be Aware\nhttps://orcid.org/0000-0002-9868-9736André Diogo diogomig91@gmail.com Caldeira Mónica Gouveia Fabiana Nascimento Rafael Chaves António Braza˜o Maria Hospital Central Do Funchal, Madeira Island, Funchal, Portugal\nAcademic Editor: Pier Paolo Piccaluga\n\n\n2020 \n19 11 2020 \n2020 612562610 3 2020 27 9 2020 9 11 2020 Copyright © 2020 Diogo André 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 Iatrogenic agranulocytosis (IA), by nonchemotherapeutic drugs, is a rare adverse event, resulting in a neutrophil count under 0.5 × 109 cells/L with fever or other suggestive signs of infection. \n\nMethods\n This paper discusses the possible mechanisms responsible for agranulocytosis induced by nonchemotherapeutic drugs. It also describes three cases as well as potential ways to handle such iatrogenic situations. \n\nConclusion\n Neutropenia under 0.1 × 109 cells/L predispose patients to potentially fatal infections. Empiric broad-spectrum antibiotic and hematopoietic growth factors may be helpful in shortening hospitalization and prevent further infectious complications. Not all drugs associated with IA require frequent hematological monitoring, except medications such as clozapine, ticlopidine, and antithyroids.\n==== Body\n1. Introduction\nIatrogenic agranulocytosis (IA), induced by nonchemotherapeutic drugs, is a rare adverse effect characterized by the presence of fever or other suggestive signs of infection and an absolute neutrophil count below 0.5 × 109 cells/L [1, 2].\n\nThe mortality rate due to IA ranges from 0 to 23%, and avoidance of the responsible agent is vital. However, as a rule, it is difficult to establish this causal relationship between the drug and agranulocytosis [1].\n\nThere are two mechanisms by which drugs can induce neutropenia/agranulocytosis [3]. Immune-mediated agranulocytosis results from irreversible binding of the drug metabolite to the neutrophil membrane, resulting in the production of antibodies or stimulation of targeted T cells against the corrupted cell membrane. Just an intermittent exposure is enough, as suggested, with the intake of antithyroids [2, 3]. Direct toxic agranulocytosis results from prolonged exposure of the drug that negatively impacts the bone marrow, culminating in a hypoplastic marrow. It is even admitted that the metabolic detoxification of these drugs results in IA, predetermined by a genetic component [2, 3]. Both mechanisms appear to be mediated by reactive metabolite. The most likely enzyme system responsible is the NADPH oxidase/myeloperoxidase, present in neutrophils and monocytes. However, the exact process responsible for the formation of a chemically active compound still requires further investigation [2, 4].\n\nIts incidence increases with age, as more than half of the cases are reported in individuals older than 60 years and is doubly more frequent in women, reflecting older age multimedication and female longevity [2].\n\nDespite the introduction of new drugs, this incidence is stabilized due to more stringent drug surveillance [2].\n\nRisk factors contributing to IA can be identified, namely, autoimmune diseases (rheumatoid arthritis and captopril), renal insufficiencies under probenecid, and infectious mononucleosis and agranulocytosis secondary to levamisol [3].\n\nThere is even evidence of genetic susceptibility to agranulocytosis, namely, the association between HLA-B27/HLA-B38 and clozapine intake as well as the combination of the HLA DRB1∗08032 allele in Graves disease with methimazole [3].\n\nThe drugs most often associated with agranulocytosis are clozapine, antithyroid, sulfasalazine, and ticlopidine. Most cases of severe neutropenia or agranulocytosis usually occur within the first three months after initiation of the responsible drug [3].\n\nTherefore, a blood count study is vital, as well as educating patients about the most common symptoms of agranulocytosis, as it may contribute to an early diagnosis [5].\n\nNeutropenic AI patients usually manifest as a feverish condition, feeling sick, chills, myalgia/arthralgia, and odynophagia [2, 5].\n\n2. Case Series\n\nCase 1: a 43-year-old woman with recurrent outpatient infections admitted with an oral ulcer, a nodular lesion in the right inguinal region with purulent drainage and thyroid nodules, was treated for a month with methimazole (MM). Her blood count showed 1.8 × 103 μL polymorphonuclear leukocytes (PMNL) with 0.0 × 103 μL neutrophils. Upon completion of broad-spectrum antibiotics, the patient was found to have agranulocytosis due to MM. Normalization of neutrophil counts occurred 11 days after cessation of MM.\n\nCase 2: a 41-year-old male with schizo-affective disorder receiving clozapine (Cl) had a fever and decreased PMNL count with 0.0 × 103 μL neutrophils. The patient was hospitalized for febrile neutropenia due to neuroleptics, complicated by acute otitis and pneumonia. Following administration of broad-spectrum antibiotics and filgrastim, neutrophil count normalization occurred within 14 days without Cl.\n\nCase 3: a 61-year-old man with bipolar disorder under Cl was referred for internal medical consultation due to asymptomatic leukopenia with 1.0 × 103 μL neutrophils. Following the suspension of Cl, normalization of the neutrophil count was found 16 days later.\n\n\n\n\n3. Discussion\nNeutropenia usually resolves within one to three weeks after discontinuation of the drug in question [3].\n\nHowever, patients with high-risk factors that may dictate a poor prognosis, such as advanced age, renal failure, and septic shock, should be admitted to a hospital unit [2, 3]. Low-risk patients should also be hospitalized, but they can be monitored and treated on an outpatient basis, if possible [2].\n\nA neutrophil count of less than 0.1 × 109 cells/L has been suggested as a poor prognostic criterion and an indication for treatment with growth factors [1]. Although hematopoietic growth factors—granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF)—are reserved for particular life-threatening situations, there are no studies with significant associations between the reduction of fatal cases of agranulocytosis and the use of growth factors [1, 2].\n\nNot all drugs, despite a rare association with agranulocytosis, require frequent monitoring. The exception includes medicines such as clozapine, ticlopidine and antithyroid [2].\n\nClozapine has a cumulative risk of 0.8 to 1.5% per year of determining agranulocytosis. This risk, whose mechanism is likely to be autoimmune in nature, is greatest after 4 to 20 weeks of therapy [4].\n\nMethimazole is one of the drugs often prescribed to control hyperthyroidism. Agranulocytosis, also of an immunological nature, occurs in 0.35% of patients, and it occurs essentially within the first 3 months of therapy [5].\n\nAlthough, over the last two decades, there has been a decline in cases of agranulocytosis at European level, it is still vital reporting all cases of iatrogenic agranulocytosis, as well as the need for further case-control studies to quantify and assess the individual risk found with the administration of a given drug [2].\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest in relation to this article.\n==== Refs\n1 Andersohn F. Konzen C. Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs Annals of Internal Medicine 2007 146 9 p. 657 10.7326/0003-4819-146-9-200705010-00009 2-s2.0-34248372109 17470834 \n2 Andrès E. Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia Current Opinion in Hematology 2008 15 1 15 21 10.1097/moh.0b013e3282f15fb9 2-s2.0-36549023531 18043241 \n3 Coates T. D. Drug-induced neutropenia and agranulocytosis 2019 UpToDate https://www.uptodate.com/contents/drug-induced-neutropenia-and-agranulocytosis?search=Drug-Induced-Neutropenia-And-Agranulocytosis&source=search_result&selectedTitle=1%7E124&usage_type=default&display_rank=1 \n4 Wiciński M. Węclewicz M. M. Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring Current Opinion in Hematology 2018 25 1 22 28 10.1097/MOH.0000000000000391 2-s2.0-85036507161 28984748 \n5 Yang J. Zhong J. Zhou L.-Z. Hong T. Xiao X.-H. Wen G.-B. Sudden onset agranulocytosis and hepatotoxicity after taking methimazole Internal Medicine 2012 51 16 2189 2192 10.2169/internalmedicine.51.7845 2-s2.0-84865147520 22892501\n\n",
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"title": "Acute Iatrogenic Agranulocytosis: A Rare and Dire Case of an Adverse Drug Reaction to Be Aware.",
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"abstract": "Chorioamnionitis is an acute inflammation of the membranes and chorion of the placenta typically due to ascending polymicrobial infection in the setting of membrane rupture. It is a common complication of pregnancy associated with significant maternal, perinatal, and long-term adverse outcomes. We present a case of placental infection leading to preterm delivery, severe neonatal sepsis, maternal wound infection, postnatal readmission, and prolonged hospital stay. This virulent infection was caused by multidrug-resistant extended-spectrum beta-lactamase (ESBL)-producing Escherichia Coli (E. Coli), which represent a major worldwide threat according to the Centre for Disease Control and Prevention (CDC). It was managed with appropriate antibiotic therapy, patient-centered approach, and multidisciplinary team involvement that led to favourable maternal and neonatal outcome.",
"affiliations": "Department of Obstetrics and Gynaecology Al Wakra Hospital Hamad Medical Corporation Doha Qatar.;Department of Obstetrics and Gynaecology Al Wakra Hospital Hamad Medical Corporation Doha Qatar.;Infectious Disease Unit Division of Medicine Al Wakra Hospital Hamad Medical Corporation Doha Qatar.;Department of Obstetrics and Gynaecology Al Wakra Hospital Hamad Medical Corporation Doha Qatar.",
"authors": "Shittu|Saheed Akinola|SA|https://orcid.org/0000-0001-8998-6360;Athar|Sufia|S|;Shaukat|Adila|A|;Alansari|Lolwa|L|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.5078\nCCR35078\nCase Report\nCase Report\nChorioamnionitis and neonatal sepsis due to extended‐spectrum beta‐lactamase‐producing Escherichia coli infection: a case report\nSHITTU et al.\nShittu Saheed Akinola https://orcid.org/0000-0001-8998-6360\n1 SShittu@hamad.qa\ns2akinola@yahoo.com\n\nAthar Sufia 1\nShaukat Adila 2\nAlansari Lolwa 1\n1 Department of Obstetrics and Gynaecology Al Wakra Hospital Hamad Medical Corporation Doha Qatar\n2 Infectious Disease Unit Division of Medicine Al Wakra Hospital Hamad Medical Corporation Doha Qatar\n* Correspondence\nSaheed Akinola Shittu, Department of Obstetrics and Gynaecology, Al Wakra Hospital, Hamad Medical Corporation, P. O. Box 82228, Doha, Al Wakra, Qatar.\nEmails: SShittu@hamad.qa; s2akinola@yahoo.com\n\n22 11 2021\n11 2021\n9 11 10.1002/ccr3.v9.11 e0507815 10 2021\n13 9 2021\n22 10 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nChorioamnionitis is an acute inflammation of the membranes and chorion of the placenta typically due to ascending polymicrobial infection in the setting of membrane rupture. It is a common complication of pregnancy associated with significant maternal, perinatal, and long‐term adverse outcomes. We present a case of placental infection leading to preterm delivery, severe neonatal sepsis, maternal wound infection, postnatal readmission, and prolonged hospital stay. This virulent infection was caused by multidrug–resistant extended‐spectrum beta‐lactamase (ESBL)‐producing Escherichia Coli (E. Coli), which represent a major worldwide threat according to the Centre for Disease Control and Prevention (CDC). It was managed with appropriate antibiotic therapy, patient‐centered approach, and multidisciplinary team involvement that led to favourable maternal and neonatal outcome.\n\nChorioamnionitis is a fetomaternal condition that can be caused by ESBL‐producing E. coli which pose challenging infection control issues and are a serious global threat. Screening strategies to monitor them could be useful in women from endemic areas to prevent perinatal transmission and introduction of multiresistant strains to the maternity wards.\n\nchorioamnionitis\nE. coli\nextended‐spectrum beta‐lactamase\nneonatal sepsis\nwound infection\nQatar National Library source-schema-version-number2.0\ncover-dateNovember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:23.11.2021\nShittu SA , Athar S , Shaukat A , Alansari L . Chorioamnionitis and neonatal sepsis due to extended‐spectrum beta‐lactamase‐producing Escherichia coli infection: a case report. Clin Case Rep. 2021;9 :e05078. 10.1002/ccr3.5078\n\nFunding information\n\nFunding for open access publication of this study is provided by Qatar National library\n==== Body\npmc1 INTRODUCTION\n\nChorioamnionitis is a common infection of pregnancy, typically occurring in the setting of prolonged prelabor rupture of membranes (PROM) or labor. It complicates 1%–4% of all births in the United States. 1 However, its frequency varies significantly with gestational age, specific risk factors, and diagnostic criteria. It may be diagnosed clinically, microbiologically, or by histopathological examination of the placenta and umbilical cord. 2 , 3\n\nAssociated risk factors include obesity, anaemia, diabetes, prolonged PROM, prolonged labor, nulliparity, African American ethnicity, multiple vaginal examinations, meconium‐stained liquor, smoking and drug abuse, epidural anaesthesia, compromised immunity and colonisation with GBS, bacterial vaginosis, sexually transmissible genital infection, and vaginal colonisation with ureaplasma. 2 , 3 , 4\n\nThe main preventative strategy is administration of antibiotics to women with preterm PROM, which reduces the incidence of clinical chorioamnionitis, prolongs the time to delivery, and improves neonatal outcomes. Optimal management of clinical chorioamnionitis includes antibiotic therapy and delivery of the infected products of conception. 5 , 6 , 7\n\nWe present a case of clinical chorioamnionitis associated with fetal compromise, neonatal sepsis, and severe maternal wound infection caused by multidrug–resistant ESBL‐producing E. coli and the challenges associated with its management.\n\n2 CASE PRESENTATION\n\nA 33‐year‐old Indian lady, G3P1 reported to the emergency department at 33 weeks with history of passing clear fluid vaginally for 1 hour. She had no associated fever, urinary symptoms, or vaginal discharge. Her previous delivery was by Caesarean section (CS) in 2014. She was on metformin for gestational diabetes diagnosed at 28 weeks.\n\nOn examination, she was clinically stable (pulse rate (PR)‐76/min, regular, blood pressure (BP)‐100/60 mmHg, and oral temperature 36.4°C). Systemic examination was unremarkable. Abdominal examination revealed fundal height of 32 cm, with normal uterine tone and regular fetal heart rate. The admission cardiotocography (CTG) was normal. Speculum examination revealed clear amniotic fluid leakage. Routine laboratory tests were sent. Antenatal steroids were offered, blood sugar monitoring with diet control was advised and sliding dose of insulin Injection was initiated. Oral Erythromycin was started for GBS prophylaxis. The patient and her family were counselled in detail regarding the conservative management and risks of chorioamnionitis and prematurity.\n\nHer admission laboratory test results were normal (Hemoglobin‐11.6 g/dl, blood group O positive, white blood cell count (WBC) was 9.5 × 103/µl, absolute neutrophil count (ANC) −7 × 103/µl, and C‐reactive protein (CRP) −7 mg/L). Ultrasound scan revealed a small for date fetus with growth corresponding to <7th centile with oligohydramnios and normal uterine artery Dopplers. She was clinically stable in the first 48 h and twice‐daily CTG remained normal. However, she later developed tachycardia (PR‐122/min) and increased WBC (12.9 × 103/µl) and ANC (10.9 × 103/µl) were noted in her blood count but she was afebrile. CTG done at this time revealed baseline tachycardia of 180 bpm, reduced variability of 3–5 bpm; no acceleration, but had unprovoked recurrent decelerations followed by prolonged deceleration for more than 3 minutes.\n\nIn view of pathological CTG findings shown in Figure 1, she had emergency CS for fetal compromise as the cervix was only 1‐cm dilated. Routine prophylactic antibiotics, cefazolin and azithromycin, were administered prior to surgery as she was afebrile at that time. The baby was male weighing 1570 g, and Apgar scores were 91,105. The liquor was meconium stained and foul smelling. The arterial pH and the venous pH were 7.30 and 7.36, respectively. The base excess was −0.7 and −0.6 mmol/L for the arterial and venous sample. Placental tissue was sent for culture and sensitivity as clinical diagnosis of chorioamnionitis was made and broad‐spectrum antibiotics (ceftriaxone and metronidazole) were started.\n\nFIGURE 1 Cardiotocography (CTG) prior the decision for delivery\n\nHowever, she had persistent tachycardia with increasing CRP levels (420 mg/L). The culture result of placental tissue and high‐vaginal swab (HVS) confirmed profuse growth of ESBL‐producing E. coli. confirming microbiological chorioamnionitis. Infectious disease team was involved and IV (intravenous) Ertapenem was commenced based on sensitivity profile of the result of culture. She remained clinically stable for 72 h, and WBC counts and CRP were showing a decreasing trend (Figures 2 and 3). She was discharged home on IV Ertapenem to be taken on outpatient basis. However, on post‐operative day 6, she was readmitted because of wound infection and oral temperature was 38.2℃. Wound swab culture also grew ESBL‐producing E. coli and antibiotic was changed to IV Meropenem. Wound care team was involved.\n\nFIGURE 2 White blood count (WBC) and absolute neutrophil count (ANC) of the patient from admission\n\nFIGURE 3 C‐reactive protein (CRP) levels of the patient from admission\n\nAfter instituting Meropenem, she recovered well, and the blood counts and CRP were reduced to near normal. Meropenem was continued for 7 days. She was discharged home in clinically stable condition.\n\nThe baby born vigorous was initially on continuous positive airway pressure, but within few hours of birth developed signs of sepsis (PR‐186 bpm, BP‐44/30 mmHg, temperature 37.9°C, and SpO2 dropped to 93%) with respiratory distress syndrome and was intubated and required inotropes (dopamine infusion). Broad‐spectrum antibiotics (Amikacin and Ampicillin) were given. Blood culture confirmed growth of gram‐negative ESBL‐producing E. coli within 9 hours of birth, so Meropenem was added, and Ampicillin was discontinued. Fetal Echocardiography showed dilated inferior vena cava with evidence of pulmonary hypertension.\n\nBaby developed high fever (39.5°C) on second day of birth, requiring paracetamol. Total parenteral nutrition (TPN) was initiated. Laboratory results were suggestive of leucopenia (WBC 4.5 × 103/µl), low platelet count (96 × 103/µl), high CRP (56 mg/L), high serum Urea (9.7mmol/L), high serum creatinine (76 umol/L), and high total bilirubin levels(142.3µmol/L). Due to persistent hypotension, higher doses of Dopamine infusion were given. On day 4, hemoglobin level dropped from 19 g/dl to 15 g/dl so skull X‐ray and brain ultrasound were performed and intracranial bleeding was excluded. In addition to sepsis, neonatal jaundice was noted, and ABO incompatibility was diagnosed. Lumber puncture was performed, which revealed leukocytosis (216/µl and raised RBCs (11/µl). Though culture showed no growth, he was treated for meningitis.\n\nGradually in 10 days, the baby improved clinically. TPN was continued for 12 days and then oral feeding was commenced. Neonatal Jaundiced settled without the need for phototherapy. Antibiotic (Meropenem) was given for four weeks. Baby was discharged on 28th day of admission.\n\n3 DISCUSSION\n\nThe patient was afebrile earlier unlike most cases of clinical chorioamnionitis 1 , 3 , 4 ; hence, the diagnosis of clinical chorioamnionitis was confirmed during the CS by foul‐smelling liquor and broad‐spectrum antibiotics were commenced post‐operatively. The risk factors were preterm PROM and gestational diabetes. This confirmed that knowing the risk factors can add to the diagnostic accuracy, as in all situation treatment needs to be initiated based on clinical diagnosis. 2 , 4\n\nThe definition of chorioamnionitis varies according to the key diagnostic criteria, which can be given as follows: clinical, based on the presence of typical findings such as maternal fever, tachycardia and foul‐smelling liquor, or vaginal discharge; microbiological, based on the culture of microbes from amniotic fluid obtained by amniocentesis or placenta; and histological, based on microscopic evidence of maternal or fetal inflammatory response on examination of placenta or membranes. Histological chorioamnionitis is a more common diagnosis as it includes both subclinical and clinical chorioamnionitis. Funisitis occurs when infection/inflammation extends to the umbilical cord. 1 , 2 , 3 , 4\n\nThe clinical diagnosis of chorioamnionitis in women with preterm PROM should be made by use of a combination of clinical assessment (including CTG) and tests discussed below (WBC, CRP, etc.). It is important that the results of the clinical assessment or any of the tests are consistent with each other, or else observation and repetition of the tests should be considered. 7\n\nOur patient's CTG was pathological as shown in Figure 1 and suggestive of fetal compromise, but the cord pH and base excess were normal. The role of CTG in the diagnosis of chorioamnionitis is uncertain as it is a test widely used for fetal hypoxia; but chorioamnionitis causes nonhypoxic fetal compromise. 6 Be that as it may, CTG abnormalities are frequent among patients with chorioamnionitis. Baseline fetal tachycardia more than 160 bpm is a time‐honored early sign of chorioamnionitis. Other CTG features such as reduced variability, deceleration, lack of accelerations, and lack of cycling with or without features of tachysystole or hyperstimulation may be markers of chorioamnionitis that may be associated with adverse perinatal outcome as seen in our patient. 5 , 6\n\nWhen chorioamnionitis is suspected in the absence typical clinical signs (subclinical chorioamnionitis), biochemical, serum or amniotic fluid tests may be used to make diagnosis. Amniocentesis for amniotic fluid culture is the best method for diagnosis of subclinical chorioamnionitis in preterm gestations but it is considered invasive. Other tests that can be obtained rapidly include WBC, CRP level, leukocyte esterase level, gram stain and glucose concentration, and cytokine level (IL‐6). 1 , 5 , 6 , 7 , 8\n\nBlood culture was not done in our patient, as she initially did not have fever. Ideally, this should be done prior to administration of antibiotics which should be given within an hour of recognition of severe sepsis and sepsis bundle protocol should be implemented. Critical care outreach team should be contacted if indicated. 8\n\nThe definitive diagnosis of chorioamnionitis in this case was based on microbiological test of placenta culture growing ESBL organism. Unfortunately, placental histology was not obtained. Chorioamnionitis confirmed on histopathology is associated with an increase in CS rate due to fetal heart rate changes, increased risk of wound infection in mothers, and increased admission of the babies to neonatal intensive care units as seen in this case. More importantly, it is a reliable indicator of infection even when the infection is not clinically apparent. 12\n\nThe maternal complications of chorioamnionitis are postpartum hemorrhage, endometritis, wound infection, sepsis, and death. The neonatal complications include premature birth, stillbirth, neonatal sepsis, chronic lung disease and brain injury causing cerebral palsy, and other neuro‐developmental disabilities. 1 , 5 , 6\n\nRoute of infection is ascending infection in 96% of cases. The remainder is from haematogenous spread due to maternal septicemia 13 , iatrogenic from procedures such as amniocentesis and chorionic villous sampling. Infection from the peritoneum via the fallopian tubes has been postulated. 1 , 2\n\nThe most common organisms identified in pregnant women dying from sepsis are genital mycoplasmas, Lancefield group A beta hemolytic streptococcus and E. coli. 10 While GBS and E. coli are the two most common pathogenic organisms for early‐onset neonatal sepsis, ESBL‐producing multidrug–resistant E. coli has emerged as the major pathogen responsible particularly in preterm infants. 10 , 11\n\nEscherichia coli belongs to the family of Enterobacteriaceae—a large order of different types of bacteria that commonly cause infections both in healthcare settings and in communities. To survive the effects of antibiotics, some Enterobacteriaceae produce ESBL enzyme that destroys and renders ineffective commonly used antibiotics such as penicillins and cephalosporins, but not cephamycin and carbapenems. This resistance means fewer antibiotic options are available to treat ESBL‐producing bacterial infections and even more common infections caused by such organisms may require more complex treatment requiring prolonged hospitalisation and intravenous carbapenem antibiotics—a class of highly effective antibiotic agents commonly reserved for the treatment of severe or high‐risk multidrug–resistant bacterial infections. 9 , 11 Therefore, appropriate and justified use of these antibiotics is necessary to decrease the risk of emergence of resistance.\n\nOur patient's cultured organism from placental tissue and the wound culture was resistant to commonly used antibiotics and was sensitive only to Meropenem, Ertapenem and Gentamicin. Resistance that renders these antibiotics ineffective are on the rise too. The more we rely on these antibiotics, the greater the risk of spreading resistance to them. This mandates the practice of sending appropriate specimens for culture before initiating antimicrobial therapy and the implementation of stewardship programs to regulate the appropriate use of antimicrobials as well as, robust infection control practices that help to prevent cross transmission of infection. 15\n\nExtended‐Spectrum Beta‐Lactamase ‐producing organisms were first found in Europe, and the earliest cases were identified in the USA in 1988. 14 A pooled prevalence of faecal colonisation of 14% globally was estimated by a systematic review, 16 and Villa HE et al. 14 in Argentina quoted 5.4% of pregnant women in their study had ESBL‐producing E. coli vaginal colonisation revealing that colonisation with resistant E. coli is significant in pregnancy. A higher prevalence of 22% was reported in South‐Asia 16 where our patient came from.\n\nAccording to CDC, ESBL‐producing E. coli pose challenging infection control issues and are a serious global threat that requires prompt and sustained action. 16 Appropriate use of antibiotic therapy under the guidance of infectious disease team is imperative. Prophylactic use of antibiotics during conservative management of PROM and prompt delivery when indicated will help reduce the sequelae of infection. Screening strategies designed to monitor for ESBL‐producing E. coli could be useful in women from endemic areas to prevent perinatal transmission and the introduction of multiresistant strains to the maternity ward.\n\nCONFLICT OF INTEREST\n\nThe authors have no conflict of interest to disclose.\n\nAUTHOR CONTRIBUTION\n\nSAS and SA conceived the idea and reviewed literature. SAS, SA, AS, and LA contributed to care of patient and her neonate and drafting of the manuscript. All authors read and approved the final version.\n\nETHICAL APPROVAL\n\nInstitutional ethics committee approval was obtained for this case report, and written informed consent was obtained from all participants.\n\nCONSENT\n\nWritten informed consent was obtained from the patient/parents for their anonymized information to be published in this article. Documentation of the written consent will be provided to the journal upon request.\n\nACKNOWLEDGEMENTS\n\nWe would like to thank our other obstetric, anaesthetic, and neonatology colleagues who contributed to the care of the patient and her baby. We are also grateful to Mrs. Ramya Nambiyath for proofreading the manuscript.\n\nDATA AVAILABILITY STATEMENT\n\nAll data containing relevant information to support the study findings are provided in the manuscript.\n==== Refs\nREFERENCES\n\n1 Tita AT , Andrews WW . Diagnosis and management of clinical chorioamnionitis. Clin Perinatol. 2010;37 (2 ):339‐354. 10.1016/j.clp.2010.02.003 20569811\n2 Gibbs RS , Duff P . Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol. 1991;164 (5 ):1317‐1326.2035575\n3 Soper DE , Glen Mayhall C , Dalton HP . Risk factors for intraamniotic infection: a prospective epidemiologic study. Am J Obstet Gynecol. 1989;161 (3 ): 562‐566; discussion 566‐8.2782335\n4 Newton ER . Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol. 1993;36 (4 ):795‐808.8293582\n5 Higgins RD , Saade G , Polin RA , et al. Evaluation and management of women and newborns with a maternal diagnosis of chorioamnionitis: summary of a workshop. Obstet Gynecol. 2016;127 (3 ):426‐436.26855098\n6 Galli L , Whelehan V , Archer A , Dall’asta A , Chandraharan E . Cardiotocographic (CTG) changes observed with clinical and subclinical chorioamnionitis. Eur J Obstet Gynecol Reprod Biol. 2019;234 :e177. 10.1016/j.ejogrb.2018.08.547\n7 Thomson AJ , on behalf of the Royal College of Obstetricians and Gynaecologists . Care of women presenting with suspected preterm prelabour rupture of membranes from 24+0 weeks of gestation. BJOG. 2019;126 :e152‐e166.31207667\n8 Kacerovsky M , Musilova I , Hornychova H , et al. Bedside assessment of amniotic fluid interleukin‐6 in preterm prelabor rupture of membranes. Am J Obstet Gynecol. 2014;211 (4 ):385.e1‐e385.e9. 10.1016/j.ajog.2014.03.069 24705131\n9 Chaemsaithong P , Romero R , Korzeniewski SJ , et al. A point of care test for interleukin‐6 in amniotic fluid in preterm prelabor rupture of membranes: a step toward the early treatment of acute intra‐amniotic inflammation/infection. J Matern Fetal Neonatal Med. 2016;29 :360.25758620\n10 Zhu M , Jin Y , Duan Y , He M , Lin Z , Lin J . Multi‐drug resistant Escherichia coli causing early‐onset neonatal sepsis – a single center experience from China. Infect Drug Resist. 2019;12 :3695‐3702. 10.2147/IDR.S229799 31819551\n11 Conde‐Agudelo A , Romero R , Jung EJ , Garcia Sánchez ÁJ . Management of clinical chorioamnionitis: an evidence‐based approach. Am J Obstet Gynecol. 2020;223 (6 ):848‐869. 10.1016/j.ajog.2020.09.044. https://www.sciencedirect.com/science/article/pii/S0002937820311674 33007269\n12 Sukumaran S , Pereira V , Mallur S , Chandraharan E . Cardiotocograph (CTG) changes and maternal and neonatal outcomes in chorioamnionitis and/or funisitis confirmed on histopathology. Eur J Obstet Gynecol Reprod Biol. 2021;260 :183‐188. 10.1016/j.ejogrb.2021.03.029. Epub 2021 Mar 30 PMID: 33838555.33838555\n13 Kennard A , Foley MR , Jordan P . A case of haematogenous spread of E. coli causing clinical chorioamnionitis. Clin Med Rev Case Rep. 2015;2 (2 ):2378‐3656. 2:017 ISSN. 10.23937/2378-3656/1410017\n14 Villar HE , Aubert V , Baserni MN , Jugo MB . Maternal carriage of extended‐spectrum beta‐lactamase‐producing Escherichia coli isolates in Argentina. J Chemother. 2013;25 (6 ):324‐327. 10.1179/1973947813Y.0000000081. Epub 2013 Dec 6 PMID: 24091027.24091027\n15 Dolma K , Summerlin TL , Wongprasert H , Lal CV , Philips Iii JB , Winter L . Early‐onset neonatal sepsis with extended spectrum beta‐lactamase producing Escherichia coli in infants born to south and south‐east Asian immigrants: a case series. AJP Rep. 2018;08 (04 ):e277‐e279. 10.1055/s-0038-1675336. Epub 2018 Oct 29. PMID: 30377552; PMCID: PMC6205855.\n16 Alrowaily N , D'Souza R , Dong S , Chowdhury S , Ryu M , Ronzoni S . Determining the optimal antibiotic regimen for chorioamnionitis: a systematic review and meta‐analysis. Acta Obstet Gynecol Scand. 2021;100 (5 ):818‐831.33191493\n\n",
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"title": "Chorioamnionitis and neonatal sepsis due to extended-spectrum beta-lactamase-producing Escherichia coli infection: a case report.",
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{
"abstract": "There are little data on the pre- and post-liver transplantation (LT) outcomes of patients having autoimmune hepatitis-primary biliary cholangitis (AIH-PBC), AIH-primary sclerosing cholangitis (AIH-PSC), and AIH-small-duct PSC (AIH-SDPSC). The aim of this study was to analyze pre- and post-LT outcomes and survival of patients having different overlap syndromes (OS) undergoing LT.\n\n\n\nPatients with compatible clinical and pathologic features of AIH-PBC (n = 86), AIH-PSC (n = 22), and AIH-SDPSC (n = 9) were included in the study. Demographic, laboratory, clinical, and survival data were analyzed. Multivariable analyses were performed to determine factors predicting transplant-free survival.\n\n\n\nAIH-primary sclerosing cholangitis patients were less treatment-responsive and were more likely to undergo LT than other OS. No survival difference was noted among the 3 groups. Liver decompensation was independently associated with higher mortality (HR 21.78; 95% CI 2.50-190.01). Thirteen patients with OS underwent LT. One-year survival post-LT was 91.7%. Overall recurrence rate for OS post-LT was 8%.\n\n\n\nAIH-primary sclerosing cholangitis patients were more likely to require LT compared with patients having AIH-PBC. Transplant-free survival was similar among the three AIH-overlap syndromes. Allograft recurrence of OS occurred in about 10% of cases. Patients with OS appear to have good short- and medium-term post-LT outcomes in terms of graft function and overall survival.",
"affiliations": "Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.;Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Recanati-Miller Transplantation Institute, New York, NY, USA.",
"authors": "Chayanupatkul|Maneerat|M|0000-0002-1649-5373;Fiel|Maria Isabel|MI|;Schiano|Thomas D|TD|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13841",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "34(5)",
"journal": "Clinical transplantation",
"keywords": "clinical characteristics; liver transplantation; outcomes; overlap syndromes",
"medline_ta": "Clin Transplant",
"mesh_terms": "D015209:Cholangitis, Sclerosing; D019693:Hepatitis, Autoimmune; D006801:Humans; D008105:Liver Cirrhosis, Biliary; D016031:Liver Transplantation; D016019:Survival Analysis; D013577:Syndrome",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e13841",
"pmc": null,
"pmid": "32073690",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The clinical characteristics, pre- and post-liver transplantation outcomes in patients having autoimmune overlap syndromes.",
"title_normalized": "the clinical characteristics pre and post liver transplantation outcomes in patients having autoimmune overlap syndromes"
} | [
{
"companynumb": "NVSC2020TH068680",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "The aim of this study was to evaluate the performance of radiologists in the diagnosis of acute intestinal ischemia using specific multi-detector CT findings. The abdominal CT scans of 90 patients were retrospectively reviewed by three radiologists: an abdominal imaging specialist, an experienced general radiologist, and a senior resident. Forty-seven patients had surgically proven intestinal ischemia and comprised the case group, while 43 patients had no evidence of intestinal ischemia at surgery and comprised the control group. Images were reviewed in a random and blinded fashion. Radiologists' performance in diagnosing bowel ischemia from other bowel pathologies was evaluated. The sensitivity, specificity, and accuracy for diagnosing bowel ischemia were 89%, 67%, and 79% for the abdominal imager; 83%, 67%, and 76% for the general radiologist; and 66%, 83%, and 74% for the senior resident, respectively. The calculated kappa value for inter-observer agreement regarding the presence of bowel ischemia was 0.79. CT findings that significantly distinguished bowel ischemia from other bowel pathologies were decreased or absent bowel wall enhancement, filling defect in the superior mesenteric artery, small bowel pneumatosis, and gas in the portal veins or superior mesenteric vein. For most of these signs, there was good inter-observer agreement. Radiologists' performance in diagnosing bowel ischemia is good, but lower than previously reported since a significant amount of cases are evaluated using a suboptimal CT technique. Radiologists' experience and expertise have an important impact on their performance.",
"affiliations": "Department of Radiology, Tel Aviv Sourasky Medical Center, 6 Weitzman Street, Tel Aviv 64239, Israel. ablachar@gmail.com",
"authors": "Blachar|Arye|A|;Barnes|Sophie|S|;Adam|Sharon Z|SZ|;Levy|Gad|G|;Weinstein|Iuliana|I|;Precel|Ronit|R|;Federle|Michael P|MP|;Sosna|Jacob|J|",
"chemical_list": "D003287:Contrast Media; D007483:Iothalamic Acid; D007472:Iohexol; C002587:ioxitalamic acid",
"country": "United States",
"delete": false,
"doi": "10.1007/s10140-011-0965-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-3004",
"issue": "18(5)",
"journal": "Emergency radiology",
"keywords": null,
"medline_ta": "Emerg Radiol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002983:Clinical Competence; D002985:Clinical Protocols; D003287:Contrast Media; D005260:Female; D006801:Humans; D007422:Intestines; D007472:Iohexol; D007483:Iothalamic Acid; D007511:Ischemia; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9431227",
"other_id": null,
"pages": "385-94",
"pmc": null,
"pmid": "21655965",
"pubdate": "2011-10",
"publication_types": "D016428:Journal Article",
"references": "11152781;11687686;20308497;17157468;17502217;12601205;10992012;12591685;9530294;14620718;11706217;7568858;11756093;12944600;18425546;10228517;9356638;21132342;10682769;18690454;12006685;17449781;11312162;17114622;11717075;9240545;18356421;20393776;15159262;11090385;19155403",
"title": "Radiologists' performance in the diagnosis of acute intestinal ischemia, using MDCT and specific CT findings, using a variety of CT protocols.",
"title_normalized": "radiologists performance in the diagnosis of acute intestinal ischemia using mdct and specific ct findings using a variety of ct protocols"
} | [
{
"companynumb": "IL-PFIZER INC-2016419011",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE SODIUM SUCCINATE"
},
"drugaddit... |
{
"abstract": "Patients with diabetes mellitus are often susceptible to hypoglycemic episodes while on therapy. Most of these are attributed to inappropriate dosing of hypoglycemic agents, dietary indiscretion, or acute illness. Medications being used concomitantly should be reviewed closely when the etiology of hypoglycemia is unclear. A fifty-six-year-old woman with a history of diabetes mellitus (on metformin monotherapy) was found unresponsive at home. Her fingerstick glucose was 15 mg/dL for which she received 50% dextrose intravenously. The patient never had any previous documented hypoglycemic episodes. She had recently been diagnosed with pneumonia and was prescribed oral levofloxacin therapy. The patient had taken 4 doses of levofloxacin before the onset of hypoglycemia. These episodes recurred over the next 2 days needing close intensive care unit monitoring, dextrose infusion, and glucagon administration. Basic blood/urine investigations, cortisol and thyroid profile were normal except for low blood glucose and renal insufficiency (serum creatinine 1.4 mg/dL and creatinine clearance 42 mL/min). HbA1c was 6.8% (4.4%-6.4%), insulin 51.3 μU/mL (2.6-24.9 μU/mL), IGF-1 301 ng/mL (27-223 ng/mL), and C peptide 9.3 ng/mL (0.8-3.5 ng/mL). These levels were elevated but were deemed nondiagnostic because of fluctuating glucose values after glucagon administration. A blood screen for sulfonylureas and metaglinides was negative. A seventy-two-hour fast was performed to rule out hyperinsulinemic hypoglycemic syndromes; however, blood glucose values remained consistently above 120 mg/dL during this period. Thus, after exclusion of other causes, we utilized the adverse drug reaction probability scale and concluded that hypoglycemia was probably related to recent use of levofloxacin.",
"affiliations": "1Departments of Internal Medicine and 2Gastroenterology, SUNY Upstate Medical University, Syracuse, NY.",
"authors": "Bansal|Nidhi|N|;Manocha|Divey|D|;Madhira|Bhaskar|B|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D064704:Levofloxacin",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e31829ed212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "22(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001786:Blood Glucose; D003128:Coma; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D064704:Levofloxacin; D008875:Middle Aged; D011014:Pneumonia",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e48-51",
"pmc": null,
"pmid": "23896743",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-threatening metabolic coma caused by levofloxacin.",
"title_normalized": "life threatening metabolic coma caused by levofloxacin"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US01829",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nA case report of the use of linezolid and daptomycin for the treatment of multidrug-resistant right-sided infective endocarditis is presented.\n\n\nCONCLUSIONS\nA 36-year-old patient with a history of intravenous drug use was hospitalized for treatment of native tricuspid valve endocarditis resulting in persistent methicillin-resistant Staphylococcus aureus bacteremia. During the admission the patient was unsuccessfully treated with vancomycin monotherapy (final E-test minimum inhibitory concentration, 4 μg/mL). The patient's treatment was switched to daptomycin and gentamicin, with no improvement in blood culture results over 4 days. Gentamicin was discontinued, and linezolid was administered in combination with daptomycin; bacteremia was cleared after 13 days of linezolid and daptomycin combination therapy. Due to daptomycin resistance (minimum inhibitory concentration, 4 μg/mL), gentamicin was substituted for daptomycin due to the former agent's synergistic effects with linezolid. After 23 days of therapy the patient was transferred to another facility for a tricuspid valve replacement procedure, which was completed without complications. The patient was transferred in stable condition to a skilled nursing facility to continue antibiotic therapy lasting 6 weeks from the date of surgery. The patient's blood cultures remained negative.\n\n\nCONCLUSIONS\nA 36-year-old woman with resistant tricuspid valve endocarditis was successfully treated with linezolid in combination with daptomycin.",
"affiliations": "College of Pharmacy, Western University, Pomona, CA.;Pharmacy, San Leandro Hospital, San Leandro, CA.",
"authors": "Galanter|Kayla M|KM|;Ho|Jackie|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins; D014640:Vancomycin; D000069349:Linezolid; D017576:Daptomycin",
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxz101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "76(14)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": " daptomycin resistance; linezolid synergy; multidrug-resistant endocarditis; salvage therapy; vancomycin-resistant Staphylococcus aureus",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D017576:Daptomycin; D024901:Drug Resistance, Multiple, Bacterial; D057915:Drug Substitution; D004357:Drug Synergism; D004697:Endocarditis, Bacterial; D005260:Female; D005839:Gentamicins; D006801:Humans; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D014261:Tricuspid Valve; D014640:Vancomycin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1033-1036",
"pmc": null,
"pmid": "31201773",
"pubdate": "2019-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of tricuspid valve endocarditis with daptomycin and linezolid therapy.",
"title_normalized": "treatment of tricuspid valve endocarditis with daptomycin and linezolid therapy"
} | [
{
"companynumb": "US-AXELLIA-002528",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 61-year-old woman with chronic lymphocytic leukaemia, with Richter's transformation to a diffuse, large, B-cell lymphoma, treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone and in complete remission, presented to the hospital after her platelets were found to be 2×10³/µL in outpatient laboratory studies. She initially underwent a platelet transfusion without improvement. This was followed by 4 days of high-dose dexamethasone and intravenous immunoglobulin, which again yielded no meaningful effect. Even a single-dose rituximab failed to achieve a platelet increase after 5 days of monitoring. The patient was then given 2 mg of intravenous vincristine along with a high-dose of dexamethasone and IVIG and demonstrated substantial recovery in platelets to >50×10³/µL within 48 hours. This case study provides an overview of the current management strategies for idiopathic thrombocytopenic purpura that is unresponsive to conventional medical therapy and particularly sheds light on their therapeutic benefits and potential adverse effects.",
"affiliations": "Department of Internal Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.;Department of Hematology-Oncology, Louisville School of Medicine, Louisville, Kentucky, USA.;Department of Hematology-Oncology, Louisville School of Medicine, Louisville, Kentucky, USA.;Department of Hematology-Oncology, Louisville School of Medicine, Louisville, Kentucky, USA.",
"authors": "Reynolds|Samuel Benjamin|SB|;Hashmi|Hamza|H|;Ngo|Phuong|P|;Kloecker|Goetz|G|",
"chemical_list": "D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D050257:Tubulin Modulators; D014750:Vincristine; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227717",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(1)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); malignant and benign haematology; pathology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002985:Clinical Protocols; D003907:Dexamethasone; D058492:Drug Repositioning; D018432:Drug Resistance, Multiple; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D017713:Platelet Transfusion; D016553:Purpura, Thrombocytopenic, Idiopathic; D016896:Treatment Outcome; D050257:Tubulin Modulators; D014750:Vincristine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30642865",
"pubdate": "2019-01-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17698634;29234214;29738335;12944568;28695025;25448666",
"title": "Rescue therapy for acute idiopathic thrombocytopenic purpura unresponsive to conventional treatment.",
"title_normalized": "rescue therapy for acute idiopathic thrombocytopenic purpura unresponsive to conventional treatment"
} | [
{
"companynumb": "US-TEVA-2019-US-1017187",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) in patients with metastatic renal cell carcinoma (RCC).\n\n\nMETHODS\nBetween June 1998 and February 1999, 41 patients with metastatic RCC were enrolled onto this multi-institutional phase II study of gemcitabine 600 mg/m(2) over 30 minutes on days 1, 8, and 15 and 5-FU 150 mg/m(2)/d via continuous IV infusion through a permanent catheter on days 1 to 21 of a 28-day cycle. Patients had a Cancer and Leukemia Group B performance status of 0 or 1, with a median time since diagnosis of metastatic disease of 10 months (range, 0 to 129 months). Thirty-three patients (80%) had multiple metastatic sites, and 34 patients (83%) had prior chemotherapy or immunotherapy.\n\n\nRESULTS\nOf the 39 assessable patients, there were no complete responses but seven partial responses (objective response rate = 17%; 95% confidence interval, 8% to 34%). Five minor responses (25% to 50% decreased tumor size) were also observed. The duration of response for the seven partial responders was 2, 3, 7, 8, 10, 11, and 14 months. Median progression-free survival for the gemcitabine/5-FU group was 28.7 weeks versus 8 weeks for a similar cohort of patients treated on previous phase II studies at the University of Chicago (P =.008). The regimen was well tolerated, with fatigue, mucositis, nausea/vomiting, and grade 2 hematologic toxicities being most common.\n\n\nCONCLUSIONS\nWeekly gemcitabine with continuous infusion 5-FU is an active combination in patients with metastatic RCC. Therapy was well tolerated and produced an improvement in progression-free survival over historical controls.",
"affiliations": "Section of Hematology/Oncology, University of Chicago Hospitals, IL 60637-1470, USA. brini@medicine.bsd.uchicago.edu",
"authors": "Rini|B I|BI|;Vogelzang|N J|NJ|;Dumas|M C|MC|;Wade|J L|JL|;Taber|D A|DA|;Stadler|W M|WM|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2000.18.12.2419",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "18(12)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell; D003841:Deoxycytidine; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2419-26",
"pmc": null,
"pmid": "10856102",
"pubdate": "2000-06",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer.",
"title_normalized": "phase ii trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer"
} | [
{
"companynumb": "CA-PFIZER INC-2017550997",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nWhether intravenous recombinant tissue plasminogen activator (r-TPA) therapy can be administered in acute ischemic stroke patients treated with novel oral anticoagulants (NOACs), including rivaroxaban, remains controversial.\nA 76-year-old woman with nonvalvular atrial fibrillation, who had been receiving 15 mg rivaroxaban once daily, was brought to the emergency department with right-side hemiparesis and aphasia. The onset of neurological deficits occurred 8 hours after the last dose of rivaroxaban administration.\n\n\nMETHODS\nThe patient was diagnosed with acute ischemic stroke.\n\n\nMETHODS\nIntravenous infusion of 0.6 mg/kg of r-TPA (total dose: 29 mg) was performed 9 hours and 40 minutes after the last rivaroxaban administration. During r-TPA infusion, improvement in the patient's neurological deficit was observed.\n\n\nRESULTS\nThe clinical picture evidently improved from with National Institutes of Health Stroke Scale 21 to 16 on completion of r-TPA treatment.\n\n\nCONCLUSIONS\nAlthough current guidelines do not recommend administering thrombolytics in patients using NOACs with a doubtful anticoagulation status and administered within the last 24 or, even more strictly, 48 hours, this and other case studies suggest that r-TPA treatment could be considered in selected acute ischemic stroke patients receiving rivaroxaban or other Xa inhibitors, taking the patient's clinical condition and the prospective clinical benefits of r-TPA into account.",
"affiliations": "Department of Neurology, Taipei Medical University, Shuang Ho Hospital.;Department of Neurology, Taipei Medical University, Shuang Ho Hospital.;Department of Neurology, Taipei Medical University, Shuang Ho Hospital.",
"authors": "Chao|Yen-Tung|YT|;Hu|Chaur-Jong|CJ|;Chan|Lung|L|",
"chemical_list": "D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D000069552:Rivaroxaban; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000014560",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30813169MD-D-18-0760710.1097/MD.0000000000014560145605300Research ArticleClinical Case ReportThrombolysis in an acute ischemic stroke patient with rivaroxaban anticoagulation A case reportChao Yen-Tung MDaHu Chaur-Jong MDabcChan Lung MD, PhDabc∗NA. a Department of Neurology, Taipei Medical University, Shuang Ho Hospitalb Department of Neurology, School of Medicine, College of Medicinec Taipei Neuroscience Institute, Taipei Medical University, New Taipei City, Taiwan.∗ Correspondence: Lung Chan, College of Medicine and Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan (e-mail: cjustinmd@gmail.com).2 2019 22 2 2019 98 8 e1456019 10 2018 14 1 2019 23 1 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nWhether intravenous recombinant tissue plasminogen activator (r-TPA) therapy can be administered in acute ischemic stroke patients treated with novel oral anticoagulants (NOACs), including rivaroxaban, remains controversial.\n\nPatient concerns:\nA 76-year-old woman with nonvalvular atrial fibrillation, who had been receiving 15 mg rivaroxaban once daily, was brought to the emergency department with right-side hemiparesis and aphasia. The onset of neurological deficits occurred 8 hours after the last dose of rivaroxaban administration.\n\nDiagnosis:\nThe patient was diagnosed with acute ischemic stroke.\n\nInterventions:\nIntravenous infusion of 0.6 mg/kg of r-TPA (total dose: 29 mg) was performed 9 hours and 40 minutes after the last rivaroxaban administration. During r-TPA infusion, improvement in the patient's neurological deficit was observed.\n\nOutcomes:\nThe clinical picture evidently improved from with National Institutes of Health Stroke Scale 21 to 16 on completion of r-TPA treatment.\n\nLessons:\nAlthough current guidelines do not recommend administering thrombolytics in patients using NOACs with a doubtful anticoagulation status and administered within the last 24 or, even more strictly, 48 hours, this and other case studies suggest that r-TPA treatment could be considered in selected acute ischemic stroke patients receiving rivaroxaban or other Xa inhibitors, taking the patient's clinical condition and the prospective clinical benefits of r-TPA into account.\n\nKeywords\nischemic strokenovel oral anticoagulantsrivaroxabanthrombolysistissue plasminogen activatorOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nWhether intravenous recombinant tissue plasminogen activator (r-TPA) therapy can be administered in acute ischemic stroke patients treated with rivaroxaban remains controversial.[1–12] Approximately, 1% to 2% of patients with nonvalvular atrial fibrillation will experience an acute ischemic stroke despite receiving novel oral anticoagulants (NOACs).[13] Thus far, r-TPA treatment has not been recommended for patients receiving rivaroxaban because of the increased risk of intracranial hemorrhage, in the absence of adequate drug elimination, and clearance or specific tests validating the lack of an anticoagulant effect.[14,15] However, many of these patients will be critically evaluated at emergency rooms for eligibility for acute recanalization therapies including r-TPA and the use of intravenous thrombolysis could be safe under certain conditions. Withholding r-TPA therapy with no exception to all patients with acute ischemic stroke under rivaroxaban may also deny a considerable number of stroke patients an effective and innocuous treatment.\n\n2 Case report\nWe report the case of a 76-year-old woman with a history of nonvalvular atrial fibrillation and hypertension, who had been receiving 15 mg rivaroxaban once daily since an episode of right middle cerebral arterial territory infarction 19 months earlier. Her CHADS2-VASc was 6. Adequate adherence to treatment was confirmed by her son. She arrived in the emergency department with an abrupt onset of consciousness disturbance, expressive aphasia, and right hemiparesis that occurred 30 minutes before the initial evaluation. The National Institutes of Health Stroke Scale (NIHSS) was 21. The onset of neurological deficits occurred 8 hours after the last dose of rivaroxaban administration. Clinical data on admission were as follows: blood pressure, 121/76 mmHg; prothrombin time (PT), 16.4 seconds (control: 11.0–14.5 seconds); international normalized ratio (INR), 1.41; activated partial thromboplastin time (aPTT), 137.0 seconds (normal: 32.0–45.1 seconds); thrombocyte count, 133 × 103 mm3 (normal: 130 × 103–400 × 103 mm3); and creatinine level, 0.71 mg/dL, with an estimated glomerular filtration rate of 85.1 mL/min/1.73 m2. Electrocardiography revealed atrial fibrillation. Conventional brain noncontrast computed tomography (CT) showed encephalomalacia at the right fronto-temporo-parietal lobe due to a previous infarction of the right middle cerebral arterial territory. CT angiography revealed luminal narrowing of the right cavernous internal carotid artery, left cavernous internal carotid artery, and basilar artery. An acute ischemic stroke was diagnosed. We did not initiate endovascular intervention because her son did not agree to this invasive treatment, citing personal reasons. After considering the patient's clinical condition and the prospective clinical benefits of r-TPA, we decided to treat the patient in spite of the guideline recommending an at least 24-hour interval between rivaroxaban intake and thrombolysis. Intravenous infusion of 0.6 mg/kg of r-TPA (total dose: 29 mg) was thus performed 9 hours and 40 minutes after the last rivaroxaban administration, with informed consent. During r-TPA infusion, improvement in the patient's neurological deficit was observed (NIHSS score, 16 on completion of infusion), and her blood pressure and heart rate were adequately controlled. Brain magnetic resonance imaging (Fig. 1A) showed gyriform diffusion restriction in the left frontal, occipito-temporal, and parietal cortico-juxtacortical imaging series 16 hours after the onset of symptoms. A brain CT scan (Fig. 1B) performed 24 hours after r-TPA administration revealed no hemorrhagic change, with an NIHSS score of 14. After 4 weeks, the patient was discharged with an NIHSS score of 13 and remaining neurological sequelae of the right hemiparesis and motor aphasia.\n\nFigure 1 (A) Diffusion-weighted image. Hyperintense areas are observed in the left cortex and the posterior part of the middle cerebral arterial territory. (B) Computed tomography showing left cerebral infarction without hemorrhagic changes in the same site.\n\n3 Discussion\nThe safety and protocol for use of thrombolytic therapy after recent NOAC intake has still not been established. No randomized trials on the safety of r-TPA with rivaroxaban have been performed. Both the guidelines on thrombolysis and many studies insist on the necessity of normal coagulant tests as crucial criteria for r-TPA eligibility.[16,17] However, conventional tests such as prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) are unreliable for measuring the anticoagulant effects of any NOACs.[4,18] Although anti-Xa activity assays measure rivaroxaban concentration more precisely, they are not generally accessible, and their results may not be immediately available.[19,20] Several other cases describing thrombolytic treatment in patients receiving rivaroxaban without hemorrhagic complications have been reported.[1,6,8,21,22] The r-TPA dosages administered in such patients, including the standard protocol (0.9 mg/kg) and adjusted dose (0.6 mg/kg), are variably performed, with quite different outcomes.[1,2,4–11] Fatal intraperitoneal hemorrhage with no clinical improvement was reported in a patient receiving r-TPA treatment at a dose of 0.6 mg/kg.[2] Considering the prolonged aPTT test and uncertain anticoagulation status, we adopted a strategy of low-dose (0.6 mg/kg) r-TPA treatment. Nevertheless, one retrospective study indicated that intravenous r-TPA in NOAC patients (including 129 cases with rivaroxaban), as selected by their treating physician, is not associated with statistically significantly increased symptomatic intracranial hemorrhage risk (either serious systemic hemorrhage or r-TPA complication) compared with patients receiving warfarin or without an oral anticoagulant.[23] Although rivaroxaban may favor hemorrhagic transformation, no correlation exists with the patient's clinical severity after intravenous thrombolysis.[24] Moreover, one study on Wistar rats revealed downregulation of protease-activated receptor (PAR)-1 and PAR-2 expression in peri-ischemic lesions in the rivaroxaban group compared with the warfarin group. PAR-1 and PAR-2 play a role in modulating the effects of coagulation factors such as thrombin, factor Xa, and TPA and are associated with inflammation and neurodegeneration in stroke.[25] This mechanism may also explain why, after induced cerebral artery occlusion and reperfusion with r-TPA, Wistar rats on rivaroxaban had a significantly lower intracranial hemorrhage volume.[25]\n\nIn our case, blood sampling was performed 9 hours and r-TPA administered 9 hours and 40 minutes after the last rivaroxaban intake, when the anticoagulant effect of rivaroxaban could be potent. Specifically, intravenous infusion of 0.6 mg/kg of r-TPA (total dose: 29 mg) was performed in a patient with extended aPTT. Considering at once the stroke severity, the expected clinical benefit, and the lack of alternative treatment, we explained the risks and benefits of this treatment to her relatives and performed it with their informed consent. No adverse events or intracranial hemorrhage occurred. The results in this case could imply that routine coagulation tests cannot precisely reflect plasma concentration or the anticoagulant effect of rivaroxaban mentioned in other studies.[26] However, this may also have been only a special case, so that whether the same clinical improvement and outcome could be reproduced is debatable.\n\n4 Conclusion\nLittle information is available regarding cases treated with intravenous r-TPA while receiving rivaroxaban. Although current guidelines do not recommend administering thrombolytics in patients using NOACs with a doubtful anticoagulation status and administered within the last 24 or, even more strictly, 48 hours, this and other case studies, although limited and debatable, suggest that low-dosage and, if possible, individualized r-TPA treatment could be considered in selected acute ischemic stroke patients receiving rivaroxaban or other Xa inhibitors. However, additional studies are necessary to establish the optimal treatment strategy and safety profiles of thrombolysis with r-TPA in stroke patients treated with NOACs.\n\nAcknowledgments\nThis manuscript was edited by Wallace Academic Editing.\n\nAuthor contributions\nConceptualization: Yen Tung Chao.\n\nData curation: Yen Tung Chao.\n\nFormal analysis: Yen Tung Chao.\n\nProject administration: Chaur-Jong Hu.\n\nResources: Yen Tung Chao.\n\nSoftware: Yen Tung Chao.\n\nSupervision: Lung Chan, Chaur-Jong Hu.\n\nValidation: Lung Chan.\n\nWriting – original draft: Yen Tung Chao.\n\nWriting – review & editing: Yen Tung Chao, Lung Chan.\n\nYen Tung Chao orcid: 0000-0001-8812-6748.\n\nAbbreviations: aPTT = activated partial thromboplastin time, INR = international normalized ratio, NIHSS = National Institutes of Health Stroke Scale, NOACs = novel oral anticoagulants, PAR = protease-activated receptors, PT= prothrombin time, r-TPA = recombinant tissue plasminogen activator, Xa = ten activated.\n\nExempt from informed consent for the case, Taipei Medical University - Joint Institutional Review Board (TMU-JIRB) approval No. N201809044.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Ishihara H Torii H Imoto H \nIntravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban . J Stroke Cerebrovasc Dis \n2014 ;23 :e457–9 .25280819 \n[2] Anan C Oomura M Saeki T \nFatal intraperitoneal bleeding after intravenous administration of tissue plasminogen activator . J Stroke Cerebrovasc Dis \n2015 ;24 :e177–8 .25899160 \n[3] Korya D Dababneh H Moussavi M \nIntravenous thrombolysis in a patient using factor Xa inhibitor . J Vasc Interv Neurol \n2014 ;7 :1–4 .\n[4] Kawiorski MM Alonso-Canovas A de Felipe Mimbrera A \nSuccessful intravenous thrombolysis in acute ischaemic stroke in a patient on rivaroxaban treatment . Thromb Haemost \n2014 ;111 :557–8 .24196421 \n[5] van Hooff RJ Nieboer K De Smedt A \nIntravenous thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke in a patient treated with rivaroxaban . Clin Neurol Neurosurg \n2014 ;122 :133–4 .24813326 \n[6] Landais A Ginoux C \nIntravenous thrombolysis for acute ischemic stroke in a patient receiving rivaroxaban . J Stroke Cerebrovasc Dis \n2015 ;24 :e73–4 .25561312 \n[7] Fluri F Heinen F Kleinschnitz C \nIntravenous thrombolysis in a stroke patient receiving rivaroxaban . Cerebrovasc Dis Extra \n2013 ;3 :153–5 .24348499 \n[8] Nardetto L Tonello S Zuliani L \nIntravenous thrombolysis for acute stroke in a patient on treatment with rivaroxaban . Neurol Sci \n2015 ;36 :2291–2 .26209928 \n[9] Bornkamm K Harloff A \nSafe intravenous thrombolysis in acute stroke despite treatment with rivaroxaban . J Clin Neurosci \n2014 ;21 :2012–3 .24938385 \n[10] Neal AJ Campbell BC Chandratheva A \nIntravenous thrombolysis for acute ischaemic stroke in the setting of rivaroxaban use . J Clin Neurosci \n2014 ;21 :2013–5 .24984844 \n[11] Seiffge DJ Traenka C Gensicke H \nIntravenous thrombolysis in stroke patients receiving rivaroxaban . Eur J Neurol \n2014 ;21 :e3–4 .25133279 \n[12] Seiffge DJ Hooff RJ Nolte CH \nRecanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome . Circulation \n2015 ;132 :1261–9 .26232277 \n[13] Powers WJ Derdeyn CP Biller J \n2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment . Stroke \n2015 ;46 :3020–35 .26123479 \n[14] Heidbuchel H Verhamme P Alings M \nUpdated European heart rhythm association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: executive summary . Eur Heart J \n2017 ;38 :2137–49 .27282612 \n[15] Heidbuchel H Verhamme P Alings M \nUpdated European heart rhythm association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation . Europace \n2015 ;17 :1467–507 .26324838 \n[16] Jauch EC Saver JL Adams HP \nGuidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association . Stroke \n2013 ;44 :870–947 .23370205 \n[17] Alberts MJ Bernstein RA Naccarelli GV \nUsing dabigatran in patients with stroke: a practical guide for clinicians . Stroke \n2012 ;43 :271–9 .22156688 \n[18] Folyovich A Varga V Béres-Molnár KA \nDilemmaof indication for thrombolysis in a patient with acuteischemic stroke treated with a novel oral anticoagulant . J Stroke Cerebrovasc Dis \n2014 ;23 :580–2 .23721623 \n[19] Samama MM Contant G Spiro TE \nLaboratory assessment of rivaroxaban: a review . Thromb J \n2013 ;11 :11.23822763 \n[20] Samama MM Contant G Spiro TE \nEvaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls . Thromb Haemost \n2012 ;107 :379–87 .22187012 \n[21] Cappellari M Bovi P \nIntravenous thrombolysis for stroke in patients taking non-VKA oral anticoagulants: an update . Thromb Haemost \n2015 ;114 :440–4 .25809649 \n[22] Penge J Hashi S Simister R \nSuccessful intravenous thrombolysis following full dose rivaroxaban 5 hours before ictus . Br J Hosp Med (Lond) \n2015 ;76 :244–5 .25853357 \n[23] Xian Y Federspiel JJ Hernandez AF \nUse of intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke who take non-vitamin K antagonist oral anticoagulants before stroke . Circulation \n2017 ;135 :1024–35 .28119380 \n[24] Rota E Bruzzone G Agosti S \nA case report of parenchymal hematoma after intravenous thrombolysis in a rivaroxaban-treated patient . Medicine (Baltimore) \n2017 ;96 :e9435.29390574 \n[25] Morihara R Yamashita T Kono S \nReduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2 . J Neurosci Res \n2017 ;95 :1818–28 .28035779 \n[26] Jauch EC Saver JL Adams HP Jr \nGuidelines for the early management of patients with acuteischemic stroke: a guideline for healthcare professionalsfrom the American Heart Association/American Stroke Association . Stroke J Cereb Circ \n2013 ;44 :870–947 .\n\n",
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"issue": "98(8)",
"journal": "Medicine",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D002545:Brain Ischemia; D065427:Factor Xa Inhibitors; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D007262:Infusions, Intravenous; D000069552:Rivaroxaban; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed",
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"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22156688;22187012;23370205;23721623;23822763;24196421;24348499;24813326;24938385;24984844;25133279;25280819;25298850;25561312;25809649;25853357;25899160;26123479;26209928;26232277;26324838;27282612;28035779;28119380;29390574",
"title": "Thrombolysis in an acute ischemic stroke patient with rivaroxaban anticoagulation: A case report.",
"title_normalized": "thrombolysis in an acute ischemic stroke patient with rivaroxaban anticoagulation a case report"
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"abstract": "Primary amebic meningoencephalitis is a rare, usually fatal disease, caused by Naegleria fowleri. This case highlights the challenging clinicopathologic diagnosis in a 13-year-old boy who swam in freshwater in northern Florida where a previous case had exposure to a body of water on the same property in 2009.",
"affiliations": "Department of Pediatrics, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 36210, USA.;Department of Pediatrics, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 36210, USA.;Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 32610, USA.;Division of Disease Control and Health Protection, Florida Department of Health, 200 Ringling Blvd, Sarasota, FL, 34237, USA.;Division of Disease Control and Health Protection, Florida Department of Health, 200 Ringling Blvd, Sarasota, FL, 34237, USA.;National Center for Emerging and Zoonotic Infectious Diseases, Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA.;National Center for Emerging and Zoonotic Infectious Diseases, Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA.;National Center for Emerging and Zoonotic Infectious Diseases, Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA.;Department of Pediatrics, Division of Hospital Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 36210, USA.;Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 32610, USA.;Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 36210, USA.",
"authors": "Anjum|Saad K|SK|;Mangrola|Karna|K|;Fitzpatrick|Garrett|G|;Stockdale|Kimberly|K|;Matthias|Laura|L|;Ali|Ibne Karim M|IKM|;Cope|Jennifer R|JR|;O'Laughlin|Kevin|K|;Collins|Shelley|S|;Beal|Stacy G|SG|;Saccoccio|Frances M|FM|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.idcr.2021.e01208",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00164-5\n10.1016/j.idcr.2021.e01208\ne01208\nCase Report\nA case report of primary amebic meningoencephalitis in North Florida\nAnjum Saad K. a\nMangrola Karna a\nFitzpatrick Garrett b\nStockdale Kimberly c\nMatthias Laura c\nAli Ibne Karim M. d\nCope Jennifer R. d\nO’Laughlin Kevin de\nCollins Shelley f\nBeal Stacy G. b\nSaccoccio Frances M. fsaccoccio@peds.ufl.edu\ng⁎\na Department of Pediatrics, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 36210, USA\nb Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 32610, USA\nc Division of Disease Control and Health Protection, Florida Department of Health, 200 Ringling Blvd, Sarasota, FL, 34237, USA\nd National Center for Emerging and Zoonotic Infectious Diseases, Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA\ne Epidemic Intelligence Service, Division of Foodborne, Waterborne, and Environmental Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA, 30329, USA\nf Department of Pediatrics, Division of Hospital Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 36210, USA\ng Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Florida, 1600 SW Archer Rd, Gainesville, FL, 36210, USA\n⁎ Corresponding author. fsaccoccio@peds.ufl.edu\n28 6 2021\n2021\n28 6 2021\n25 e0120823 6 2021\n26 6 2021\n27 6 2021\n© 2021 Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPrimary amebic meningoencephalitis is a rare, usually fatal disease, caused by Naegleria fowleri. This case highlights the challenging clinicopathologic diagnosis in a 13-year-old boy who swam in freshwater in northern Florida where a previous case had exposure to a body of water on the same property in 2009.\n\nKeywords\n\nNaegleria fowleri\nPrimary amebic meningoencephalitis\nCNS protozoal infections\n==== Body\nIntroduction\n\nPrimary amebic meningoencephalitis (PAM) is a rapid and usually fatal disease of the central nervous system caused by Naegleria fowleri, a free-living ameba that lives in warm freshwater. The ameba enters the body through the nasal passage, crosses the cribriform plate, and travels to the brain [1]. The Centers for Disease Control and Prevention (CDC) identified 148 cases in the United States from 1962 through 2019. The majority of these cases occurred in the southern United States in males (76 %) with a median age of 12 years [2]. Recently, CDC estimated that there are 16 cases of PAM in the United States annually [3].\n\nCase report\n\nA 13-year-old Caucasian boy with a history of headaches had been on a camping trip in July 2020 that included swimming at a water park in northern Florida. Three days after he returned, he developed a severe headache, fevers and intractable emesis. On the day of symptom onset, he did not respond to acetaminophen and ibuprofen. His parents sought evaluation at an urgent care provider where he tested negative for COVID-19. He then went to a hospital where he received ondansetron, acetaminophen, ibuprofen, diphenhydramine, ketorolac, chlorpromazine, and benzylpenicillin for a tonsillolith. He remained symptomatic and was brought to our hospital. Initial workup included a comprehensive metabolic panel within normal limits, a complete blood count with a white blood cell count of 12,700/ɥL with segmented neutrophil predominance (87.8 %), and a C-reactive protein (CRP) of 14.9 mg/L. His emesis continued along with poor oral intake. Thus, he was admitted for further workup.\n\nHe began demonstrating hemodynamic instability, altered mental status, and meningeal signs approximately 6 h into admission. Vital signs suggested increased intracranial pressure (ICP) prompting an urgent computed tomography (CT) scan. Fluid resuscitation was initiated, and ceftriaxone was given. His care was escalated to the Pediatric Intensive Care Unit (PICU). A lumbar puncture was performed. Opening pressure was >36 cm H2O; cerebrospinal fluid (CSF) was turbid with a glucose of 26 mg/dL, protein of 389 mg/dL, and leukocyte count of 670/cu mm (90 % segmented neutrophils). This raised concern for bacterial etiology that may have been partially treated with benzylpenicillin. The preliminary pathology report described a predominance of mature neutrophils with scattered lymphocytes and macrophages. Acyclovir and vancomycin were started in addition to ceftriaxone for suspected severe meningitis. A repeat CRP was performed on day 4 of admission and showed an increase to 285 mg/L.\n\nIn the PICU, 12 h into admission, he continued to show signs of increased ICP. He was treated with mannitol and 3% normal saline due to concern for cerebral edema. His mentation improved momentarily, but he developed respiratory failure and was intubated. A brain magnetic resonance imaging (MRI) study revealed leptomeningeal enhancement without herniation. Neurosurgery was consulted for the increased ICP and placed an external ventricular drain (EVD). His symptoms persisted, and another CT scan suggested early transtentorial herniation. Neurosurgery thus placed a second EVD. A CSF sample from this EVD showed protein of >1gm/dL, and a Wright-Giemsa stain showed amebic trophozoites with exuberant neutrophilic response (Fig. 1). Per CDC recommendations, he was started on miltefosine, amphotericin B, fluconazole, rifampin, azithromycin, and dexamethasone approximately 62 h after symptom onset. Despite aggressive intervention, there was no response on repeat neurological examination. His parents withdrew care four days after presentation.Fig. 1 Wright-Giemsa stain of CSF demonstrating N. fowleri organisms and inflammatory cells. A) Three organisms (arrowheads) adjacent a segmented neutrophil showing prominent vacuolation (arrow). B) Three vacuolated trophozoites are pictured on high-magnification. A single small, pale nucleus can be identified in each organism, each of which is smaller than the individual segments of surrounding segmented neutrophils. C) A single trophozoite is present at the bottom of the field (arrowhead), not to be confused with a macrophage (black arrow) or vacuolated lymphocyte (white arrow) at the top of the image. D) A cluster of organisms (arrowheads) and inflammatory cells of multiple types. Multiple similar clusters were present on the slide, some of which showed nearly completely obscured trophozoites.\n\nFig. 1\n\nA real-time PCR performed at the CDC on a CSF sample confirmed N. fowleri. The strain belonged to genotype I based on the internal transcribed spacer 1 sequence [4]. CDC and the Florida Department of Health (FDOH) collaborated to investigate the patient’s water exposures. The most probable exposure was a campground in Madison County, FL, with treated and untreated bodies of water. The treated water bodies included a water slide, swimming pool, and human-made river. The untreated areas included a lake for fishing, retention pond, and another lake with an obstacle course. The family reported the patient swam in both treated and untreated water.\n\nFDOH conducted a site visit on August 5, 2020. Maintenance logs for the pool and lazy river indicated that the chlorine level and pH were acceptable on the days of exposure. Testing during the site visit also showed appropriate free chlorine levels and a pH of 7.3. The recreational lake is human made, has a sand bottom, and has a surface area of 2.2 acres with the greatest depth measured at 9 feet. Water chemistry parameters were measured at two locations; both had a temperature of 90⁰F, pH of 8+, and an undetectable chlorine level. A dye was added to give the lake a bluer appearance. No other chemicals were added and there was no thermal pollution of the lake. The lake had not been drained recently and the water level was normal. The owners were informed and closed the recreational lake. At the time of assessment, there were no plans to reopen and signs prohibiting swimming were posted.\n\nDiscussion\n\nPAM presents a multifaceted clinicopathologic challenge. Early diagnosis and treatment have the potential to prevent a nearly universal fatal outcome. This depends on communication between clinicians and the clinical laboratory. While practices vary, knowledge of how CSF samples are processed by the institution’s laboratory is essential to understanding the diagnostic challenges.\n\nSeveral studies are routinely ordered on CSF samples in cases of suspected meningitis, including culture and gram stain, molecular diagnostic assays, cell count with differential, and chemistry studies. CSF chemistry in PAM mimics that of bacterial meningitis with increased protein and decreased glucose. Amebae are not reliably detected on gram stain or other routine studies. Furthermore, N. fowleri does not grow on standard culture medium, as it requires bacteria-enriched agar.\n\nWithout access to rapid confirmatory molecular testing, microscopic examination of the CSF plays a key role in identification with inherent challenges. Microscopy is only reliable when “clearly motile” N. fowleri trophozoites are seen on wet prep of a fresh CSF sample. Motility can commonly be diminished by inappropriate handling of the CSF (for example, refrigeration of CSF), or anti-amebic treatment. Additionally, early in the infection, there may be too few organisms to detect. These challenges can be overcome by molecular assays, such as real-time PCRs, which can provide reliable diagnosis.\n\nIf a Wright-Giemsa stain is performed on centrifuged CSF, non-motile N. fowleri trophozoites may be identified by their distinct cytologic appearance: a small nucleus accompanied by pale nuclear staining, a rim of enhancement at the periphery, and clustering of organisms. Additionally, the size of N. fowleri trophozoites (10–20 microns) overlaps with different types of leukocytes. Their cytoplasmic color and vacuolation may also resemble that of macrophages and lymphocytes.\n\nImportantly, neither wet preps nor Wright-Giemsa stained slides are routinely reviewed by pathologists. In cases of suspected meningitis, cell counts and differential are typically performed by medical technologists who may alert the pathologist about concerning findings. The experience and vigilance of medical technologists are paramount. Given the rarity of N. fowleri infections, diagnostic challenges, and importance of rapid diagnosis, communication with the clinical laboratory is critical if PAM is suspected.\n\nWithin the context of this case, the aforementioned challenges were encountered before accurate diagnosis. Initial microscopic review was difficult to discern ameba as their motility or counts were not seen. It was not until re-sampling of the CSF that ameba were visualized by Wright-Giemsa staining. However, given the aggressive nature of PAM, diagnosis needs to be prompt for the best outcomes. The intrinsic difficulty of this case resided in the arduous nature of diagnosis and the presentation mimicking a typical bacterial meningitis at onset.\n\nThe site visit showed a facility that met requirements for operating a treated swimming pool. However, the facility also maintained an untreated lake with an obstacle course, diving platform, and slide. These features allow people to enter the water with more speed and force, increasing the possibility of water entering the nose. The warm, untreated water forcibly entering the nose most likely allowed exposure to N. fowleri. A previous case was investigated at the same facility in 2009 when the campground was under a different name. In the 2009 case, the patient was a 13-year-old boy who swam in a human-made body of water. When comparing aerial views from 2009 and present, that lake appears to no longer exist. Although the two cases separated by 11 years were likely in different human-made bodies of water, the bodies were both on the same property, supplied with well water, treated with blue dye, and had built-in features such as water slides.\n\nThe CDC estimates that 16 cases of PAM occur annually [3]. Appropriate history-taking and knowledge of the pathology of PAM can allow for earlier diagnosis. A previous case report denotes successful treatment with amphotericin B, azithromycin, fluconazole, rifampin, miltefosine, and dexamethasone [5]. The case presented here demonstrates the unusual nature of N. fowleri infections. Despite N. fowleri being frequently found in the environment, and presumably frequent exposures given the millions of swimming visits every year, infections remain rare. Further investigation is needed to explain the two cases of PAM resulting from water exposure on the same property.\n\nFunding\n\nThis work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\n\nNo ethical approval was required for this publication.\n\nConsent\n\nVerbal consent was obtained from the patient’s legal guardians.\n\nAuthor contribution\n\nSKA, KM, SC, and FMS provided direct patient care. GF and SGB provided pathological review for the patient and developed Fig. 1. KS and LM conducted the site visit. IK, JRC, and KO provided confirmatory molecular diagnostic testing. All authors participated in writing and editing of this report.\n\nAuthor statement\n\nSaad K Anjum: conceptualization, writing – original draft.\n\nKarna Mangrola: conceptualization, writing – original draft, review & editing.\n\nGarrett Fitzpatrick: Investigation (pathological diagnosis), visualization (designed figure).\n\nKimberly Stockdale: Investigation (epidemiologic, including site visit), writing – original draft, review & editing.\n\nLaura Matthias: Investigation (epidemiologic, including site visit), writing – original draft.\n\nIbne Karim M Ali: Investigation (molecular diagnosis), writing – original draft.\n\nJennifer R Cope: Investigation (molecular diagnosis), writing – original draft.\n\nKevin O’Laughlin: Investigation (molecular diagnosis), writing – original draft, review & editing.\n\nShelley Collins: conceptualization, writing – review & editing.\n\nStacy G Beal: Investigation (pathological diagnosis), visualization (designed figure).\n\nFrances M Saccoccio: conceptualization, supervision, writing – review & editing.\n\nDisclaimer\n\nThe findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention.\n\nDeclaration of Competing Interest\n\nThe authors report no declarations of interest.\n\nAcknowledgement\n\nNone.\n==== Refs\nReferences\n\n1 Marciano-Cabral F. Cabral G.A. The immune response to Naegleria fowleri amebae and pathogenesis of infection FEMS Immunol Med Microbiol 51 2007 243 259 17894804\n2 CDC. Parasites – Naegleria fowleri – Primary Amebic Meningoencephalitis (PAM) – Amebic Encephalitis; Centers for Disease Control and Prevention. https://www.cdc.gov/parasites/naegleria/index.html. [Accessed 11 September 2020].\n3 Matanock A. Mehal J.M. Liu L. Blau D.M. Cope J.R. Estimation of undiagnosed Naegleria fowleri primary amebic meningoencephalitis, United States Emerg Infect Dis 24 2008 162 164\n4 Zhou L. Sriram R. Visvesvara G.S. Xiao L. Genetic variations in the internal transcribed spacer and mitochondrial small subunit rRNA gene of Naegleria spp J Eukaryot Microbiol Suppl. (50) 2003 522 526 14736150\n5 Linam W.M. Ahmed M. Cope J.R. Chu C. Visvesvara G.S. da Silva A.J. Successful treatment of an adolescent with Naegleria fowleri primary amebic meningoencephalitis Pediatrics 135 2015 e744 748 25667249\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "25()",
"journal": "IDCases",
"keywords": "CNS protozoal infections; Naegleria fowleri; Primary amebic meningoencephalitis",
"medline_ta": "IDCases",
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"nlm_unique_id": "101634540",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "14736150;17894804;25667249;29260676",
"title": "A case report of primary amebic meningoencephalitis in North Florida.",
"title_normalized": "a case report of primary amebic meningoencephalitis in north florida"
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"abstract": "Sunitinib which is used in the treatment of kidney cancer, gastrointestinal stromal tumor, and advanced pancreatic neuroendocrine tumor is a multi-targeted tyrosine kinase inhibitor. Although sunitinib is associated with some side effects, it is generally well tolerated. In the present case, the diagnosis of gastrointestinal stromal tumor was four years ago. The patient had multiple liver metastases at the time of diagnosis. Sunitinib was initiated with a dose of 50 mg daily for four weeks and two weeks off, because of resistance of imatinib. The patient was admitted to the hospital with purpuric rash on her arms and body in the eighth week of treatment. No other disorders or drugs which may cause purpuric rash were detected in the patient. Purpuric rash disappeared two weeks after sunitinib discontinuation without any further intervention.",
"affiliations": "Department of Medical Oncology, Acıbadem Kayseri Hospital, Kayseri, Turkey doktorhasanmutlu@gmail.com.;Department of Internal Medicine, Acıbadem University School of Medicine, Istanbul, Turkey.;Department of Radiation Oncology, Mersin Government Hospital, Mersin, Turkey.;Department of Medical Oncology, Acıbadem Kayseri Hospital, Kayseri, Turkey.",
"authors": "Mutlu|Hasan|H|;Büyükçelik|Abdullah|A|;Akça|Zeki|Z|;Kaya|Nilgün|N|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000068877:Imatinib Mesylate; D000077210:Sunitinib",
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"keywords": "Sunitinib; adverse event; gastrointestinal stromal tumor; vasculitis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D005076:Exanthema; D005260:Female; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000077210:Sunitinib",
"nlm_unique_id": "9511372",
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"pages": "298-301",
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"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sunitinib-induced reversible purpuric rash in a patient with gastrointestinal stromal tumor.",
"title_normalized": "sunitinib induced reversible purpuric rash in a patient with gastrointestinal stromal tumor"
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"abstract": "Holmium laser enucleation of prostate (HoLEP) is being performed with increasing frequency as a minimally invasive alternative to transurethral resection of the prostate (TURP) for the surgical management of benign prostatic hyperplasia (BPH). HoLEP offers the advantage of use of normal saline for irrigation, instead of glycine which is utilized in TURP, decreasing the likelihood of fluid absorption and effects on serum electrolytes. We describe a patient who underwent HoLEP for BPH and subsequently developed non-ion gap metabolic acidosis and hemodilution associated with volume overload.",
"affiliations": "Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Urology, Mayo Clinic, Rochester, MN, USA.;Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. gali.bhargavi@mayo.edu.",
"authors": "Dodd|Sarah E|SE|;Jankowski|Christopher J|CJ|;Krambeck|Amy E|AE|;Gali|Bhargavi|B|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s00540-016-2256-4",
"fulltext": null,
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"issn_linking": "0913-8668",
"issue": "30(6)",
"journal": "Journal of anesthesia",
"keywords": "CBI; Fluid overload; HoLEP; TURP",
"medline_ta": "J Anesth",
"mesh_terms": "D000138:Acidosis; D000368:Aged; D006438:Hemodilution; D006801:Humans; D053685:Laser Therapy; D053844:Lasers, Solid-State; D008297:Male; D011470:Prostatic Hyperplasia; D007507:Therapeutic Irrigation; D016896:Treatment Outcome; D001743:Urinary Bladder",
"nlm_unique_id": "8905667",
"other_id": null,
"pages": "1060-1062",
"pmc": null,
"pmid": "27714450",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17338621;16406990;26069886;15379651;24082919;25108273;23773260",
"title": "Metabolic acidosis with hemodilution due to massive absorption of normal saline as bladder irrigation fluid following holmium laser enucleation of prostate.",
"title_normalized": "metabolic acidosis with hemodilution due to massive absorption of normal saline as bladder irrigation fluid following holmium laser enucleation of prostate"
} | [
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"companynumb": "US-B. BRAUN MEDICAL INC.-2021726",
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"activesubstancename": "ROCURONIUM BROMIDE"
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"abstract": "Little is known about in utero exposure to and postnatal clearance of anti-tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life.\n\n\n\nWe performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected.\n\n\n\nThe time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94-1.49) and 1.97 for infliximab (95% CI, 1.50-2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9-5.0) and 7.3 months for infliximab (95% CI, 6.2-8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09-6.78; P = .02).\n\n\n\nIn a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.",
"affiliations": "Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark; Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: mjn@clin.au.dk.;Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark.;Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.;Department of Medicine, Christchurch Hospital, University of Otago, Christchurch, New Zealand.;Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.;Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark.;Department of Biostatistics, University of Aarhus, Aarhus, Denmark.;Department of Obstetrics and Gynaecology, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark.;Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.;Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.;Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark.;Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.;Department of Gastroenterology, Odense University Hospital, University of Odense, Odense, Denmark.;Department of Medicine, Køge Hospital, University of Copenhagen, Køge, Denmark.;Department of Medicine, Herning Hospital, Herning, Denmark.;Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.;Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia.;Department of Gastroenterology, Liverpool Hospital, Sydney, New South Wales, Australia.;Inflammatory Bowel Diseases Unit, Royal Brisbane and Women's Hospital, University of Queensland School of Medicine, Brisbane, Queensland, Australia.;School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, Western Australia, Australia; Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Western Australia, Australia.;Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia.;Department of Gastroenterology, Royal North Shore Hospital, Sydney, Australia.;Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.",
"authors": "Julsgaard|Mette|M|;Christensen|Lisbet A|LA|;Gibson|Peter R|PR|;Gearry|Richard B|RB|;Fallingborg|Jan|J|;Hvas|Christian L|CL|;Bibby|Bo M|BM|;Uldbjerg|Niels|N|;Connell|William R|WR|;Rosella|Ourania|O|;Grosen|Anne|A|;Brown|Steven J|SJ|;Kjeldsen|Jens|J|;Wildt|Signe|S|;Svenningsen|Lise|L|;Sparrow|Miles P|MP|;Walsh|Alissa|A|;Connor|Susan J|SJ|;Radford-Smith|Graham|G|;Lawrance|Ian C|IC|;Andrews|Jane M|JM|;Ellard|Kathrine|K|;Bell|Sally J|SJ|",
"chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab; D000068879:Adalimumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0016-5085",
"issue": "151(1)",
"journal": "Gastroenterology",
"keywords": "ERA Study; Inflammatory Bowel Diseases; Safety; Vaccination",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D001315:Australia; D003718:Denmark; D005260:Female; D005312:Fetal Blood; D005765:Gastrointestinal Agents; D006801:Humans; D007231:Infant, Newborn; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D008431:Maternal-Fetal Exchange; D009035:Mothers; D009520:New Zealand; D011247:Pregnancy; D011248:Pregnancy Complications; D011446:Prospective Studies",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "110-9",
"pmc": null,
"pmid": "27063728",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection.",
"title_normalized": "concentrations of adalimumab and infliximab in mothers and newborns and effects on infection"
} | [
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"companynumb": "DK-HIKMA PHARMACEUTICALS CO. LTD-2017DK003719",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugaddit... |
{
"abstract": "Thiazide diuretics are prescribed daily and rarely hepatotoxic. We report the case of 86-year-old woman who was admitted in hospital for jaundice after taking hydrochlorothiazide. All differential diagnoses have been eliminated. The liver biopsy was compatible with drug-induced hepatitis. Clinical and biological manifestations improved after discontinuation of the treatment. The reported case is compared to three other cases in the literature.",
"affiliations": "Liver and Transplantation Unit, St-Eloi University Hospital, Montpellier, France.;Liver and Transplantation Unit, St-Eloi University Hospital, Montpellier, France. Electronic address: lucy.meunier@chu-montpellier.fr.;Department of Pathology, St-Eloi University Hospital, Montpellier, France.;Liver and Transplantation Unit, St-Eloi University Hospital, Montpellier, France.",
"authors": "Malézieux|Emilie|E|;Meunier|Lucy|L|;Rivière|Benjamin|B|;Larrey|Dominique|D|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.clinre.2020.101599",
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"issn_linking": "2210-7401",
"issue": "45(5)",
"journal": "Clinics and research in hepatology and gastroenterology",
"keywords": "Acute hepatitis; DILI; Hepatotoxicity; Hydrochlorothiazide; Thiazide diuretics",
"medline_ta": "Clin Res Hepatol Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101553659",
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"pmid": "33676268",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydrochlorothiazide-induced hepatotoxicity: A rare case of DILI.",
"title_normalized": "hydrochlorothiazide induced hepatotoxicity a rare case of dili"
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"companynumb": "FR-UNICHEM PHARMACEUTICALS (USA) INC-UCM202103-000252",
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"activesubstancename": "HYDROCHLOROTHIAZIDE"
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... |
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"abstract": "The anaesthetic management of patients presenting with laryngeal tumours and airway obstruction is difficult. We present the case of a pregnant woman at 30 weeks gestation who underwent surgical removal of two vocal cord polyps under general anaesthesia using jet ventilation",
"affiliations": "Department of Anaesthesia, Royal Victoria Hospital, McGill University Health Center, Montreal, Quebec, Canada.",
"authors": "el Shobary|H|H|;Gauthier|M|M|;Schricker|T|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"issue": "39(6)",
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"mesh_terms": "D000328:Adult; D058109:Airway Management; D000402:Airway Obstruction; D000768:Anesthesia, General; D004487:Edema; D005260:Female; D006611:High-Frequency Jet Ventilation; D006801:Humans; D016343:Monitoring, Intraoperative; D011127:Polyps; D011247:Pregnancy; D012141:Respiratory Tract Infections; D014827:Vocal Cords",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "1136-8",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Jet ventilation for the excision of vocal cord polyps in a pregnant patient.",
"title_normalized": "jet ventilation for the excision of vocal cord polyps in a pregnant patient"
} | [
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"companynumb": "CA-AUROBINDO-AUR-APL-2021-016646",
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... |
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"abstract": "BACKGROUND\nThe understanding of coronavirus disease 2019 (COVID-19) is rapidly evolving. Although it is primarily a respiratory illness, other manifestations, such as Guillain-Barré syndrome, immune thrombocytopenia, and immune-mediated thrombotic thrombocytopenic purpura, have been described. We present a case of a patient with hemophagocytic lymphohistiocytosis secondary to COVID-19 treated with tocilizumab with a marked biochemical improvement.\n\n\nMETHODS\nIn this case report we present a Caucasian patient with COVID-19 who developed a marked elevation of inflammatory parameters with ferritin 36,023 μg/L, but also elevated C-reactive protein 334 mg/L and lactate dehydrogenase 1074 U/L, 1 week after admission to the intensive care unit. He met five of eight criteria for hemophagocytic lymphohistiocytosis, but he lacked the high fever and cytopenia seen in the majority of cases. He was treated with tocilizumab, a monoclonal antibody targeting the interleukin-6 receptor, and over the next days, a rapid decrease in ferritin and C-reactive protein levels was observed. However, his respiratory failure only improved gradually, and he was weaned off the respirator 11 days later.\n\n\nCONCLUSIONS\nCOVID-19 may induce a hyperinflammatory clinical picture and in some cases develop into hemophagocytic lymphohistiocytosis. In our patient's case, therapeutic interleukin-6 blockade abrogated signs of hyperinflammation but did not seem to improve pulmonary function. Measurement of ferritin and C-reactive protein, as well as quantification of interleukin-6 on indication, should be performed in patients with severe COVID-19. Specific treatment in such patients must also be contemplated, preferably in randomized controlled trials.",
"affiliations": "Department of Internal Medicine, Molde Hospital, Molde, Norway. birgitte.tholin@helse-mr.no.;Department of Internal Medicine, Molde Hospital, Molde, Norway.;Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.;Department of Anesthesiology, Molde Hospital, Molde, Norway.;Section of Hematology, Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway.",
"authors": "Tholin|Birgitte|B|http://orcid.org/0000-0001-6768-541X;Hauge|Marit Teigen|MT|;Aukrust|Pål|P|;Fehrle|Lutz|L|;Tvedt|Tor Henrik|TH|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D002097:C-Reactive Protein; D005293:Ferritins; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02503-9",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2503\n10.1186/s13256-020-02503-9\nCase Report\nHemophagocytic lymphohistiocytosis in a patient with COVID-19 treated with tocilizumab: a case report\nhttp://orcid.org/0000-0001-6768-541XTholin Birgitte birgitte.tholin@helse-mr.no 1 Hauge Marit Teigen 12 Aukrust Pål 34 Fehrle Lutz 5 Tvedt Tor Henrik 6 1 grid.416049.e0000 0004 0627 2824Department of Internal Medicine, Molde Hospital, Molde, Norway \n2 grid.416049.e0000 0004 0627 2824Department of Microbiology, Molde Hospital, Molde, Norway \n3 grid.55325.340000 0004 0389 8485Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway \n4 grid.55325.340000 0004 0389 8485Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway \n5 grid.416049.e0000 0004 0627 2824Department of Anesthesiology, Molde Hospital, Molde, Norway \n6 grid.412008.f0000 0000 9753 1393Section of Hematology, Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway \n15 10 2020 \n15 10 2020 \n2020 \n14 1878 5 2020 17 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe understanding of coronavirus disease 2019 (COVID-19) is rapidly evolving. Although it is primarily a respiratory illness, other manifestations, such as Guillain-Barré syndrome, immune thrombocytopenia, and immune-mediated thrombotic thrombocytopenic purpura, have been described. We present a case of a patient with hemophagocytic lymphohistiocytosis secondary to COVID-19 treated with tocilizumab with a marked biochemical improvement.\n\nCase presentation\nIn this case report we present a Caucasian patient with COVID-19 who developed a marked elevation of inflammatory parameters with ferritin 36,023 μg/L, but also elevated C-reactive protein 334 mg/L and lactate dehydrogenase 1074 U/L, 1 week after admission to the intensive care unit. He met five of eight criteria for hemophagocytic lymphohistiocytosis, but he lacked the high fever and cytopenia seen in the majority of cases. He was treated with tocilizumab, a monoclonal antibody targeting the interleukin-6 receptor, and over the next days, a rapid decrease in ferritin and C-reactive protein levels was observed. However, his respiratory failure only improved gradually, and he was weaned off the respirator 11 days later.\n\nConclusion\nCOVID-19 may induce a hyperinflammatory clinical picture and in some cases develop into hemophagocytic lymphohistiocytosis. In our patient’s case, therapeutic interleukin-6 blockade abrogated signs of hyperinflammation but did not seem to improve pulmonary function. Measurement of ferritin and C-reactive protein, as well as quantification of interleukin-6 on indication, should be performed in patients with severe COVID-19. Specific treatment in such patients must also be contemplated, preferably in randomized controlled trials.\n\nKeywords\nCOVID-19HLHHemophagocytic lymphohistiocytosisIL-6TocilizumabCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nSevere coronavirus disease 2019 (COVID-19) infection, particularly in those with acute respiratory distress syndrome (ARDS), is characterized by marked inflammation and immune activation with elevated levels of inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor [1]. Significantly elevated levels of ferritin as a marker of extensive macrophage activation have also been reported [2]. We describe a case of a patient with a marked systemic immune reaction with features of hemophagocytic lymphohistiocytosis (HLH) who was treated with the IL-6 receptor antagonist tocilizumab.\n\nCase presentation\nA Caucasian man in his 70s was admitted to his local hospital because of fever, diarrhea, and abdominal pain for the previous 10 days. His past medical history was significant for diverticulosis, and he was also being treated for locally advanced prostate cancer with goserelin and for chronic back pain with prednisolone 2.5 mg once daily.\n\nOn admission, his blood pressure was 134/85 mmHg, body temperature was 38.7 °C, heart rate was 87 beats/minute, respiratory rate was 18 breaths/minute, and oxygen saturation was 92% without oxygen support. He was slightly overweight with a body mass index (BMI) of 27 kg/m2, but the findings of his physical examination were otherwise normal. His laboratory test values, presented in Table 1, showed elevated C-reactive protein (CRP), thrombocytopenia, and moderately elevated ferritin. Arterial blood gas analysis revealed respiratory alkalosis with hypoxemia and normal lactate. A radiographic examination showed scattered consolidations in the right lung.\nTable 1 An overview of relevant laboratory parameters during the clinical course\n\nParameter\tReference range\tAdmission\nDay 0\tICU\nDay 2\tDay 5\tDay 6\tDay 7\tDay 8\tExtubation\nDay 18\t\nHemoglobin (g/dl)\t13.7–16.5\t12.9\t11.7\t11.3\t11.8\t11.1\t11.3\t8.8\t\nNeutrophils (109/L)\t1.5–5.7\t6.6\t–\t–\t20.3\t31.3\t30.5\t8.0\t\nLymphocytes (109/L)\t1.3–3.4\t1.6\t–\t–\t–\t–\t–\t–\t\nPlatelet count (109/L)\t145–390\t95\t107\t179\t197\t190\t177\t222\t\nCreatinine (mg/dl)\t60–105\t115\t91\t297\t339\t233\t155\t156\t\nCRP (mg/L)\t0–4\t167\t224\t315\t348\t276\t63\t12\t\nFerritin (μg/L)\t23–431\t544\t635\t6399\t36,023\t75,920\t20,730\t625\t\nBilirubin (μmol/L)\t5–25\t8\t7\t32\t39\t47\t60\t10\t\nLD (U/L)\t115–255\t522\t583\t–\t1074\t1559\t973\t438\t\nFibrinogen (g/L)\t2–4\t–\t–\t–\t6.5\t5.9\t–\t–\t\nTriglyceride (mmol/L)\t0.45–2.60\t–\t–\t–\t5.27\t5.71\t–\t–\t\nAbbreviations: CRP C-reactive protein, ICU Intensive care unit, LDH Lactate dehydrogenase\n\n\n\nThe patient had a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on real-time reverse transcriptase polymerase chain reaction of a nasopharyngeal specimen. Empirical treatment with cefotaxime and ciprofloxacin was prescribed for suspected bacterial superinfection as well as an antiviral regime of lopinavir-ritonavir and hydroxychloroquine according to local guidelines at the time.\n\nTwelve hours later, the patient’s condition deteriorated, with rapidly progressing respiratory failure, oxygen saturation at 86% on 12-L oxygen, and a respiratory frequency of 40 breaths/minute. This prompted transfer to the intensive care unit (ICU) and intubation. A new chest x-ray revealed extensive bilateral coalescent opacities qualifying as severe ARDS (ratio of arterial oxygen partial pressure to fractional inspired oxygen [FiO2], ≤ 100 mmHg).\n\nDuring the first 36 hours in the ICU, the patient was in unstable cardiopulmonary condition. He required high FiO2 and norepinephrine in moderate doses, and he developed supraventricular tachyarrhythmia that was treated with repeated electrical and pharmacological cardioversion. By day 7, he had accumulated significant amounts of fluid (positive fluid balance of 8 L). His creatinine levels were rising, and he responded poorly to diuretics. Continuous venovenous hemodiafiltration was initiated to ensure a negative fluid balance.\n\nThe antiviral drug regimen was discontinued after 3 days due to a national agreement that all SARS-CoV-2 viral drug treatments should be administered through randomized controlled studies. Due to rising CRP and leukocyte counts, the antibiotics were changed to meropenem.\n\nOne week after admission, the patient achieved circulatory stability and exhibited a slowly decreasing oxygen demand, but his ferritin had risen markedly to 36,023 μg/L. This was accompanied by occasional fever and marked increases in CRP (334 mg/L), lactate dehydrogenase (LDH) (1074 U/L), neutrophil count (20.3 × 109/L), and triglycerides (5.27 mmol/L). His triglycerides were analyzed during parenteral nutrition and must be interpreted with caution.\n\nThis raised concern that the patient had developed HLH secondary to SARS-CoV-2. His soluble IL-2 receptor level was considerably elevated at 6809 U/ml (> 623 U/ml indicates immune activation and T-cell activation in particular), and a bone marrow smear demonstrated hemophagocytosis. Flow cytometry of peripheral blood showed a significant decrease in circulating CD4+ and CD8+ T cells (161/μl and 32/μl, respectively) but an expanded population of clonal B cells that expressed kappa, CD5, CD19, CD20 (weakly), CD43, CD45, and CD200. Due to the absence of lymphocytosis, and after a review of laboratory records, this was classified as monoclonal B-cell lymphocytosis (MBL) and not as chronic lymphocytic leukemia (CLL), which requires > 5000 cells/μl. A trephine biopsy confirmed MBL but no other lymphoproliferative disorders.\n\nThe patient fulfilled five of eight HLH-2004 diagnostic criteria, and his H-score estimated the probability of HLH to be 96–98% [3, 4]. A decision was made to give the patient tocilizumab 800 mg intravenously, a monoclonal antibody against the IL-6 receptor that is used when cytokine release syndrome (CRS) is seen following the infusion of chimeric antigen receptor T cells.\n\nThe following day, the patient’s CRP declined rapidly, followed by a significant but slow decline in ferritin and LDH levels (Table 1, Fig. 1). After the administration of tocilizumab, no fever was observed. Three days later, the patient also received one dose of intravenous immunoglobulins pending the result of protein electrophoresis, which was normal. His clinical state improved 5–7 days later, and he was successfully extubated.\nFig. 1 Plot of relevant laboratory values: ferritin, leukocytes, C-reactive protein, and lactate dehydrogenase. The horizontal axis represents days from admission, and the vertical axis represents the laboratory values in proportion to the peak value\n\n\n\nAfter the patient’s improvement, we analyzed serum levels of selected cytokines on the same day as tocilizumab was given (samples taken before administration) by enzyme-linked immunosorbent assay. Interestingly, his IL-6 levels were markedly elevated at 84 pg/ml (< 5 pg/ml), whereas TNF and IL-10 were moderately elevated at 55 pg/ml (< 20 pg/ml) and 38 pg/ml (< 5 pg/ml), respectively. His IL-8 (66 pg/ml) and IL-1β (< 5 pg/ml) were within the normal range of the laboratory that did the tests (Sahlgrenska University Hospital, Gothenburg, Sweden).\n\nDiscussion and conclusions\nWe report a case of a patient with marked immune activation accompanied by ARDS with a biochemical pattern consistent with secondary HLH who responded biochemically after one dose of the IL-6 receptor antagonist tocilizumab. HLH is characterized by hyperinflammation; fever; multiorgan involvement; and, in severe cases, marked hemophagocytosis with cytopenia. Although primary HLH is caused by genetic defects that impair natural killer (NK) or T-cell function, secondary HLH is caused by various disorders, most commonly malignancies, infections, and autoimmune disorders. HLH is diagnosed either by detection of HLH-associated mutations (diagnostic for primary HLH) or by verification of a minimum of five of the following eight criteria: fever > 38.5 °C, splenomegaly, cytopenia, fasting hypertriglyceridemia (> 265 mg/dl) and/or hypofibrinogenemia (< 150 mg/dl), hemophagocytosis, low or absent NK cell activity, ferritin > 500 ng/ml, and soluble IL-2receptor elevated 2 SD above age-adjustedlaboratory-specific norms. Macrophage activation syndrome (MAS) shares some feature of HLH, such as strong macrophage activation and excessive hyperferritinemia. MAS is associated with autoimmune diseases, especially juvenile idiopathic arthritis, systemic lupus erythematosus, Kawasaki disease, and juvenile dermatomyositis [5].\n\nBoth primary and secondary HLH can be triggered by viral infections, Epstein-Barr virus infection in particular [6]. There are several reports of cytokine “storm” or hyperinflammation in patients with COVID-19 with elevated levels of several inflammatory cytokines, but in most of these cases, there are no other signs of HLH, and the ferritin level is seldom > 35,000 μg/L as in our patient’s case [1, 7]. The mechanisms of this SARS-CoV-2–triggered “immune storm” that can develop into HLH are currently unclear, but several not mutually exclusive mechanisms could be operating. In vitro studies have suggested that SARS-CoV-2 could activate NLRP3 inflammasomes that are potent activators of macrophages, with a marked release of IL-1β as a consequence, which subsequently contributes to IL-6 release [8]. Furthermore, molecular docking analysis predicts spontaneous interaction between the spike glycoprotein of SARS-CoV-2 and Toll-like receptors 5 (TLR5). TLR5 is expressed on monocytes and significantly contributes to IL-6 release thorough activation of nuclear factor-κB activation [9]. Moreover, through downregulation of the angiotensin (AT)-converting enzyme 2, the putative SARS-CoV-2 receptor, the virus could induce a downregulation of the antiproliferative and anti-inflammatoryAT-1–7 pathway [10].\n\nInfection with SARS-CoV-2 induces a great variety of clinical symptoms, ranging from asymptomatic to mild or critical. Although severe illness can occur in otherwise healthy individuals of all ages, it predominantly occurs in individuals older than 65 years of age [11]. One factor associated with a severe course of SARS-CoV-2 infection is impaired or delayed T-cell response [12]. Interestingly, we were able to verify the presence of clonal B cells with the CLL immunophenotype in our patient. Due to the low number of circulating lymphocytes, the condition was characterized as MBL. Clonal lymphocytosis occurs in < 0.5% of the population under the age of 40 but increases significantly with age and can be demonstrated in 10–20% of individuals over 70 years old, increasing even more with age [13]. MBL increases susceptibility to viral infections through several mechanisms, including hypogammaglobulinemia, the accumulation of incompetent lymphocytes with an impaired response to immunological stimuli, and a reduced cytotoxic capacity of CD8+ cells due to reduced granzyme levels and the nonpolarized degranulation of vesicles [14]. Furthermore, it is well known that the immune dysfunction in some patients with CLL can result in HLH [15].\n\nOther possible influencing factors in our patient were prolonged obesity, treatment with low-dose steroid, and medical castration with goserelin. Goserelin has not been reported to have immunological side effects but is associated with a weight increase in approximately 5% of patients. This, in addition to steroids, could have contributed to his raised BMI which is a recognized risk factor for developing severe COVID-19. Whether these factors influenced the clinical course in our patient is speculative.\n\nSecondary HLH, MAS, and CRS constitute a heterogeneous group of conditions that are all characterized by macrophage activation and excessive cytokine production, and IL-6 seems to be involved in various degrees in all these conditions. Such mechanisms could also be operating in severe COVID-19 infection. Thus, there are some reports of beneficial effects of tocilizumab in severe COVID-19, and randomized studies are ongoing [16]. Our patient had markedly elevated IL-6 levels and a profound and rapid decline in CRP as a biomarker of IL-6 activity, further supporting a role for IL-6–driven inflammation in severe COVID-19 infection. Notably, whereas there was a rapid decline in CRP, there was an incidental increase in ferritin following administration of tocilizumab before a significant decline, suggesting that the effect of tocilizumab on macrophage activation involves secondary effects of IL-6. An early and significant rise in IL-6 levels during SARS-CoV-2 infections is associated with a poor outcome. One should consider screening with ferritin and CRP in cases of severe COVID-19 with apparent hyperinflammation, particularly because CRP is known to be an indirect marker of IL-6 [17]. With significantly elevated levels, the diagnosis could be further supported by quantitating IL-6.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nAll authors contributed to the writing and revision of the manuscript. BT and THT were responsible for the final version of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNA.\n\nEthics approval and consent to participate\nApproval from an ethics committee was not required according to national policy. Patient consent has been obtained and can be displayed upon request.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Mehta P McAuley DF Brown M COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 2020 395 1033 1034 10.1016/S0140-6736(20)30628-0 32192578 \n2. Lambotte O Cacoub P Costedoat N Le Moel G Amoura Z Piette JC High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation J Rheumatol 2003 30 5 1027 1028 12734900 \n3. Jordan MB Allen CE Weitzman S Filipovich AH McClain KL How I treat hemophagocytic lymphohistiocytosis Blood 2011 118 15 4041 4052 10.1182/blood-2011-03-278127 21828139 \n4. Debaugnies F Mahadeb B Ferster A Performances of the H-score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients Am J Clin Pathol 2016 145 6 862 870 10.1093/ajcp/aqw076 27298397 \n5. Lin CI Yu HH Lee JH Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases Clin Rheumatol 2012 31 8 1223 1230 10.1007/s10067-012-1998-0 22615046 \n6. Filipovich A McClain K Grom A Histiocytic disorders: recent insights into pathophysiology and practical guidelines Biol Blood Marrow Transplant 2010 16 1 Suppl S82 S89 10.1016/j.bbmt.2009.11.014 19932759 \n7. Zhang C Wu Z Li JW Zhao H Wang GQ Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality Int J Antimicrob Agents 2020 55 5 105954 10.1016/j.ijantimicag.2020.105954 32234467 \n8. Zhao C Zhao W NLRP3 inflammasome—a key player in antiviral responses Front Immunol 2020 11 211 10.3389/fimmu.2020.00211 32133002 \n9. Bhattacharya M Sharma AR Patra P Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): immunoinformatics approach J Med Virol 2020 92 6 618 631 10.1002/jmv.25736 32108359 \n10. Tignanelli CJ Ingraham NE Sparks MA Antihypertensive drugs and risk of COVID-19? Lancet Respir Med 2020 8 5 e30 e31 10.1016/S2213-2600(20)30153-3 32222166 \n11. Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese] Zhonghua Liu Xing Bing Xue Za Zhi 2020 41 2 145 151 32064853 \n12. Zheng HY Zhang M Yang CX Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients Cell Mol Immunol 2020 17 5 541 543 10.1038/s41423-020-0401-3 32203186 \n13. Strati P Shanafelt TD Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification Blood 2015 126 4 454 462 10.1182/blood-2015-02-585059 26065657 \n14. Lanasa MC Weinberg JB Immunologic aspects of monoclonal B-cell lymphocytosis Immunol Res 2011 49 1–3 269 280 10.1007/s12026-010-8188-4 21161696 \n15. Bailey C Dearden C Ardeshna K Haemophagocytic lymphohistiocytosis as a consequence of untreated B-cell chronic lymphocytic leukaemia BMJ Case Rep 2017 2017 bcr2016219057 10.1136/bcr-2016-219057 \n16. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-10975. 10.1073/pnas.2005615117.\n17. Del Giudice M Gangestad SW Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters Brain Behav Immun 2018 70 61 75 10.1016/j.bbi.2018.02.013 29499302\n\n",
"fulltext_license": "CC BY",
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"journal": "Journal of medical case reports",
"keywords": "COVID-19; Case report; HLH; Hemophagocytic lymphohistiocytosis; IL-6; Tocilizumab",
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"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000073640:Betacoronavirus; D002097:C-Reactive Protein; D000086382:COVID-19; D018352:Coronavirus Infections; D005293:Ferritins; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D058873:Pandemics; D011024:Pneumonia, Viral; D012121:Respiration, Artificial; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
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"pubdate": "2020-10-15",
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"title": "Hemophagocytic lymphohistiocytosis in a patient with COVID-19 treated with tocilizumab: a case report.",
"title_normalized": "hemophagocytic lymphohistiocytosis in a patient with covid 19 treated with tocilizumab a case report"
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"abstract": "BACKGROUND\nThis study evaluated the effectiveness and safety of preoperative chemoradiotherapy with capecitabine in patients with locally advanced resectable rectal cancer. This report summarizes the results of the phase II study together with long-term (5-year) follow-up.\n\n\nMETHODS\nBetween June 2004 and January 2005, 57 patients with operable, clinical stage II-III adenocarcinoma of the rectum entered the study. Radiation dose was 45 Gy delivered as 25 fractions of 1.8 Gy. Concurrent chemotherapy with oral capecitabine 825 mg/m² twice daily was administered during radiotherapy and at weekends. Surgery was scheduled 6 weeks after the completion of the chemoradiotherapy. Patients received four cycles of postoperative chemotherapy comprising either capecitabine 1250 mg/m² bid days 1-14 every 3 weeks or bolus i.v. 5-fluorouracil 425 mg/m²/day and leucovorin 20 mg/m²/day days 1-5 every 4 weeks (choice was at the oncologist's discretion). Study endpoints included complete pathological remission, proportion of R0 resections and sphincter-sparing procedures, toxicity, survival parameters and long-term (5-year) rectal and urogenital morbidity assessment.\n\n\nRESULTS\nOne patient died after receiving 27 Gy because of a pulmonary embolism. Fifty-six patients completed radiochemotherapy and had surgery. Median follow-up time was 62 months. No patients were lost to follow-up. R0 resection was achieved in 55 patients. A complete pathological response was observed in 5 patients (9.1%); T-, N- and overall downstaging rates were 40%, 52.9% and 49.1%, respectively. The 5-year overall survival rate, recurrence-free survival, and local control was 61.4% (95% CI: 48.9-73.9%), 52.4% (95% CI: 39.3-65.5%), and 87.4% (95% CI: 75.0-99.8%), respectively. In 5 patients local relapse has occurred; dissemination was observed in 19 patients and secondary malignancies have occurred in 2 patients. The most frequent side-effect of the preoperative combined therapy was dermatitis (grade 3 in 19 patients). The proportion of patients with severe late (SOMA grade 3 and 4) rectal, bladder and sexual toxicity was 40%, 19.2% and 51.7%, respectively.\n\n\nCONCLUSIONS\nThis study confirms data from other non-randomised studies that capecitabine-based preoperative chemoradiation is a feasible treatment option for locally advanced rectal cancer, with positive 5-year overall survival, recurrence-free survival, and local control rates.",
"affiliations": "Department of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia. vvelenik@onko-i.si",
"authors": "Velenik|Vaneja|V|;Oblak|Irena|I|;Anderluh|Franc|F|",
"chemical_list": "D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
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"fulltext": "\n==== Front\nRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central 1748-717X-5-882092027610.1186/1748-717X-5-88ResearchLong-term results from a randomized phase II trial of neoadjuvant combined-modality therapy for locally advanced rectal cancer Velenik Vaneja 1vvelenik@onko-i.siOblak Irena 1ioblak@onko-i.siAnderluh Franc 1fanderluh@onko-i.si1 Department of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia2010 29 9 2010 5 88 88 3 7 2010 29 9 2010 Copyright ©2010 Velenik et al; licensee BioMed Central Ltd.2010Velenik et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThis study evaluated the effectiveness and safety of preoperative chemoradiotherapy with capecitabine in patients with locally advanced resectable rectal cancer. This report summarizes the results of the phase II study together with long-term (5-year) follow-up.\n\nMethods\nBetween June 2004 and January 2005, 57 patients with operable, clinical stage II-III adenocarcinoma of the rectum entered the study. Radiation dose was 45 Gy delivered as 25 fractions of 1.8 Gy. Concurrent chemotherapy with oral capecitabine 825 mg/m2 twice daily was administered during radiotherapy and at weekends. Surgery was scheduled 6 weeks after the completion of the chemoradiotherapy. Patients received four cycles of postoperative chemotherapy comprising either capecitabine 1250 mg/m2 bid days 1-14 every 3 weeks or bolus i.v. 5-fluorouracil 425 mg/m2/day and leucovorin 20 mg/m2/day days 1-5 every 4 weeks (choice was at the oncologist's discretion). Study endpoints included complete pathological remission, proportion of R0 resections and sphincter-sparing procedures, toxicity, survival parameters and long-term (5-year) rectal and urogenital morbidity assessment.\n\nResults\nOne patient died after receiving 27 Gy because of a pulmonary embolism. Fifty-six patients completed radiochemotherapy and had surgery. Median follow-up time was 62 months. No patients were lost to follow-up. R0 resection was achieved in 55 patients. A complete pathological response was observed in 5 patients (9.1%); T-, N- and overall downstaging rates were 40%, 52.9% and 49.1%, respectively. The 5-year overall survival rate, recurrence-free survival, and local control was 61.4% (95% CI: 48.9-73.9%), 52.4% (95% CI: 39.3-65.5%), and 87.4% (95% CI: 75.0-99.8%), respectively. In 5 patients local relapse has occurred; dissemination was observed in 19 patients and secondary malignancies have occurred in 2 patients. The most frequent side-effect of the preoperative combined therapy was dermatitis (grade 3 in 19 patients). The proportion of patients with severe late (SOMA grade 3 and 4) rectal, bladder and sexual toxicity was 40%, 19.2% and 51.7%, respectively.\n\nConclusions\nThis study confirms data from other non-randomised studies that capecitabine-based preoperative chemoradiation is a feasible treatment option for locally advanced rectal cancer, with positive 5-year overall survival, recurrence-free survival, and local control rates.\n==== Body\nIntroduction\nSurgical resection remains the cornerstone of treatment for patients with stage II or III rectal cancer. However, curative resection is not always possible, and local relapses or metastases occur even after high-quality surgery. The use of a multidisciplinary approach, which integrates surgery, radiotherapy and chemotherapy, has become of increasing importance in this type of cancer.\n\nFor a number of years now preoperative (neoadjuvant), rather than postoperative, radiotherapy has been shown to be effective at reducing local relapses in a variety of cancer types [1-6]. In locally advanced rectal cancer, the addition of 5-fluorouracil (5-FU) to preoperative radiotherapy has been shown to improve pathological complete response rate, tumour downstaging [7] and locoregional control [8,9] compared with radiotherapy alone. Furthermore, preoperative chemoradiotherapy improves locoregional control with less toxicity when compared with postoperative radiochemotherapy [10]. Thus, preoperative radiochemotherapy with continuous infusional 5-FU has become the standard of care in rectal cancer, especially in tumours of the lower and middle rectum.\n\nThe oral fluoropyrimidine capecitabine has demonstrated efficacy comparable with intravenous 5-FU in metastatic colorectal cancer as well as in the adjuvant setting in colon cancers [11-15]. Capecitabine has also been investigated in a variety of protocols in rectal and other gastrointestinal cancers in combination with radiotherapy [16], with equivalence of capecitabine plus radiotherapy and 5-FU plus radiotherapy as preoperative therapy in locally advanced rectal cancer being demonstrated in the systematic review by Saif et al. [17].\n\nA recent retrospective analysis from a single centre compared preoperative capecitabine to infusional 5-FU, combined with radiotherapy: once again, capecitabine showed more favourable results and higher downstaging rates [18].\n\nThe aim of this study was to evaluate the effectiveness and safety of preoperative chemoradiotherapy with capecitabine in patients with locally advanced rectal cancer. Here we summarize the results of the phase II study together and provide long-term (5-year) follow-up data.\n\nPatients and Methods\nDesign and inclusion criteria\nThe trial design, eligibility criteria, treatment and initial outcome variables have been published previously in detail [19]. In brief, the trial included patients with histologically confirmed locally advanced non-metastatic resectable rectal cancer. Inclusion criteria were clinical stage II or III [UICC TNM classification]; no prior radiotherapy and/or chemotherapy; World Health Organization (WHO) performance status <2; age at diagnosis of ≥18 years; and adequate bone marrow, liver, renal and cardiac function (no history of ischemic heart disease). A history of prior malignancy other than non-melanoma skin cancer or in situ carcinoma of the cervix rendered the patient ineligible.\n\nPrior to treatment, all patients received detailed oral and written information on the treatment protocol and possible side effects, and signed an informed consent. The trial was approved by the ethic committees of the Institute of Oncology, Ljubljana, Slovenia and of the Republic of Slovenia and was in agreement with the Declaration of Helsinki.\n\nTreatment protocol\nRadiotherapy was delivered using 15 MV photon beams and four-field box technique, once per day, 5 days a week for 5 weeks. The small pelvis received 45 Gy in 25 fractions over 5 weeks. Three-dimensional CT-based treatment planning was performed. Patients were treated in the prone position with a full bladder during irradiation, and no devices were used to displace the small bowel out of the irradiated volume. A multileaf collimator was used for shaping the fields and for the protection of normal tissues.\n\nChemotherapy with capecitabine was administered concomitantly with radiotherapy at a dose of 825 mg/m2 twice daily (bid) during the whole period of radiotherapy (days 1-33) without weekend breaks. Capecitabine doses were given 12 hours apart with one of the doses being taken 2 hours prior to irradiation. If radiotherapy was interrupted chemotherapy was not administered.\n\nDefinitive surgery was scheduled 6 weeks after the completion of the chemoradiotherapy. Surgical management included a sphincter preservation approach whenever possible, using the total mesorectal excision technique.\n\nFour courses of chemotherapy were planned postoperatively. This comprised either capecitabine 1250 mg/m2 bid on days 1 to 14 every 3 weeks for 4 cycles or bolus i.v. 5-fluorouracil 425 mg/m2/day and leucovorin 20 mg/m2/day on days 1 to 5 of each cycle repeated every 4 weeks. The choice of post-operative chemotherapy was left to the oncologist's discretion.\n\nDuring preoperative treatment, patients were evaluated weekly for acute toxicity and compliance with the protocol. Clinical examination and complete blood count were performed and body weight was measured. Toxic side effects were assessed according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) (version 2.0) [20]. Patients were followed every three month for the first two years after the last cycle of adjuvant chemotherapy and thereafter every six month up to 5th year.\n\nThe primary endpoint of the study was pathological complete response (pCR) rate. Secondary endpoints included the proportion of R0 resections, sphincter-sparing procedures, toxicity evaluation, survival parameters and long-term rectal and urogenital morbidity assessment. To assess long-term rectal and urogenital morbidity, all patients still alive, without recurrence of the disease and with a minimum follow up of 1 year were asked to complete a questionnaire about their rectal, voiding and sexual function, which was assessed using the Subjective, Objective, Management and Analytic/Late Effects on Normal Tissues scale (SOMA/LENT) [21].\n\nStatistics\nThe study aimed to evaluate whether a 12% pCR rate could be produced using this treatment approach. Setting 4% as the lowest pCR rate of interest, and with an alpha error of 5% and a power of 80%, at least 55 evaluable patients were needed.\n\nOverall survival was defined as the time from inclusion to the date of death from any cause or to the date of last follow-up. Relapse-free survival was defined as the time from inclusion to the first occurrence of disease relapse (local or distant), death or date of last follow-up.\n\nThe Kaplan-Meier method was used to estimate the rates of overall survival, relapse-free survival and local relapse-free survival. A subgroup analysis was performed regarding relapse-free survival and the parameters that were investigated included sex, age, tumour location in the rectum (low, middle, upper third), type of surgical procedure (abdominoperineal amputation, sphincter sparing), and pathological T and N status. The log-rank test was used to test the significance between the subgroups for this endpoint. The cumulative incidence approach was used to estimate the rates for disease specific mortality, local recurrence and distant metastasis.\n\nStatistical analysis was performed using the SPSS statistical software package, version 12 (SPSS Inc., Chicago, IL, USA).\n\nResults\nPatients' baseline characteristics\nBetween June 2004 and January 2005, 57 patients entered the study. The study population has been described elsewhere [19]. Briefly, median age was 67 years, 75.5% were males, and 63.2% presented with stage III disease. The WHO performance status was 1 in 12.3% of patients. The median distance of the tumour from the anal verge was 5.5 cm (range 1-12 cm), and in 49.1% of patients the primary tumour was sited ≤5 cm from the anal verge. The flow of the patients through the trial is shown in Figure 1.\n\nFigure 1 Distribution of patients through the trial.\n\nNeoadjuvant therapy\nOne patient died after receiving 27 Gy of radiotherapy as a result of a pulmonary embolism. The remaining 56 patients (98%) completed the preoperative chemoradiotherapy according to the treatment protocol. The median preoperative treatment duration was 33 days. Preoperative chemoradiotherapy grade 3 toxicity comprised radiodermatitis (19/56 patients; 33.9%), diarrhea (2/56 patients; 3.6%), proctitis (1/56 patients; 1.8%), infection (1/56 patients; 1.8%), impaired heart function (1/56 patients; 1.8%), and leucopenia (1/56 patients; 1.8%).\n\nSurgery\nSurgery was performed following chemoradiotherapy after a median of 45 days. In one patient only explorative laparotomy was performed as the tumour was deemed to be inoperable. As determined by histopathological examination of surgical specimens, the resection was radical (R0) in 54 patients. In one patient, microscopic foci of cancer cells were found in the radial surgical margin (R1 resection). The overall sphincter preservation rate was 65.5% and in the 27 patients where the tumour was located ≤5 cm of the anal verge the rate was 37%.\n\nPost surgery, one patient died because of sepsis during the early perioperative period. The most frequent perioperative complication was delayed wound healing (12/56 patients; 21.8%). Re-hospitalisation was necessary for 7 patients; 2 underwent another operation because of anastomotic leak and ileus, respectively. Late surgical morbidity included urosepsis (n = 1; 1.8%), pararectal abscess (n = 1; 1.8%), and in 3 patients reoperation was required (intra-abdominal abscess, enterocutane fistula and stoma occlusion).\n\nThirty-six of the 39 patients (92.3%) returned the SOMA/LENT questionnaire. The proportion of patients with severe late (SOMA grade 3 and 4) rectal, bladder and sexual toxicity was 40%, 19.2% and 51.7%, respectively. More details on late toxicity have been reported previously [22].\n\nTumour response\nTumour response was evaluated in 55 patients who had definitive surgery. A complete pathological response was observed in 5 patients (9.1%); T-, N- and overall downstaging rates were 40%, 52.9% and 49.1%, respectively.\n\nAdjuvant chemotherapy\nEleven patients never received adjuvant chemotherapy either because of: death during the perioperative period for 1 patient (1.8%); cardiotoxicity experienced in preoperative treatment in 1 patient (1.8%); postoperative pathological echocardiogram in 1 patient (1.8%); surgical complications in 5 patients (9%); and time from operation more than 8 weeks in 3 patients (5.5%). Postoperative chemotherapy was administered to 44 of 55 radically operated patients (80%); 18/44 (40.9%) patients received bolus 5-fluorouracil/leucovorin (5-fluorouracil 425 mg/m2 plus leucovorin 20 mg/m2 for 5 days, every 28 days) - 17 patients received 4 cycles and 1 patient received 3 cycles because of a grade 3urinary infection; 26/44 patients (59.1%) received capecitabine 1250 mg/m² for 14 days, every 21 days - 16 patients received 4 cycles, 1 patient received 1 cycle because of grade 3cardiotoxicity and 1 patient received 3 cycles because of prolonged grade 2 leukopenia. Eleven (20%) radically operated patients did not received postoperative chemotherapy. The choice of chemotherapy regimen was at the discretion of the investigator.\n\nTreatment outcome\nThe median follow-up time for patients still alive in this trial was 62 months. The median time to disease recurrence was 19.5 months (range: 3.3-58 months). The pattern of first recurrence was predominantly distant metastases, which were observed in 18 patients (33.3%). Local progression was the site of failure in 4 patients (7.4%), whereas 1 patient (1.8%) had synchronous local and distant disease. The 5-year local control rate was 87.4% (95% CI: 75.0-99.8) (Figure 2). In 5 patients local relapse occurred; dissemination was observed in 19 patients and secondary malignancies occurred in 2 patients. Nineteen patients (35.2%) developed distant metastases of which two were discovered during surgery. The latest local and distant failures were observed after 42 and 58 months, respectively. Relapse-free survival rate was 52.4% (95% CI: 39.3-65.5) (Figure 3). It was found that survival was independent of gender (p = 0.47), age (p = 0.58), tumour location in the rectum (p = 0.32), type of operation (p = 0.22) and pathological T status (p = 0.35), but it was significantly better in patients with pathological negative nodes than in patients with positive nodes (66.5% vs. 36.4%; p = 0.01). As of April 2010, 22 patients (38.6%) of the entire study population have died. One patient (1.8%) died of treatment complications, 15 (26.3%) died of rectal cancer, 1 (1.8%) of a second primary cancer and the remaining 5 patients of other causes (8.7%). The 5-year overall survival rate was 61.4% (95% CI: 48.9-73.9) (Figure 4).\n\nFigure 2 Local recurrence-free survival (n = 56).\n\nFigure 3 Recurrence-free survival (n = 57).\n\nFigure 4 Overall survival (n = 57).\n\nDiscussion\nPatients with locally advanced stage II/III rectal cancer should preferably receive some form of neoadjuvant treatment to downstage the tumour and enable a potentially curative resection. Fluoropyrimidine-based chemoradiation is currently a well-accepted approach in the management of locally advanced rectal cancer with several retrospective and prospective trials suggesting that preoperative capecitabine is at least equivalent to infusional 5-FU when combined with radiotherapy, and may improve tumour downstaging. Since 2009, capecitabine has been recommended by the US National Comprehensive Cancer Network as an acceptable alternative to 5-FU in this setting [20].\n\nIn the initial part of this study the complete pathological response rate was 9.1%, tumour (T), lymph nodes (N), and overall downstaging rates were 40%, 52.9%, and 49.1%, respectively, the total sphincter preservation rate was 65.5% (36 out of 55 patients) and the rate in 27 patients with tumours located within 5 cm of the anal opening was 37% (10 out of 27 patients) [19]. These findings are similar to some other studies using single-agent capecitabine, such as Dunst et al. [23] and Craven et al [24] where the complete pathological response rates were 7% and 9%, respectively; that said, in small studies with oral capecitabine the complete pathological response rate has ranged from 0 to 31% [23-39], while in the study by Kim et al. [40], which is one of the largest studies to date, the rate was 12%. It is noteworthy that the findings from this study are comparable to studies using single-agent 5-FU [41].\n\nOverall, a number of phase II studies with comparable designs to that used here have shown favorable toxicity profiles and pathological complete response rates with capecitabine chemoradiotherapy [25-39]. Thus, these studies have shown comparable results suggesting that the combination of capecitabine and pelvic radiation is safe and effective and that capecitabine can replace continuous infusional 5-FU. The toxicity of the combination of capecitabine chemotherapy and radiotherapy was low, as expected, and has been reported elsewhere [22]. The most frequent side-effect of the preoperative combined therapy was dermatitis (grade 3 in 19 patients). These safety data compare favorably with the results of other phase I/II studies in rectal cancers. Long-term toxicity found the proportion of patients with severe late (SOMA grade 3 and 4) rectal, bladder and sexual toxicity was 40%, 19.2% and 51.7%, respectively.\n\nIn 2008, Dunst et al. [23] was the first to report long-term follow-up on survival and local control in patients with locally advanced rectal cancer having undergone neoadjuvant capecitabine-based chemoradiotherapy followed by surgery. Here, in what we believe to be only the second long-term follow-up, in 55 patients with locally advanced rectal cancer who underwent surgery considered curative the 5-year overall survival rate, recurrence-free survival rate, and local control rate were 61.4%, 52.4%, and 87.4%, respectively. The 5-year overall survival reported here is similar to the 65% reported by Dunst et al. [23]. However, the rate of local recurrence reported here (12.3%) was lower than the cumulative risk of local recurrence after 5 years reported by Dunst et al. [21] (17%).\n\nWhile many questions regarding the use of adjuvant therapy in patients with locally advanced rectal cancer have yet to be answered, and data regarding capecitabine in this setting are limited, it is clear that capecitabine is an effective and more convenient alternative to 5-FU when combined with radiotherapy in the preoperative treatment of patients with locally advanced rectal cancer. A number of on-going trials are taking place that incorporate capecitabine as an integral part of the design with the aim to refine the management of this patient group and, as such, is likely to assume a major role in the treatment of rectal cancer in the future.\n\nConclusion\nThe results of this long-term study confirm data from other non-randomised studies that capecitabine-based preoperative chemoradiation is a feasible treatment option for locally advanced rectal cancer, with positive 5-year overall survival, recurrence-free survival, and local control rates. Complete pathological response rates were similar to those reported with single-agent 5-FU.\n\nAbbreviations\n5-FU: 5-fluorouracil.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nVV: contributions to conception and design, acquisition of data, analysis and interpretation of data; involvement in drafting and reviewing the manuscript. IO: contributions to acquisition of data. FA: contributions to acquisition of data, analysis and interpretation of data; involvement in drafting and reviewing the manuscript. All authors have read and approved the final version of the manuscript.\n==== Refs\nCammà C Giunta M Fiorica F Pagliaro L Craxì A Cottone M Preoperative radiotherapy for resectable rectal cancer: A meta-analysis JAMA 2000 284 1008 1015 10.1001/jama.284.8.1008 10944647 \nColorectal Cancer Collaborative Group Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials Lancet 2001 358 1291 1304 10.1016/S0140-6736(01)06409-1 11684209 \nGagel B Piroth M Pinkawa M Pinkawa M Reinartz P Zimny M Fischedik K Stanzel S Breuer C Skobel E Asadpour B Schmachtenberg A Buell U Eble MJ Gemcitabine concurrent with thoracic radiotherapy after induction chemotherapy with gemcitabine/vinorelbine in locally advanced non-small cell lung cancer. A phase I study Strahlenther Onkol 2006 182 263 269 10.1007/s00066-006-1485-0 16673059 \nKortmann B Reimer T Gerber B Klautke G Fietkau R Concurrent radiochemotherapy of locally recurrent or advanced sarcomas of the uterus Strahlenther Onkol 2006 182 318 324 10.1007/s00066-006-1491-2 16703286 \nRades D Schulte R Yekebas EF Homann N Schild SE Dunst J Radio(chemo)therapy plus resection versus radio(chemo)therapy alone for the treatment of stage III esophageal cancer Strahlenther Onkol 2007 183 10 16 10.1007/s00066-007-1583-7 17225940 \nSemrau S Gerber B Reimer T Klautke G Fietkau R Concurrent radiotherapy and taxane chemotherapy in patients with locoregional recurrence of breast cancer Strahlenther Onkol 2006 182 596 603 10.1007/s00066-006-1549-1 17013573 \nBosset JF Calais G Mineur L Maingon P Radosevic-Jelic L Daban A Bardet E Beny A Briffaux A Collette L Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results - EORTC 22921 J Clin Oncol 2005 23 5620 5627 10.1200/JCO.2005.02.113 16009958 \nBosset JF Collette L Calais G Mineur L Maingon P Radosevic-Jelic L Daban A Bardet E Beny A Ollier JC EORTC Radiotherapy Group Trial 22921 Chemotherapy with preoperative radiotherapy in rectal cancer N Engl J Med 2006 355 1114 1123 10.1056/NEJMoa060829 16971718 \nGérard JP Conroy T Bonnetain F Bouché O Chapet O Closon-Dejardin MT Untereiner M Leduc B Francois E Maurel J Seitz JF Buecher B Mackiewicz R Ducreux M Bedenne L Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203 J Clin Oncol 2006 24 4620 4625 10.1200/JCO.2006.06.7629 17008704 \nSauer R Becker H Hohenberger W Rödel C Wittekind C Fietkau R Martus P Tschmelitsch J Hager E Hess CF Karstens JH Liersch T Schmidberger H Raab R German Rectal Cancer Study Group Preoperative versus postoperative chemoradiotherapy for rectal cancer N Engl J Med 2004 351 1731 1740 10.1056/NEJMoa040694 15496622 \nBajetta E Beretta E Di Bartolomeo M Mariani L Valvo F Ferrario E Mancin M Dognini G Buzzoni R Capecitabine chemoradiation for rectal cancer after curative surgery J Chemother 2006 18 85 89 16572898 \nCassidy J Twelves C Van Cutsem E Hoff P Bajetta E Boyer M Bugat R Burger U Garin A Graeven U McKendric J Maroun J Marshall J Osterwalder B Pérez-Manga G Rosso R Rougier P Schilsky RL Capecitabine Colorectal Cancer Study Group First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin Ann Oncol 2002 13 566 575 10.1093/annonc/mdf089 12056707 \nTwelves C Wong A Nowacki MP Abt M Burris H Carrato A Cassidy J Cervantes A Fagerberg J Georgoulias V Husseini F Jodrell D Koralewski P Kröning H Maroun J Marschner N McKendrick J Pawlicki M Rosso R Schüller J Seitz JF Stabuc B Tujakowski J Van Hazel G Zaluski J Scheithauer W Capecitabine as adjuvant treatment for stage III colon cancer N Engl J Med 2005 352 2696 2704 10.1056/NEJMoa043116 15987918 \nVan Cutsem E Findlay M Osterwalder B Kocha W Dalley D Pazdur R Cassidy J Dirix L Twelves C Allman D Seitz JF Schölmerich J Burger HU Verweij J Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study J Clin Oncol 2000 18 1337 1345 10715306 \nVan Cutsem E Hoff PM Harper P Bukowski RM Cunningham D Dufour P Graeven U Lokich J Madajewicz S Maroun JA Marshall JL Mitchell EP Perez-Manga G Rougier P Schmiegel W Schoelmerich J Sobrero A Schilsky RL Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomized, phase III trials Br J Cancer 2004 90 1190 1197 10.1038/sj.bjc.6601676 15026800 \nGlynne-Jones R Dunst J Sebag-Montefiore D The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful have we been? Ann Oncol 2006 17 361 371 10.1093/annonc/mdj052 16500912 \nSaif MW Hashmi S Zelterman D Almhanna K Kim R Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review Int J Colorectal Dis 2008 23 139 145 10.1007/s00384-007-0382-z 17909820 \nKim DY Jung KH Kim TH Kim DW Chang HJ Jeong JY Kim YH Son SH Yun T Hong CW Sohn DK Lim SB Choi HS Jeong SY Park JG Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer Int J Radiat Oncol Biol Phys 2007 67 378 384 17097835 \nVelenik V Anderlih F Oblak I Strojan P Zakotnik B Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced respectable rectal cancer: prospective phase II trial Croat Med J 2006 47 693 700 17042060 \nNational Comprehensive Cancer Network National Comprehensive Cancer Network clinical practice guidelines, Rectal cancer http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site\nLENT SOMA tables Radiother Oncol 1995 35 17 60 10.1016/0167-8140(95)90055-1 7569012 \nVelenik V Anderluh F Oblak I Strojan P Segedin B Zakotnik B Preoperative capecitabine and concomitant radiotherapy in operable rectal cancer: a phase II study with 2 years follow-up Science and multidisciplinary management of GI malignancies: Proceedings book 2008 Alexandria, VA: American Society of Clinical Oncology 325 \nDunst J Debus J Rudat V Wulf J Budach W Hoelscher T Reese T Mose S Roedel C Zuehlke H Hinke A Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer Strahlenther Onkol 2008 184 450 456 10.1007/s00066-008-1751-4 19016023 \nCraven I Crellin A Cooper R Melcher A Byrne P Sebag-Montefiore D Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer Br J Cancer 2007 97 1333 1337 10.1038/sj.bjc.6604042 17987042 \nChau I Brown G Cunningham D Tait D Wotherspoon A Norman AR Tebbutt N Hill M Ross PJ Massey A Oates J Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor risk rectal cancer J Clin Oncol 2006 24 668 674 10.1200/JCO.2005.04.4875 16446339 \nDe Paoli A Chiara S Luppi G Friso ML Beretta GD Del Prete S Pasetto L Santantonio M Sarti E Mantello G Innocente R Frustaci S Corvò R Rosso R Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable rectal cancer: a multicentric phase II study Ann Oncol 2006 17 246 251 10.1093/annonc/mdj041 16282246 \nDesai SP El-Rayes BF Ben-Josef E Greenson JK Knol JA Huang EH Griffith KA Philip PA McGinn CJ Zalupski MM A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer Am J Clin Oncol 2007 30 340 345 10.1097/COC.0b013e318033ed63 17762432 \nDunst J Reese T Sutter T Zühlke H Hinke A Kölling-Schlebusch K Frings S Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer J Clin Oncol 2002 20 3983 3991 10.1200/JCO.2002.02.049 12351595 \nDupuis O Vie B Liedo G Hennequin C Noirclerc M Bennamoun M Jacob JH Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR phase II study Oncology 2007 73 169 176 10.1159/000127383 18418009 \nFreedman GM Meropol NJ Sigurdson ER Hoffman J Callahan E Price R Cheng J Cohen S Lewis N Watkins-Bruner D Rogatko A Konski A Phase I trial of preoperative hypofractionated intensity-modulated radiotherapy with incorporated boost and oral capecitabine in locally advanced rectal cancer Int J Radiat Oncol Biol Phys 2007 67 1389 1393 17394942 \nKim JS Kim JS Cho MJ Song KS Yoon WH Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer Int J Radiat Oncol Biol Phys 2002 54 403 408 12243814 \nKocakova I Svoboda M Klocova K Chrenko V Roubalova E Krejci E Sefr R Slampa P Frgala T Zaloudik J Combined therapy of locally advanced rectal adenocarcinoma with capecitabine and concurrent radiotherapy Proc Am Soc Clin Oncol 2004 23 299 abstract 3720 \nKorkolis DP Boskos CS Plataniotis GD Gontikakis E Karaitianos IJ Avgerinos K Katopodi A Xinopoulos D Dimitroulopoulos D Beroukas K Vassilopoulos PP Pre-operative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer Anticancer Res 2007 27 541 545 17348439 \nLay GC Caraul B Dessi M Orrù S Murtas R Deidda MA Farigu R Farci D Maxia L Casula G Amichetti M Phase II study of preoperative irradiation and chemotherapy with capecitabine in patients with locally advanced rectal carcinoma J Exp Clin Cancer Res 2007 26 61 70 17550133 \nLin EH Skibber J Delcos M A phase II study of capecitabine and concomitant boost radiotherapy (XRT) in patients with locally advanced rectal cancer J Clin Oncol 2005 23 Suppl 16 269s abstract 3593 \nNgan SY Michael M Mackay J McKendrick J Leong T Lim Joon D Zalcberg JR A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer Br J Cancer 2004 91 1019 1024 15305186 \nShen W Liu Y Ma X Capecitabine combined with radiotherapy in Chinese patients with advanced or relapsed rectal carcinoma Proc Am Soc Clin Oncol 2004 23 287 abstract 3671 \nVeerasarn V Phromratanapongse P Lorvidhava V Lertsanguansinchai P Lertbutsayanukul C Panichevaluk A Boonnuch W Chinswangwatanakul V Lohsiriwat D Rojanasakul A Thavichaigarn P Jivapaisarnpong P Preoperative capacitabine with pelvic radiotherapy for locally advanced rectal cancer (phase I trial) J Med Assoc Thai 2006 89 1874 1884 17205868 \nWong SJ Sadasiwan C Erickson B A phase I trial of preoperative capecitabine and concurrent radiation for locally advanced rectal cancer Proc Am Soc Clin Oncol 2004 23 312 abstract 3771 \nKim JC Kim TW Kim JH Yu CS Kim HC Chang HM Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer Int J Radiat Oncol Biol Phys 2005 63 346 353 10.1016/j.ijrobp.2005.05.005 15913913 \nDas P Lin EH Bhatia S Skibber JM Rodriguez-Bigas MA Feig BW Chang GJ Hoff PM Eng C Wolff RA Delclos ME Krishnan S Janjan NA Crane CH Preoperative chemoradiation with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis Int J Radiat Oncol Biol Phys 2006 66 1378 1383 17056196\n\n",
"fulltext_license": "CC BY",
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"journal": "Radiation oncology (London, England)",
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"medline_ta": "Radiat Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D000069287:Capecitabine; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D013505:Digestive System Surgical Procedures; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D012004:Rectal Neoplasms; D013995:Time",
"nlm_unique_id": "101265111",
"other_id": null,
"pages": "88",
"pmc": null,
"pmid": "20920276",
"pubdate": "2010-09-29",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "15496622;17056196;11684209;15987918;18418009;17205868;16500912;7569012;19016023;16673059;17394942;17550133;12243814;17225940;16446339;17987042;17909820;17013573;10944647;16572898;16009958;16971718;16703286;12056707;17042060;17762432;10715306;17348439;15305186;17097835;17008704;15913913;12351595;15026800;16282246",
"title": "Long-term results from a randomized phase II trial of neoadjuvant combined-modality therapy for locally advanced rectal cancer.",
"title_normalized": "long term results from a randomized phase ii trial of neoadjuvant combined modality therapy for locally advanced rectal cancer"
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"abstract": "T-cell posttransplant lymphoproliferative disorders after solid-organ transplant are rare and may be clinically aggressive. A 3-year-old boy had liver transplant from his grandfather because of hepatoblastoma. The immunosuppressive regimen was based on tacrolimus and prednisolone. At 22 months after transplant (age, 5 years), the patient presented to the hospital because of severe cough. Computed tomography scan of the chest showed a large left mediastinal mass (9 × 7.2 × 7 cm) and left pleural effusion. A Tru-Cut biopsy of the mediastinal mass showed diffuse infiltration with blast cells, and the diagnosis of T-cell acute lymphoblastic leukemia was made. Immunohistochemical examination of blasts showed strong and diffuse terminal deoxynucleotidyl transferase and CD3 antibody expression; Ki-67 proliferation index was > 95%, and tumor cells were negative for Epstein-Barr virus. Tacrolimus was stopped, sirolimus was started, and chemotherapy was given, but he died 2 months after diagnosis because of chemotherapy-induced sepsis. Monomorphic T-cell posttransplant lymphoproliferative disorder with features of acute lymphoblastic leukemia and lymphoblastic lymphoma is rare after liver transplant.",
"affiliations": "Department of Pathology, Baskent University Faculty of Medicine, Ankara, Turkey.",
"authors": "Akar Özkan|Eylem|E|;Özdemir|B Handan|BH|;Yılmaz Akçay|Eda|E|;Ok Atılgan|Alev|A|;Haberal|Mehmet|M|",
"chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "12 Suppl 1()",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000970:Antineoplastic Agents; D001706:Biopsy; D002675:Child, Preschool; D017809:Fatal Outcome; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D018805:Sepsis; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "139-41",
"pmc": null,
"pmid": "24635812",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "T-cell acute lymphoblastic leukemia after liver transplant.",
"title_normalized": "t cell acute lymphoblastic leukemia after liver transplant"
} | [
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"companynumb": "TR-MYLANLABS-2014S1010386",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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{
"abstract": "BACKGROUND\nEndogenous endophthalmitis is a sight-threatening condition caused by microorganisms crossing the blood-ocular barrier and inducing profound intraocular inflammation.\n\n\nMETHODS\nA 65-year-old female experienced bilateral loss of vision after developing infective endocarditis as a complication of combined Bentall procedure and coronary artery bypass grafting. She was diagnosed with bilateral endogenous endophthalmitis secondary to Serratia marcescens. Despite aggressive treatment with intravitreal injections of antibiotics and steroids, intensive topical and systemic antibiotic therapy, there was permanent loss of sight in both eyes.\n\n\nCONCLUSIONS\nThe case highlights the importance of early recognition of the symptoms and signs of endogenous endophthalmitis in any patient with systemic infection by all clinicians and the necessity of prompt ophthalmological referral if a useful level of vision is to be preserved.",
"affiliations": "Tennent Institute of Ophthalmology, Gartnavel General Hospital, UK. douglasamlyall@gmail.com",
"authors": "Lyall|D A M|DA|;Gregory|M E|ME|;McDonnell|J|J|;De Villiers|F|F|;Tejwani|D|D|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1177/0036933013482647",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-9330",
"issue": "58(2)",
"journal": "Scottish medical journal",
"keywords": "Endogenous endophthalmitis; Serratia marcescens; blood–ocular barrier; endocarditis; intraocular inflammation",
"medline_ta": "Scott Med J",
"mesh_terms": "D000368:Aged; D001011:Aorta; D001021:Aortic Valve; D001026:Coronary Artery Bypass; D017548:Echocardiography, Transesophageal; D004696:Endocarditis; D009877:Endophthalmitis; D005260:Female; D006801:Humans; D011183:Postoperative Complications; D016868:Serratia Infections; D012706:Serratia marcescens",
"nlm_unique_id": "2983335R",
"other_id": null,
"pages": "e1-6",
"pmc": null,
"pmid": "23728762",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral endogenous Serratia marcescens endophthalmitis secondary to endocarditis following cardiac surgery.",
"title_normalized": "bilateral endogenous serratia marcescens endophthalmitis secondary to endocarditis following cardiac surgery"
} | [
{
"companynumb": "GB-MYLANLABS-2021M1093652",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "Anticoagulant therapy with vitamin K antagonists (AVK) is an effective treatment and prevention of thrombosis. One of the major disadvantages of the AVK is a risk for serious bleeding. Prothrombin complex concentrates (PCC), fresh frozen plasma (FFP) and vitamin K1 are available for control of these situations. The experience of special team ofthe Scientific Center for Hematology was the basis for presented retrospective study. Three regimens of warfarin-related bleeding were compared: PCC+ VK for several bleeding, FFP+ VK for different clinical situations and VKfor light bleeding. PCC showed himself as effective and safe hemostatic agent. Transfusions of FFP were sometimes not effective, sometimes led to TACO. Supplementation of vitamin K1 for patients of I and II groups provided more stable control of hemostasis. In III group VK vas effective to stop bleeding. Two impotent sings for conclusion: necessary of laboratory monitoring, TEG first of all; individual balance of hemostasis base of bleeding or thrombotic risks.",
"affiliations": null,
"authors": "Prasolov|N V|NV|;Shulutko|E M|EM|;Bulanov|A Yu|AY|;Yatskov|K V|KV|;Shcherbakov|O V|OV|",
"chemical_list": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D006490:Hemostatics; C025667:prothrombin complex concentrates; D014859:Warfarin; D010837:Vitamin K 1",
"country": "Russia (Federation)",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0201-7563",
"issue": "60(2)",
"journal": "Anesteziologiia i reanimatologiia",
"keywords": null,
"medline_ta": "Anesteziol Reanimatol",
"mesh_terms": "D000925:Anticoagulants; D001777:Blood Coagulation; D001779:Blood Coagulation Factors; D005260:Female; D006470:Hemorrhage; D006490:Hemostatics; D006801:Humans; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D010951:Plasma Exchange; D012189:Retrospective Studies; D016896:Treatment Outcome; D010837:Vitamin K 1; D014859:Warfarin",
"nlm_unique_id": "7705399",
"other_id": null,
"pages": "72-6",
"pmc": null,
"pmid": "26148369",
"pubdate": "2015",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "EMERGENCY TREATMENT OF BLEEDING IN PATIENTS TAKING WARFARIN.",
"title_normalized": "emergency treatment of bleeding in patients taking warfarin"
} | [
{
"companynumb": "PHHY2015RU120857",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "OBJECTIVE\nTo investigate the clinical features, response to corticosteroids, and prognosis of autoimmune hepatitis (AIH)-induced liver failure in China.\n\n\nMETHODS\nA total of 22 patients (19 female and 3 male; average age 51 ± 15 years) with AIH-induced liver failure treated in our hospital from 2004 to 2012 were retrospectively analyzed. Clinical, biochemical and pathological characteristics of the 22 patients and responses to corticosteroid treatment in seven patients were examined retrospectively. The patients were divided into survivor and non-survivor groups, and the clinical characteristics and prognosis were compared between the two groups. The t test was used for data analysis of all categorical variables, and overall survival was calculated by the Kaplan-Meier method.\n\n\nRESULTS\nAt the time of diagnosis, mean IgG was 2473 ± 983 mg/dL, with three (18.8%) patients showing normal levels. All of the patients had elevated serum levels of antinuclear antibody (≥ 1:640). Liver histology from one patient showed diagnostic pathological changes, including massive necrosis and plasma cell infiltration. Four patients survived (18.2%) and 18 died (81.8%) without liver transplantation. The results showed that patients with low admission Model for End-Stage Liver Disease (MELD) scores (21.50 ± 2.08 vs 30.61 ± 6.70, P < 0.05) and corticosteroid therapy (100% vs 16.7%, P < 0.05) had better prognosis. A total of seven patients received corticosteroid therapy, of whom, four responded and survived, and the other three died. Survivors showed young age, shorter duration from diagnosis to corticosteroid therapy, low MELD score, and absence of hepatic encephalopathy at the time of corticosteroid administration. Six patients who were administered corticosteroids acquired fungal infections but recovered after antifungal therapy.\n\n\nCONCLUSIONS\nEarly diagnosis and corticosteroid therapy are essential for improving the prognosis of patients with AIH-induced liver failure without liver transplantation.",
"affiliations": "Bing Zhu, Shao-Li You, Zhi-Hong Wan, Hong-Ling Liu, Yi-Hui Rong, Hong Zang, Shao-Jie Xin, Liver Failure Treatment and Research Center, 302 Military Hospital, Beijing 100039, China.;Bing Zhu, Shao-Li You, Zhi-Hong Wan, Hong-Ling Liu, Yi-Hui Rong, Hong Zang, Shao-Jie Xin, Liver Failure Treatment and Research Center, 302 Military Hospital, Beijing 100039, China.;Bing Zhu, Shao-Li You, Zhi-Hong Wan, Hong-Ling Liu, Yi-Hui Rong, Hong Zang, Shao-Jie Xin, Liver Failure Treatment and Research Center, 302 Military Hospital, Beijing 100039, China.;Bing Zhu, Shao-Li You, Zhi-Hong Wan, Hong-Ling Liu, Yi-Hui Rong, Hong Zang, Shao-Jie Xin, Liver Failure Treatment and Research Center, 302 Military Hospital, Beijing 100039, China.;Bing Zhu, Shao-Li You, Zhi-Hong Wan, Hong-Ling Liu, Yi-Hui Rong, Hong Zang, Shao-Jie Xin, Liver Failure Treatment and Research Center, 302 Military Hospital, Beijing 100039, China.;Bing Zhu, Shao-Li You, Zhi-Hong Wan, Hong-Ling Liu, Yi-Hui Rong, Hong Zang, Shao-Jie Xin, Liver Failure Treatment and Research Center, 302 Military Hospital, Beijing 100039, China.;Bing Zhu, Shao-Li You, Zhi-Hong Wan, Hong-Ling Liu, Yi-Hui Rong, Hong Zang, Shao-Jie Xin, Liver Failure Treatment and Research Center, 302 Military Hospital, Beijing 100039, China.",
"authors": "Zhu|Bing|B|;You|Shao-Li|SL|;Wan|Zhi-Hong|ZH|;Liu|Hong-Ling|HL|;Rong|Yi-Hui|YH|;Zang|Hong|H|;Xin|Shao-Jie|SJ|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v20.i23.7473",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "20(23)",
"journal": "World journal of gastroenterology",
"keywords": "Autoantibody; Autoimmune hepatitis; Corticosteroid therapy; Liver failure; Prognosis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D015415:Biomarkers; D002681:China; D042241:Early Diagnosis; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D053208:Kaplan-Meier Estimate; D017093:Liver Failure; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "7473-9",
"pmc": null,
"pmid": "24966618",
"pubdate": "2014-06-21",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18318440;19343322;9314137;16995974;22964153;26201805;9049195;12839709;8596574;12143059;15224287;15841455;21269383;22825549;21554505;20188523;16629940;19125945;18328067;7666914;17705297;1729033;21274872;17370334;20821236;12424720;12484709;17370335;10580593;18537184",
"title": "Clinical characteristics and corticosteroid therapy in patients with autoimmune-hepatitis-induced liver failure.",
"title_normalized": "clinical characteristics and corticosteroid therapy in patients with autoimmune hepatitis induced liver failure"
} | [
{
"companynumb": "CN-PFIZER INC-2014190930",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,... |
{
"abstract": "Spinal subarachnoid hemorrhage (SSH) is a rare yet potentially devastating complication of neuraxial procedures. We present a case of SSH after inadvertent lumbar spinal drain removal while on clopidogrel. The contrast between the patient's mild clinical symptoms compared to his impressive magnetic resonance imaging (MRI) highlights the variable presentations that can be seen with spinal and epidural hematomas. Despite sophisticated electronic warnings systems available to improve patient safety, better efforts are needed to improve interprofessional communication with providers taking care of patients with indwelling neuraxial catheters.",
"affiliations": "From the Department of Anesthesiology, Northwestern Memorial Hospital, Chicago, Illinois.;Department of Anesthesiology, University of Chicago, Chicago, Illinois.",
"authors": "Aboumerhi|Hassan|H|;Elmofty|Dalia H|DH|",
"chemical_list": "D000077144:Clopidogrel",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "13(11)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000368:Aged; D000077144:Clopidogrel; D020878:Device Removal; D004322:Drainage; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D013345:Subarachnoid Hemorrhage",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "436-439",
"pmc": null,
"pmid": "31577536",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Self-Limited Spinal Subarachnoid Hemorrhage After Lumbar Spinal Drain Removal While on Clopidogrel: A Case Report.",
"title_normalized": "self limited spinal subarachnoid hemorrhage after lumbar spinal drain removal while on clopidogrel a case report"
} | [
{
"companynumb": "US-TEVA-2020-US-1227996",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nTherapeutic approaches for B-cell malignancies continue to evolve, especially with regard to combination approaches. We assessed the safety and efficacy of the triplet ublituximab, umbralisib, and ibrutinib in patients with advanced B-cell malignancies.\n\n\nMETHODS\nWe did an open-label, phase 1 study with dose-escalation and dose-expansion phases, at five centres in the USA. Eligible patients were aged 18 years or older with histologically confirmed lymphocytic leukaemia or relapsed or refractory B-cell non-Hodgkin lymphoma, had measurable disease, adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patients with known CNS lymphoma, active hepatitis B or C infection, or HIV were excluded. In the dose-escalation cohort, patients were treated in cycles of 28 days with escalating doses of oral umbralisib (400, 600, or 800 mg) and fixed doses of intravenous ublituximab (900 mg) and oral ibrutinib (420 mg for patients with chronic lymphocytic leukaemia; 560 mg for patients with B-cell non-Hodgkin lymphoma) in a standard 3 × 3 design until disease progression or intolerance. In the dose-expansion phase, patients were given the recommended dose of the drug combination as determined from the dose-escalation phase. The primary endpoints were safety, dose-limiting toxicities, and the maximum tolerated dose of umbralisib, when given in combination with ublituximab and ibrutinib. Safety was assessed in patients who received at least one dose of study drug; activity was assessed in all patients who had at least one post-treatment efficacy measurement. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02006485.\n\n\nRESULTS\nBetween Sept 2, 2014, and Nov 6, 2017, we enrolled 46 patients: 24 in the dose-escalation cohort (n=14 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=10 B-cell non-Hodgkin lymphoma) and 22 in the dose-expansion cohort (n=9 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=13 B-cell non-Hodgkin lymphoma). 46 patients received at least one dose of study drug. The maximum tolerated dose of umbralisib was not reached. The recommended dose for the dose-expansion phase was umbralisib 800 mg orally once daily plus ibrutinib orally once daily and intravenous ublituximab 900 mg administered on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and on day 1 of cycles 9 and 12. 37 (84%) of 44 patients achieved an overall response (complete or partial response). The most common any-grade adverse events were diarrhoea (n=27 [59%]), fatigue (n=23 [50%]), infusion-related reaction (n=20 [43%]), dizziness (n=17 [37%]), nausea (n=17 [37%]), and cough (n=16 [35%]). Grade 3-4 adverse events were manageable with the most common being neutropenia (n=10 [22%]) and cellulitis (n=6 [13%]). Serious adverse events occurred in 11 (24%) of 46 patients and included rash (n=2 [4%]), pneumonia (n=2 [4%]), atrial fibrillation (n=2 [4%]), sepsis (n=2 [4%]), abdominal pain (n=1 [2%]), syncope (n=1 [2%]), cellulitis (n=1 [2%]), pneumonitis (n=1 [2%]), headache (n=1 [2%]), lung infection (n=1 [2%]), skin infection (n=1 [2%]), pleural effusion (n=1 [2%]), pericardial infusion (n=1 [2%]), upper gastrointestinal bleeding (n=1 [2%]), diarrhoea (n=1 [2%]), and weakness (n=1 [2%]). No deaths related to adverse events occurred.\n\n\nCONCLUSIONS\nThe combination of ublituximab, umbralisib, and ibrutinib seems to be tolerable and is associated with encouraging activity in advanced chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma. This triplet combination will require further investigation in future studies to improve understanding of this novel, chemotherapy-free triplet combination in the management of these cancers.\n\n\nBACKGROUND\nTG Therapeutics.",
"affiliations": "The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: lnastoupil@mdanderson.org.;University of Nebraska Medical Center, Omaha, NE, USA.;University of Nebraska Medical Center, Omaha, NE, USA.;Clearview Cancer Institute, Huntsville, AL, USA.;City of Hope National Medical Center, Duarte, CA, USA.;Emory University Winship Cancer Institute, Atlanta, GA, USA.;Emory University Winship Cancer Institute, Atlanta, GA, USA.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;University of California Irvine Cancer Center, Orange, CA, USA.;TG Therapeutics, New York, NY, USA.;TG Therapeutics, New York, NY, USA.;TG Therapeutics, New York, NY, USA.;TG Therapeutics, New York, NY, USA.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Nastoupil|Loretta J|LJ|;Lunning|Matthew A|MA|;Vose|Julie M|JM|;Schreeder|Marshall T|MT|;Siddiqi|Tanya|T|;Flowers|Christopher R|CR|;Cohen|Jonathon B|JB|;Burger|Jan A|JA|;Wierda|William G|WG|;O'Brien|Susan|S|;Sportelli|Peter|P|;Miskin|Hari P|HP|;Purdom|Michelle A|MA|;Weiss|Michael S|MS|;Fowler|Nathan H|NH|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; C000626319:umbralisib; D000225:Adenine; C000619007:ublituximab",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(18)30216-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "6(2)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000225:Adenine; D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004305:Dose-Response Relationship, Drug; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D012449:Safety",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e100-e109",
"pmc": null,
"pmid": "30709431",
"pubdate": "2019-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial.",
"title_normalized": "tolerability and activity of ublituximab umbralisib and ibrutinib in patients with chronic lymphocytic leukaemia and non hodgkin lymphoma a phase 1 dose escalation and expansion trial"
} | [
{
"companynumb": "US-JNJFOC-20190227733",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "1",
"d... |
{
"abstract": "Methadone continues to be a widely used maintenance therapy for opiate dependence. However, methadone-related deaths have been reported frequently for over 4 decades now. Anoxic brain injury with pulmonary edema secondary to respiratory depression is the recognized mechanism of methadone death, although pathological intracranial findings are rarely described in methadone deaths. A selective area of brain injury has never been reported with methadone use. We present a case of a 23-year-old man who had acute necrosis of the bilateral globi pallidi in the brain and systemic rhabdomyolysis after ingesting methadone and nasally insufflating alprazolam. We also present a review of the literature on deaths following opioid use and associated brain injury.",
"affiliations": "Department of Pathology and Laboratory Medicine and Waisman Center, University of Wisconsin, Madison, WI 53792, USA. RCorliss@uwhealth.org",
"authors": "Corliss|Robert F|RF|;Mandal|Rakesh|R|;Soriano|Benjamin J|BJ|",
"chemical_list": "D006993:Hypnotics and Sedatives; D009294:Narcotics; D008691:Methadone; D000525:Alprazolam",
"country": "United States",
"delete": false,
"doi": "10.1097/PAF.0b013e31823a8b1e",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "34(1)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000281:Administration, Intranasal; D000328:Adult; D000525:Alprazolam; D001921:Brain; D049429:Forensic Pathology; D053593:Forensic Toxicology; D015600:Glasgow Coma Scale; D005917:Globus Pallidus; D006801:Humans; D006993:Hypnotics and Sedatives; D020300:Intracranial Hemorrhages; D007668:Kidney; D008297:Male; D008691:Methadone; D009294:Narcotics; D009336:Necrosis; D009474:Neurons; D012206:Rhabdomyolysis; D019966:Substance-Related Disorders",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "23361067",
"pubdate": "2013-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral acute necrosis of the globi pallidi and rhabdomyolysis due to combined methadone and benzodiazepine toxicity.",
"title_normalized": "bilateral acute necrosis of the globi pallidi and rhabdomyolysis due to combined methadone and benzodiazepine toxicity"
} | [
{
"companynumb": "PHHY2013US104833",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIACETYLMORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "The increasing use of extracorporeal membrane oxygenation (ECMO) in critical care introduces new challenges with medication dosing. Voriconazole, a commonly used antifungal and the first-choice agent for the treatment of invasive aspergillosis, is a poorly water-soluble and highly protein-bound drug. Significant sequestration in ECMO circuits can be expected; however, no specific dosing recommendations are available. We report on the therapeutic drug monitoring and clinical evolution of a patient treated with voriconazole for invasive pulmonary aspergillosis while receiving ECMO therapy. Voriconazole trough levels were persistently low (<1 µg/mL) after initiation of ECMO despite additional loading doses and dose increases. Voriconazole dose had to be increased to 6.5 mg/kg three times daily to obtain therapeutic trough levels. The inability to achieve therapeutic levels of voriconazole for a prolonged period (a minimum of 9 days) while undergoing ECMO therapy is believed to have been a significant contributing factor in the patient's fatal outcome. Therapeutic trough levels of voriconazole cannot be guaranteed with standard dosing in patients undergoing ECMO and much higher doses may be necessary. Empirical use of higher doses and/or combination therapy may be reasonable and frequent therapeutic drug monitoring is mandatory.",
"affiliations": "From the Department of Pharmacy, Centre Hospitalier de l'Université de Montréal, 1051 Rue Sanguinet, Montréal, Québec, Canada Immunopathology Axis, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Montréal, Québec, Canada Innovation Hub Axis, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, 900 rue Saint-Denis, Montréal, Québec, Canada Microbiology, Infectious Diseases and Immunology Department, Université de Montréal, 2900 Boulevard Édouard Montpetit, Montréal, Québec, Canada Department of Laboratory Medicine, Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, Québec, Canada Department of Anesthesiology, Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, Québec, Canada.",
"authors": "Mathieu|Alexandre|A|;Thiboutot|Zoé|Z|;Ferreira|Victor|V|;Benoit|Patrick|P|;Grandjean Lapierre|Simon|S|;Hétu|Pierre-Olivier|PO|;Halwagi|Antoine|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MAT.0000000000001427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-2916",
"issue": null,
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": null,
"nlm_unique_id": "9204109",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33788798",
"pubdate": "2021-03-29",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Voriconazole Sequestration During Extracorporeal Membrane Oxygenation for Invasive Lung Aspergillosis: A Case Report.",
"title_normalized": "voriconazole sequestration during extracorporeal membrane oxygenation for invasive lung aspergillosis a case report"
} | [
{
"companynumb": "CA-ALVOGEN-2021-ALVOGEN-116870",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CASPOFUNGIN"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nUse of liposomal bupivacaine (LB) in surgery is reported with decreased postoperative opioid requirements. The efficacy of LB versus standard bupivacaine injections at laparoscopic port sites during bariatric surgery is unknown.\n\n\nOBJECTIVE\nTo determine whether there was a difference in postoperative hospital opioid requirements after port site injections of LB versus standard bupivacaine during laparoscopic bariatric surgeries. Primary endpoint was total in hospital opioid use expressed as morphine-equivalent use. Secondary endpoints included home opioid use, pain scores, hospital length of stay, and adverse events.\n\n\nMETHODS\nAcademic-affiliated private practice.\n\n\nMETHODS\nA 2-group randomized, double-blinded trial from November 2017 to August 2018 with patients randomly assigned to receive either LB or bupivacaine alone at trocar site injections during laparoscopic Roux-en-Y gastric bypass (LRYGB) or vertical sleeve gastrectomy (VSG). All patients underwent enhanced recovery after bariatric surgery protocols.\n\n\nRESULTS\nAll patients undergoing LRYGB or VSG assessed for eligibility. Of 682 patients undergoing LRYGB or VSG, 231 met inclusion criteria, 52 patients excluded intraoperatively. Among 231 patients (mean age, 39.2 years; 79% women; mean body mass index 45.0), 179 patients (77%) completed the trial. Patients randomly assigned to receive either LB (n = 89) or bupivacaine alone (n = 90) at trocar site injection during LRYGB or VSG. Postoperative morphine-equivalent use were similar (LB 8.3 [standard deviation 4.0-13.9] versus bupivacaine group 7.5 [standard deviation 3.6-13.1] P = .94) with highest requirement in first 4 hours after surgery. There was no significant difference in length of stay, pain scores, or complications. There were more patients in the bupivacaine group that did not take pain medications on postoperative days 2 to 4 (P = .032, P = .23, P = .005, respectively). There were more patients in the bupivacaine group 48.1% (n = 39) compared with the LB group 34.2% (n = 27) that did not consume any narcotic tablets at home but this not found to be statistically significant (P value = .07).\n\n\nCONCLUSIONS\nAmong patients undergoing primary bariatric surgery under enhanced recovery after bariatric surgery protocol, there was no significant difference in postoperative hospital opioid use in those receiving LB compared with standard bupivacaine. A greater percentage of patients in the standard bupivacaine group did not require any narcotics at home, which was significant on postoperative days 2 to 4. To become completely opioid free after bariatric surgery, resources should be focused on multimodal approaches instead of reliance on type of anesthetic medication used.",
"affiliations": "Advanced Laparoscopic Surgery Associates, Department of Surgery, University of California San Francisco, Fresno, California. Electronic address: pma@fresno.ucsf.edu.;Fresno Heart and Surgical Hospital, Fresno, California.;Fresno Heart and Surgical Hospital, Fresno, California.;Advanced Laparoscopic Surgery Associates, Department of Surgery, University of California San Francisco, Fresno, California.;Advanced Laparoscopic Surgery Associates, Department of Surgery, University of California San Francisco, Fresno, California.;Fresno Heart and Surgical Hospital, Fresno, California.;Advanced Laparoscopic Surgery Associates, Department of Surgery, University of California San Francisco, Fresno, California.;Advanced Laparoscopic Surgery Associates, Department of Surgery, University of California San Francisco, Fresno, California.;Advanced Laparoscopic Surgery Associates, Department of Surgery, University of California San Francisco, Fresno, California.",
"authors": "Ma|Pearl|P|;Lloyd|Aaron|A|;McGrath|Morgan|M|;Shuchleib Cung|Ariel|A|;Akusoba|Ikemefuna|I|;Jackson|Alice|A|;Swartz|Daniel|D|;Boone|Keith|K|;Higa|Kelvin|K|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D008081:Liposomes; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.soard.2019.06.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-7289",
"issue": "15(9)",
"journal": "Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery",
"keywords": "Bariatric surgery; ERAS; Liposomal bupivacaine; Opioids; Pain; Randomized control trial",
"medline_ta": "Surg Obes Relat Dis",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D050110:Bariatric Surgery; D002045:Bupivacaine; D004311:Double-Blind Method; D000080482:Enhanced Recovery After Surgery; D005260:Female; D006801:Humans; D007267:Injections; D010535:Laparoscopy; D007902:Length of Stay; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid; D010147:Pain Measurement; D010149:Pain, Postoperative",
"nlm_unique_id": "101233161",
"other_id": null,
"pages": "1554-1562",
"pmc": null,
"pmid": "31375443",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy of liposomal bupivacaine versus bupivacaine in port site injections on postoperative pain within enhanced recovery after bariatric surgery program: a randomized clinical trial.",
"title_normalized": "efficacy of liposomal bupivacaine versus bupivacaine in port site injections on postoperative pain within enhanced recovery after bariatric surgery program a randomized clinical trial"
} | [
{
"companynumb": "US-PACIRA-201900270",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Spontaneous perirenal hemorrhage (SPH) or Wunderlich syndrome, is a rare but potentially life-threatening condition. It is characterized by an unexpected bleeding in the kidneys and usually presents as an abdominal pain. Angiography and more recently selective renal arterial embolization are emerging as effective modalities for the diagnosis and treatment of SPH. In this article, we report a total of three cases of SPH in hemodialysis (HD) patients.\n\n\n\nThis is the experience of diagnosis and treatment of SPH in HD patients.\n\n\n\nAll three were female, between 37 and 54 years of age and were undergoing HD for end stage renal disease (ESRD). Two of patients presented with left flank or abdominal pain after termination of HD therapy, while the third patient presented with left abdominal pain during the dialysis session. All patients received anti-coagulation therapy for HD, but no abnormal levels of coagulation index were found. These patients were diagnosed using CT and two of them were diagnosed with acquired cystic kidney disease (ACKD). Selective renal arterial embolization was performed in the case of active bleeding.\n\n\n\nWe are aware that HD patients have elevated risk of bleeding related complications, additionally the presence of an acute abdominal pain increases the suspicion of SPH as a possible cause. ACKD can be considered one of the possible risk factors for SPH in long-term HD patients. Interventional treatment for kidney injury is useful and safe for active bleeding in most cases.",
"affiliations": "Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.;International Renal Research Institute of Vicenza (IRRIV), Vicenza, Italy.;Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.;Department of Nephrology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.;International Renal Research Institute of Vicenza (IRRIV), Vicenza, Italy.",
"authors": "Xie|Yun|Y|;Yang|Bo|B|;Jiang|Gengru|G|;Lu|Wei|W|;Ronco|Claudio|C|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12607",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "22(2)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Spontaneous perirenal hemorrhage; hemodialysis; selective arterial embolization",
"medline_ta": "Hemodial Int",
"mesh_terms": "D000328:Adult; D004621:Embolization, Therapeutic; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D012307:Risk Factors",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "222-227",
"pmc": null,
"pmid": "29152881",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Spontaneous perirenal hemorrhage in hemodialysis patient treated with selective embolization: A case series and review of the literature.",
"title_normalized": "spontaneous perirenal hemorrhage in hemodialysis patient treated with selective embolization a case series and review of the literature"
} | [
{
"companynumb": "CN-MYLANLABS-2018M1035493",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nEven though alectinib is a potent second-generation ALK inhibitor with a favorable safety profile, alectinib-induced interstitial lung disease (ILD) could be fatal. There are case reports described successful alectinib rechallenge in mild ILD. However, the feasibility and safety of rechallenge in severe cases remains to be elucidated.\n\n\nMETHODS\nA 76-year-old female was a case of stage IV lung adenocarcinoma harboring ALK rearrangement. Respiratory failure following severe ILD developed one month after alectinib administration. She received mechanical ventilation in intensive care uint. ILD subsided gradually after methylprednisolone pulse therapy and discontinuation of alectinib.Management and outcome: After the recovery from ILD, the patient attempted a re-escalation of alectinib from a lower dose under close clinical and radiological monitoring. No ILD happened even after 480 days of alectinib rechallenge.\n\n\nCONCLUSIONS\nGiven that the ALK inhibitors are the treatment of choice for advanced lung cancer patients with ALK rearrangement. Our report demonstrated the potential feasibility of alectinib re-use in cases of severe druginduced ILD.",
"affiliations": "Department of Chest Medicine, Taipei Veterans General Hospital, Taipei.;General Chest Medicine, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei.;General Chest Medicine, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei.",
"authors": "Huang|Jhong-Ru|JR|https://orcid.org/0000-0002-3820-6966;Chou|Chung-Wei|CW|https://orcid.org/0000-0003-4385-5212;Chao|Heng-Sheng|HS|https://orcid.org/0000-0002-0309-0983",
"chemical_list": "D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C582670:alectinib",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220961557",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Alectinib; interstitial lung disease; lung cancer; rechallenge",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000368:Aged; D002227:Carbazoles; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D010880:Piperidines; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1311-1314",
"pmc": null,
"pmid": "33054691",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful rechallenge of alectinib after remission of severe alectinib-induced interstitial lung disease.",
"title_normalized": "successful rechallenge of alectinib after remission of severe alectinib induced interstitial lung disease"
} | [
{
"companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-306774",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "Sarcopenia has been associated with treatment-related toxicities and poor survival in cancer patients. Our aim was to investigate the prevalence of sarcopenia in postoperative recurrent esophageal squamous cell carcinoma (ESCC) patients receiving chemoradiotherapy (CRT) and evaluate associations with treatment-related toxicity and prognosis.\nOne hundred and eighty-four patients with postoperative locoregional recurrent ESCC receiving CRT between January 2014 and December 2016 were included. The skeletal muscle area (SMA) was measured at the third lumbar vertebra level. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) less than 47.24/cm2/m2 for men and 36.92/cm2/m2 for women. Association of sarcopenia with overall survival (OS) was analyzed using univariate and multivariate cox regression models.\nSarcopenia was observed in 94 of 184 (51.1%) patients. Sarcopenic patients had significantly higher rates of grade 3-4 toxicities compared to those without sarcopenia (36.2% vs 21.1%, p = 0.034). The survival rate at 12 and 24 months was 36.2% and 3.2% in the sarcopenic patients and 57.8% and 17.8% in the non-sarcopenic patients (p < 0.001). Multivariate cox regression analysis showed that sarcopenia was significantly associated with decreased OS (HR = 1.729, 95% CI 1.231-2.428, p = 0.002).\nSarcopenia is an independent indicator of poor survival in postoperative locoregional recurrent ESCC patients treated with CRT. Early nutritional interventions before treatment may improve the prognosis.",
"affiliations": "Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.;Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.;Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.;Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.;Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.;Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.;Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.;Department of Radiation Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.",
"authors": "Xu|Ying-Ying|YY|;Zhou|Xi-Lei|XL|;Yu|Chang-Hua|CH|;Wang|Wan-Wei|WW|;Ji|Fu-Zhi|FZ|;He|Dong-Cheng|DC|;Zhu|Wei-Guo|WG|;Tong|Yu-Suo|YS|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.655071",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.655071\nOncology\nOriginal Research\nAssociation of Sarcopenia With Toxicity and Survival in Postoperative Recurrent Esophageal Squamous Cell Carcinoma Patients Receiving Chemoradiotherapy\nXu Ying-Ying †\n\nZhou Xi-Lei †\n\nYu Chang-Hua\n\nWang Wan-Wei\n\nJi Fu-Zhi\n\nHe Dong-Cheng\nZhu Wei-Guo *\n\nTong Yu-Suo *\n\nDepartment of Radiation Oncology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China\nEdited by: Xi Yang, Fudan University, China\n\nReviewed by: Qing Guo, Jiangsu Taizhou People’s Hospital, China; Xiufeng Cao, Nanjing No. 1 Hospital, China\n\n*Correspondence: Wei-Guo Zhu, jshazwg@126.com; Yu-Suo Tong, tongyusuo@163.com\nThis article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work and share first authorship\n\n08 7 2021\n2021\n11 65507118 1 2021\n24 6 2021\nCopyright © 2021 Xu, Zhou, Yu, Wang, Ji, He, Zhu and Tong\n2021\nXu, Zhou, Yu, Wang, Ji, He, Zhu and Tong\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.\nBackground\n\nSarcopenia has been associated with treatment-related toxicities and poor survival in cancer patients. Our aim was to investigate the prevalence of sarcopenia in postoperative recurrent esophageal squamous cell carcinoma (ESCC) patients receiving chemoradiotherapy (CRT) and evaluate associations with treatment-related toxicity and prognosis.\n\nMethods\n\nOne hundred and eighty-four patients with postoperative locoregional recurrent ESCC receiving CRT between January 2014 and December 2016 were included. The skeletal muscle area (SMA) was measured at the third lumbar vertebra level. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) less than 47.24/cm2/m2 for men and 36.92/cm2/m2 for women. Association of sarcopenia with overall survival (OS) was analyzed using univariate and multivariate cox regression models.\n\nResults\n\nSarcopenia was observed in 94 of 184 (51.1%) patients. Sarcopenic patients had significantly higher rates of grade 3-4 toxicities compared to those without sarcopenia (36.2% vs 21.1%, p = 0.034). The survival rate at 12 and 24 months was 36.2% and 3.2% in the sarcopenic patients and 57.8% and 17.8% in the non-sarcopenic patients (p < 0.001). Multivariate cox regression analysis showed that sarcopenia was significantly associated with decreased OS (HR = 1.729, 95% CI 1.231-2.428, p = 0.002).\n\nConclusions\n\nSarcopenia is an independent indicator of poor survival in postoperative locoregional recurrent ESCC patients treated with CRT. Early nutritional interventions before treatment may improve the prognosis.\n\nsarcopenia\nesophageal squamous cell carcinoma\nprognosis\nchemoradiotherapy\nsurvival\n==== Body\nIntroduction\n\nEsophageal cancer (EC) is one of the most common cancers worldwide and esophageal squamous cell carcinoma (ESCC) accounts for about 70% of all cases (1). ESCC is highly prevalent in China, and approximate 90% of new cases are ESCC (2). Radical esophagectomy with two-field or three-field lymph node dissection is the primary treatment in locally advanced ESCC. However, the survival of patients treated with surgery alone is poor, with 5-year survival rates of only 25%-39% (3, 4). After surgery, 43%-53% of patients develop locoregional recurrence or distant metastasis (5). For these patients, palliative chemotherapy or chemoradiotherapy (CRT) are commonly used to control cancer-related symptoms and prolong survival. Although these approaches have been demonstrated to be effective in around 50% of patients (6), it is also associated with severe hematological and gastrointestinal toxicities. Thus, discovering factors that could predict CRT-related toxicity and survival in ESCC patients are urgent needs.\n\nSarcopenia is a common geriatric syndrome, which is initially defined by Baumgartner et al. to describe age-related loss of skeletal muscle mass and skeletal muscle strength (7). Age is the main cause, but not the sole cause of sarcopenia. Malnutrition, low levels of physical activity, several chronic diseases and cancer also induce sarcopenia (8). Many studies have demonstrated that systemic inflammation, inadequate energy and protein intake, as well as increased metabolic rate are independent risk factors for sarcopenia (9). These risk factors are prevalent in ESCC. In a recent study by Anandavadivelan P. et al, sarcopenia and sarcopenic obesity was observed in 43% and 14% of EC patients, and the presence of sarcopenic obesity was a risk factor for developing dose limiting toxicity during neoadjuvant chemotherapy (10). Currently, skeletal muscle area (SMA) on abdomen CT imaging at the level of third lumbar vertebra is widely used for detection of sarcopenia, and it has been demonstrated as a reliable method for whole body muscle mass assessment (11). Sarcopenia is frequently seen in patients with advanced tumor. Prior studies have demonstrated that sarcopenia is associated with poorer overall survival (OS) for a number of malignancies, such as pancreatic cancer, renal cell carcinoma, colorectal cancer (12–14). In an Asian study of ESCC patients receiving neoadjuvant CRT, Ozawa Y et al. found that pretherapeutic sarcopenia was significantly correlated with treatment response and worse disease free survival (15). However, its impact on patients with recurrent or metastatic ESCC remains largely unknown. Thus far, only one study investigated sarcopenia in advanced esophagogastric cancer patients and reported that there was no association between sarcopenia and survival and treatment-related toxicity during palliative chemotherapy (16). However, that study comprised a limited number of patients (only 88 patients included) and the majority of patients were adenocarcinoma (83%). The effect of sarcopenia remains unclear in patients with postoperative locoregional recurrent ESCC.\n\nTherefore, the current study aimed to determine the incidence of sarcopenia in patients with postoperative locoregional recurrent ESCC and to evaluate the relationship between sarcopenia on treatment-related toxicity and OS in patients treated with CRT.\n\nMaterials and Methods\n\nPatients and Study Design\n\nIn this retrospective analysis, patient with ESCC who were treated at our institution from January 1, 2014, to December 31, 2016, for locoregional recurrences after surgery were screened. This time period was chosen in order to have adequate follow-up time for analysis of OS. Postoperative recurrences were confirmed by biopsy, CT, and/or positron emission tomography (PET)/-CT fusion scans. Eligible patients were less than 75 years old; Karnofsky performance status (KPS) score ≥ 70; had histopathologically confirmed ESCC; had local postoperative recurrence (anastomotic recurrence and/or locoregional lymph node metastasis); had upper abdominal CT scan within 3 weeks of treatment start. Patients were excluded if they had incomplete resection, were treated with neoadjuvant or postoperative radiotherapy, had distant metastasis (other than metastasis to supraclavicular or celiac lymph node), or with severe comorbidities. The 7th edition of tumor-node-metastasis (TNM) classification for esophageal carcinoma (UICC, 2009) was used to stage the primary disease after surgery. This study was approved by the institutional review board of Huai’an First Hospital. Informed consent was exempted due to the retrospective nature of the study.\n\nTreatment Details\n\nRadiotherapy: Patients received either 3-dimensional conformal radiation therapy or intensity modulated radiation therapy. Treatment-planning CT scans (16-slice Philips Brilliance Big Bore CT) using intravenous contrast with a slice thickness of 5 mm were performed for all patients in the supine position. In the present study, all patients were treated with involved field radiotherapy. The gross tumor volume (GTV) included the recurrent tumor or the metastatic lymph nodes. The clinical target volume (CTV) was generated by using 0.8-1 cm radial margin and 1.5-2.0 cm longitudinal margins to the GTV. The planning target volume (PTV) was defined as the CTV plus a 0.5 cm margin in all directions. The prescribed dose was 50 to 66Gy (1.8-2.0 Gy/fraction, 5 days a week) for PTV.\n\nChemotherapy regimens: Most patients received docetaxel and cisplatin (DP) based chemotherapy in our institution. Among them, 71 patients received concurrent chemotherapy comprising docetaxel (25 mg/m2) and cisplatin (25 mg/m2) weekly for 5-6 weeks. Another 42 patients received docetaxel and cisplatin regimen consisted of 75 mg/m2 docetaxel on days 1 and 22, and 25 mg/m2 cisplatin on days 1-3 and 22-24. Approximately 4 to 5 weeks after completion of radiotherapy, at least 2 cycles of adjuvant chemotherapy (docetaxel 75 mg/m2 on day 1, cisplatin 25 mg/m2 on days 1-3) were given to patients who still have sufficient performance status.\n\nFrom January 2016, patients aged older than 70 years were treated with S-1 (70 mg/m2, twice per day, on days 1–14 and days 22–36) based concurrent chemotherapy to avoid the severe adverse events. In these patients, adjuvant chemotherapy with S-1 (70 mg/m2, on days 1-21 every 4 weeks) was done after radiotherapy if possible.\n\nBody Composition Analysis\n\nRegional muscle tissues were measured by the upper abdominal CT from electronically stored images, which has been done within 3 weeks of radiotherapy. The third lumbar vertebra (L3) was selected as the landmark. Two consecutive CT images extending from L3 were used to measure total muscle cross-sectional area and the mean cross-sectional area (cm2) was calculated from each patient. The total SMA including psoas, paraspinal and the abdominal wall muscles ( Figure 1 ) were hand-drawn by a senior radiotherapy oncologist. Skeletal muscle was identified and quantified within a Hounsfield unit (HU) range of -29 to +150 HU (17) using the Monaco TPS software (Elekta). The mean cross-sectional areas were normalized to the square of body height (cm2/m2) and presented as skeletal muscle index (SMI). Sarcopenia was defined as SMI less than 47.24/cm2/m2 for men and 36.92/cm2/m2 for women, using previously published cut-off values associated survival in patients with EC (18).\n\nFigure 1 Axial computed tomography (CT) images at the level of L3 with skeletal muscle highlighted in red. Representative CT images in patients with (A, a-67-year-old male patient, SMA =122.85 cm2, BMI = 21.38 kg/m2, SMI=41.04 cm2/m2) and without sarcopenia (B, a-62-year-old male patient, SMA =158.64 cm2, BMI = 21.51 kg/m2, SMI=56.88 cm2/m2). SMA, skeletal muscle area; BMI, body mass index; SMI, skeletal muscle index.\n\nPatient Data\n\nThe present study collected pre-treatment data including patient demographics, serum albumin, weight, height, and body mass index (BMI). The BMI was calculated as weight (kg)/height (m2). Underweight, normal weight and overweight were defined as BMI < 18.5, 18.5-24.9, and ≥ 25 kg/m2, respectively (19).\n\nToxicity Assessment and Follow-up\n\nToxicity was classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0. In the first 2 years after treatment, patients were followed every 3 months, and every 4-6 months thereafter. The final data collection was May, 2020.\n\nStatistical Analysis\n\nStatistical analysis was performed using SPSS 20.0. Continuous variables are presented as median and range, and categorical variables are presented as number and percentage. For continuous variables, differences between groups were performed using Student’s t test or the Mann–Whitney U test. Categorical variables were compared using Chi-square test or Fisher’s exact test. OS was calculated as the time from the last date of radiotherapy to the date of death due to any cause or last follow-up. Data from patients that had not died by the time of analysis were censored. The Kaplan-Meier method was used to determine effects of each variable on OS, and log-rank test was used to compare survival between groups. Univariate and multivariate cox proportional hazards regression models were used to identify prognostic factors of survival. Any factors with p value less than 0.10 in the univariate analysis were included in the multivariate analysis. All p values were two sided, and level of significance was p less than 0.05.\n\nResults\n\nPatient and Treatment Characteristics\n\nBetween January 1, 2014, and December 31, 2016, 215 patients with postoperative locoregional recurrent ESCC who had received radiotherapy were retrospectively reviewed. Seventeen patients were excluded because the pretreatment CT images were not available for body composition analysis, 14 were excluded due to the lack of complete clinical data. Therefore, a total of 184 patients met inclusion criteria in the final analysis.\n\nBaseline characteristics are displayed in Table 1 . Of the 184 patients, 141 (76.6%) were male, and the median age was 63 (range, 54-75 years). Almost 90% of patients (166/184) had KPS score ≥ 80. Fifty-seven (31.0%) patients had anastomotic recurrence +/- regional lymph node metastasis, and 127 (69.0%) had only lymph node recurrence (supraclavicular in 28, mediastinal in 39, celiac in 14, and multiregional lymph node metastasis in 46). The diagnosis of recurrence was based on biopsies in 64 patients (34.8%). Follow-up CT and the clinical course were sufficient for diagnosis in the other 120 patients (65.2%). The median time between CT scan and the start of radiotherapy was 7 days (range, 5-21 days).\n\nTable 1 Patient and treatment characteristics.\n\nCharacteristics\tNumber (%)\t\nAge (year) median (range)\t62 (51-75)\t\nSex\t\t\n Male\t141 (76.6%)\t\n Female\t43 (23.4%)\t\nKPS\t\t\n ≥80\t166 (90.2%)\t\n 70\t18 (9.8%)\t\nPrimary tumor location\t\t\n Upper third\t21 (11.4%)\t\n Middle third\t124 (67.4%)\t\n Lower third\t39 (21.2%)\t\nStage of primary tumor\t\t\n Stage I-II\t77 (41.8%)\t\n Stage III\t107 (58.2%)\t\nRecurrence pattern\t\t\n Anastomosis +/-regional lymph node\t57 (31.0%)\t\n Regional lymph node\t127 (69.0%)\t\nTreatment\t\t\n Radiotherapy alone\t20 (10.9%)\t\n CRT\t164 (89.1%)\t\n Radiation dose (Gy) median (range)\t50.4 (36-66)\t\nConcurrent chemotherapy regimen\t\t\n Docetaxel + cisplatin\t113 (61.4%)\t\n S-1\t51 (27.7%)\t\nChemotherapy after radiotherapy\t\t\n Yes\t157 (85.3%)\t\n No\t27 (14.7%)\t\nWeight loss in 6 months\t\t\n ≥ 5%\t64 (34.8%)\t\n < 5%\t120 (65.2%)\t\nBMI (kg/m2)\t\t\n < 18.5\t36 (19.6%)\t\n 18.5-24.9\t131 (71.2%)\t\n ≥ 25\t17 (9.2%)\t\nAlbumin (g/L)\t\t\n < 35\t32 (17.4%)\t\n ≥ 35\t152 (82.6%)\t\nDiabetes\t\t\n Yes\t17 (9.2%)\t\n No\t167 (90.8%)\t\nSMI (cm2/m2) median (range)\t46.26 (28.62-65.84)\t\nKPS, karnofsky performance status; CRT, chemoradiotherapy; BMI, body mass index; SMI, skeletal muscle index.\n\nAll patients were treated with local radiotherapy, and only 4 patients (2.2%) received less than 40Gy because of treatment-related toxicities. Finally, 171 patients (92.9%) completed radiotherapy as planned. The majority of patients (89.1%, 164/184) were treated with concurrent chemotherapy, 113 (61.4%) received concurrent DP and 51 (27.7%) received S-1. Reasons for not received concurrent chemotherapy were KPS score < 80 in 9 patients, refusal in 6, and other reasons in 5.\n\nBefore radiotherapy, approximately 34.8% of patients (64/184) had lost ≥ 5% of their body weight in the previous 6 months. The median BMI was 20.35 kg/m2 (range, 15.26-27.40 kg/m2), and 36 patients (19.6%) were underweight. Overall, the median SMI in all cases was 46.26 cm2/m2 (range, 28.62-65.84 cm2/m2).\n\nPrevalence of and Factors Associated With Sarcopenia\n\nOverall, sarcopenia was found in 94 patients (51.1%). Patients with sarcopenia had worse KPS (p = 0.024, Table 2 ) and lower mean BMI (p < 0.001, Table 2 ) than those without sarcopenia. Moreover, weight loss ≥ 5% in the previous 6 months (46.8% versus 22.2%, p = 0.001, Table 2 ) and serum albumin < 35 g/L (23.4% vs 11.1%, p = 0.033, Table 2 ) were more frequently observed in the sarcopenic patients than in non-sarcopenia patients. With regard to tumor stage and patterns of recurrence, there was no significant difference between the two groups. Patients older than 70 years had a slightly higher prevalence of sarcopenia than those < 70 years (58.5% vs 47.1%, p = 0.166, Table 2 ), but the difference was not statistically significant.\n\nTable 2 Comparisons between patients with and without sarcopenia.\n\nCharacteristics\tSarcopenic\tNon-sarcopenic\tp\t\nn = 94\tn = 90\t\nAge\t\t\t0.166\t\n < 70\t56 (59.6%)\t63 (70.0%)\t\t\n ≥ 70\t38 (40.4%)\t27 (30.0%)\t\t\nSex\t\t\t0.384\t\n Male\t75 (79.8%)\t66 (73.3%)\t\t\n Female\t19 (20.2%)\t24 (26.7%)\t\t\nKPS\t\t\t0.024\t\n ≥ 80\t80 (85.1%)\t86 (95.6%)\t\t\n 70\t14 (14.9%)\t4 (4.4%)\t\t\nStage of primary tumor\t\t\t0.457\t\n Stage I-II\t42 (44.7%)\t35 (38.9%)\t\t\n Stage III\t52 (55.3%)\t55 (61.1%)\t\t\nRecurrence pattern\t\t\t0.265\t\n Anastomosis\t33 (35.1%)\t24 (26.7%)\t\t\n Regional lymph node\t61 (64.9%)\t66 (73.3%)\t\t\nDiabetes\t\t\t0.126\t\n Yes\t12 (12.8%)\t5 (5.6%)\t\t\n No\t82 (87.2%)\t85 (94.4%)\t\t\nWeight loss in 6 months\t\t\t0.001\t\n ≥ 5%\t44 (46.8%)\t20 (22.2%)\t\t\n < 5%\t50 (53.2%)\t70 (77.8%)\t\t\nBMI (kg/m2), mean (SD)\t19.87 ± 2.58\t21.15 ± 2.86\t< 0.001\t\n < 18.5\t25 (26.6%)\t11 (12.2%)\t0.016\t\n ≥ 18.5\t69 (73.4%)\t79 (87.8%)\t\t\nAlbumin (g/L)\t\t\t0.033\t\n < 35\t22 (23.4%)\t10 (11.1%)\t\t\n ≥ 35\t72 (76.6%)\t80 (88.9%)\t\t\nKPS, karnofsky performance status; BMI, body mass index.\n\nSarcopenia and Treatment-Related Toxicities\n\nGrade 3-4 treatment-related toxicities are shown in Table 3 . Patients with sarcopenia had significantly higher rates of grade 3-4 toxicities compared to those without sarcopenia (36.2% vs 21.1%, p = 0.034). The main treatment-related toxicities of grade 3-4 were leukopenia (sarcopenic vs non-sarcopenic: 25 [26.6%] vs 14 [15.6%], p = 0.074), neutropenia (19 [20.2%] vs 8 [8.8%], p = 0.037), esophagitis (13 [13.8%] vs 10 [11.1%], p = 0.828), and anorexia (13 [13.8%] vs 4 [4.4%], p = 0.040).\n\nTable 3 Comparisons of treatment-related toxicities between patients with and without sarcopenia.\n\nToxicities\tSarcopenic\tNon-sarcopenic\tp\t\nn = 94\tn = 90\t\nOverall toxicity ≥3\t34 (36.2%)\t19 (21.1%)\t0.034\t\nLeukopenia\t25 (26.6%)\t14 (15.6%)\t0.074\t\nNeutropenia\t19 (20.2%)\t8 (8.8%)\t0.037\t\nAnemia\t7 (7.4%)\t4 (4.4%)\t0.537\t\nThrombocytopenia\t4 (4.3%)\t5 (5.6%)\t0.743\t\nEsophagitis\t13 (13.8%)\t10 (11.1%)\t0.828\t\nNausea/vomiting\t11 (11.7%)\t8 (8.9%)\t0.631\t\nAnorexia\t13 (13.8%)\t4 (4.4%)\t0.040\t\n\nWith regard to treatment-related death, 2 patients (1 from trachea-esophageal fistula, and 1 from pulmonary embolism) died in the sarcopenic group versus 1 (gastrointestinal bleeding) in the non-sarcopenic group.\n\nPrognostic Significance of Sarcopenia in ESCC Patients\n\nAs of May 18, 2020, median follow-up in this study was 11 months (range, 1-50 months), and 8 patients remained alive at the time of analysis. As observed in the Kaplan-Meier curve, patients with sarcopenia had worse survival compared to those without sarcopenia (p < 0.001, Figure 2 ). Kaplan-Meier estimated 12-month OS rate was 36.2% in the sarcopenic patients versus 57.8% in the non-sarcopenic patients. The 24-month OS rate for sarcopenic patients was 3.2% compared to 17.8% for non-sarcopenic patients. In univariate analysis, KPS, the use of chemotherapy, weight loss in 6 months, BMI and sarcopenia were significantly associated with poor OS ( Table 4 ).\n\nFigure 2 Sarcopenia at presentation and overall survival (OS). Patients with sarcopenia had worse OS than those without sarcopenia (p < 0.001).\n\nTable 4 Univariate and multivariate cox regression analysis for predictors of overall survival.\n\nVariable\tUnivariate analysis\tMultivariate analysis\t\nHR\t95% CI\tp value\tHR\t95% CI\tp value\t\nAge (years)\t\t\t\t\t\t\t\n < 70\t1.00\t\t\t\t\t\t\n ≥ 70\t0.788\t0.577-1.076\t0.134\t\t\t\t\nSex\t\t\t\t\t\t\t\n Female\t1.00\t\t\t\t\t\t\n Male\t1.331\t0.936-1.893\t0.112\t\t\t\t\nKPS\t\t\t\t\t\t\t\n ≥ 80\t1.00\t\t\t\t\t\t\n 70\t2.201\t1.342-3.611\t0.002\t2.331\t1.296-4.190\t0.005\t\nPrimary Tumor location\t\t\t\t\t\t\t\n Upper third\t1.00\t\t\t\t\t\t\n Middle third\t0.864\t0.539-1.382\t0.541\t\t\t\t\n Lower third\t0.962\t0.564-1.640\t0.887\t\t\t\t\nStage of primary tumor\t\t\t\t\t\t\t\n Stage I-II\t1.00\t\t\t\t\t\t\n Stage III\t1.313\t0.967-1.782\t0.081\t1.373\t1.005-1.874\t0.046\t\nRecurrence pattern\t\t\t\t\t\t\t\n Anastomosis\t1.00\t\t\t\t\t\t\n Regional lymph node\t1.163\t0.846-1.598\t0.353\t\t\t\t\nConcurrent chemotherapy\t\t\t\t\t\t\t\n Yes\t1.00\t\t\t\t\t\t\n No\t1.674\t1.044-2.683\t0.032\t1.869\t0.721-4.844\t0.198\t\nChemotherapeutic regimen\t\t\t\t\t\t\t\n Docetaxel + cisplatin\t1.00\t\t\t\t\t\t\n S-1\t0.833\t0.588-1.182\t0.307\t\t\t\t\nRadiation dose (Gy)\t\t\t\t\t\t\t\n ≥ 60\t1.00\t\t\t\t\t\t\n < 60\t0.768\t0.546-1.081\t0.130\t\t\t\t\nChemotherapy after radiotherapy\t\t\t\t\t\t\t\n Yes\t1.00\t\t\t\t\t\t\n No\t1.661\t1.094-2.521\t0.017\t0.633\t0.256-1.565\t0.322\t\nWeight loss in 6 months\t\t\t\t\t\t\t\n < 5%\t1.00\t\t\t\t\t\t\n ≥ 5%\t1.404\t1.028-1.917\t0.033\t1.282\t0.924-1.779\t0.138\t\nBMI (kg/m2)\t\t\t\t\t\t\t\n > 18.5\t1.00\t\t\t\t\t\t\n ≤ 18.5\t1.511\t1.041-2.193\t0.030\t1.455\t0.996-2.125\t0.053\t\nBaseline albumin (g/L)\t\t\t\t\t\t\t\n ≥ 35\t1.00\t\t\t\t\t\t\n < 35\t0.993\t0.669-1.472\t0.970\t\t\t\t\nSMI\t\t\t\t\t\t\t\n Non-sarcopenic\t1.00\t\t\t\t\t\t\n Sarcopenic\t1.907\t1.397-2.602\t< 0.001\t1.729\t1.231-2.428\t0.002\t\nHR, hazard ratio; CI, confidence interval; KPS, karnofsky performance status; BMI, body mass index; SMI, skeletal muscle index.\n\nVariables with p < 0.10 in univariate analysis were included in the multivariate logistic regression analysis. In multivariate model, the presence of sarcopenia was the most significant independent prognostic factor of poor OS (p = 0.002) followed by worse KPS and advanced tumor stage ( Table 4 ).\n\nDiscussion\n\nIt is well established that sarcopenia is a significant factor of poor survival across various cancer types (20–22). However, to our knowledge, there are no reports discussing the relationship between sarcopenia and survival in postoperative locoregional recurrent ESCC patients. Thus, in the present study, we first investigated the incidence of sarcopenia in 184 patients with postoperative locoregional recurrent ESCC and then evaluated associations with treatment toxicity and survival. Our results confirmed that over 50% of patients had sarcopenia. These patients were more likely to present grade ≥ 3 toxicities compared with non-sarcopenic patients. In addition, the multivariable analysis showed that sarcopenia was a significant independent prognostic factor for poor survival.\n\nThe prevalence of sarcopenia in patients with ESCC fluctuates significantly, with reports ranging from 16% to 75% (23). However, these studies vary in the definition of sarcopenia, tumor stage and histological type. In this study, inclusion criteria were limited to patient with postoperative locoregional recurrent diseases, and 51.1% (94/184) of patients had sarcopenia at presentation, which is higher than a prior study (16%) involving patients with locally advanced EC (9). However, because the majority of patients (81.2%) in that study were esophageal adenocarcinoma and 43% was visceral obesity, direct comparison with the current study is difficult. To date, the optimal cut-off values chosen to diagnose sarcopenia remain a matter of debate. In western countries, the sex-specific cut-off values for L3 SMI (52.4/cm2/m2 for men and 38.5/cm2/m2 for women) proposed by Prado et al. are most commonly used to evaluate sarcopenia in patients with cancer (24). Using the Prado’s criteria, the population of sarcopenia in the present study would increase to 129 (70.1%), which was consistent with that in Siegal SR study in patients with EC (25). However, this criteria might not be applicable to Chinese ESCC patients because the BMI differs considerably between Asian and western populations. In the present population, we diagnosed sarcopenia according to the cut-off values proposed by Nakashima Y (18). As the population of that study is very similar to our population. In ESCC, the nutritional impairment due to dysphagia, pain, systemic inflammation and increased metabolic rate may have promoted the development of sarcopenia.\n\nSeveral studies have reported that patients with sarcopenia had higher rates of treatment-related toxicity in various malignancies (26). In a study on patients with metastatic breast cancer, chemotherapy toxicity was more commonly observed among sarcopenic patients (27).. In locally advanced EC patients treated with neoadjuvant radiochemotherapy, Panje CM et al. showed that the incidence of grade ≥ 3 toxicity was significantly higher in sarcopenic compared with non-sarcopenic patients (28). In EC patients treated by esophagectomy, Ida S et al. revealed that sarcopenia was closely associated with higher rates of respiratory complications (29). In our study, patients with sarcopenia had greater risk of grade 3-4 CRT-related toxicity, so we believe that the clinical management of patients with sarcopenia before CRT, such as physical exercise, nutrition management, as well as pharmacologic treatment, could prevent toxicity.\n\nSarcopenia has been correlated with shorter survival in certain solid cancers such as oropharyngeal squamous cell carcinoma, non-small cell lung cancer, and nasopharyngeal carcinoma (30–32). Currently, to our knowledge, 6 studies investigated the effect of sarcopenia on survival in EC patients who received surgical resection (9, 18, 33–36). Three of these studies reported that sarcopenia was significantly associated with poor survival. However, the impact of sarcopenia on survival after CRT has not been clearly established in patients with postoperative locoregional recurrent ESCC. In the current study, we found that the 12-month and 24-month OS were significantly lower for patients with sarcopenia compared to those without, which is consistent with 2 recent studies on patients with unresectable advanced EC treated with CRT (37, 38). In contrast, in another study of 300 patients who treated with trimodality therapy, sarcopenia was not associated with poor OS in a subset of 61 patients who underwent neoadjuvant radiochemotherapy (28). This may be because the numbers of patients were relatively small and the cut-off values used for sarcopenia were looser than ours. Furthermore, differences in treatments and stage of disease may also affect the results.\n\nOur study has several limitations. Firstly, the conclusions are drawn from a sing-institute retrospective analysis and the sample size was small. Secondly, given its retrospective design, evaluation of muscle strength and physical activity were not available. Thirdly, a small proportion of patients (21.7%) received anlotinib-targeted therapy or PD-1 inhibitor after tumor progression. This may have affected our results. Thus, further multi-institutional prospective clinical trials are needed to confirm our results.\n\nIn conclusion, our results show that sarcopenia is significantly associated with treatment-related toxicity and poorer outcomes in postoperative locoregional recurrent ESCC patients receiving CRT.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Huai’an First Hospital. 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\nY-YX, X-LZ, W-GZ, and YT conceived and designed the experiments and were responsible for data analysis and writing the manuscript. C-HY, W-WW, and F-ZJ were responsible for providing the clinical samples. D-CH was responsible for data collection. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by grants from National Nature Science Foundation of China (Grant No. 82002536) and Huai’an Natural Science Research Project (HAB201930). These funding agencies were not involved in the study design, the collection, analysis and interpretation of data, writing the report, and the decision to submit the article 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\nThe authors acknowledge Juan Tan for his professional statistical analysis.\n==== Refs\nReferences\n\n1 Smyth EC Lagergren J Fitzgerald RC Lordick F Shah MA Lagergren P . Oesophageal Cancer. Nat Rev Dis Primers (2017) 3 :17048. 10.1038/nrdp.2017.48 28748917\n2 Yang H Liu H Chen Y Zhu C Fang W Yu Z . Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial. 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Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment. Clin Cancer Res (2009) 15 :2920–6. 10.1158/1078-0432.CCR-08-2242\n28 Panje CM Höng L Hayoz S Baracos VE Herrmann E Garcia Schüler H,M . Skeletal Muscle Mass Correlates With Increased Toxicity During Neoadjuvant Radiochemotherapy in Locally Advanced Esophageal Cancer: A SAKK 75/08 Substudy. Radiat Oncol (2019) 14 :166. 10.1186/s13014-019-1372-3 31511012\n29 Ida S Watanabe M Yoshida N Baba Y Umezaki N Harada K . Sarcopenia is a Predictor of Postoperative Respiratory Complications in Patients With Esophageal Cancer. Ann Surg Oncol (2015) 22 :4432–7. 10.1245/s10434-015-4559-3\n30 Olson B Edwards J Stone L Jiang A Zhu X Holland J . Association of Sarcopenia With Oncologic Outcomes of Primary Surgery or Definitive Radiotherapy Among Patients With Localized Oropharyngeal Squamous Cell Carcinoma. JAMA Otolaryngol Head Neck Surg (2020) 146 :714. 10.1001/jamaoto.2020.1154 32525518\n31 Nakamura R Inage Y Tobita R Yoneyama S Numata T Ota K . Sarcopenia in Resected NSCLC: Effect on Postoperative Outcomes. J. Thorac Oncol (2018) 13 :895–903. 10.1016/j.jtho.2018.04.035\n32 Hua X Liao J-F Huang X Huang H-Y Wen W Long Z-Q . Sarcopenia is Associated With Higher Toxicity and Poor Prognosis of Nasopharyngeal Carcinoma. Ther Adv Med Oncol (2020) 12 :175883592094761. 10.1177/17588359\n33 Harada K Ida S Baba Y Ishimoto T Kosumi K Tokunaga R . Prognostic and Clinical Impact of Sarcopenia in Esophageal Squamous Cell Carcinoma. Dis Esophagus (2016) 29 :627–33. 10.1111/dote.12381\n34 Grotenhuis BA Shapiro J van Adrichem S de Vries M Koek M Wijnhoven BP . Sarcopenia/Muscle Mass is Not a Prognostic Factor for Short- and Long-Term Outcome After Esophagectomy for Cancer. World J Surg (2016) 40 :2698–704. 10.1007/s00268-016-3603-1\n35 Srpcic M Jordan T Popuri K Sok M . Sarcopenia and Myosteatosis at Presentation Adversely Affect Survival After Esophagectomy for Esophageal Cancer. Radiol Oncol (2020) 54 :237–46. 10.2478/raon-2020-0016\n36 Tamandl D Paireder M Asari R Baltzer PA Schoppmann SF Ba-Ssalamah A . Markers of Sarcopenia Quantified by Computed Tomography Predict Adverse Long-Term Outcome in Patients With Resected Oesophageal or Gastro-Oesophageal Junction Cancer. Eur Radiol (2016) 26 :1359–67. 10.1007/s00330-015-3963-1\n37 Sato S Kunisaki C Suematsu H Tanaka Y Miyamoto H Kosaka T . Impact of Sarcopenia in Patients With Unresectable Locally Advanced Esophageal Cancer Receiving Chemoradiotherapy. Vivo (2018) 32 :603–10. 10.21873/invivo.11282\n38 Onishi S Tajika M Tanaka T Hirayama Y Hara K Mizuno N . Prognostic Significance of Sarcopenia in Patients With Unresectable Advanced Esophageal Cancer. J Clin Med (2019) 8 :1–12. 10.3390/jcm8101647\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "chemoradiotherapy; esophageal squamous cell carcinoma; prognosis; sarcopenia; survival",
"medline_ta": "Front Oncol",
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"title": "Association of Sarcopenia With Toxicity and Survival in Postoperative Recurrent Esophageal Squamous Cell Carcinoma Patients Receiving Chemoradiotherapy.",
"title_normalized": "association of sarcopenia with toxicity and survival in postoperative recurrent esophageal squamous cell carcinoma patients receiving chemoradiotherapy"
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"abstract": "BACKGROUND\nA high degree of vigilance is warranted for a spinal infection, particularly in a patient who has undergone an invasive procedure such as a spinal injection. The average delay in diagnosing a spinal infection is 2-4 mo. In our patient, the diagnosis of a spinal infection was delayed by 1.5 mo.\n\n\nMETHODS\nA 60-year-old male patient with a 1-year history of right-sided lumbar radicular pain failed conservative treatment. Six weeks to prior to surgery he received a spinal injection, which was followed by increasing lumbar radicular pain, weight loss and chills. This went unnoticed and surgery took place with right-sided L4-L5 combined microdiscectomy and foraminotomy via a posterior approach. The day after surgery, the patient developed left-sided lumbar radicular pain. Blood cultures grew Staphylococcus aureus (S. aureus). Magnetic resonance imaging showed inflammatory aberrations, revealing septic arthritis of the left-sided L4/L5 facet joint as the probable cause. Revision surgery took place and S. aureus was isolated from bacteriological samples. The patient received postoperative antibiotic treatment, which completely eradicated the infection.\n\n\nCONCLUSIONS\nThe development of postoperative lower back pain and/or lumbar radicular pain can be a sign of a spinal infection. A thorough clinical and laboratory work-up is essential in the preoperative evaluation of patients with spinal pain.",
"affiliations": "Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France.;Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France.;Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France. thaisdutravieira@hotmail.com.;Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France.;Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France.;Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France.",
"authors": "Kerckhove|Michiel Frederik Vande|MFV|;Fiere|Vincent|V|;Vieira|Thais Dutra|TD|;Bahroun|Sami|S|;Szadkowski|Marc|M|;d'Astorg|Henri|H|",
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"doi": "10.12998/wjcc.v9.i15.3637",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i15.pg3637\n10.12998/wjcc.v9.i15.3637\nCase Report\nPostoperative pain due to an occult spinal infection: A case report\nVande Kerckhove MF et al. Occult spinal infection\nKerckhove Michiel Frederik Vande Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France\n\nFiere Vincent Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France\n\nVieira Thais Dutra Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France. thaisdutravieira@hotmail.com\n\nBahroun Sami Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France\n\nSzadkowski Marc Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France\n\nd'Astorg Henri Centre Orthopédique Santy, Hopital Privé Jean Mermoz, Ramsay-Générale de Santé, Lyon, France\n\nAuthor contributions: Vande Kerckhove MF, Fiere V, Vieira TD, Bahroun S, Szadkowski M, and d'Astorg H substantially contributed to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Vande Kerckhove MF, Vieira TD, Szadkowski M, and d’Astorg H drafted the work or revising it critically for important intellectual content; all authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; and all authors made final approval of the version to be published.\n\nCorresponding author: Thais Dutra Vieira, MD, Research Scientist, Surgeon, Centre Orthopedique Santy, 24 Avenue Paul Santy, Lyon 69008, France. thaisdutravieira@hotmail.com\n\n26 5 2021\n26 5 2021\n9 15 36373643\n7 10 2020\n28 12 2020\n19 3 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nA high degree of vigilance is warranted for a spinal infection, particularly in a patient who has undergone an invasive procedure such as a spinal injection. The average delay in diagnosing a spinal infection is 2-4 mo. In our patient, the diagnosis of a spinal infection was delayed by 1.5 mo.\n\nCASE SUMMARY\n\nA 60-year-old male patient with a 1-year history of right-sided lumbar radicular pain failed conservative treatment. Six weeks to prior to surgery he received a spinal injection, which was followed by increasing lumbar radicular pain, weight loss and chills. This went unnoticed and surgery took place with right-sided L4-L5 combined microdiscectomy and foraminotomy via a posterior approach. The day after surgery, the patient developed left-sided lumbar radicular pain. Blood cultures grew Staphylococcus aureus (S. aureus). Magnetic resonance imaging showed inflammatory aberrations, revealing septic arthritis of the left-sided L4/L5 facet joint as the probable cause. Revision surgery took place and S. aureus was isolated from bacteriological samples. The patient received postoperative antibiotic treatment, which completely eradicated the infection.\n\nCONCLUSION\n\nThe development of postoperative lower back pain and/or lumbar radicular pain can be a sign of a spinal infection. A thorough clinical and laboratory work-up is essential in the preoperative evaluation of patients with spinal pain.\n\nArthritis\nSeptic\nLumbar region\nDisc herniated\nSpinal injections\nCase report\n==== Body\nCore Tip: This is the case report of a 60-year-old male patient with right-sided L4-L5 Lumbar disc herniation who underwent right-sided transforaminal injection with no improvement and a decision was made to carry out surgery. On day 1 postoperatively he developed excruciating left-sided lumbar radicular pain. Investigations and retrospective analyses demonstrated left-sided septic L4-L5 facet joint arthritis caused by Staphylococcus aureus, most probably as a result of the spinal injections 6 wk prior to surgery. The infection was successfully treated with revision surgery and antibiotic therapy.\n\nINTRODUCTION\n\nLumbar disc herniation (LDH) is a common cause of lower back pain and lumbar radicular pain. Conservative treatment consisting of analgesic drugs, anti-inflammatory drugs and adapted movement is generally favourable in the general population, with complete recovery in 70%-80% of cases[1]. Spinal injections are commonly used as an additional treatment. One of the potential risks of spinal injection is infection. A review by Windsor et al[2] reported the occurrence of infections after 1%-2% and severe infections after 0.01%-0.1% of all spinal injections. Staphylococcus aureus (S. aureus) is the most common organism isolated and is thought to be introduced through the skin by needle puncture[3].\n\nWe report the case of a patient with right-sided L4-L5 LDH. During conservative treatment he underwent right-sided transforaminal injection. This did not lead to an improvement in his symptoms and a decision was made to carry out surgery. In the immediate postoperative period, he progressed favourably with temporary relief of pain, but on day 1 postoperatively he developed excruciating left-sided lumbar radicular pain. Investigations and retrospective analyses demonstrated left-sided septic L4-L5 facet joint arthritis caused by S. aureus, most probably as a result of the spinal injections 6 wk prior to surgery. The infection was successfully treated with revision surgery and antibiotic therapy.\n\nStatement of informed consent\n\nThe patient was informed that data concerning the case would be submitted for publication and gave his consent. The study received institutional review board approval (COS-RGDS-2020-04-002-DASTORG-H).\n\nCASE PRESENTATION\n\nChief complaints\n\nA 60-year-old male patient was admitted to hospital for treatment of right-sided lumbar radicular pain.\n\nHistory of present illness\n\nClinically, there was irradiating right leg pain in the L4 dermatome. The patient had a 1-year history of this symptom.\n\nHistory of past illness\n\nHe did not have a past history of low back pain or LDH.\n\nPersonal and family history\n\nThe patient had no clinically relevant comorbidities, except for being overweight (body mass index of 27). The patient had no prior relevant medical history. He was a non-smoker, had no allergies and was not diabetic. The patient didn’t have any family history related to low back pain or LDH.\n\nPhysical examination\n\nPhysical examination demonstrated a motor deficit of his right quadriceps, with 4/5 strength.\n\nLaboratory examinations\n\nPreoperative laboratory tests showed a white blood cell (WBC) count of 11 000/µl, normal creatinine and normal haemostatic parameters. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were not measured preoperatively as this is not done routinely in our department for non-instrumented spinal surgery.\n\nImaging examinations\n\nA magnetic resonance imaging (MRI) scan performed 2 d before the last infiltration, 1.5 mo prior to surgery, showed right-sided L4-L5 foraminal LDH, with compression of the right L4 nerve root. Intra-articular fluid collection was seen in the facet joints of L4-L5, without the presence of other inflammatory findings in the L4-L5 area (Figure 1).\n\nFigure 1 Magnetic resonance imaging scan done 2 d before the last infiltration, 1.5 mo preoperatively. A: T2-weighted axial magnetic resonance imaging (MRI) image; B: T2-weighted right-sided sagittal MRI image showing right-sided foraminal lumbar disc herniation at L4-L5 (orange arrows), with compression of the right-sided exiting L4-nerve root; C: T2-weighted left-sided sagittal MRI image showing a slight bulging of the L4-L5 disc, without compression of the exiting nerve root. In (A) and (C) fluid collections can be seen in both facet joints (yellow arrows), without visible signs of edema.\n\nHe underwent extensive but unsuccessful conservative treatment with oral analgesics (paracetamol 1 g (1-1-1-1) and ibuprofen 600 mg (1-1-1)), rest and two right-sided L4-L5 transforaminal injections over a period of 1 year, with no clinical improvement. Over the last 3 mo, his level of pain had increased significantly, with a combination of irradiating right-sided leg pain and lower back pain.\n\nSix weeks prior to surgery, our patient received a second right-sided transforaminal injection with cortisone. In the period following this injection, his pain level increased further, with a combination of irradiating right-sided leg pain and lower back pain. His treating physician subsequently increased his oral pain medication to level 3 analgesia with oxycodon 10 mg (1-1-1), but this failed to provide pain relief. In addition, cortisone-therapy with intramuscular solumedrol was instituted without success. This led to the consultation for surgery.\n\nBilateral microdecompression and right-sided L4-L5 combined microdiscectomy and foraminotomy by the posterior approach were carried out successfully. Preoperative antibiotic prophylaxis consisted of 2 g intravenous (IV) cefazolin. There were no clear intra-operative findings suggestive of infection. In the immediate postoperative period, the patient had complete relief from right-sided irradiating leg pain and was very satisfied. On the first day after the operation, he developed an excruciating irradiating pain in his left leg, which was contralateral to the side of the original herniation. The pain persisted and an MRI scan was carried out on day 4 postoperatively. This was almost normal, with bilateral decompression of L4-L5 and a small fluid collection in the left-sided facet joint of L4-L5 (Figure 2). No recurrent LDH, haematoma, or middle- to high-grade compressive pathology that could explain the new pattern of irradiating pain in the left leg was noted.\n\nFigure 2 Magnetic resonance imaging scan on day 4 postoperatively. A: T2-weighted axial magnetic resonance imaging (MRI) image showing a central decompression on L4-L5, with removal of the right-sided foraminal herniation. A fluid collection can be seen in both L4-L5 facet joints (yellow arrows); B and C: Right-sided and left-sided T2-weighted sagittal MRI images showing removal of the right-sided foraminal disc herniation; D: T2-weighted central sagittal MRI image showing a fluid collection (blue arrow), with small air collections (orange arrow) and a drain (purple arrow).\n\nThe patient remained in hospital for further observation. On day 5 post-surgery he developed a fever of 39 °C and chills. The clinical appearance of his wound was normal. As a standard measure in our hospital, with fever > 38.5 °C, blood cultures were taken and these grew S. aureus. With the high-level of suspicion of an infection, a second MRI scan was carried out on day 6 postoperatively, showing an increase in fluid collection in the posterior spine and the presence of air collections and inflammatory changes around the left-sided facet joint of L4-L5 (Figure 3).\n\nFigure 3 Magnetic resonance imaging scan on day 6 postoperatively. A: Axial T1-TSE-FS-weighted magnetic resonance imaging (MRI) image at the level of L4-L5 showing a fluid collection in both facet joints; B and C: Right-sided and left-sided T1-TSE-weighted sagittal MRI image showing an increase in fluid collections, especially left-sided (blue arrows), and an increase in edema in the bone, facet joint and muscles surrounding the facet joints (light blue arrows); D: T1-TSE-weighted central sagittal MRI image showing an increase in fluid collection (blue arrow), with an increase in air collections (orange arrow).\n\nFINAL DIAGNOSIS\n\nSeptic arthritis of the left-sided L4/L5 facet joint, with S. aureus.\n\nTREATMENT\n\nRevision surgery was performed 6 d after the first operation, with evacuation of the fluid collection. Bacteriological samples were taken, drainage, debridement and lavage were performed. Antibiotic therapy was instituted, initially empirically with IV vancomycin 1 g (1-0-1) and IV cloxacillin 3 g (1-1-1-1) for 5 d. In view of the antibiogram (Table 1), his antibiotic therapy was switched to IV cefazolin (2 g; 1-1-1) for 23 d, at home, through a central catheter inserted peripherally. After this time, his antibiotic therapy was switched to oral ofloxacin (400 mg; 1-0-0) and rifampicin (600 mg; 1-0-0) for 2 wk.\n\nTable 1 Antibiogram: Sensitivity tests of the intra-operatively isolated Staphylococcus aureus to different antibiotics\n\nAntibiotic\t\t\nPenicillin G\tResistant\t\nOxacillin\tSensitive\t\nGentamicin\tSensitive\t\nKanamycin\tSensitive\t\nTobramycin\tSensitive\t\nOfloxacin\tSensitive\t\nErythromycin\tSensitive\t\nLincomycin\tSensitive\t\nPristinamycin\tSensitive\t\nLinezolid\tSensitive\t\nTeicoplanin\tSensitive\t\nVancomycin\tSensitive\t\nTetracycline\tSensitive\t\nFosfomycin\tSensitive\t\nNitrofurantoin\tSensitive\t\nFusidic acid\tSensitive\t\nRifampicin\tSensitive\t\nTrimetoprim sulfametoxazol\tSensitive\t\n\nOUTCOME AND FOLLOW-UP\n\nHis inflammatory parameters returned to normal over a period of 3 wk. Three months after surgery, he was not taking any pain medication and had no leg pain, although there was a persisting motor deficit of the right quadriceps, with 4/5 strength, and he was easily fatigued. Through a rehabilitation program his physical condition improved significantly, so that at his 9-mo follow-up appointment he was already playing sport again, with a lot of walking and swimming.\n\nA detailed medical history was taken after his revision surgery and he stated that, during the 6 wk prior to surgery, he had lost 12 kg in weight, which he had attributed to the pain, and chills, which he had attributed to the use of opioids and which he had not reported to the medical staff. These cardinal symptoms of an infection, weight loss and chills, started 4 d after the last right-sided transforaminal L4-L5 injection.\n\nDISCUSSION\n\nIn our patient, the diagnosis of a spinal infection was delayed by 6 wk. It should be noted that the average delay in diagnosing a spinal infection is 2-4 mo[4]. This shows that a high level of vigilance for a spinal infection is warranted, especially in patients who are more susceptible to developing an infection, such as those who are immunocompromised, diabetic, dialysis-dependent, have permanent vascular access, or are IV drug abusers[5]. A high degree of vigilance is also necessary in patients undergoing invasive procedures such as spinal injections[2]. In this case, we presume that the first surgery resulted in a stress response, as proposed by Bardram et al[6], which might have decreased the immune response to the infection and, as such, might have led to an increase in the extent of the infection.\n\nMonitoring for a possible spinal infection can be achieved by focusing on history taking, clinical examination and laboratory results. Typical signs of an infection are fever, night sweats, chills, night pain, pain resistant to analgesics and weight loss. In this case, these symptoms were not mentioned by the patient and were not discovered by the clinicians prior to surgery. Routine questioning about these symptoms could improve the sensitivity of detection of an underlying infection.\n\nA literature review by Yoon et al[7] showed that approximately 50% of cases of septic arthritis of the facet joint have leukocytosis and all previous case reports (n = 61) except for one, had an elevated ESR and/or CRP. In our patient, ESR and CRP were not measured in the preoperative work-up as this is not done routinely in our hospital for non-instrumented spinal surgery. Our patient’s WBC count was at the upper limit of normal at 11000/μL. Routine measurement of ESR and CRP levels could improve the sensitivity of detection of an underlying infection. Moreover, patients with fever and back pain following an invasive procedure should have blood cultures performed routinely, as these are positive in around 60% of cases of bacterial spondylodiscitis[8]. In our hospital, sequential blood cultures are performed as a standard procedure in patients with fever > 38.5 °C, and in the present case, they were positive for S. aureus. In the first few day’s post-surgery, body temperature rises frequently as a result of the inflammatory reaction to surgical trauma, but in most of these cases blood cultures remain negative. In our patient, a positive blood culture was a milestone since his MRI scan showed no conclusive results.\n\nThere is no gold-standard treatment for septic arthritis of the facet joint and treatment is based on a retrospective evaluation of case series[9]. The majority of cases are treated conservatively with IV and oral antibiotics. The literature provides no clear guidance regarding the duration and route of administration of antibiotic therapy[10]. Generally, antibiotics are given for a period of 6-8 wk[11-14]. Sometimes this treatment has to be accompanied by bed rest and an orthosis for pain management[15]. Surgery is not usually indicated and is reserved for patients with an infection that is refractory to antibiotics, or with the presence of neurological deficits[12,16]. In the present case, due to the pattern of excruciating left-sided lumbar radicular pain, surgery was performed and led to a quick and significant improvement in his pain levels. He was then treated with IV and oral antibiotics for a period of approximately 6 wk. We do not have a clear explanation as to why the signs and symptoms of infection developed on the contralateral side to the surgery. We presume that this could be due to direct spread from the infiltration to the contralateral side, or due to an infiltration of the wrong-side.\n\nThe limitations of a case report design are well recognized, especially regarding external validity. However, given the rarity of this condition, the level of evidence for the optimal diagnosis of spine septic arthritis is not well-established, therefore we consider this case report important.\n\nCONCLUSION\n\nThe development of post-operative lower back pain and/or lumbar radicular pain can be a signal of a spinal infection. A thorough clinical and laboratory work-up (CRP, ESR, leukocyte count) is essential for the preoperative evaluation of spinal patients, to identify any underlying infection.\n\nInformed consent statement: The patient was informed that data concerning the case would be submitted for publication: COS-RGDS-2020-04-002) and gave his consent.\n\nConflict-of-interest statement: One or more of the authors has declared a potential conflict of interest: d'Astorg H reports personal fees from Clariance, outside the submitted work; Fiere V reports personal fees from Clariance, personal fees from Medicrea, outside the submitted work; Szadkowski M reports personal fees from Clariance, outside the submitted work.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: October 7, 2020\n\nFirst decision: November 14, 2020\n\nArticle in press: March 19, 2021\n\nSpecialty type: Orthopedics\n\nCountry/Territory of origin: France\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Higa K S-Editor: Liu M L-Editor: A P-Editor: Wu YXJ\n==== Refs\n1 Boos N Aebi M Spinal Disorders: Fundamentals of Diagnosis and Treatment. 1st ed. Springer-Verlag Berlin Heidelberg, 2008\n2 Windsor RE Storm S Sugar R Prevention and management of complications resulting from common spinal injections Pain Physician 2003 6 473 483 16871300\n3 Goodman BS Posecion LW Mallempati S Bayazitoglu M Complications and pitfalls of lumbar interlaminar and transforaminal epidural injections Curr Rev Musculoskelet Med 2008 1 212 222 19468908\n4 Gasbarrini AL Bertoldi E Mazzetti M Fini L Terzi S Gonella F Mirabile L Barbanti Bròdano G Furno A Gasbarrini A Boriani S Clinical features, diagnostic and therapeutic approaches to haematogenous vertebral osteomyelitis Eur Rev Med Pharmacol Sci 2005 9 53 66 15852519\n5 Babic M Simpfendorfer CS Infections of the Spine Infect Dis Clin North Am 2017 31 279 297 28366222\n6 Bardram L Funch-Jensen P Jensen P Crawford ME Kehlet H Recovery after laparoscopic colonic surgery with epidural analgesia, and early oral nutrition and mobilisation Lancet 1995 345 763 764 7891489\n7 Yoon J Efendy J Redmond MJ Septic arthritis of the lumbar facet joint. Case and literature review J Clin Neurosci 2020 71 299 303 31843439\n8 Mylona E Samarkos M Kakalou E Fanourgiakis P Skoutelis A Pyogenic vertebral osteomyelitis: a systematic review of clinical characteristics Semin Arthritis Rheum 2009 39 10 17 18550153\n9 André V Pot-Vaucel M Cozic C Visée E Morrier M Varin S Cormier G Septic arthritis of the facet joint Med Mal Infect 2015 45 215 221 25958100\n10 Duarte RM Vaccaro AR Spinal infection: state of the art and management algorithm Eur Spine J 2013 22 2787 2799 23756630\n11 Halpin DS Gibson RD Septic arthritis of a lumbar facet joint J Bone Joint Surg Br 1987 69 457 459 3584201\n12 Muffoletto AJ Ketonen LM Mader JT Crow WN Hadjipavlou AG Hematogenous pyogenic facet joint infection Spine (Phila Pa 1976) 2001 26 1570 1576 11462088\n13 Klekot D Zimny A Czapiga B Sąsiadek M Isolated septic facet joint arthritis as a rare cause of acute and chronic low back pain - a case report and literature review Pol J Radiol 2012 77 72 76\n14 Ergan M Macro M Benhamou CL Vandermarcq P Colin T L'Hirondel JL Marcelli C Septic arthritis of lumbar facet joints. A review of six cases Rev Rhum Engl Ed 1997 64 386 395 9513611\n15 Narváez J Nolla JM Narváez JA Martinez-Carnicero L De Lama E Gómez-Vaquero C Murillo O Valverde J Ariza J Spontaneous pyogenic facet joint infection Semin Arthritis Rheum 2006 35 272 283 16616150\n16 Rajeev A Choudhry N Shaikh M Newby M Lumbar facet joint septic arthritis presenting atypically as acute abdomen - A case report and review of the literature Int J Surg Case Rep 2016 25 243 245 27414995\n\n",
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"journal": "World journal of clinical cases",
"keywords": "Arthritis; Case report; Disc herniated; Lumbar region; Septic; Spinal injections",
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"title": "Postoperative pain due to an occult spinal infection: A case report.",
"title_normalized": "postoperative pain due to an occult spinal infection a case report"
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{
"abstract": "Systemic sclerosis (SSc) presents stiffness of extremities due to sclerosis of the tissue especially at fingers, hands, and forearms. Here we report the case of a patient with diffuse cutaneous SSc who was administered anti-interleukin-6 receptor antibody tocilizumab (TCZ). Skin condition of SSc is evaluated by pinching the skin according to the Rodnan skin score, but sometimes tissue atrophy results in overestimation of the condition. To understand how the extremities softened after initiation of TCZ, we observed mobility of extremities. Range of motion (ROM) of joints was measured every four months after initiation of TCZ. The patient presented not only reduction of Rodnan score but also amelioration of mobility of extremities. The Rodnan skin score reduced from 35 to 7 within sixteen months, and ROM of most joints except ankle was expanded.",
"affiliations": "Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine , 2-2 Yamada-oka, 565-0871, Suita City, Osaka , Japan.",
"authors": "Shima|Yoshihito|Y|;Hosen|Naoki|N|;Hirano|Toru|T|;Arimitsu|Junsuke|J|;Nishida|Sumiyuki|S|;Hagihara|Keisuke|K|;Narazaki|Masashi|M|;Ogata|Atsushi|A|;Tanaka|Toshio|T|;Kishimoto|Tadamitsu|T|;Kumanogoh|Atsushi|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.3109/14397595.2013.874749",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "25(1)",
"journal": "Modern rheumatology",
"keywords": "Range of joint motion; Systemic sclerosis; Tocilizumab",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D007596:Joints; D008875:Middle Aged; D016059:Range of Motion, Articular; D012595:Scleroderma, Systemic; D016896:Treatment Outcome",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "134-7",
"pmc": null,
"pmid": "24533556",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Expansion of range of joint motion following treatment of systemic sclerosis with tocilizumab.",
"title_normalized": "expansion of range of joint motion following treatment of systemic sclerosis with tocilizumab"
} | [
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"companynumb": "JP-ACTELION-A-CH2016-142034",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "BOSENTAN"
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"abstract": "A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months, the patient developed a severe bleeding disorder. The bleeding was due to fibrin polymerization defect that upon sequencing was shown to be dysfibrinogenemia Krakow III. Elimination of the mTor inhibitor ameliorated the clinical bleeding state.",
"affiliations": "Department of Medicine, Hematology and Oncology, Case Western Reserve University, Cleveland, OH, United States.;Department of Medicine, Hematology and Oncology, Case Western Reserve University, Cleveland, OH, United States.;Department of Medicine, Cardiovascular Medicine, Case Western Reserve University, Cleveland, OH, United States.;Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, United States.;Department of Genetic Medicine and Development, University Medical Center Geneva, Geneva, Switzerland.;Department of Medicine, Hematology and Oncology, Case Western Reserve University, Cleveland, OH, United States.",
"authors": "Merkulova|Alona A|AA|;Mitchell|Steven C|SC|;Merkulov|Sergei|S|;Wolberg|Alisa S|AS|;Neerman-Arbez|Marguerite|M|;Schmaier|Alvin H|AH|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2020.591546",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X Frontiers Media S.A. \n\n10.3389/fmed.2020.591546\nMedicine\nCase Report\nCase Report: Unmasked Inherited Dysfibrinogenemia After Everolimus Therapy\nMerkulova Alona A. 1 Mitchell Steven C. 1 Merkulov Sergei 2 Wolberg Alisa S. 3 Neerman-Arbez Marguerite 45 Schmaier Alvin H. 16* 1Department of Medicine, Hematology and Oncology, Case Western Reserve University, Cleveland, OH, United States\n2Department of Medicine, Cardiovascular Medicine, Case Western Reserve University, Cleveland, OH, United States\n3Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, United States\n4Department of Genetic Medicine and Development, University Medical Center Geneva, Geneva, Switzerland\n5Division of Angiology and Haemostasis, University Hospital, Geneva, Switzerland\n6Department of Medicine, Hematology and Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States\nEdited by: Giancarlo Castaman, University of Florence, Italy\n\nReviewed by: Gary Eugene Gilbert, Harvard Medical School, United States; Roland Schroers, Ruhr University Bochum, Germany; Cristina Santoro, Sapienza University of Rome, Italy\n\n*Correspondence: Alvin H. Schmaier schmaier@case.eduThis article was submitted to Hematology, a section of the journal Frontiers in Medicine\n\n\n27 11 2020 \n2020 \n7 59154604 8 2020 05 11 2020 Copyright © 2020 Merkulova, Mitchell, Merkulov, Wolberg, Neerman-Arbez and Schmaier.2020Merkulova, Mitchell, Merkulov, Wolberg, Neerman-Arbez and SchmaierThis 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.A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months, the patient developed a severe bleeding disorder. The bleeding was due to fibrin polymerization defect that upon sequencing was shown to be dysfibrinogenemia Krakow III. Elimination of the mTor inhibitor ameliorated the clinical bleeding state.\n\ndysfibrinogenemiaeverolimusCVIDfibrin polymerizationdysfibrinogenemia Krakow IIIOffice of Extramural Research, National Institutes of Health10.13039/100006955AI130131CA223301HL143402HL144113\n==== Body\nA 45 yo woman with a history of common variable immunodeficiency (CVID) was referred for a bleeding disorder. In 2009, this patient was diagnosed with common variable hypogammaglobulinemia. In 2011, the disorder manifested with immune thrombocytopenia and a splenectomy was performed. At that time, she had a normal prothrombin time (PT) and activated partial thromboplastin time (aPTT) and had no abnormal bleeding at surgery. In 2013, she developed hepatomegaly. In 2016, the hepatomegaly was symptomatic and she was started on everolimus by her liver immunologists as part of a protocol to reduce her liver size.\n\nSerious, spontaneous bleeding started 3–6 months after starting everolimus. It began with recurrent lower GI hemorrhages. Since 2016, this patient has had multiple hospitalizations for spontaneous GI bleedings, intra-abdominal hemorrhages, and hematomas in the right sacral plexus, right ankle, and multiple soft tissue locations. The sacral plexus bleed gave the patient a persistent right foot drop. On presentation at our hospital, the patient had a slightly prolonged aPTT [43 ± 6.6 (Mean ± SD) (normal 28–38 s)] but a normal PT [11.4 ± 0.7 (normal 9.7–12.7s)] (Figure 1A). Blood coagulation factors XII (1.41 U/ml), prekallikrein (1.38 U/ml), high molecular weight kininogen (0.85 U/ml), XI (0.63–0.79 U/ml), IX (0.79–1.17 U/ml), VIII (1.27 U/ml), VII (0.68–1.02 U/ml), X (0.69–0.89 U/ml), V (0.95 U/ml), and II (0.65–0.99 U/ml) were always normal. The reported range of values for factors XI, IX, VII, X, and II are from multiple assays over a 3-years period.\n\nFigure 1 (A) Summary of coagulation studies. Patient samples were collected in 3.2% sodium citrate (1:9 anticoagulant to total blood volume ratio). The aPTT, PT, clottable fibrinogen, fibrinogen antigen, thrombin clotting time, and reptilase time were performed in the Clinical Laboratories of University Hospital Cleveland Medical Center, Cleveland, OH. Thrombin time mixing studies were performed by a 1:1 incubation of patient or normal human plasma (NHP) with NHP or buffer, respectively, and incubated: one set was incubated overnight 16 h at 4°C, and a second set was incubated 2 h at 37°C. At the conclusion of the incubation, the samples received an equal volume of 8 NIH Units/ml of human α-thrombin (Enzyme Research Laboratories 3,000 U/mg specific activity) in 30 mM calcium chloride and the time to clot formation was recorded with a stop watch. The final thrombin concentration was 4 NIH U/ml or 0.5 nM α -thrombin. (B) Fibrin polymerization studies. Patient or NHP were added to 96-well microtiter plates. Upon the addition of buffer containing 8–32 nM human α-thrombin and 30 mM CaCl2, continuous visible light recording for turbidity at 405 nm were performed every 20 s for 20 min. The figure shows the mean ± SD of progress curves of three samples of patient or normal plasma treated with the indicated concentration of α-thrombin. (C) Family Genetic Studies. The figure is the sequence of the glycine 16 region of human γ-chain of fibrinogen from DNA isolated from buffy coat of Control (normal donor), Patient, and Patient's Mother and Father. Sequence was determined by PCR amplification followed by Sanger sequencing.\n\nThe patient's clottable fibrinogen [305 ± 72 mg/dL (normal 200–400 mg/dl)] and fibrinogen antigen [428 ± 115 mg/dL (normal 196–441)] were both normal (Figure 1A). However, the clottable fibrinogen-to-fibrinogen antigen ratio was low (0.71 ± 0.06). The patient's reptilase time was normal [20 ± 2.2 (normal 14–23 s)], but her thrombin time was persistently prolonged [19 ± 1.6 (normal 10–16 s)]. On mixing test of patient plasma 1:1 with normal plasma for 2 h at 37°C or overnight at 4°C, there was nothing in the patient plasma that prolonged the thrombin clotting of normal human plasma (Figure 1A). The patient had slightly elevated alpha-1-antitrypin, [231 mg/dl (normal 84–218)], but normal antithrombin activity [105% (normal 80–130)] and antigen [91 (normal 80–120)].\n\nIn general, a normal reptilase time with an abnormal thrombin time suggests a fibrinopeptide B release defect (1, 2). However, fibrinopeptide B defects are not associated with bleeding (2). Therefore the combined clinical and laboratory data suggest a fibrin polymerization defect. In a fibrin polymerization assay, the patient required 4-fold greater concentrations of human alpha-thrombin (32 vs. 8 nM) to achieve complete fibrin polymerization (Figure 1B). Since recognizing this fibrin polymerization defect, the patient's bleeding episodes have been controlled by cryoprecipitate infusions to raise her baseline fibrinogen values by 150–250 mg/dl with normal fibrinogen.\n\nSequencing of fibrinogen coding regions following PCR amplification of leukocyte genomic DNA revealed that the patient was heterozygous for a mutation in fibrinogen gamma chain exon 3 [FGGc.124G>A, p.Gly42Ser (Gly16Ser in the mature protein without the signal peptide)] (Figure 1C). This defect was previously described in a bleeding patient with similar blood coagulation studies as Fibrinogen Krakow III (3). Neither a control DNA sample from a normal donor nor the patient's father have this mutation. However, the patient's mother has the identical heterozygous mutation. The patient's mother, who is otherwise healthy, has no bleeding history. Our patient also is heterozygous for Fibrinogen Krakow III but never had a bleeding problem until everolimus treatment was instituted to manage her CVID.\n\nThe original hypothesis for these investigations was that treatment with everolimus caused an “acquired” bleeding state. Everolimus is an mTor inhibitor and mTor is a major regulator of protein synthesis (4). Further, mTor inhibition itself blocks fibrin clot retraction (5). Later, the patient also was found to have a heterozygous genetic polymorphism in her fibrinogen's gamma chain that interferes with fibrin polymerization. Thus, the patient's congenital fibrinogen mutation and everolimus treatment combined to give this patient a serious bleeding disorder. Upon urging the patient and treating physicians, the everolimus therapy was stopped and she has not had a major bleeding incident in 18 months. She does, however, have frequent minor mucous membrane bleeding (e.g., epistaxis). She persists in having an abnormal thrombin time and reduced fibrinogen activity/antigen ratio of 0.7.\n\nData Availability Statement\nThe authors acknowledge that the data presented in this study must be deposited and made publicly available in an acceptable repository, prior to publication. Frontiers cannot accept a article that does not adhere to our open data policies.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by University Hospitals Cleveland Medical Center IRB. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAM, SMi, SMe, AW, and MN-A contributed experimental studies. AS conceived the project. AS, AW, and MN-A wrote the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe appreciate the efforts of Ms. Pamela Douglas in aiding us to perform these studies.\n\nFunding. This study was not supported by any specific grants, but laboratory operations and PI support to AHS was through NIH grants AI130131, HL144113, HL143402, and CA223301. MN-A was supported by a grant from the Swiss National Science Foundation (grant #31003A_172864).\n==== Refs\nReferences\n1. Hanna LS Scheraga HA Francis CW Marder VJ . Comparison of structure of various fibrinogens and a derivative thereof by a study of the kinetics of release of fibrinopepetides\n. Biochemistry. (1984 ) 23 :4681 –7\n. 10.1021/bi00315a025 6238619 \n2. Nawarawong W Wyshock E Meloni FJ Weitz J Schmaier AH . The rate of fibrinopeptide B release modulates the rate of clot formation: a study with an acquired inhibitor to fibrinopeptide B release\n. Br J Haematol . (1991 ) 79 :296 –301\n. 10.1111/j.1365-2141.1991.tb04536.x 1958489 \n3. Pietrys D Balwierz W Iwaniec T Vorjohann S Neerman-Arbez M Undas A . Two different fibrinogen gene mutations associated with bleeding in the same family (A αGly13Glu and γGly16Ser) and their impact on fibrin clot properties: fibrinogen Krakow II and Krakow III\n. Thromb Haemost. (2011 ) 106 :558 –60\n. 10.1160/TH11-02-0102 21725578 \n4. Reiter AK Anthony TG Anthony JC Jefferson LS Kimball SR . The mTor signaling pathway mediates control of ribosomal protein mRNA translation in rat liver\n. Int J Biochem Cell Biol. (2004 ) 2169 –79\n. 10.1016/j.biocel.2004.04.004 15313464 \n5. Weyrich AS Denis MM Schwertz H Tolley ND Foulks J Spencer E . mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets\n. Blood. (2007 ) 109 :1975 –83\n. 10.1182/blood-2006-08-042192 17110454\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "7()",
"journal": "Frontiers in medicine",
"keywords": "CVID; dysfibrinogenemia; dysfibrinogenemia Krakow III; everolimus; fibrin polymerization",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "591546",
"pmc": null,
"pmid": "33330551",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "6238619;21725578;17110454;15313464;1958489",
"title": "Case Report: Unmasked Inherited Dysfibrinogenemia After Everolimus Therapy.",
"title_normalized": "case report unmasked inherited dysfibrinogenemia after everolimus therapy"
} | [
{
"companynumb": "US-MYLANLABS-2020M1006390",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "A 25-year-old male (Case 1) was waiting for a bone marrow transplant for myelodysplastic syndrome. Due to acute appendicitis, he was advised to undergo gastroenterological surgery. After blood transfusion, he underwent an emergency laparoscopic appendectomy, as no blood cell recovery was expected. The postoperative course was uneventful, and he was discharged. A 71-year-old female (Case 2) developed acute appendicitis during chemotherapy for acute myeloid leukemia (AML). At the time of onset, since her myelosuppression was expected to improve in approximately 1 week, a conservative treatment was administered. However, due to the progression of AML, the expected blood cell recovery did not occur. Therefore, laparoscopic appendectomy was performed 25 days after onset. She was discharged without postoperative adverse events. In cases of acute appendicitis in patients with hematologic disease accompanied by pancytopenia, it is important to establish a careful treatment plan considering the possibility of recovery from myelosuppression and the need to control an intraperitoneal infection in conjunction with a hematologist. Laparoscopic surgery, which is minimally invasive, was an effective surgical procedure.",
"affiliations": "Department of Surgery, Japan Community Health care Organization Sagamino Hospital, Sagamihara, Japan.;Department of Surgery, Japan Community Health care Organization Sagamino Hospital, Sagamihara, Japan.;Department of Surgery, Japan Community Health care Organization Sagamino Hospital, Sagamihara, Japan.;Department of Surgery, Japan Community Health care Organization Sagamino Hospital, Sagamihara, Japan.;Department of Surgery, Japan Community Health care Organization Sagamino Hospital, Sagamihara, Japan.;Department of Surgery, Japan Community Health care Organization Sagamino Hospital, Sagamihara, Japan.",
"authors": "Kojima|Keita|K|;Nakamura|Takatoshi|T|;Habiro|Takeyoshi|T|;Waraya|Mina|M|;Hayashi|Keiko|K|;Ishii|Ken-Ichiro|KI|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.23922/jarc.2020-077",
"fulltext": "\n==== Front\nJ Anus Rectum Colon\nJ Anus Rectum Colon\nJournal of the Anus, Rectum and Colon\n2432-3853\nThe Japan Society of Coloproctology\n\n10.23922/jarc.2020-077\nCase Report\nLaparoscopic Appendectomy for Acute Appendicitis Complicated by Pancytopenia in Two Patients with Hematologic Diseases\nKojima Keita 1\nNakamura Takatoshi 12\nHabiro Takeyoshi 1\nWaraya Mina 1\nHayashi Keiko 1\nIshii Ken-Ichiro 1\n1 Department of Surgery, Japan Community Health care Organization Sagamino Hospital, Sagamihara, Japan\n2 First Department of Surgery, Dokkyo Medical University, Shimotsuga, Japan\nCorresponding author: Keita Kojima, dm15010b@st.kitasato-u.ac.jp\n\n2021\n28 4 2021\n5 2 188191\n6 10 2020\n14 12 2020\nCopyright © 2021 by The Japan Society of Coloproctology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Journal of the Anus, Rectum and Colon is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 25-year-old male (Case 1) was waiting for a bone marrow transplant for myelodysplastic syndrome. Due to acute appendicitis, he was advised to undergo gastroenterological surgery. After blood transfusion, he underwent an emergency laparoscopic appendectomy, as no blood cell recovery was expected. The postoperative course was uneventful, and he was discharged. A 71-year-old female (Case 2) developed acute appendicitis during chemotherapy for acute myeloid leukemia (AML). At the time of onset, since her myelosuppression was expected to improve in approximately 1 week, a conservative treatment was administered. However, due to the progression of AML, the expected blood cell recovery did not occur. Therefore, laparoscopic appendectomy was performed 25 days after onset. She was discharged without postoperative adverse events. In cases of acute appendicitis in patients with hematologic disease accompanied by pancytopenia, it is important to establish a careful treatment plan considering the possibility of recovery from myelosuppression and the need to control an intraperitoneal infection in conjunction with a hematologist. Laparoscopic surgery, which is minimally invasive, was an effective surgical procedure.\n\nacute appendicitis\nlaparoscopic appendectomy\npancytopenia\n==== Body\nIntroduction\n\nCurrently, there is no consensus as to whether emergency surgery should be performed for acute abdomen in patients with pancytopenia due to cancer chemotherapy or hematological disorders. Thus, gastroenterological surgeons are often forced to make urgent and difficult decisions. In fact, during leukemia treatments, some cases require gastroenterological surgery[1,2]. Here, we report two cases of acute appendicitis accompanied by pancytopenia due to myelodysplastic syndromes (MDS) and pancytopenia that occurred during chemotherapy for acute myeloid leukemia (AML).\n\nCase Report\n\nCase 1: A 25-year-old male.\n\nChief complaint: Chills, lower abdominal pain.\n\nPast history: No special notes.\n\nHistory of present illness: The patient was diagnosed with MDS and was waiting for a bone marrow transplant. At the time of the first visit, he was referred for chills and lower abdominal pain. He was diagnosed with acute appendicitis and then further referred for surgery.\n\nPresent medical condition: The patient's height is 176.4 cm; weight, 71.2 kg; body temperature, 39.6°C; blood pressure, 109/53 mmHg; and pulse, 80/min. Abdominal examination revealed tenderness in the lower right abdomen. However, there were no signs of peritoneal irritation.\n\nBlood test findings: White blood cell (WBC) count was 900/μL; neutrophil count, 335/μL; hemoglobin concentration, 6.8 g/dL; platelet count, 2.7 × 104/μL; and C-reactive protein (CRP) concentration, 13.8 mg/dL.\n\nAbdominal contrast-enhanced computed tomography (CT) (Figure 1): The appendix wall was thickened and swollen and the surrounding fat concentration increased. Moreover, a small amount of ascites was observed. There was no perforation of the appendix or abscess.\n\nFigure 1. Abdominal contrast-enhanced computed tomography images of Case 1. The appendix was swollen, and disproportionate fat stranding was observed (arrows).\n\nBased on the above, we diagnosed the patient with acute appendicitis complicated by MDS. We planned an emergency surgery as recovery of the bone marrow function was not possible. The surgery was planned to be performed after red blood cell and platelet transfusion for pancytopenia. However, allergies (urticaria and pharyngeal pruritus) were observed during transfusion. The day after onset, the allergic symptoms resolved; thus, laparoscopic appendectomy was performed.\n\nSurgical findings: A small amount of bloody ascites accumulated in the abdominal cavity, which resulted in the congestion of the mesoappendix. The appendix had no noticeable adhesions; appendectomy was then performed. The operation time was 1 h and 7 min, and there was almost no bleeding.\n\nHistopathological findings: Neutrophils infiltrated into all layers of the appendix, suggesting phlegmonous appendicitis.\n\nPostoperative course: The patient was treated with antibiotics in addition to the use of an immunoglobulin preparation, as is normally done for severe infections. The postoperative course was uneventful. He was discharged 8 days following the operation, after which he underwent bone marrow transplant.\n\n \n\nCase 2: A 71-year-old female.\n\nChief complaint: Diarrhea and right lower abdominal pain.\n\nPast history: Anti-human leukocyte antigen antibody positive and platelet transfusion refractory state.\n\nHistory of present illness: The patient had been receiving idarubicin/cytosine arabinoside remission induction therapy for AML. She had diarrhea and right lower abdominal pain on the 13th day of the treatment. Upon further examination, she was diagnosed with acute appendicitis. She was referred for surgery.\n\nPresent medical condition: The patient's height is 162 cm; weight, 46.7 kg; body temperature, 38.6°C; blood pressure, 102/52 mmHg; and pulse, 90/min. Abdominal examination revealed rebound tenderness in the lower right abdomen.\n\nBlood test findings: WBC count was 300/μL; neutrophil count, 11/μL; hemoglobin concentration, 8.6 g/dL; platelet count, 0.4 × 104/μL; and CRP concentration, 11.8 mg/dL.\n\nAbdominal contrast-enhanced CT: Swelling and thickening of the appendix wall, which had a contrast effect, were observed. No perforation or abscess formation was noted.\n\nBased on the above, the patient was diagnosed with acute appendicitis associated with pancytopenia due to AML chemotherapy. Her attending physician, a hematologist, expected that bone marrow function recovery would be achieved in approximately 1 week. Considering the perioperative complications, we administered conservative treatment under strict control and planned the surgery to be performed after the bone marrow function has recovered. The patient's abdominal findings gradually improved, and CRP demonstrated a decreasing trend (Figure 2-A). However, 2 weeks after the onset of appendicitis, her WBC count remained at around 500/μL. Therefore, bone marrow examination was conducted 17 days after the onset. The examination revealed that the AML had not responded to chemotherapy and that the disease had progressed. Abdominal contrast-enhanced CT performed 23 days after the disease onset revealed residual inflammation of the appendix and a liver abscess (Figure 2-B). We speculated that the liver abscess was caused by appendicitis. Since her blood cells did not recover, she underwent laparoscopic appendectomy on the 25th day with the hope of continuing AML chemotherapy.\n\nFigure 2. A: After conservative treatment, the C-reactive protein (CRP) level tended to decrease. However, the white blood cell (WBC) count increased to approximately 500, even at 2 weeks after the onset of appendicitis. Neut: neutrophil\n\nB: This figure presents the findings of abdominal contrast-enhanced computed tomography of Case 2 at 23 days after the onset. The swelling of the appendix remained, and an amount of abscess formed in the liver (arrows).\n\nSurgical findings: Due to severe inflammation of the appendix, partial resection of the cecum was performed. The operation time was 1 h and 12 min, and there was almost no bleeding.\n\nHistopathological findings: Inflammatory cells had infiltrated into the submucosa, a finding associated with gangrenous inflammation. No atypical cells were observed.\n\nPostoperative course: The patient received antibiotics and immunoglobulin preparations. The postoperative course was uneventful. She was discharged 21 days after surgery. On imaging, although the liver abscess had shrunk, it still remained. However, as her physical findings improved and the CRP became negative, she has continued chemotherapy for AML.\n\nDiscussion\n\nOf the acute abdominal issues that occur in patients with leukemia, the frequency of acute appendicitis is reported to be about 0.5%[3,4]. We searched for case reports in Japan from the Japan Medical Abstracts Society during the period 1990-2019 using the keywords “appendicitis,” “leukemia,” and “MDS” (excluding the proceedings). Out of the 31 case reports discovered, 29 cases of acute appendicitis were found to be associated with leukemia treatment and 2 cases with MDS. Emergency surgery was performed in 17 cases at the time of diagnosis, with the main reason being that myelosuppression was prolonged. Contrarily, conservative treatment had been administered to 14 patients. Among them, 57% (8/14) successfully responded to the treatment; however, 50% (4/8) had a relapse. The major reasons for proceeding with the conservative treatment were mild abdominal symptoms and increased postoperative complications due to myelosuppression. In patients with improved abdominal symptoms, surgery was performed after waiting for bone marrow function recovery. The use of laparoscopic appendectomy as an operative procedure for patients with hematologic disease has been reported in 10 cases in Japan.\n\nWhen using component transfusions and antibiotic treatments, perioperative complications need to be appropriately managed. Due to the fear of postoperative infections[5], we have commonly used gamma globulin. However, in the above conditional search, we found that only 5 of the 31 cases reported in Japan used gamma globulin. Also, we did not use the granulocyte colony-stimulating factor (G-CSF) formulation, although it has been reportedly used in 6 of the 31 cases in Japan. As it has been pointed out that the use of G-CSF for leukemia could possibly result in leukemic cell proliferation[6], this treatment should only be used under the guidance of a hematologist. Furthermore, a facility with a bio-clean operating room may be the best place to perform this procedure[7]. However, the use of such a facility will only help prevent airborne infections. This is because, as has been observed in implant surgeries, the appropriate use of antibiotics is important to prevent postoperative infections[8]. Therefore, we consider that a bio-clean room is not essential when treating acute appendicitis in patients with myelosuppression.\n\nOne of the most annoying aspects of these treatment choices is that patients exhibit reduced bone marrow function. The difference between the two cases reported here was whether or not the blood cells were likely to recover at the time of diagnosis of acute appendicitis. Because the patient with MDS was waiting for a bone marrow transplant, blood cell recovery was not expected over the short term. In contrast, in patients with AML, cytopenia due to chemotherapy is normally expected, as well as blood cell recovery at the time of diagnosis. Therefore, emergency surgery was performed in the current patient with MDS, while conservative treatment was prioritized for the patient with AML in conjunction with a strict follow-up. We believe that an environment wherein bone marrow biopsy can be performed in a timely manner to evaluate the disease progression in patients with delayed blood cell recovery, such as in Case 2, is meaningful with regard to the determination of the treatment strategies.\n\nThe treatment principle for acute appendicitis is surgery. But from the viewpoint of the underlying disease along with treatment continuation for patients with hematological disorders, resection is also desirable. However, in patients with pancytopenia, the timing of the surgery becomes a problem from the viewpoint of the risk of perioperative systemic complications and susceptibility to infection. In conclusion, we propose the following as a treatment strategy for patients with myelosuppression accompanied by acute appendicitis. Emergency surgery should only be considered under strict control if severe intraperitoneal infection becomes difficult to control or blood cell recovery is not expected. Contrarily, if blood cell recovery is expected in the short term and the infection is controllable, a conservative treatment should be prioritized to avoid perioperative complications. However, after a conservative treatment is administered, interval appendectomy should be considered due to the high incidence of appendicitis in patients with leukemia[9]. In addition, it has been found that laparoscopic surgery for appendicitis is useful in reducing the incidence of wound infections[10]. The findings in the 10 patients with leukemia who underwent laparoscopic appendectomy and our two case study patients indicate that there is no significant difference in the surgical procedure for laparoscopic appendectomy between general patients and patients with myelosuppression. Therefore, laparoscopic surgery should be aggressively considered as a less-invasive treatment in patients with pancytopenia.\n\nConflicts of Interest\n\nThere are no conflicts of interest.\n\nAuthor Contributions\n\nAll authors have contributed to this manuscript and reviewed and approved the current form of the manuscript to be submitted.\n\nInformed Consent\n\nWritten informed consent was obtained from the patients.\n==== Refs\n1. Wallace J, Schwaitzberg S, Miller K. Sometimes it really is appendicitis: case of a CML patient with acute appendicitis. Ann Hematol 1998 Jul-Aug; 77(1-2): 61-4.\n2. Chirletti P, Barillari P, Sammartino P, et al. The surgical choice in neutropenic patients with hematological disorders and acute abdominal complications. Leuk Lymphoma. 1993 Feb; 9(3): 237-41.\n3. Angel CA, Rao BN, Wrenn E Jr, Lobe TE, Kumar AP. Acute appendicitis in children with leukemia and other malignancies: still a diagnostic dilemma. J Pediatr Surg. 1992 Apr; 27(4): 476-9.\n4. Hunter TB, Bjelland JC. Gastrointestinal complications of leukemia and its treatment. Am J Roentgenol 1984 Mar;142: 513-8.\n5. Negi VS, Elluru S, Sibéril S, et al. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol 2007 May; 27(3): 233-45.\n6. Takamatsu H, Nakao S, Ohtake S, et al. Granulocyte colony-stimulating factor-dependent leukemic cell proliferation in vivo in acute promyelocytic leukemia. Blood 1993 Jun 15; 81(12): 3485-6.\n7. Sakamoto K, Fukuchi T. Two cases of acute celiopathy which occurred in the bone marrow inhibition stage during the treatment of leukemia and performed surgical treatment. Jpn J Gastroenterol Surg. 1996; 29(5): 1064-8.\n8. Lidwell OM, Elson RA, Lowbury EJ, et al. Ultraclean air and antibiotics for prevention of postoperative infection. A multicenter study of 8,052 joint replacement operations. Acta Orthop Scand. 1987 Feb; 58(1): 4-13.\n9. Wiegering VA, Kellenberger CJ, Bodmer N, et al. Conservative management of acute appendicitis in children with hematologic malignancies during chemotherapy-induced neutropenia. J Pediatr Hematol Oncol. 2008 Jun; 30(6): 464-7.\n10. Wang D, Dong T, Shao Y, Gu T, Xu Y, Jiang Y. Laparoscopy versus open appendectomy for elderly patients, a meta-analysis and systematic review. BMC Surg. 2019 May; 19(1): 54.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2432-3853",
"issue": "5(2)",
"journal": "Journal of the anus, rectum and colon",
"keywords": "acute appendicitis; laparoscopic appendectomy; pancytopenia",
"medline_ta": "J Anus Rectum Colon",
"mesh_terms": null,
"nlm_unique_id": "101718055",
"other_id": null,
"pages": "188-191",
"pmc": null,
"pmid": "33937560",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "6607636;1522462;18525466;8471983;31138196;9760155;17351760;7685207;3107337",
"title": "Laparoscopic Appendectomy for Acute Appendicitis Complicated by Pancytopenia in Two Patients with Hematologic Diseases.",
"title_normalized": "laparoscopic appendectomy for acute appendicitis complicated by pancytopenia in two patients with hematologic diseases"
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"abstract": "OBJECTIVE\nCarney complex (CNC) is a rare autosomal dominant multiple neoplasia syndrome characterized by the presence of endocrine and non-endocrine tumors. More than 125 different germline mutations of the protein Kinase A type 1-α regulatory subunit (PRKAR1A) gene have been reported. We present a novel PRKAR1A gene germline mutation in a patient with severe osteoporosis and recurrent vertebral fractures.\n\n\nMETHODS\nClinical case report.\n\n\nMETHODS\nA 53-year-old male with a medical history of surgically removed recurrent cardiac myxomas was evaluated for repeated low-pressure vertebral fractures and severe osteoporosis. Physical examination revealed spotty skin pigmentation of the lower extremities and papules in the nuchal and thoracic region. The presence of hypercortisolism due to micronodular adrenal disease and the history of cardiac myxomas suggested the diagnosis of CNC; the patient underwent detailed imaging investigation and genetic testing.\n\n\nMETHODS\nStandard imaging and clinical testing; DNA was sequenced by the Sanger method.\n\n\nRESULTS\nSequence analysis from peripheral lymphocytes DNA revealed a novel heterozygous point mutation at codon 172 of exon 2 (c.172G>T) of the PRKAR1A gene, resulting in early termination of the PRKAR1A transcript [p.Glu58Ter (E58X)].\n\n\nCONCLUSIONS\nWe report a novel point mutation of the PRKAR1A gene in a patient with CNC who presented with significant osteoporosis and fractures. Low bone mineral density along with recurrent myxomas should point to the diagnosis of CNC.",
"affiliations": "Department of Endocrinology and Diabetes Center, \"G. Gennimatas\" General Hospital, Athens, Greece.;Department of Endocrinology and Diabetes Center, \"G. Gennimatas\" General Hospital, Athens, Greece.;Department of Endocrinology and Diabetes Center, \"G. Gennimatas\" General Hospital, Athens, Greece.;Department of Endocrinology and Diabetes Center, \"G. Gennimatas\" General Hospital, Athens, Greece.;Department of Pathology, \"G. Gennimatas\" General Hospital, Athens, Greece.;Department of Pathology, \"G. Gennimatas\" General Hospital, Athens, Greece.;Department of Surgery, \"G. Gennimatas\" General Hospital, Athens, Greece.;Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA.;Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA.;Department of Endocrinology and Diabetes Center, \"G. Gennimatas\" General Hospital, Athens, Greece.",
"authors": "Papanastasiou|Labrini|L|;Fountoulakis|Stelios|S|;Voulgaris|Nikos|N|;Kounadi|Theodora|T|;Choreftaki|Theodosia|T|;Kostopoulou|Akrivi|A|;Zografos|George|G|;Lyssikatos|Charalampos|C|;Stratakis|Constantine A|CA|;Piaditis|George|G|",
"chemical_list": "D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human",
"country": "Switzerland",
"delete": false,
"doi": "10.14310/horm.2002.1627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1109-3099",
"issue": "15(1)",
"journal": "Hormones (Athens, Greece)",
"keywords": null,
"medline_ta": "Hormones (Athens)",
"mesh_terms": "D056733:Carney Complex; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D005598:Fractures, Spontaneous; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010024:Osteoporosis",
"nlm_unique_id": "101142469",
"other_id": null,
"pages": "129-35",
"pmc": null,
"pmid": "27377598",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural; D016454:Review",
"references": "12213893;19915019;16901990;24571724;24618615;9843463;10523219;19293268;24170103;8609225;18241045;11115848;15371594;3083749;12424709;18451138;24789151;10973256;22112814;24571725;24506536;15282353;20358582;4010501;16464939",
"title": "Identification of a novel mutation of the PRKAR1A gene in a patient with Carney complex with significant osteoporosis and recurrent fractures.",
"title_normalized": "identification of a novel mutation of the prkar1a gene in a patient with carney complex with significant osteoporosis and recurrent fractures"
} | [
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"companynumb": "GR-AMGEN-GRCSP2016099869",
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"abstract": "Recently, attention has been focused on methotrexate-induced lymphoproliferative disease (MTX-LPD), and atypical phenotypes are occasionally documented. We encountered two patients with rheumatoid arthritis (RA) who were diagnosed with non-specific LPD (LPD-nos). Biopsy samples were not obtained during the initial examination when the LPD development was discovered, and the patients achieved a complete response after MTX cessation (case 1) or steroid pulse therapy (case 2). However, the tumors flared up 1.5 years later, and LPD-nos was determined following biopsies of the lymph node (LN, case 1) and liver (case 2). Prednisolone was subsequently administered instead of chemotherapy; however, multiple masses, including in the spine (case 1), and severe icterus with liver dysfunction (case 2) were exacerbated within a few months. Although the re-biopsy of LN proved the presence of HL and radiation followed by aggressive chemotherapy rescued the patient (case 1), the superficially accessible biopsy site was not found, and autopsy finally revealed HL (case 2). In both cases, the underlying pathogenesis along with the B symptoms and laboratory abnormalities suggested MTX-LPD, HL in particular. Therefore, even if the pathological diagnosis does not confirm the specific LPD subtype, the administration of aggressive chemotherapy should be considered if the LPD activity flares severely.",
"affiliations": "Department of Hematology, Saitama Medical Center, Saitama Medical University.",
"authors": "Tokuhira|Michihide|M|;Tabayashi|Takayuki|T|;Tanaka|Yuka|Y|;Takahashi|Yasuyuki|Y|;Kimura|Yuta|Y|;Tomikawa|Tatsuki|T|;Anan-Nemoto|Tomoe|T|;Momose|Shuju|S|;Higashi|Morihiro|M|;Okuyama|Ayumi|A|;Watanabe|Reiko|R|;Amano|Koichi|K|;Tamaru|Jun-Ichi|JI|;Kizaki|Masahiro|M|",
"chemical_list": "D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D011239:Prednisolone; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.3960/jslrt.56.165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-4280",
"issue": "56(3)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": null,
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D001172:Arthritis, Rheumatoid; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011239:Prednisolone; D012008:Recurrence; D012074:Remission Induction",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "165-169",
"pmc": null,
"pmid": "28331131",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12746895;15722257;16443552;17117491;17654684;1967942;21933041;23560463;24334644;27102806;3883172;6259211;8385742",
"title": "The aggressive clinical courses of Hodgkin lymphoma primarily diagnosed as methotrexate-induced non-specific lymphoproliferative disorder in patients with rheumatoid arthritis.",
"title_normalized": "the aggressive clinical courses of hodgkin lymphoma primarily diagnosed as methotrexate induced non specific lymphoproliferative disorder in patients with rheumatoid arthritis"
} | [
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"companynumb": "JP-MYLANLABS-2017M1027597",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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... |
{
"abstract": "Idiopathic pulmonary hemosiderosis (IPH) is a rare disease in children, with unknown etiology. The classical clinical triad is hemoptysis, hypochromic anemia and diffuse parenchymal infiltrations on chest X-ray. Liposteroid dexamethasone palmitate, which was developed in Japan, has shown good efficacy for IPH. We present the case of a patient with IPH, who suffered from a life-threatening respiratory dysfunction, and was rescued by a trial administration of liposteroid with methylprednisolone (mPSL). A 6-year-old girl was admitted to our hospital for repeated dyspnea and blood-stained sputum. She was diagnosed with IPH at the age of three-months by iron staining of gastric fluid and sputum studies. Her cumulative dose of steroids (equivalent to prednisolone (PSL)) was 1062 mg/kg. However, she could not achieve remission. We decided to initiate liposteroid therapy. We administered an infusion of liposteroid 0.8 mg/kg intravenously, for three consecutive days as a therapy for acute bleeding. After administration of liposteroid, she developed high fever with CRP elevation. We suspected that the inflammation was caused by palmitate, which is present as a lipo base in liposteroid. Hence, we added 2 mg/kg mPSL per day for 1 week. As a maintenance treatment, a single infusion of liposteroid was administered followed by mPSL administration for 6 days in every week. Her respiratory condition slowly improved. Tracheostomy was performed for airway management. She was shifted out of the ICU on the 34th day. Steroid is a key therapy for hemosiderosis. When IPH is diagnosed, oral prednisone therapy is initiated. Although this is effective, there are limitations due to significant adverse effects. Maintaining drug therapy is very important for IPH patients to keep the disease under control. Liposteroid has the same mechanism of action as dexamethasone. It has a Lipo-base, palmitate, which could induce pro-inflammatory cytokine activation. We used mPSL to inhibit the inflammation following liposteroid administration. This was effective. A combination of liposteroid and mPSL administration was useful method of treatment for the patient.",
"affiliations": "Department of Pediatrics, Faculty of Life Science, Kumamoto University, Kumamoto Japan.;Department of Pediatrics, Faculty of Life Science, Kumamoto University, Kumamoto Japan.;Department of Pediatrics, Faculty of Life Science, Kumamoto University, Kumamoto Japan.;Department of Pediatrics, Faculty of Life Science, Kumamoto University, Kumamoto Japan.",
"authors": "Sakamoto|Rieko|R|;Matsumoto|Shiro|S|;Mitsubuchi|Hiroshi|H|;Nakamura|Kimitoshi|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2018.03.011",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30417-310.1016/j.rmcr.2018.03.011Case ReportLiposteroid and methylprednisolone combination therapy for a case of idiopathic lung hemosiderosis Sakamoto Rieko hrieko48@kuh.kumamoto-u.ac.jp∗Matsumoto Shiro Mitsubuchi Hiroshi Nakamura Kimitoshi Department of Pediatrics, Faculty of Life Science, Kumamoto University, Kumamoto Japan∗ Corresponding author. 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556, Japan. hrieko48@kuh.kumamoto-u.ac.jp20 3 2018 2018 20 3 2018 24 22 24 6 1 2018 15 3 2018 18 3 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Idiopathic pulmonary hemosiderosis (IPH) is a rare disease in children, with unknown etiology. The classical clinical triad is hemoptysis, hypochromic anemia and diffuse parenchymal infiltrations on chest X-ray. Liposteroid dexamethasone palmitate, which was developed in Japan, has shown good efficacy for IPH. We present the case of a patient with IPH, who suffered from a life-threatening respiratory dysfunction, and was rescued by a trial administration of liposteroid with methylprednisolone (mPSL).\n\nA 6-year-old girl was admitted to our hospital for repeated dyspnea and blood-stained sputum. She was diagnosed with IPH at the age of three-months by iron staining of gastric fluid and sputum studies. Her cumulative dose of steroids (equivalent to prednisolone (PSL)) was 1062 mg/kg. However, she could not achieve remission. We decided to initiate liposteroid therapy. We administered an infusion of liposteroid 0.8 mg/kg intravenously, for three consecutive days as a therapy for acute bleeding. After administration of liposteroid, she developed high fever with CRP elevation. We suspected that the inflammation was caused by palmitate, which is present as a lipo base in liposteroid. Hence, we added 2 mg/kg mPSL per day for 1 week. As a maintenance treatment, a single infusion of liposteroid was administered followed by mPSL administration for 6 days in every week. Her respiratory condition slowly improved. Tracheostomy was performed for airway management. She was shifted out of the ICU on the 34th day.\n\nSteroid is a key therapy for hemosiderosis. When IPH is diagnosed, oral prednisone therapy is initiated. Although this is effective, there are limitations due to significant adverse effects. Maintaining drug therapy is very important for IPH patients to keep the disease under control. Liposteroid has the same mechanism of action as dexamethasone. It has a Lipo-base, palmitate, which could induce pro-inflammatory cytokine activation. We used mPSL to inhibit the inflammation following liposteroid administration. This was effective. A combination of liposteroid and mPSL administration was useful method of treatment for the patient.\n\nKeywords\nIdiopathic pulmonary hemosiderosisLiposteroid\n==== Body\n1 Introduction\nIdiopathic pulmonary hemosiderosis (IPH) is a rare disease in children, with unknown etiology [1,2]. It is pathologically characterized by recurrent intra-alveolar pulmonary hemorrhage. The patients exhibit symptoms such as dyspnea, cough, and blood-stained sputum. The classical clinical triad is hemoptysis, hypochromic anemia, and diffuse parenchymal infiltrations on chest X-ray. The clinical course can progress aggressively, with death in several cases. Liposteroid dexamethasone palmitate is known for the treatment of rheumatoid arthritis. This drug, which was developed in Japan, is a lipid emulsion containing dexamethasone [[3], [4], [5]].\n\nThis drug has shown good efficacy for some immunological diseases such as hemophagocytic syndrome, graft-versus-host disease, and pulmonary hemosiderosis. This efficacy is due to easy uptake of the drug by phagocytes and retention of the drug in macrophages. Doi et al. reported the long-term outcomes of liposteroid in nine children with IPH. Almost all patients showed long remission and normal level of KL6 [6].\n\nWe present the case of a patient with pulmonary hemosiderosis, who suffered from a life-threatening respiratory dysfunction, and was rescued by a trial administration of liposteroid.\n\n2 Case presentation\nA 6-year-old girl was admitted to our hospital for repeated dyspnea and hemoptysis, with a low oxygen-saturation of 91% in ambient air. She showed labored breathing. On admission, her SpO2 was 94% with 6 L/min oxygen from a reservoir mask. Computed tomography of chest showed infiltrative shadow in the lower field of both lungs (Fig. 1).Fig. 1 Computed tomography of chest showed an infiltrative shadow in the lower field of both lungs.\n\nFig. 1\n\nWhen she was 3 months old, she was admitted to our hospital with repeated cough and hemoptysis. Her chest X-ray showed ground glass opacity. Hypochromic anemia was also observed. When she was 10 months old, she was diagnosed with IPH based on the results of iron staining of gastric fluid and sputum studies (Fig. 2). Oral or intravenous steroids were administered to the patient several times, but her respiratory condition did not improve. The cumulative dose of steroids (equivalent to prednisolone [PSL]) administered to her was 1062 mg/kg.Fig. 2 Pathological findings of gastric fluid showed phagocytosis of hemosiderin.\n\nFig. 2\n\nDuring the most recent admission, intravenous corticosteroid was administered in addition to the usual treatment (oxygen, bronchodilators, and steroid inhaler). However, her respiratory condition worsened despite a high dose of dexamethasone equivalent to a pulse dose of methylprednisolone (mPSL) for 3 days. We decided to initiate liposteroid therapy, which has shown good prognosis over long-term use in patients with IPH [6]. After informed consent and approval of the ethics committee, we administered an infusion of liposteroid 0.8 mg/kg intravenously, for three consecutive days as a therapy for acute bleeding in accordance with the protocol reported by Doi et al. [6]. On the second day of liposteroid therapy, she displayed restlessness and irritability, which was considered an adverse effect of the drug. Her respiratory condition worsened and it was difficult to maintain an SpO2 of >90%, even with 10 L/min oxygen. Her blood pressure was 180/100 mmHg. Posterior reversible encephalopathy (PRES) syndrome due to adverse effect of liposteroid was suspected. Mechanical ventilation was initiated in the ICU. We provided mechanical ventilation in airway pressure release ventilation (APRV) mode, to allow spontaneous respiration. Liposteroid was administered on the third day with continuous infusion of sedative drugs. Her clinical course in the ICU is shown in Fig. 3. After administration of liposteroid for 3 days, she developed high fever with CRP elevation (22.99 g/dL). Antibiotics and gamma globulin were initiated for suspected severe bacterial infection, though her vital signs were stable and procalcitonin was not significantly elevated (0.62 ng/mL). We also suspected that the inflammation was caused by palmitate, which is present as a lipo-base in lipoprotein dexamethasone. Hence, we added 2 mg/kg mPSL per day for 4 days. A single infusion of liposteroid was administered 1 week after the first therapy, as maintenance treatment. During the first single infusion of maintenance therapy, we reduced the dose to 0.5 mg/kg, to prevent the adverse effect; however, she complained of pruritus. We decreased the dosage to 0.2 mg/kg during the second week of single infusion. After liposteroid infusion, we administered 0.8–2 mg/kg mPSL for 6 days every week. Her respiratory condition improved slowly. Tracheostomy was performed for airway management on the 21st day in the ICU. She was shifted out of the ICU on the 34th day and was discharged from the hospital 5 months after initiation of liposteroid therapy.Fig. 3 Clinical course in the ICU. Liposteroid was administered for three consecutive days followed by mPSL administration. The dosage of liposteroid and mPSL was changed according to the data or the patient's condition. *APRV: airway pressure release ventilation; **PS: pressure support.\n\nFig. 3\n\n3 Discussion\nPatients with lung hemosiderosis show symptoms such as asthma, severe cough, wheezing, and dyspnea in addition to iron-deficiency anemia. Maintenance therapy such as bronchodilator, inhaler and/or oral steroid administration is necessary even if the patient is in a good clinical condition with few symptoms. Hemosiderosis can recur over the years. Physicians should closely observe the patients at fixed intervals and ensure good compliance of medicine. Steroid is a key therapy for hemosiderosis. When IPH is diagnosed, oral prednisone therapy is initiated. Although this is effective, there are limitations due to significant adverse effects. The adverse effects of steroid administration are sometimes aggravated in a child on long-term therapy. The adverse effect can cause growth retardation, osteoporosis, fatty liver, hypertrichosis, etc. Maintaining drug therapy is very important for IPH patients to keep the disease under control. Liposteroid has the same mechanism of action as dexamethasone. However, it has a lipo-base, palmitate, which is saturated fatty acid. Saturated fatty acid is more deleterious to the non-adipose tissue than unsaturated fatty acid [7]. Kim et al. reported that palmitate strongly induced apoptosis of macrophages, which can lead to endoplasmic reticulum stress and cause proliferation of reactive oxygen species [7]. This palmitate-induced lipotoxicity to the macrophages, might be beneficial for immune-mediated conditions, in addition to high transferability and retention in the target tissues [8,9]. Wang et al. reported that palmitate induced NLRP3 inflammasome activation leads to caspase-1 activation, which induces pyroptosis [9]. Caspase 1 induces pro-inflammatory cytokine activation such as interleukin-1 (IL1) and interleukin-18 (IL18). This mechanism could be the reason for CRP elevation and high fever after administration of liposteroid in our case [10,11]. The initial dose might have been too high, leading to CRP elevation and high fever, in addition to mental instability in the patient. We decided the dose of liposteroid based on the protocol reported by Doi et al. [6]. Liposteroid was administered to the patient in May 2015. However, an erratum for that article was issued in September 2015, and the dose of liposteroid was corrected to 10% of the original dose [12]. Moreover, since the patient had gained weight due to long-term steroid administration, the dose calculation should have been done using lean body mass. We used mPSL to inhibit the inflammation following liposteroid administration. As a result, the dose of liposteroid (0.2 mg/kg) did not have any adverse effect following mPSL administration. Although the dose was higher than the corrected dose of liposteroid [12], it could be considered an appropriate dose if followed by mPSL administration.\n\nThe combination of liposteroid and mPSL administration was a useful method for the treatment of our patient.\n\n4 Conclusions\nLiposteroid administration is effective for a steroid resistant IPH patient. It is necessary to calculate the dose accurately and watch for adverse effects after initial administration. Combination with mPSL was effective probably due to the inhibition of inflammatory response caused by liposteroid, in addition to the inhibition of IPH progression.\n\nFinancial disclosure\nNone of the authors has any conflicts of interest with the contents.\n\nProprietary statement\nNone of the authors has commercial or proprietary interest in any drug, device, or equipment mentioned in the submitted article.\n\nSource of financial support\nNone.\n\nDeclarations of interest\nNone.\n==== Refs\nReferences\n1 Nuesslein T.G. Teig N. Rieger C.H.L. Pulmonary haemosiderosis in infants and children Paediatr. Respir. Rev. 7 2006 45 48 16473816 \n2 Ioachimescu O.C. Sieber S. Kotch A. Idiopathic pulmonary haemosiderosis revisited Eur. Respir. J. 24 2004 162 170 15293620 \n3 Wakiguchi H. Ohga S. Clinical utility of the liposteroid therapy: potential effects on the macrophage activation Jpn. J. Clin. Immunol. 39 2016 190 196 \n4 Mizushima Y. Hamano T. Yokoyama K. Tissue distribution and anti-inflammatory activity of corticosteroids incorporated in lipid emulsion Ann. Rheum. Dis. 41 1982 263 267 6896429 \n5 Mullewr S.H. Diaz J.H. Kaye A.D. Clinical applications of intravenous lipid emulsion therapy J. Anesth. 29 2015 920 926 26049929 \n6 Doi T. Ohga S. Ishimura M. Long-term liposteroid therapy for idiopathic pulmonary hemosiderosis Eur. J. Pediatr. 172 2013 1475 1481 23812505 \n7 Kim D.H. Cho Y.M. Lee K.H. Jeong S.W. Kwon O.J. Oleate protects macrophages from palmitate-induced apoptosis through the downregulation of CD36 expression Biochem. Biophys. Res. Commun. 488 2017 477 482 28522296 \n8 Lee E. Choi J. Lee H.S. Palmitate induces mitochondrial superoxide generation and activates AMPK in podocytes J. Cell. Physiol. 232 2017 3209 3217 28214337 \n9 Wang L. Chen Y. Li X. Zhang Y. Gulbins E. Zhang Y. Enhancement of endothelial permeability by free fatty acid through lysosomal cathepsin B-mediated Nlrp3 inflammasome activation Oncotarget 7 2016 73229 73241 27689324 \n10 Doitsh G. Galloway N.L. Geng X. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection Nature 505 2014 509 514 24356306 \n11 Jorgensen I. Miao E.A. Pyroptotic cell death defends against intracellular pathogens Immunol. Rev. 265 2015 130 142 25879289 \n12 Doi T. Ohga S. Ishimura M. Erratum to: long-term liposteroid therapy for idiopathic pulmonary hemosiderosis Eur. J. Pediatr. 174 2015 1701 26424556\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "24()",
"journal": "Respiratory medicine case reports",
"keywords": "Idiopathic pulmonary hemosiderosis; Liposteroid",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "22-24",
"pmc": null,
"pmid": "29977750",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
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"title": "Liposteroid and methylprednisolone combination therapy for a case of idiopathic lung hemosiderosis.",
"title_normalized": "liposteroid and methylprednisolone combination therapy for a case of idiopathic lung hemosiderosis"
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"abstract": "Fluid accumulation is associated with adverse outcomes such as acute kidney injury (AKI) in critically ill patients. This study aimed to describe the factors associated with AKI in individuals with influenza A H1N1 severe pneumonia, and explore the relation of fluid accumulation with AKI and mortality.\n\n\n\nWe reviewed medical records of individuals with influenza A H1N1 severe pneumonia and no history of chronic kidney disease, attending a national referral center for respiratory diseases between November 2014 and May 2015. Demographic information, risk factors for AKI, physiologic and laboratory data, outcomes and information on fluid intake and output were recorded. Categorical variables were compared using the chi-square test. Quantitative variables were compared using the Mann-Whitney test. Factors associated with AKI and mortality were identified by binary logistic regression. Linear models of fluid accumulation rates for individuals and groups were estimated using segmented linear regression.\n\n\n\nOf 60 patients studied, 43 developed AKI (71.6%). Male gender was protective for AKI (p = 0.019). AKI was associated with nephrotoxic drugs (p = 0.016); PEEP>10 cm H2O on admission (p = 0.031); mortality (p = 0.037); and fluid accumulation ≥10% (fluid overload) at day 7 of hospitalization (p = 0.00026). Mortality was associated with older age (p = 0.009); nephrotoxic drugs (p = 0.034); and higher Pneumonia Severity Index score (112 vs. 76, p = 0.008) on admission. The Deceased-AKI group had a higher rate of fluid accumulation (expressed as ml/kg/body weight) than the Survivors-No AKI group during the study period of 7 days (Survivors-No AKI = 13.31 vs. Deceased-AKI = 22.76, p = 0.019). During the highest phase of fluid accumulation, the Survivors-No AKI group had a slower rate of fluid accumulation than the Survivors-AKI group (14.91 vs. 28.49, p = 0.001).\n\n\n\nA high rate of fluid accumulation was associated with AKI and mortality. We support the approach of resuscitation in acute illness, with an early transition to neutral and then negative fluid balances.",
"affiliations": "Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.;Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.;Servicio Clínico 5, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.;Departamento de Epidemiología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.;Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.;Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.;Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.",
"authors": "Casas-Aparicio|Gustavo Alejandro|GA|;León-Rodríguez|Isabel|I|;Hernández-Zenteno|Rafael de Jesús|RJ|;Castillejos-López|Manuel|M|;Alvarado-de la Barrera|Claudia|C|;Ormsby|Christopher E|CE|;Reyes-Terán|Gustavo|G|0000-0001-7295-8240",
"chemical_list": null,
"country": "United States",
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"doi": "10.1371/journal.pone.0192592",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0192592PONE-D-17-29430Research ArticleMedicine and Health SciencesInfectious DiseasesViral DiseasesInfluenzaMedicine and Health SciencesPulmonologyPneumoniaBiology and life sciencesOrganismsVirusesRNA virusesOrthomyxovirusesInfluenza virusesInfluenza A virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensOrthomyxovirusesInfluenza virusesInfluenza A virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensOrthomyxovirusesInfluenza virusesInfluenza A virusBiology and life sciencesOrganismsVirusesViral pathogensOrthomyxovirusesInfluenza virusesInfluenza A virusBiology and Life SciencesAnatomyRenal SystemKidneysMedicine and Health SciencesAnatomyRenal SystemKidneysBiology and Life SciencesZoologyAnimal DiseasesAnimal InfluenzaSwine InfluenzaMedicine and Health SciencesInfectious DiseasesZoonosesSwine InfluenzaBiology and life sciencesOrganismsVirusesRNA virusesOrthomyxovirusesInfluenza virusesInfluenza A virusH1N1Biology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensOrthomyxovirusesInfluenza virusesInfluenza A virusH1N1Medicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensOrthomyxovirusesInfluenza virusesInfluenza A virusH1N1Biology and life sciencesOrganismsVirusesViral pathogensOrthomyxovirusesInfluenza virusesInfluenza A virusH1N1Biology and Life SciencesPhysiologyPhysiological ParametersBody WeightMedicine and Health SciencesPhysiologyPhysiological ParametersBody WeightMedicine and Health SciencesNephrologyChronic Kidney DiseaseAggressive fluid accumulation is associated with acute kidney injury and mortality in a cohort of patients with severe pneumonia caused by influenza A H1N1 virus Fluid accumulation and acute kidney injury in severe influenza A H1N1 virus infectionCasas-Aparicio Gustavo Alejandro ConceptualizationMethodology1León-Rodríguez Isabel Data curationInvestigationValidationWriting – original draft1Hernández-Zenteno Rafael de Jesús Supervision2Castillejos-López Manuel Formal analysis3Alvarado-de la Barrera Claudia VisualizationWriting – review & editing1Ormsby Christopher E. Software1http://orcid.org/0000-0001-7295-8240Reyes-Terán Gustavo Project administration1*1 \nCentro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México2 \nServicio Clínico 5, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México3 \nDepartamento de Epidemiología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, MéxicoBurdmann Emmanuel A EditorUniversity of Sao Paulo Medical School, BRAZILCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: gustavo.reyesteran@gmail.com15 2 2018 2018 13 2 e01925928 8 2017 28 1 2018 © 2018 Casas-Aparicio et al2018Casas-Aparicio et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introduction\nFluid accumulation is associated with adverse outcomes such as acute kidney injury (AKI) in critically ill patients. This study aimed to describe the factors associated with AKI in individuals with influenza A H1N1 severe pneumonia, and explore the relation of fluid accumulation with AKI and mortality.\n\nMaterial and methods\nWe reviewed medical records of individuals with influenza A H1N1 severe pneumonia and no history of chronic kidney disease, attending a national referral center for respiratory diseases between November 2014 and May 2015. Demographic information, risk factors for AKI, physiologic and laboratory data, outcomes and information on fluid intake and output were recorded. Categorical variables were compared using the chi-square test. Quantitative variables were compared using the Mann-Whitney test. Factors associated with AKI and mortality were identified by binary logistic regression. Linear models of fluid accumulation rates for individuals and groups were estimated using segmented linear regression.\n\nResults\nOf 60 patients studied, 43 developed AKI (71.6%). Male gender was protective for AKI (p = 0.019). AKI was associated with nephrotoxic drugs (p = 0.016); PEEP>10 cm H2O on admission (p = 0.031); mortality (p = 0.037); and fluid accumulation ≥10% (fluid overload) at day 7 of hospitalization (p = 0.00026). Mortality was associated with older age (p = 0.009); nephrotoxic drugs (p = 0.034); and higher Pneumonia Severity Index score (112 vs. 76, p = 0.008) on admission. The Deceased-AKI group had a higher rate of fluid accumulation (expressed as ml/kg/body weight) than the Survivors-No AKI group during the study period of 7 days (Survivors-No AKI = 13.31 vs. Deceased-AKI = 22.76, p = 0.019). During the highest phase of fluid accumulation, the Survivors-No AKI group had a slower rate of fluid accumulation than the Survivors-AKI group (14.91 vs. 28.49, p = 0.001).\n\nConclusions\nA high rate of fluid accumulation was associated with AKI and mortality. We support the approach of resuscitation in acute illness, with an early transition to neutral and then negative fluid balances.\n\nThe author(s) received no specific funding for this work.The authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information file.Data Availability\nAll relevant data are within the paper and its Supporting Information file.\n==== Body\nIntroduction\nInfluenza A H1N1 virus infection is associated with a spectrum of illnesses, ranging from upper respiratory infection, to multiple organ dysfunction and death. In critical patients with severe influenza A H1N1 disease, acute kidney injury (AKI) is a common complication. AKI is associated with development of chronic kidney disease [1], increased mortality, adverse outcomes and longer periods of intensive care unit stay [2, 3]. In most cases, AKI develops from a combination of factors including hypovolemia, sepsis, nephrotoxins and hemodynamic perturbations [4]. In order to restore cardiac output, systemic blood pressure and renal perfusion in critically ill patients, an adequate fluid resuscitation is necessary [5]. However, fluid administration beyond the correction of hypovolemia is associated with AKI, longer periods of hospital stay, increased mortality [6], organ dysfunction and worse clinical outcomes [7]. Fluid overload (FO) may derive from the combination of oliguria and fluid administration, leading to a positive fluid balance [8, 9]. Due to the dichotomy between traditional teaching and evolving evidence, wide variations in clinical fluid management exist and traditional practice involving administration of large fluid volumes is being questioned [5]. Prolonged fluid resuscitation leads to edema in the kidneys and other organs. As an encapsulated organ, the kidney is particularly affected by fluid congestion and raised venous pressures with a disproportionate elevation of intracapsular pressure, which leads to a decrease in renal blood flow and glomerular filtration rate [10].\n\nThe association between FO and AKI has been consistently reported, but the cause-effect relationship remains unclear. The aim of this study was to describe the factors associated with the development of AKI in critically ill individuals with influenza A H1N1 severe pneumonia, and we had a particular interest in exploring the relation of fluid accumulation on the development of AKI and mortality.\n\nMaterial and methods\nStudy population\nThis study was conducted at the National Institute of Respiratory Diseases (INER), a national referral center in Mexico City. We retrospectively reviewed the medical records of individuals with severe pneumonia caused by influenza A H1N1 attending our institution between November 2014 and May 2015. Patients with influenza A H1N1 severe pneumonia were those with clinical data of respiratory distress, bilateral alveolar opacities in 2 or more lobes, a ratio of PaO2/FiO2 < 200 mm Hg, and a positive result for the influenza A H1N1-rRT-PCR assay in nasopharyngeal swab or bronchoalveolar lavage samples.\n\nProcedures\nThe retrospective review of medical records included demographic and anthropometric variables, comorbidities, clinical and laboratory data, initiation and termination dates of mechanical ventilation, days on intensive care unit (ICU), initial mechanical-ventilator settings and use of vancomycin or other nephrotoxic drugs. The Acute Physiology and Chronic Health Evaluation (APACHE) II score, as well as the Sequential Organ Failure Assessment (SOFA) and the Pneumonia Severity Index (PSI) scores were calculated on admission. Information on fluid intake and output was obtained from fluid balance monitoring charts. Daily fluid balance was determined from all intakes and outputs recorded. All available intake and output data from 7 days in hospital were included in the analyses. We computed fluid balance for each day using the sum of daily fluid intake (L) from which we subtracted total output (L). To quantify cumulative fluid balance in relation to body weight, we used the following formula: (∑ daily (fluid intake (L)–total output (L)) / body weight (in kilograms). We used the term ‘percentage of fluid accumulation’ to define the percentage of cumulative fluid balance adjusted for body weight. Baseline body weight was based on initial hospital admission weight [11]. Total output included urinary volume, evacuations and insensible losses.\n\nThe relation of fluid accumulation with AKI and mortality was explored by comparing the frequency of these outcomes in individuals with fluid accumulation <10% versus those with fluid accumulation ≥10% (FO).\n\nInclusion and exclusion criteria\nWe included individuals with diagnosis of severe pneumonia caused by influenza A H1N1, confirmed by real-time reverse transcription–polymerase chain reaction (rRT-PCR); age 18 or older; estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2 on admission using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; no history of chronic kidney disease (CKD); and ratio of partial pressure arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) <200 mm Hg on admission. Pregnant women were not included in the study. The Research and Ethics Committee of the INER approved the study and waived the requirement for informed consent due to the retrospective design of the study.\n\nDefinitions\nFluid overload was defined as fluid accumulation greater than or equal to 10% of the baseline body weight [12]. Serum creatinine (sCr) was adjusted for fluid accumulation at the moment of AKI diagnosis [13]. Adjusted sCr (sCr′) was calculated as:\n sCr′=sCr[1+(CumulativeFB0.6BW)] \nWhere FB is fluid balance and 0.6BW is 60% of body weight in kg, equivalent to total body water.\n\nDiagnosis of AKI was based on a rapid reduction of kidney function, defined by an absolute increase in adjusted sCr >0.3 mg/dL within 48 hours compared to baseline; a sCr increase of 1.5 times within 7 days compared to baseline; or a decrease in urinary output >0.5 ml/kg/hour for more than six hours. AKI stage was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) staging system [14]. AKI stage 1 corresponded to a sCr increase of 1.5–2 times baseline; AKI stage 2 corresponded to a sCr increase 2.0–3.0 times baseline; and AKI stage 3 corresponded to a sCr increase of >3 times baseline or initiation of renal replacement therapy (RRT). Information about administration of nephrotoxic drugs before AKI was also retrieved from clinical files. Nephrotoxic drugs were defined as those causing tubular or renal hemodynamic toxicity, and included nonsteroidal anti-inflammatory drugs, aminoglycosides, vancomycin, colistine and amphotericin B.\n\nStatistical analysis\nCategorical variables were compared using the chi-square test. Median and interquartile ranges (IQRs) were calculated for quantitative variables and differences between groups were analyzed using the Mann-Whitney test. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using logistic regression analyses. A two-sided P value <0.05 was considered to be significant. Statistical analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL).\n\nWe explored if a fluid accumulation ≥10% body weight gain was a predictor of AKI or death. Then we analyzed if the rate of fluid balance increase, indicated by the slope of the relation of body weight gain/day, was a predictor of AKI or mortality. This analysis was performed considering total volume or volume per kg of body weight. We estimated individual linear models having one or more segmented relationships in the linear predictor. Individuals with no converging segments were assumed to have a single segment across the follow-up period of 7 days. Estimates of the slopes and the possibly multiple breakpoints for each patient were obtained by segmented linear regression, using Package segmented version 0.5–1.4 for the R statistical language, Muggeo V.M.R. [15].\n\nResults\nDuring the period between November 2014 and May 2015, 184 individuals were diagnosed with severe pneumonia at our institution. Of those, 124 were deemed ineligible for this study because they did not fulfill the inclusion criteria (8 were under 18 years of age; 22 had incomplete clinical files; 9 had non-H1N1 pneumonia; and on the remaining 85 individuals, either influenza A H1N1 could not be confirmed by rRT-PCR, or they had PaO2/FiO2 >200 mm Hg). We thus included 60 individuals in the study. Of those, 39 were men (65%). The median age was 47.5 years, IQR, 44.2–50.9; 56.7% were obese; 21.7% had systemic arterial hypertension; 8.3% had diabetes mellitus; 6.7% had pneumopathies; and 38.3% had a smoking history. Only 1.7% of this cohort had been vaccinated against influenza. Sudden onset of influenza symptoms (<72 hours) was observed in 63.3% of the cases. The median APACHE II score on admission was 13.5 (IQR, 9.25–17). Forty-three individuals developed AKI (the AKI group). Of those, 9 had AKI stage 1 (20.8%); 16 had AKI stage 2 (37.1%) and 18 had AKI stage 3 (41.7%). Four patients requiring replacement therapy (6.7%) received sustained low-efficiency dialysis, and all of them survived.\n\nFactors associated with acute kidney injury\nDemographic and clinical characteristics of the AKI group (n = 43) vs. the non-AKI group (n = 17) on admission are shown in Table 1.\n\n10.1371/journal.pone.0192592.t001Table 1 Characteristics of the Acute Kidney Injury Group and the non-Acute Kidney Injury Group on admission.\nVariables\tAKI, n = 43\nMedian (% or IQR)\tNon-AKI, n = 17\nMedian (% or IQR)\tP\t\nMale\t24 (55.8%)\t15 (88.2%)\t0.019\t\nDiabetes\t5 (11.6%)\t0 (0%)\t0.309\t\nHypertension\t12 (27.9%)\t1 (5.9%)\t0.086\t\nObesity\t27 (62.8%)\t7 (41.2%)\t0.128\t\nSmoking\t29 (67.4%)\t8 (47.1%)\t0.143\t\nFever before admission\t41 (95.3%)\t13 (76.5%)\t0.048\t\nAntibiotics before admission\t37 (86.0%)\t12 (70.6%)\t0.265\t\nNephrotoxic drugs\t25 (58.1%)\t4 (23.5%)\t0.016\t\nPEEP level >10 (cm H2O)\t15 (34.8%)\t10 (5.9%)\t0.031\t\nDeceased\t17 (39.5%)\t2 (11.8%)\t0.037\t\nAge (years)\t45 (IQR, 38–52)\t49 (IQR, 39–56)\t0.431\t\nPSI score\t81 (IQR, 64–114)\t76 (IQR, 64–105)\t0.774\t\nAPACHE II score\t14 (IQR, 10–18)\t12 (IQR, 8–16)\t0.243\t\nSOFA score\t7 (IQR, 4–10)\t5 (IQR, 3.5–9)\t0.204\t\npH\t7.39 (IQR, 7.34–7.46)\t7.42 (IQR, 7.39–7.46)\t0.650\t\nPaO2 (mmHg)\t39 (IQR, 31–52)\t35 (IQR, 28–42)\t0.325\t\npCO2 (mmHg)\t33 (IQR, 28–50)\t33 (IQR, 27–40)\t0.935\t\nHCO3 (mmol/L)\t22 (IQR, 18–26)\t25 (IQR, 22–26)\t0.118\t\nPaO2/FIO2 (mmHg)\t93 (IQR, 61–132)\t118 (IQR, 62–154)\t0.333\t\nHemoglobin (g/dL)\t15 (IQR, 14–17)\t16 (IQR, 14–16.5)\t0.659\t\nLeucocytes (x109/L)\t7400 (IQR, 5800–11300)\t7900 (IQR, 5200–12600)\t0.799\t\nPlatelets (x109/L)\t170 (IQR, 142–232)\t199 (IQR, 136.5–265.5)\t0.827\t\nUrea nitrogen (mg/dL)\t20 (IQR, 12–29)\t16 (IQR, 12–24.6)\t0.275\t\nCreatinine (mg/dL)\t1.0 (IQR, 0.95–1.73)\t1.0 (IQR, 0.97–1.46)\t0.264\t\nAlbumin (g/L)\t2.74 (IQR, 2.1–3.0)\t2.88 (IQR, 2.64–3.25)\t0.272\t\nLDH (U/L)\t642 (IQR, 358–1091)\t567 (IQR, 325–769)\t0.827\t\nCPK (U/L)\t205 (IQR, 113–387)\t329 (IQR, 120–1719)\t0.513\t\nAST (U/L)\t73 (IQR, 40–120)\t74 (IQR, 49.5–108)\t0.827\t\nProcalcitonin ng/mL\t1.0 (IQR, 0.07.2.79)\t0.38 (IQR, 0.05–1.89)\t0.275\t\nC-Reactive Protein (mg/L)\t13.1 (IQR, 8.4–24.2)\t2.97 (IQR, 0.78–4.1)\t0.127\t\nGlucose (mg/dL)\t150 (IQR, 111–190)\t129 (IQR, 99.5–153.5)\t0.250\t\nCKD-EPI (mL/min/1.73 m2 bs)\t70 (IQR, 46.5–98)\t86 (IQR, 58–102)\t0.268\t\nCockcroft-Gault (mL/min)\t90 (IQR, 55.40–120)\t98 (IQR, 73–113)\t0.724\t\nHospitalization (days)\t29 (IQR, 14–50)\t20 (IQR, 12–27.5)\t0.081\t\nMechanical ventilation (days)\t19.5 (IQR, 9.5–37.2)\t10 (IQR, 5.5–26)\t0.253\t\nAKI, Acute kidney injury; IQR, Interquartile range; %, Percentage; PEEP, Positive end-expiratory pressure; PSI, Pneumonia Severity Index; APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment; PaO2/FiO2, Pressure arterial oxygen/Fraction of inspired oxygen; LDH, Lactic dehydrogenase; CPK, Creatine phosphokinase; AST, Aspartate aminotransferase; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CKD-EPI is expressed in mL/min/1.73m2 body size.\n\nMale gender was protective for AKI (24 males in the AKI group vs. 15 in the non-AKI group, p = 0.019, odds ratio (OR) = 0.16, CI, 0.03–0.82). AKI was associated with the use of nephrotoxic drugs (25 individuals in the AKI group vs. 4 in the non-AKI group, p = 0.016, OR = 4.51, CI, 1.26–16); and positive end-expiratory pressure (PEEP) level >10 cm H2O (15 individuals in the AKI group vs. 10 in individuals the non-AKI group, p = 0.031, OR = 5, CI, 1.09–22.82). Mortality was significantly more frequent in the AKI group (17 individuals in the AKI group vs. 2 individuals in the non-AKI group, p = 0.037, OR = 4.9, CI, 0.99–24.2). The AKI group had higher PSI, APACHE II and SOFA scores on admission, as well as longer hospital stays and mechanical ventilation periods than the non-AKI group, but these differences were non-significant. Laboratory values and gasometric variables on admission were not significantly different between both groups.\n\nFactors associated with mortality\nDemographic and clinical characteristics of deceased individuals and survivors are shown in Table 2.\n\n10.1371/journal.pone.0192592.t002Table 2 Characteristics of deceased individuals and survivors on admission.\nVariables\tDeceased, n = 19\nMedian (% or IQR)\tSurvivors, n = 41\nMedian (% or IQR)\tP\t\nMale\t11 (57.9%)\t28 (68.3%)\t0.432\t\nDiabetes\t3 (15.8%)\t2 (4.9%)\t0.314\t\nHypertension\t6 (31.6%)\t7 (17.0%)\t0.312\t\nObesity\t10 (52.6%)\t24 (58.5%)\t0.668\t\nSmoking\t5 (26.3%)\t18 (43.9%)\t0.192\t\nFever before admission\t17 (89.5%)\t37 (90.2%)\t1.000\t\nAntibiotics before admission\t17 (89.5%)\t32 (78.0%)\t0.476\t\nNephrotoxic drugs\t13 (68.4%)\t16 (39.0%)\t0.034\t\nPEEP level >10 (cm H2O)\t12 (63.1%)\t5 (12.2%)\t0.575\t\nAge (years)\t63 (IQR, 54–76)\t54 (IQR, 43–60)\t0.009\t\nPSI score\t112 (IQR, 72–128)\t76 (IQR, 62.5–91.5)\t0.008\t\nAPACHE II score\t16 (IQR, 14.1–18.2)\t12.4 (IQR, 10.9–13.9)\t0.004\t\nSOFA score\t8 (IQR, 7–10.8)\t6.05 (IQR, 5.14–6.96)\t0.006\t\npH\t7.38 (IQR, 7.30–7.46)\t7.43 (IQR, 7.41–7.45)\t0.780\t\nPaO2 (mmHg)\t34 (IQR, 29.0–40)\t35.8 (IQR, 32.8–38.7)\t0.046\t\npCO2 (mmHg)\t34 (IQR, 29.0–40)\t35.8 (IQR, 32.8–38.7)\t0.184\t\nHCO3 (mmol/L)\t20 (IQR, 16.3–24.5)\t24 (IQR, 19.5–26.35)\t0.055\t\nPaO2/FIO2 (mmHg)\t125 (IQR, 99.6–150.5)\t140 (IQR, 126.3–152.3)\t0.361\t\nHemoglobin (g/dL)\t15 (IQR, 14–16.3)\t14.96 (IQR, 14–15.6)\t0.595\t\nLeucocytes (x109/L)\t8621 (IQR, 5975–11267)\t9534 (IQR, 8017–11051)\t0.361\t\nPlatelets (x109/L)\t163 (IQR, 116–224)\t188 (IQR, 147–253)\t0.127\t\nUrea nitrogen (mg/dL)\t27 (IQR, 17–38.16)\t21 (IQR, 17.4–24.5)\t0.633\t\nCreatinine (mg/dL)\t1.30 (IQR, 0.85–1.74)\t1.30 (IQR, 1.1–1.49)\t0.401\t\nAlbumin (g/L)\t2.58 (IQR, 2.38–2.79)\t2.84 (IQR, 2.66–3.01)\t0.077\t\nLDH (U/L)\t770 (IQR, 373–1147)\t583 (IQR, 352–767)\t0.236\t\nCPK (U/L)\t217 (IQR, 132–918)\t211 (IQR, 115–490)\t0.751\t\nAST (U/L)\t82 (IQR, 41–134)\t73.5 (IQR, 46.5–105.7)\t0.703\t\nProcalcitonin ng/mL\t2.88 (IQR, 0.32–6)\t1.85 (IQR, 0.56–3.13)\t0.604\t\nC-Reactive Protein (mg/L)\t12.2 (IQR, 10.3–13.5)\t8.9 (IQR, 3.97–28.1)\t0.864\t\nGlucose (mg/dL)\t182 (IQR, 142–223)\t144 (IQR, 126–160)\t0.053\t\nCKD-EPI (mL/min/1.73m2 bs)\t71 (IQR, 42–90)\t75 (IQR, 50–102.5)\t0.499\t\nCockcroft-Gault (mL/min)\t93 (IQR, 66–121)\t97.4 (IQR, 82.2–112.6)\t0.583\t\nHospitalization (days)\t23 (IQR, 12–41)\t27 (IQR, 14–42)\t0.399\t\nMechanical ventilation (days)\t23 (IQR, 8–41)\t16.5 (IQR, 6.75–31.5)\t0.971\t\nAKI, Acute kidney injury; IQR, Interquartile range; %, Percentage; PEEP, Positive end-expiratory pressure; PSI, Pneumonia Severity Index; APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment; PaO2/FiO2, Pressure arterial oxygen/Fraction of inspired oxygen; LDH, Lactic dehydrogenase; CPK, Creatine phosphokinase; AST, Aspartate aminotransferase; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CKD-EPI is expressed in mL/min/1.73m2 body size.\n\nOlder age was significantly associated with mortality (median age of 63 years, IQR, 54–76 in deceased individuals vs. 54 years, IQR, 43–60 in survivors, p = 0.009). The use of nephrotoxic drugs during hospitalization was significantly associated with mortality (45% in deceased individuals vs. 55% in survivors, p = 0.034). The Pneumonia Severity Index on admission was significantly higher in deceased patients than in survivors (PSI 112, IQR, 72–128 in deceased individuals vs. 76, IQR, 62.5–91.5 in survivors, p = 0.008). PaO2/FiO2 and HCO3 levels on admission were lower in deceased individuals than in survivors, but differences were non-significant.\n\nRelation of fluid accumulation with AKI and mortality\nCumulative fluid balance until day 7 of hospitalization was obtained for 53 individuals. We explored the relation of FO with AKI and mortality in this group. Fluid overload was associated with AKI (p = 0.00026, OR = 4.28). Mortality was more frequent in the group with FO, but the association was non-significant (p = 0.508, OR = 2.08).\n\nIn the group of 53 individuals, we also assessed the accumulated fluid balance per day (expressed in mL/Kg of body weight) during 7 days of hospitalization (Table 3). The accumulated fluid balance was higher in the group with AKI than in the non-AKI group on Day 3 (p = 0.001), Day 4 (p = 0.004), Day 5 (p = 0.018) and Day 6 (p = 0.023). The accumulated fluid balance was higher in the Deceased group than in Survivors on Day 7 (p = 0.038).\n\n10.1371/journal.pone.0192592.t003Table 3 Accumulated fluid balance per day during hospitalization.\n\tDay1 (mL/Kg)\tDay 2 (mL/Kg)\tDay 3 (mL/Kg)\tDay 4 (mL/Kg)\tDay 5 (mL/Kg)\tDay 6 (mL/Kg)\tDay 7 (mL/Kg)\t\nAKI\t31 (14–39)\t52 (37–76)\t84 (68–116)\t116 (86–135)\t128 (94–170)\t135 (95–180)\t143 (112–189)\t\nNo-AKI\t19 (10–35)\t42 (24–57)\t53 (37–73)\t78 (32–100)\t70 (38–121)\t84 (41–145)\t116 (57–160)\t\nAKI vs. No-AKI\tP = 0.209\tP = 0.086\tP = 0.001\tP = 0.004\tP = 0.018\tP = 0.023\tP = 0.131\t\nDeceased\t32 (17–49)\t56 (37–87)\t90 (58–118)\t122 (74–139)\t147 (106–170)\t160 (120–192)\t178 (116–210)\t\nSurvivors\t24 (11–37)\t48 (34–67)\t72 (52–90)\t94 (71–120)\t108 (60–134)\t121 (73–148)\t129 (93–154)\t\nDeceased vs. Survivors\tP = 0.185\tP = 0.321\tP = 0.103\tP = 0.059\tP = 0.106\tP = 0.067\tP = 0.038\t\nmL/kg, milliliters of fluid accumulated per kg of body weight; AKI, Acute kidney injury; CI, confidence interval.\n\nBiphasic rate of fluid accumulation during hospitalization\nIndividual values of fluid accumulation of all study participants during hospitalization are shown in Fig 1A. Fluid accumulation tended to have two phases during the study period of 7 days. That is, the first phase of approximately 3 to 4 days at a high rate of fluid balance increase, followed by a subsequent phase defined by a slower rate of fluid accumulation. For each individual, we calculated the slope of the first and the second phases by using segmented linear regression. The estimated linear model of one individual is shown in Fig 1B. In this case, the Phase I of approximately 4 days at a high rate of fluid accumulation, was followed by Phase II defined by a slower rate of fluid accumulation.\n\n10.1371/journal.pone.0192592.g001Fig 1 Fluid accumulation rate during hospitalization.\n(A) Estimated linear model including all study participants during the study period of 7 days. (B) Estimated linear model of one individual during the study period of 7 days.\n\nRates of fluid accumulation in the different outcomes\nWe explored if the rates of fluid accumulation per day were related to the different outcomes. For this, individuals who did not develop AKI and survived, constituted the Survivors-No AKI group; individuals with AKI constituted the Survivors-AKI group; and deceased individuals with AKI constituted the Deceased-AKI group. Two patients who did not develop AKI, died during the first 3 days of hospitalization. These patients were not included in this analysis, as this time period was deemed insufficient for assessing the effects of fluid accumulation. Fig 2A shows that the Survivors-No AKI group had the slower rate of fluid accumulation; the Survivors-AKI group had an intermediate rate of fluid accumulation; and the Deceased-AKI group had the highest rate of fluid accumulation, expressed as a higher slope (Survivors-No AKI group = 13.31 ml/kg/body weight vs. Deceased-AKI group = 22.76 ml/kg/body weight; p = 0.019, Fig 2B).\n\n10.1371/journal.pone.0192592.g002Fig 2 Fluid accumulation rate per groups.\n(A) Estimated linear model in the group of Survivors-No AKI; the Survivors-AKI Group; and the Deceased-AKI group during the study period of 7 days. (B) The different slopes in the group of Survivors-No AKI; the Survivors-AKI group; and the Deceased-AKI group during the study period of 7 days.\n\nConsidering that Phase I was defined by the highest rate of fluid accumulation in all three groups, we compared the linear segment corresponding to this initial phase among groups (Fig 3A). The Survivors-No AKI group had a significant slower rate of fluid accumulation than the Survivors-AKI group (Survivors-No AKI = 14.91 ml/kg/body weight vs. the Survivors-AKI group = 28.49 ml/kg/body weight, p = 0.001). Rates of fluid accumulation were similar in the Survivors-AKI group and the Deceased-AKI group (Fig 3B).\n\n10.1371/journal.pone.0192592.g003Fig 3 Phase I of fluid accumulation rate.\n(A) Estimated linear model in the group of Survivors-No AKI; the Survivors-AKI group; and the Deceased-AKI group during Phase I. (B) The different slopes in the group of Survivors-No AKI; the Survivors-AKI group; and the Deceased-AKI group during Phase I.\n\nDiscussion\nWe explored the risk factors associated with the development of AKI and the relation of the accumulated fluid balance on AKI and mortality, in a homogeneous population with primary acute respiratory distress syndrome caused by influenza A H1N1 virus infection. By using the KDIGO classification, we found that 71.6% of individuals developed AKI. This proportion is similar to that found in a Canadian cohort, of 66.7% using the RIFLE classification [3]. AKI had a significant association with the use of nephrotoxic drugs during hospitalization. In agreement with a previous study in critically ill patients with lung disease, we also found a significant association between AKI and PEEP level >10 cm H2O on admission [16]. Male gender had a protective effect for AKI. Other factors previously associated with AKI include vasopressor use, mechanical ventilation, high APACHE II score, severe acidosis, high levels of C-reactive protein and lactic dehydrogenase upon ICU admission, longer stays in the ICU [17], high body mass index, history of asthma [3], high SOFA score, and greater incidence of shock, multiorgan dysfunction syndrome and coinfection [18]. In our cohort, the AKI group had higher PSI, APACHE II and SOFA scores on admission, as well as longer hospital stays and mechanical ventilation periods than the non-AKI group, but these differences were non-significant. We found lower PaO2/FiO2 in the AKI than in the non-AKI group, as well as lower PaO2/FiO2 in deceased individuals than in survivors, but lack of statistical significance in this parameter was probably affected by the inclusion criteria of PaO2/FiO2 <200 mm Hg on admission.\n\nIn line with previous studies, mortality was significantly more frequent in the AKI group than in the non-AKI group [16, 19, 20]. The use of nephrotoxic drugs during hospitalization and older age were significantly associated with mortality. Our findings were consistent with previous reports indicating that PSI, APACHE II and SOFA scores on admission were significantly higher in deceased patients infected with influenza A H1N1 than in survivors [18, 21].\n\nWe found a significant association between FO and AKI. Likewise, death was more frequent in the group with FO, but the limited number of deceased patients may have provided insufficient evidence to establish a difference between groups. Fluid accumulation tended to have two phases during the study period of 7 days. The first phase was defined by a high rate of fluid balance increase, followed by a subsequent phase of a slower rate of fluid accumulation. The most relevant finding of our study was that the phase of higher fluid accumulation, was significantly associated with AKI and mortality. Our results are consistent with a previous study using the concept of \"slope\", and showing that the velocity of fluid accumulation is important, and the more rapidly fluid accumulation occurs, the higher the risk of dying [22]. Therefore, we consider that not only the fluid overload, but also a rapid fluid balance increase, are associated with AKI and mortality. The association between fluid accumulation and adverse outcomes is well established. In ICU patients with sepsis, a positive fluid balance has been consistently identified as an independent risk factor for the incidence of AKI [23] and mortality [24–26], while a negative fluid balance is associated with survival and preservation or organ function [27–29]. Development of AKI also has important implications for utilization of health resources within and outside of the ICU. In some cases, the consequent development of chronic kidney disease may lead to renal replacement therapy [20]. In order to minimize the adverse consequences of FO, we support the approach of resuscitation in acute illness, with an early transition to neutral and then negative fluid balances [5]. The optimal fluid status should be individualized and even in the same patient, the optimal fluid status should be adjusted when the condition changes [30].\n\nThe main limitation of our study is derived from the retrospective design. That is, we found an association of fluid accumulation with AKI and mortality, but the causal mechanism of fluid accumulation and the different strategies of fluid management as therapy for AKI should be evaluated in randomized controlled trials. Another limitation of our study is that we retrieved information about fluid balance and development of AKI during hospitalization, but a longer observation period would have provided additional information regarding the clinical outcome and the impact of AKI in the population studied. Namely, we are not reporting the proportion of individuals developing chronic renal disease in the group with AKI. An additional limitation of our study is that we were unable to determine if the positive fluid balance observed in some individuals was caused by oliguria, fluid administration or a combination of both. Finally, our study was conducted in a national referral center for respiratory diseases, and this represents a potential source of referral bias. As we included previously health individuals with severe pneumonia caused by influenza A H1N, most of them had no chronic comorbidities. By consequence, reported risk factors for the development of AKI in ICU patients such as past history of chronic heart failure, lymphoma, leukemia, cirrhosis [31], peripheral vascular disease, diabetes, high blood pressure, heart failure, renal disease and hepatic disease [32] were underrepresented in our population.\n\nConclusions\nOur results support previous findings in critically ill patients, indicating that fluid overload and rapid fluid balance increase are associated with AKI and mortality. Scientific evidence obtained from randomized clinical trials exploring more rational and flexible approaches to fluid therapy is required for minimization of the adverse consequences of fluid overload.\n\nSupporting information\nS1 File Raw data.\nThis file includes the minimal anonymized data set necessary to replicate our study findings.\n\n(CSV)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Wald R , Quinn RR , Luo J , Li P , Scales DC , Mamdani MM , et al\nChronic dialysis and death among survivors of acute kidney injury requiring dialysis . JAMA . 2009 ; 302 :1179 –1185 . doi: 10.1001/jama.2009.1322 \n19755696 \n2 Coca SG , Yusuf B , Shlipak MG , Garg AX , Parikh CR . Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and metaanalysis . Am J Kidney Dis . 2009 ; 53 : 961 –973 . doi: 10.1053/j.ajkd.2008.11.034 \n19346042 \n3 Sood MM , Rigatto C , Zarychansky R , Komenda P , Sood AR , Bueti J , et al\nAcute Kidney Injury in Critically ill Patients Infected With 2009 Pandemic Influenza A (H1N1): report From a Canadian Province . American J Kidney Dis . 2010 ; 55 : 848 –855 .\n4 Dennen P , Douglas IS , Anderson R . Acute kidney injury in the intensive care unit: an update and primer for the intensivist . Crit Care Med . 2010 ; (38 ): 261 –75 . doi: 10.1097/CCM.0b013e3181bfb0b5 \n19829099 \n5 Prowle JR , Echeverri JE , Ligabo EV , Ronco C , Bellomo R . Fluid balance and acute kidney injury . Nat Rev Nephrol . 2010 ; 6 :107 –15 . doi: 10.1038/nrneph.2009.213 \n20027192 \n6 Wang N , Jiang L , Zhu B , Wen Y , Xi XM ; Beijing Acute Kidney Injury Trial (BAKIT) Workgroup . Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study . Crit Care . 2015 ; 19 :371 \ndoi: 10.1186/s13054-015-1085-4 \n26494153 \n7 Chittawatanarat K , Pichaiya T , Chandacham K , Jirapongchareonlap T , Chotirosniramit N . Fluid accumulation threshold measured by acute body weight change after admission in general surgical intensive care units: how much should be concerning? \nTher Clin Risk Manag . 2015 ; 11 :1097 –106 . doi: 10.2147/TCRM.S86409 \n26251605 \n8 Fülöp T , Pathak MB , Schmidt DW , Lengvárszky Z , Juncos JP , Lebrun CJ , et al\nVolume-related weight gain and subsequent mortality in acute renal failure patients treated with continuous renal replacement therapy . ASAIO J . 2010 ; (56 ): 333 –7 . doi: 10.1097/MAT.0b013e3181de35e4 \n20559136 \n9 Teixeira C , Garzotto F , Piccinni P , Brienza N , Iannuzzi M , Gramaticopolo S , et al\nFluid balance and urine volume are independent predictors of mortality in acute kidney injury . Crit Care . 2013 ; (17 ): R14 \ndoi: 10.1186/cc12484 \n23347825 \n10 Firth JD , Raine AE , Ledingham JG . Raised venous pressure: a direct cause of renal sodium retention in oedema? \nLancet \n1988 ; (331 ): 1033 –35 .\n11 Bouchard J , Soroko SB , Chertow GM , Himmelfarb J , Ikizler TA , Paganini EP , et al\nProgram to Improve Care in Acute Renal Disease (PICARD) Study Group . Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury . Kidney Int . 2009 (76 ): 422 –7 . doi: 10.1038/ki.2009.159 \n19436332 \n12 Fulop T , Pathak MB , Schmidt DW , Lengvárszky Z , Juncos JP , Lebrun CJ , et al\nVolume-related weight gain and subsequent mortality in acute renal failure patients treated with continuous renal replacement therapy . ASAIO J . 2010 ; 56 : 333 –7 . doi: 10.1097/MAT.0b013e3181de35e4 \n20559136 \n13 Liu KD , Thompson BT , Ancukiewicz M , Steingrub JS , Douglas IS , Matthay MA , et al\nAcute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes . Crit Care Med . 2011 (12 ): 2665 –71 . doi: 10.1097/CCM.0b013e318228234b \n21785346 \n14 KDIGO Clinical Practice Guideline for Acute Kidney Injury . Section 2: AKI definition . Kidney Int. Suppl \n2012 ; 2 : 19 –36 .\n15 Vito V. M. R. Muggeo (2008). segmented: R Package to Fit Regression Models with Broken-Line Relationships. R News, 8/1, 20–25. URL https://cran.r-project.org/doc/Rnews/\n16 de Abreu Krasnalhia Lívia Soares , da Silva Geraldo Bezerra Junior. Acute kidney injury in critically ill patients with lung disease: kidney-lung crosstalk . Rev Bras Ter Intensiva . 2013 ; 25 : 130 –36 . doi: 10.5935/0103-507X.20130024 \n23917978 \n17 Abdulkader RC , Ho YL , de Sousa Santos S , Caires R , Arantes MF , Andrade L . Characteristics of Acute Kidney Injury in Patients Infected with the 2009 Influenza A (H1N1) Virus . Clin J Am Soc Nephrol . 2010 ; 5 :1916 –21 . doi: 10.2215/CJN.00840110 \n20671226 \n18 Martin-Loeches , Papiol E , Rodríguez A , Díaz E , Zaragoza R , Granada RM , et al\nAcute kidney injury in critical ill patients affected by influenza A (H1N1) virus infection . Crit Care . 2011 ; 15 : R66 \ndoi: 10.1186/cc10046 \n21342489 \n19 Bagshaw S , Launpland K , Doig C , Mortis G , Fick GH , Mucenski M , et al\nPrognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population–based study . Crit Care . 2005 ; 9 : R700 –R709 . doi: 10.1186/cc3879 \n16280066 \n20 Barrantes F , Tian J , Vazquez R , Amoateng-Adjepong Y , Manthous CA . Acute kidney injury criteria predict outcomes of critically ill patients . Crit Care Med . 2008 ; 36 : 1397 –1403 . doi: 10.1097/CCM.0b013e318168fbe0 \n18434915 \n21 Kute VB , Godara SM , Goplani KR , Gumber MR , Shah PR , Vanikar AV , et al\nHigh mortality in critically ill patients infected with 2009 pandemic influenza A (H1N1) with pneumonia and acute kidney injury . Saudi J Kidney Dis Transpl . 2011 ; 22 : 83 –89 . 21196619 \n22 Garzotto F , Ostermann M , Martín-Langerwerf D , Sánchez-Sánchez M , Teng J , Robert R , Marinho A , et al\nThe Dose Response Multicentre Investigation on Fluid Assessment (DoReMIFA) in critically ill patients . Crit Care . 2016 ; (20 ):196 \ndoi: 10.1186/s13054-016-1355-9 \n27334608 \n23 Wang N , Jiang L , Zhu B , Wen Y , Xi XM , Beijing Acute Kidney Injury Trial (BAKIT) Workgroup . Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study . Crit Care . 2015 ; 19 :371 \ndoi: 10.1186/s13054-015-1085-4 \n26494153 \n24 Vincent JL , Sark Y , Sprung CL , Ranieri VM , Reinhart K , Geriach H , et al\nSepsis in European intensive care units: results of the SOAP study . Crit Care Med . 2006 ; 34 :344 –53 . 16424713 \n25 De Oliveira FS , Freitas FG , Ferreira EM , de Castro I , Bafi AT , de Azevedo LC , et al\nPositive fluid balance as a prognostic factor for mortality and acute kidney injury in severe sepsis and septic shock . J Crit Care . 2015 ; 30 : 97 –101 . doi: 10.1016/j.jcrc.2014.09.002 \n25269788 \n26 Associations of fluid overload with mortality and kidney recovery in patients with acute kidney injury: A systematic review and meta-analysis . Zhang L , Chen Z , Diao Y , Yang Y , Fu P . J Crit Care . 2015 ; 4 :860 e7 –13 . doi: 10.1016/j.jcrc.2015.03.025 \n25979272 \n27 Alsous F , Khamiees M , De Girolamo A , Amoateng-Adjepong Y , Manthous CA . Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study . Chest . 2000 ; 117 : 1749 –54 . 10858412 \n28 Cordemans Colin , De laet Inneke , Van Regenmortel Niels , Schoonheydt K , Dits H , Marting G , et al\nAiming for a negative fluid balance in patients with acute lung injury and increased intra-abdominal pressure: a pilot study looking at the effects of PAL-treatment . Ann Intensive Care . 2012 ; S15 \ndoi: 10.1186/2110-5820-2-S1-S15 \n22873416 \n29 National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network , Wiedemann HP , Wheeler AP , Bernard GR , Thompson BT , Hayden D , et al\nComparison of two fluid-management strategies in acute lung injury . N Eng J Med . 2006 ; 354 : 2564 –75 .\n30 Chou YH , Chen YF , Lin SL . More is not better: fluid therapy in critically ill patients with acute kidney injury . J Formos Med Asoc . 2013 ; 3 :112 –4 . doi: 10.1016/j.jfma.2012.05.007 \n23473522 \n31 de Mendonça A , Vincent JL , Suter PM , Morenno R , Dearden NM , Antonelli M , et al\nAcute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score . Intensive Care Med \n2000 ; 26 : 915 –21 . https://doi.org/10.1007/s001340051281\n10990106 \n32 Acute kidney failure. Risk Factors. Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/kidney-failure/basics/risk-factors/con-20024029. Accessed 2017 Oct 3.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "13(2)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D015331:Cohort Studies; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D008297:Male; D008875:Middle Aged; D011024:Pneumonia, Viral; D012189:Retrospective Studies",
"nlm_unique_id": "101285081",
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"pmid": "29447205",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
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"title": "Aggressive fluid accumulation is associated with acute kidney injury and mortality in a cohort of patients with severe pneumonia caused by influenza A H1N1 virus.",
"title_normalized": "aggressive fluid accumulation is associated with acute kidney injury and mortality in a cohort of patients with severe pneumonia caused by influenza a h1n1 virus"
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"abstract": "This article reports long-term infection and treatment failure in 18 symptomatic individuals infected with Blastocystis spp. Patients were initially treated with either metronidazole, iodoquinol or triple combination therapy consisting of nitazoxanide, furazolidone and secnidazole. Following treatment, resolution of clinical symptoms did not occur and follow-up testing revealed ongoing infection with the same subtype. Patients then underwent secondary treatment with a variety of antimicrobial agents but remained symptomatic with Blastocystis spp. still present in faeces. Sequencing of the SSU rDNA was completed on all isolates and four subtypes were identified in this group: ST1, ST3, ST4 and ST5. This study highlights the lack of efficacy of several commonly used antimicrobial regimens in the treatment of Blastocystis and the chronic nature of some infections. It also demonstrates the need for further research into treatment options for Blastocystis infection.",
"affiliations": "i3 Institute, School of Medical and Molecular Sciences, University of Technology, Sydney, Ultimo, NSW, Australia.;i3 Institute, School of Medical and Molecular Sciences, University of Technology, Sydney, Ultimo, NSW, Australia.;Department of Microbiology, SydPath, St Vincent's Hospital, Victoria St., Darlinghurst, NSW, Australia.;Department of Microbiology, SydPath, St Vincent's Hospital, Victoria St., Darlinghurst, NSW, Australia.;Department of Microbiology, SydPath, St Vincent's Hospital, Victoria St., Darlinghurst, NSW, Australia.",
"authors": "Roberts|Tamalee|T|;Ellis|John|J|;Harkness|John|J|;Marriott|Deborah|D|;Stark|Damien|D|",
"chemical_list": "D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D009574:Nitro Compounds; D013844:Thiazoles; D008795:Metronidazole; D005664:Furazolidone; C016724:secnidazole; C041747:nitazoxanide",
"country": "England",
"delete": false,
"doi": "10.1099/jmm.0.065508-0",
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"issue": "63(Pt 2)",
"journal": "Journal of medical microbiology",
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"medline_ta": "J Med Microbiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000981:Antiprotozoal Agents; D016844:Blastocystis; D016776:Blastocystis Infections; D002648:Child; D002908:Chronic Disease; D015331:Cohort Studies; D016054:DNA, Protozoan; D004359:Drug Therapy, Combination; D005243:Feces; D005260:Female; D005664:Furazolidone; D005838:Genotype; D006801:Humans; D008297:Male; D008795:Metronidazole; D008875:Middle Aged; D009574:Nitro Compounds; D017422:Sequence Analysis, DNA; D013844:Thiazoles; D017211:Treatment Failure; D055815:Young Adult",
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"publication_types": "D016428:Journal Article",
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"title": "Treatment failure in patients with chronic Blastocystis infection.",
"title_normalized": "treatment failure in patients with chronic blastocystis infection"
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"abstract": "ACROSTUDY is a world-wide non-interventional, post marketing surveillance study performed to monitor the safety and outcomes of pegvisomant (PEG) in clinical practice. We report data from acromegaly patients who have been included in the Italian ACROSTUDY registry. The data of 341 acromegaly patients (171 males) were available for analysis using data freeze (12/9/2012). Patients were enrolled in 25 Italian endocrine centres. Before and during PEG treatment IGF-I, liver enzymes, metabolic parameters, and pituitary MRI were assessed. Before PEG, 54.3% patients had been treated with medical therapy and surgery, 22.9% medical therapy only, and 15.8% medical plus radiation and surgical therapy. 199 adverse events were reported in 98 patients (28.7%). Serious adverse events were documented in 29 patients (8.5%). 71.1% of patients had no significant change in tumor volume. Central MRI reading was performed in 34 patients; in 7 patients, an increase in tumor volume was found. Hormonal efficacy progressively increased since the start of PEG. After 6 years, normal IGF-I levels were found in 70.9% of patients (mean daily dose 18.1 mg). 87.1% of patients were treated with daily PEG although in 8.8% of patients, it was administered 2-6 times per week and in 3.8% with weekly injections. 74.8% received a PEG dose 10-15 mg/daily. PEG is a drug with a favorable safety profile which is efficacious also considering that in Italy it is currently available as third-line therapy.",
"affiliations": "Divisione di Endocrinologia, Diabetologia e Metabolismo, Dipartimento di Scienze Mediche, AO Città della Salute e della Scienza di Torino, Università di Torino, C.so AM Dogliotti 14, 10126, Turin, Italy, ninagro@yahoo.it.",
"authors": "Grottoli|S|S|;Maffei|P|P|;Bogazzi|F|F|;Cannavò|S|S|;Colao|A|A|;Ghigo|E|E|;Gomez|R|R|;Graziano|E|E|;Monterubbianesi|M|M|;Jonsson|P|P|;De Marinis|L|L|",
"chemical_list": "D006727:Hormone Antagonists; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C406545:pegvisomant",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-014-0393-9",
"fulltext": null,
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"issn_linking": "1355-008X",
"issue": "48(1)",
"journal": "Endocrine",
"keywords": null,
"medline_ta": "Endocrine",
"mesh_terms": "D000172:Acromegaly; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006727:Hormone Antagonists; D019382:Human Growth Hormone; D006801:Humans; D007334:Insulin-Like Growth Factor I; D007558:Italy; D008099:Liver; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D012042:Registries; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9434444",
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"pages": "334-41",
"pmc": null,
"pmid": "25150035",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19684061;16449332;20207827;17923803;10372717;24566817;22596288;19411302;19684051;17077131;19208732;12372843;10770982;19965922;22362824;16553040;17218728;11734231;16452533;23799893;18174713;21063787;20410227;19684052",
"title": "ACROSTUDY: the Italian experience.",
"title_normalized": "acrostudy the italian experience"
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"abstract": "Immune checkpoint inhibitors (ICIs), by unleashing the anticancer response of the immune system, can improve survival of patients affected by several malignancies, but may trigger a broad spectrum of adverse events, including autoimmune hypophysitis. ICI-related hypophysitis mainly manifests with anterior hypopituitarism, while the simultaneous involvement of both anterior and posterior pituitary (i.e., panhypophysitis) has rarely been described.\nIn June 2015, a 64-year-old man affected by liver metastases of a uveal melanoma was referred to us due to polyuria and polydipsia. Two months prior, he had started ipilimumab therapy (3 mg/kg iv every 21 days). The treatment was well-tolerated (only mild asthenia and diarrhea were reported). A few days before the fourth cycle, the patient complained of intense headaches, profound fatigue, nocturia, polyuria (up to 10 L urine/daily), and polydipsia. Laboratory tests were consistent with adrenal insufficiency, hypothyroidism, and transient central diabetes insipidus. The pituitary MRI showed an enlarged gland with microinfarcts, while the hypophyseal stalk was normal, and the neurohypophyseal 'bright signal' in T1 sequences was not detected. The treatment included dexamethasone (then cortisone acetate at replacement dose), desmopressin, and levothyroxine. Within the next five days, the symptoms resolved, and blood pressure, electrolytes, glucose, and urinalysis were stable within the normal ranges; desmopressin was discontinued while cortisone acetate and levothyroxine were maintained. The fourth ipilimumab dose was entirely administered in the absence of further side effects.\nAs ICIs are increasingly used as anticancer agents, the damage to anterior and/or posterior pituitary can be progressively encountered by oncologists and endocrinologists in their clinical practice. Patients on ICIs and their caregivers should be informed about that risk and be empowered to alert the referring specialists early, at the onset of panhypopituitarism symptoms, including polyuria/polydipsia.",
"affiliations": "Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.;Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, Rome, Italy.",
"authors": "Barnabei|Agnese|A|;Carpano|Silvia|S|;Chiefari|Alfonsina|A|;Bianchini|Marta|M|;Lauretta|Rosa|R|;Mormando|Marilda|M|;Puliani|Guilia|G|;Paoletti|Giancarlo|G|;Appetecchia|Marialuisa|M|;Torino|Francesco|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.582394",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.582394\nOncology\nCase Report\nCase Report: Ipilimumab-Induced Panhypophysitis: An Infrequent Occurrence and Literature Review\nBarnabei Agnese \n1\n Carpano Silvia \n2\n Chiefari Alfonsina \n1\n Bianchini Marta \n1\n Lauretta Rosa \n1\n Mormando Marilda \n1\n Puliani Guilia \n1\n Paoletti Giancarlo \n2\n Appetecchia Marialuisa \n1\n\n*\n Torino Francesco \n3\n \n1\nOncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy\n\n\n2\nDivision of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy\n\n\n3\nDepartment of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, Rome, Italy\n\nEdited by: Roberto Baldelli, San Camillo-Forlanini Hospital, Italy\n\nReviewed by: Silvia Migliaccio, Foro Italico University of Rome, Italy; Salvatore Maria Corsello, Catholic University of the Sacred Heart, Rome, Italy\n\n*Correspondence: Marialuisa Appetecchia, marialuisa.appetecchia@ifo.gov.it\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n\n01 12 2020 \n2020 \n10 58239411 7 2020 28 10 2020 Copyright © 2020 Barnabei, Carpano, Chiefari, Bianchini, Lauretta, Mormando, Puliani, Paoletti, Appetecchia and Torino2020Barnabei, Carpano, Chiefari, Bianchini, Lauretta, Mormando, Puliani, Paoletti, Appetecchia and TorinoThis 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.Background\nImmune checkpoint inhibitors (ICIs), by unleashing the anticancer response of the immune system, can improve survival of patients affected by several malignancies, but may trigger a broad spectrum of adverse events, including autoimmune hypophysitis. ICI-related hypophysitis mainly manifests with anterior hypopituitarism, while the simultaneous involvement of both anterior and posterior pituitary (i.e., panhypophysitis) has rarely been described.\n\nCase Presentation\nIn June 2015, a 64-year-old man affected by liver metastases of a uveal melanoma was referred to us due to polyuria and polydipsia. Two months prior, he had started ipilimumab therapy (3 mg/kg iv every 21 days). The treatment was well-tolerated (only mild asthenia and diarrhea were reported). A few days before the fourth cycle, the patient complained of intense headaches, profound fatigue, nocturia, polyuria (up to 10 L urine/daily), and polydipsia. Laboratory tests were consistent with adrenal insufficiency, hypothyroidism, and transient central diabetes insipidus. The pituitary MRI showed an enlarged gland with microinfarcts, while the hypophyseal stalk was normal, and the neurohypophyseal ‘bright signal’ in T1 sequences was not detected. The treatment included dexamethasone (then cortisone acetate at replacement dose), desmopressin, and levothyroxine. Within the next five days, the symptoms resolved, and blood pressure, electrolytes, glucose, and urinalysis were stable within the normal ranges; desmopressin was discontinued while cortisone acetate and levothyroxine were maintained. The fourth ipilimumab dose was entirely administered in the absence of further side effects.\n\nConclusion\nAs ICIs are increasingly used as anticancer agents, the damage to anterior and/or posterior pituitary can be progressively encountered by oncologists and endocrinologists in their clinical practice. Patients on ICIs and their caregivers should be informed about that risk and be empowered to alert the referring specialists early, at the onset of panhypopituitarism symptoms, including polyuria/polydipsia.\n\nimmune checkpoint inhibitorsipilimumabhypophysitispanhypophysitisdiabetes insipidus\n==== Body\nIntroduction\nImmune checkpoint molecules are essential in the negative modulation of the immune response, but also play a key role in cancer cell immune escape (1). Immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAb) that, by targeting specific immune checkpoints (e.g., the Cytotoxic T-Lymphocyte Antigen-4 receptor, CTLA-4; the programmed death receptor, PD; and its ligand, PD-L1), unleash the anticancer immune response blocked by the cancer itself. In recent years, ICIs have shown durable antitumor responses and improved survival in patients affected by a broad spectrum of malignancies (2).\n\nIn 2011 Ipilimumab, an ICI targeting the CTLA-4 receptor, was the first ICI approved for the treatment of patients with advanced malignancy, namely advanced melanoma. Recently, ipilimumab received FDA approval as adjuvant treatment in patients affected by high-risk non-metastatic melanoma (2).\n\nICIs, due to their mechanism of action, may trigger immune-related adverse events (irAEs), mainly involving skin (rash), gastrointestinal tract (diarrhea and colitis), liver (elevated transaminases), and endocrine system. In the context of ICI-related endocrine toxicity, the incidence of hypophysitis was higher in patients under ipilimumab–nivolumab combination therapy (6.4%) compared with those under anti-CTLA-4 therapy (3.2%), anti-PD-1 therapy (0.4%), and anti-PD-L1 therapy (<0.1%) (3).\n\nICI-induced hypophysitis mainly affects the anterior pituitary, being TSH, ACTH, and FSH/LH secreting cells that were more frequently damaged. The damage of the posterior pituitary by ICIs, manifesting with central diabetes insipidus (CDI) is anecdotic (3).\n\nHerein, we report the case of a patient diagnosed with simultaneous anterior and posterior hypophysitis (panhypophysitis) induced by ipilimumab and discuss the emerging difference in the incidence of hypophysitis/CDI among subclasses of ICIs and the related pathogenic mechanisms.\n\nCase Presentation\nIn June 2015, a 64-year-old man was referred to us due to polyuria and polydipsia, in the absence of a medical and family history of endocrine disorders and autoimmune diseases. In 2004, he underwent ocular proton beam radiotherapy for a left eye uveal melanoma, obtaining the complete disease remission. In February 2015, liver metastases were documented, and the pathology evaluation of biopsy samples showed the infiltration of wild type BRAF melanoma cells. Therefore, in March 2015, the patient started ipilimumab therapy (3 mg/kg iv every 21 days). The treatment was well-tolerated, as only grade 1 asthenia and diarrhea were reported. A few days before the fourth cycle, the patient complained of intense headaches, profound fatigue, nocturia, polyuria (up to 10 L urine daily), and polydipsia. Neither visual impairment nor diplopia were reported. Laboratory tests (\nTable 1\n) were consistent with the diagnosis of central adrenal insufficiency, hypothyroidism, and transient diabetes insipidus.\n\nTable 1 Patient biochemical parameters.\n\nBiochemical Parameters\tValues at the diagnosis\tValues before the diagnosis\tNormal Range\t\nPlasma osmolarity (mOsm/kg)\t314\tNA\t275–295\t\nUrine osmolarity (mOsm/kg)\t174\tNA\t400–1,100\t\nTSH (mcU/ml)\t0.06\t2.1\t0.5–3.5\t\nFT3 (pg/ml)\t2.3\t3.0\t2–4.4\t\nFT4 (pg/ml)\t5.2\t14.2\t9.3–17\t\nACTH (pg/ml)\t1\t22.7\t7.2–63.3\t\nBlood cortisol (mcg/l)\t2.6\t132\t62–194\t\nTestosterone (ng/ml)\t2\t4.9\t3–7\t\nFSH (mUI/ml)\t5\t11.6\t1.3–19.3\t\nLH (mUI/ml)\t3\t8.9\t1.8–12\t\nIGF-1 (ng/ml)\t97\tNA\t64–188\t\nGlycemia (mg/dl)\t133\t110\t60–110\t\nNa+ (mEq/l)\t139\t141\t135–148\t\nK+ (mEq/l)\t5.2\t4.1\t3.5–5.1\t\nCreatinine (mg/dl)\t1.06\t1.0\t0.67–1.17\t\nUrea (mg/dl)\t53\t48\t15–50\t\nThe brain magnetic resonance imaging (MRI) showed pituitary microinfarcts in an enlarged gland, while the hypophyseal stalk was normal, and the neurohypophyseal ‘bright signal’ in T1 sequences was not detected (\nFigure 1\n). As the patient refused to be hospitalized, he was prescribed home drug therapy: dexamethasone 4 mg IM every 6 h for four days, progressively tapered down and switched to cortisone acetate at replacement dose; desmopressin 60 mg tablets (modifiable according to polyuria and polydipsia); levothyroxine 50 mcg/days. The symptoms progressively resolved within five days. Desmopressin was discontinued, maintaining cortisone acetate and levothyroxine. Blood pressure, electrolytes, glucose, and urinalysis were stable within the normal ranges.\n\nFigure 1 At the magnetic resonance imaging, pituitary microinfarcts in an enlarged gland were shown; the hypophyseal stalk was normal, and the neurohypophyseal ‘bright signal’ in T1 sequences was undetectable.\n\nAs the patient completely recovered, the fourth ipilimumab dose was entirely administered with a delay of 23 days. No further side effects were reported. The malignancy remained stable for two years. In June 2017, as liver metastases progressed, nivolumab was administered. The treatment was well tolerated with mild skin and gastrointestinal toxicity, and it was continued up to July 2018, when the patient’s clinical conditions worsened, and progressive disease was shown. In August 2018, the patient died due to hepatic failure.\n\nDiscussion\nHypophysitis is classified as adenohypophysitis, infundibulo-neuro-hypophysitis, or panhypophysitis when the anterior lobe, the posterior lobe, and the stalk of the gland, or both, are damaged, respectively (4). Based on pathology, two common forms of hypophysitis (lymphocytic and granulomatous) and three rarer variants (xanthomatous, necrotizing, and plasma-cell rich) are documented (4). The etiological classification identifies primary and secondary forms. Primary hypophysitis, the most common form, has autoimmune pathogenesis with no obvious causative agent (4). Secondary hypophysitis includes local and systemic disease and treatment-related hypophysitis. For local disorders, inflammation of the pituitary appears as a reaction to a sellar disease (i.e., Rathke’s cleft cyst, craniopharyngioma, germinoma, and pituitary adenoma). For systemic diseases, hypophysitis stems from the involvement of different organs by infectious or inflammatory disorders (e.g., Wegener’s granulomatosis, sarcoidosis, tuberculosis, syphilis, or sellar metastases). Treatment-related hypophysitis may derive from complications of surgery and/or radiotherapy or as a side effect of certain drugs (4).\n\nPatients with anterior hypophysitis usually present nonspecific symptoms, including headache, visual impairment, fatigue, weakness, confusion, memory loss, erectile dysfunction and loss of libido, anorexia, labile moods, insomnia, temperature intolerance, subjective sensation of fever, and chills (4). MRI is the imaging modality of choice in the differential diagnosis of pituitary diseases, including hypophysitis (4–6). In ICI-induced hypophysitis, MRI may show a diffuse enlargement of the pituitary, irregular thickening of the infundibulum, and diffuse enhancement (4–6). However, approximately 23% of cases may have a normal MRI despite clinical evidence of ICI-induced hypophysitis (4). Notably, the entity and quality of pituitary damage triggered by ICIs may depend on the time when an MRI assessment is made in respect of the onset of symptoms and/or the treatment start. Levels of ACTH, cortisol, TSH, and/or free T4, GH, prolactin, insulin-like growth factor I (IGF-1), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone are variably altered, indicating different degrees of hypopituitarism (4).\n\nCDI results from a deficiency of vasopressin (antidiuretic hormone, ADH) due to a hypothalamic–pituitary disorder. Most CDI cases are idiopathic or result from primary or secondary cancers, or infiltrative diseases (i.e., Langerhans cell histiocytosis) (7). Less frequently, CDI may be caused by familial and congenital disorders, neurosurgery or trauma, hypoxic encephalopathy, post-supraventricular tachycardia, and anorexia nervosa (7, 8). Drugs may rarely trigger CDI, including lithium, amphotericin-b, cidofovir, demeclocycline, didanosine, foscarnet, ofloxacin, orlistat (5). Patients with CDI typically present polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia. In the case of underlying neurologic diseases, neurologic symptoms may be present as well (8). The serum sodium concentration in untreated CDI is often in the high normal range, which stimulates thirst to replace the urinary water loss. Moderate to severe hypernatremia can develop when thirst is impaired, or autonomous drinking is hampered (8). Clinical features of CDI may differ based on whether disorders act at one or more of the sites involved in ADH secretion: the hypothalamic osmoreceptors; the supraoptic or paraventricular nuclei; or the superior portion of the supra-opticohypophyseal tract (7, 8). When the damage hits the tract below the median eminence or the posterior pituitary, usually causes only transient polyuria, because ADH produced in the hypothalamus can still be secreted into the systemic circulation via the portal capillaries in the median eminence (7). In persistent CDI, MRI high signal intensity of the posterior pituitary may be absent as a result of failure to synthesize, transport, or store ADH granules, being the pituitary gland and pituitary stalk homogeneously enhanced following the administration of contrast enhancement (9).\n\nThe diagnosis of CDI is based on the polyuria–polydipsia syndrome, on serum/plasma and urine studies, and the response to exogenous vasopressin, being an absent response suggesting nephrogenic diabetes insipidus. A water deprivation test (showing failure to concentrate urine maximally) or ADH serum levels may be required to confirm the clinical diagnosis of CDI. Recently, copeptin is proposed to improve the accuracy of CDI diagnosis. CDI treatment requires desmopressin or lypressin (10).\n\nPanhypopituitarism derives from the damage to the anterior hypophysis and either one of the sites of ADH production (the supraoptic or paraventricular nuclei; or the superior portion of the supra-opticohypophyseal tract) or of storage (hypophyseal stalk and neurohypophysis). In patients with panhypopituitarism, symptoms of CDI enrich the syndrome of anterior hypophysitis. CDI is also present in 17–48% of patients diagnosed with an autoimmune hypophysitis (11).\n\nIn the past, drug-induced hypophysitis was rarely diagnosed, mainly in patients under interferon or ribavirin (12). Recently, with the advent of ICIs, hypophysitis is among the most diagnosed endocrine irAEs induced by those agents, resulting in hypopituitarism leading to central adrenal insufficiency, central hypothyroidism, and hypogonadotropic hypogonadism. GH and prolactin abnormal levels occur less frequently. The incidence of ICI-induced hypophysitis is reported between 4–20% with ipilimumab, 1,8% with tremelimumab, 0.6% with nivolumab, and 0.7% with pembrolizumab, 8% with the combination ipilimumab plus nivolumab or pembrolizumab (10). ICI-hypophysitis is reported 2–5 times more frequently in men (particularly in over 60 old ones) than in women: that is the opposite of the other forms of hypophysitis (13).\n\nIn a very recent study based on the WHO global database of individual case safety reports, Bai et al. (14) showed that, in the period from January 2011 to March 2019, a total of 6,089 ICI-related endocrine AEs were reported, of which 1,144 (18.8%) were pituitary events, including hypophysitis, hypopituitarism, and pituitary enlargement. The anti-CTLA-4 subgroup had a stronger association with hypophysitis/hypopituitarism than the anti-PD (anti-PD-1/anti-PD-L1) subgroup. Among ICI-associated hypophysitis/hypopituitarism cases, the proportion of males was higher than females (630 [63.9%] vs. 356 [36.1%]). Anti-CTLA-4 subgroup and ICI combination (ipilimumab–nivolumab) subgroup both had a significantly earlier onset time than anti-PD subgroup (67 days [48–87]; 90 [34–155]; 140 [62–218], both p <0.05). CDI was reported in seven out of 1,072 (0.7%) of the registered hypophysitis/hypopituitarism cases among patients who received an ICI as a single agent or in combination (ipilimumab–nivolumab) (14).\n\nHigh-dose corticosteroids were recommended for the treatment of ipilimumab-induced hypophysitis (15, 16). However, their use remains controversial as it lacks high level evidence (3). High-dose corticosteroids are currently recommended for patients with ICI-induced hypophysitis when severe hyponatremia or significant mass effect from pituitary swelling are shown, in the grade 3–4 endocrine irAEs, including thyroid storm and Graves’ ophthalmopathy, or in the setting of critical illness (3, 17, 18). In the other cases, corticosteroids at replacement dose are used, together with other replacement treatment(s) according to the emerged hormone deficit(s) (17).\n\nAs a result of searching the available literature, CDI was rarely reported as either in a panhypophysitis syndrome or as a single endocrine ICI-related adverse event. To the best of our knowledge, only three cases of panhypophysitis induced by ipilimumab are available in the literature: in two of them, ipilimumab was administered as a single agent (19, 20), while in the third case it was combined with nivolumab (an anti-PD-1 mAb) (21). The first patient was affected by prostate cancer, the other two were affected by cutaneous melanoma (19–21). More recently, three case reports of isolated ICI-related CDI were published. In the first case, CDI occurred in a patient affected by Merkel cell carcinoma who received avelumab (an anti-PD-L1 mAb) (22). In the second one, CDI was reported in a patient affected by lung cancer who received nivolumab (an anti-PD-1 mAb) (23), while in the third case, CDI was diagnosed in a patient affected by mesothelioma, who was treated with an experimental combination of tremelimumab (an anti-CTLA4 mAb) and durvalumab (an anti-PD-L1 mAb) (24).\n\nThe pathogenesis of ICI-related damages to anterior hypophysitis is still unclear. Multiple contributing mechanisms were suggested, including: a) the prevalent expression of CTLA-4 antigens on some pituitary cells; b) the prevalent intensity of types II and IV hypersensitivity immune reaction triggered by different ICI-subclasses; (3) the role of CTLA-4 gene polymorphisms.\n\nCTLA-4 antigens were found predominantly expressed in thyrotroph and lactotroph pituitary cells both in mice and in humans (25). Iwama et al. (26) obtained the first murine model of anti-CTLA-4-related (anterior) hypophysitis, following repeated administrations of an anti-CTLA4 mAb. They not only demonstrated pituitary infiltration with hematopoietic mononuclear cells (mainly CD45+ lymphocytes) but also production of serum antibodies directed against the anterior pituitary cells, acting through complement-mediated cell cytotoxicity. Recently, anti-pituitary autoantibodies, mainly against pituitary cells secreting TSH, FSH, and ACTH, were detected in patients with ipilimumab-induced hypophysitis (27). In specimens from the pituitary of patients who received tremelimumab, an anti-CTLA-4 IgG2 mAb, the expression of CTLA-4 was found to be increased, and the clinical-pathological features were compatible with type II and type IV hypersensitivity reactions (27).\n\nInterestingly, IgG subclasses demonstrated different potency in activating ADCC and the classical complement pathway, with IgG1 exerting the relatively more potent effects compared with IgG2 and IgG4 subclasses (28). Moreover, IgG4 are unable to activate the classical complement pathway (28). Among anti-CTLA4 mAbs, ipilimumab is an IgG1 mAb, while tremelimumab is an IgG2 mAb. Among anti-PD1/PD-1L mAbs, avelumab and durvalumab are IgG1 mAbs, while nivolumab and pembrolizumab are IgG4 mAbs (3). All the above factors may explain the occurrence of hypophysitis in patients under CTLA4-mAbs and the higher incidence of hypophysitis in patients on treatment with ipilimumab (IgG1) compared with anti-PD1/PD-L1 mAbs. These differences in drug structure may provide a further causative explanation for the different rates of pituitary toxicity among ICIs. However, the pathogenic contribution of each single mechanism in triggering ICI-related hypophysitis remains to be investigated (3, 4, 12).\n\nFinally, a potential role of some gene polymorphisms in prompting ICI-related toxicity has been envisioned (27). Some CTLA-4 polymorphisms are commonly associated with various autoimmune disorders, including endocrinopathies (i.e., type 1 diabetes mellitus, Graves’ disease, autoimmune hypothyroidism, and Addison disease) (29). Only in few studies a linkage of PD-1 polymorphisms with T1DM was suggested, while PD-L1 polymorphisms was found to be linked to type 1 diabetes mellitus, Graves’ disease, and Addison disease (3). No reports have linked PD-L2 polymorphisms to autoimmune endocrinopathies (3). Based on these data and on the well documented association between some germline genetic variants and adverse events induced by anticancer agents (30), an association between some immune checkpoint gene polymorphisms and the development of ICI-induced toxicities has been postulated (31). However, only very few studies evaluated the association between polymorphisms of immune checkpoint genes and irAEs, including immune-related endocrinopathy (32, 33). In those studies, no certain causative link was found between polymorphisms of immune checkpoint genes and toxicities induced by ICIs (3).\n\nIf the pathogenesis of anterior hypophysitis remains to be fully understood, the lack of experimental and pathology findings makes it even harder suggesting pathogenic hypotheses for the ICI-related CDI occurrence, both as ICI-related panhypophysitis and as single endocrine irAE.\n\nIn a simplifying framework, the posterior pituitary damage would theoretically derive from the extension of the ICI-induced autoimmune inflammation of the anterior pituitary to the posterior gland. On the other hand, panhypophysitis would stem from factors triggering the concurrent damage to both the anterior pituitary and to one of the anatomical sites of the hypothalamus–hypophysis axis.\n\nUnfortunately, imaging techniques, such as MRIs, may not help diagnose ICI-related CDI/hypophysitis, since pituitary MRI may be normal in patients diagnosed with hypophysitis and/or CDI (4–9).\n\nImportantly, pathology data would be of great value in clarifying the pathogenic mechanisms of ICI-related panhypophysitis. Unfortunately, the solely available autopsy report describes findings of an anterior hypophysitis, in the absence of aspects suggesting any involvement of posterior pituitary.\n\nIn parallel, the pathogenesis of ICI-induced selective damage to posterior pituitary manifesting as isolated CDI remains cryptic. An autoimmune reaction triggered by ICIs would suggest the selective hit to posterior pituitary and/or supraoptic and paraventricular nuclei. To this aim, the assessment of antibodies to ADH-secreting cells of the human hypothalamus (AHA) could be useful, as they are in the CDI diagnosis (3, 23). However, when available, the serum assessment of anti-nuclear antibodies, extractable nuclear antigen, and anti-neutrophil cytoplasmic antibodies, may not reveal the presence of an autoimmune disease (3, 23). Unfortunately, the current lack of clinic-pathological evidence renders those hypotheses merely speculative.\n\nConclusion\nThe occurrence of panhypopituitarism, despite its rarity, should be considered in patients who are treated with ipilimumab, both as a single agent or in ICI-combination. Moreover, recent reports highlight that isolated CDI may occur in patients under anti-PD1/PD-L1 mAbs.\n\nDue to the increasing clinical use of ICIs as anticancer agents in several malignancies, not only in the metastatic, but also in the adjuvant clinical setting, the consequences of ICI-induced damage to either anterior or posterior pituitary or both, can be encountered by oncologists and endocrinologists in current clinical practice. Patients on ICIs and their caregivers should be informed about the risk of ICI-induced hypophysitis and empowered to alert referring health care professionals early, at the onset of symptoms of panhypopituitarism, including polyuria/polydipsia.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.\n\nEthics Statement\nThe written informed consent was obtained from the patient for the publication of any potentially identifiable images or data.\n\nAuthor Contributions\nFT, AB, and MA wrote the manuscript. SC, AC, MB, RL, MM, and GP collected the data. AB, FT, MA, SC, and GP contributed to the project development. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 \nPardoll DM \nThe blockade of immune checkpoints in cancer immunotherapy\n. Nat Rev Cancer (2012 ) 12 :252–64. 10.1038/nrc3239 \n\n2 \nMoujaess E Haddad FG Eid R Kourie HR \nThe emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: a review\n. Immunotherapy (2019 ) 11 :1409–22. 10.2217/imt-2019-0087 \n\n3 \nChang LS Barroso-Sousa R Tolaney SM Hodi FS Kaiser UB Min L \nEndocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints\n. Endocr Rev (2019 ) 40 :17 –65\n. 10.1210/er.2018-00006 \n30184160 \n4 \nCaturegli P Newschaffer C Olivi A Pomper MG Burger PC Rose NR \nAutoimmune Hypophysitis\n. Endocr Rev (2005 ) 26 :599 –614\n. 10.1210/er.2004-0011 \n15634713 \n5 \nGutenberg A Larsen J Lupi I Rohde V Caturegli P \nA radiologic score to distinguish autoimmune hypophysitis from nonsecreting pituitary adenoma preoperatively\n. AJNR Am J Neuroradiol (2009 ) 30 :1766–72. 10.3174/ajnr.A1714 \n\n6 \nCaranci F Leone G Ponsiglione A Muto M Tortora F Muto M \nImaging findings in hypophysitis: a review\n. Radiol Med (2020 ) 125 :319–28. 10.1007/s11547-019-01120-x \n\n7 \nRose BD Post TW \nClinical Physiology of Acid-Base and Electrolyte Disorders . 5th ed \nNew York : McGraw-Hill (2001 ). p. 751 .\n8 \nBichet DG \nClinical manifestations and causes of central diabetes insipidus\n. Available at: http://www.uptodate.com (Accessed on 2020 April 17).\n9 \nShin JH Lee HK Choi CG Suh DC Kim CJ Hong SK \nMR Imaging of Central Diabetes Insipidus: A Pictorial Essay\n. Korean J Radiol (2001 ) 2 :222–30. 10.3348/kjr.2001.2.4.222 \n\n10 \nBichet DG \nTreatment of central diabetes insipidus . Available at: http://www.uptodate.com (Accessed on 2020 April 17).\n11 \nGubbi S Hannah-Shmouni F Stratakis CA Koch CA \nPrimary hypophysitis and other autoimmune disorders of the sellar and suprasellar regions\n. Rev Endocr Metab Disord (2018 ) 19 :335–47. 10.1007/s11154-018-9480-1 \n\n12 \nTorino F Barnabei A Paragliola RM Marchetti P Salvatori R Corsello SM \nEndocrine side-effects of anti-cancer drugs: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses\n. Eur J Endocrinol (2013 ) 169 :R153–64. 10.1530/EJE-13-0434 \n\n13 \nDel Rivero J Cordes LM Klubo-Gwiezdzinska J Madan RA Nieman LK Gulley JL \nEndocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management\n. Oncologist (2020 ) 25 :290 –300\n. 10.1634/theoncologist.2018-0470 \n32297436 \n14 \nBai X Chen X Wu X Huang Y Zhuang Y Chen Y \nImmune checkpoint inhibitor-associated pituitary adverse events: an observational, retrospective, disproportionality study\n. J Endocrinol Invest (2020 ) 43 (10 ):1473–83. 10.1007/s40618-020-01226-4 \n\n15 \nWeber JS Kähler KC Hauschild A \nManagement of immune-related adverse events and kinetics of response with ipilimumab\n. J Clin Oncol (2012 ) 30 :2691–7. 10.1200/JCO.2012.41.6750 \n\n16 \nCorsello SM Barnabei A Marchetti P De Vecchis L Salvatori R Torino F \nEndocrine side effects induced by immune checkpoint inhibitors\n. J Clin Endocrinol Metab (2013 ) 98 :1361–75. 10.1210/jc.2012-4075 \n\n17 \nBrahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM \nManagement of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline\n. J Clin Oncol (2018 ) 36 (17 ):1714–68. 10.1200/JCO.2017.77.6385 \n\n18 \nCorsello SM Salvatori R Barnabei A De Vecchis L Marchetti P Torino F \nIpilimumab-induced endocrinopathies: when to start corticosteroids (or not)\n. Cancer Chemother Pharmacol (2013 ) 72 :489–90. 10.1007/s00280-013-2213-y \n\n19 \nDillard T Yedinak CG Alumkal J Fleseriu M \nAnti-CTLA-4 Antibody Therapy Associated Autoimmune Hypophysitis: Serious Immune-Related Adverse Events Across a Spectrum of Cancer Subtypes\n. Pituitary (2010 ) 13 :29 –38\n. 10.1007/s11102-009-0193-z \n19639414 \n20 \nNallapaneni NN Mourya R Bhatt RV Malhotra S Ganti AK Tendulkar KK \nIpilimumab-induced hypophysitis and uveitis in a patient with metastatic melanoma and a history of ipilimumab-induced skin rash\n. J Natl Compr Canc Netw (2014 ) 12 :1077–81. 10.6004/jnccn.2014.0105 \n\n21 \nGunawan F George E Roberts A \nCombination immune checkpoint inhibitor therapy nivolumab and ipilimumab associated with multiple endocrinopathies\n. Endocrinol Diabetes Metab Case Rep (2018 ) 2018 :17 –0146\n. 10.1530/EDM-17-0146 \n\n22 \nZhao C Tella SH Del Rivero J Kommalapati A Ebenuwa I Gulley J \nAnti-PD-L1 treatment-induced central diabetes insipidus\n. J Clin Endocrinol Metab (2018 ) 103 :365–9. 10.1210/jc.2017-01905 \n\n23 \nDeligiorgi MV Siasos G Vergadis C Trafalis DT \nCentral diabetes insipidus related to anti-PD1 protein active immunotherapy\n. Int Immunopharm (2020 ) 83 :427. 10.1016/j.intimp.2020.106427 \n\n24 \nBrilli L Calabrò L Campanile M Pilli T Agostinis C Cerase A \nPermanent diabetes insipidus in a patient with mesothelioma treated with immunotherapy\n. Arch Endocrinol Metab (2020 ) 6 :S2359 –39972020005002203\n. 10.20945/2359-3997000000221 \n\n25 \nBarroso-Sousa R Ott PA Hodi FS Kaiser UB Tolaney SM Min L \nEndocrine dysfunction induced by immune checkpoint inhibitors: practical recommendations for diagnosis and clinical management\n. Cancer (2018 ) 124 :1111–21. 10.1002/cncr.31200 \n\n26 \nIwama S De Remigis A Callahan MK Slovin SF Wolchok JD Caturegli P \nPituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody\n. Sci Transl Med (2014 ) 6 :230ra45 . 10.1126/scitranslmed.3008002 \n\n27 \nCaturegli P Di Dalmazi G Lombardi M Grosso F Larman HB Larman T \nHypophysitis Secondary to Cytotoxic T-Lymphocyte Associated Protein 4 Blockade. Insights into Pathogenesis from an Autopsy Series\n. Am J Pathol (2016 ) 186 :3225–35. 10.1016/j.ajpath.2016.08.020 \n\n28 \nVidarsson G Dekkers G Rispens T \nIgG subclasses and allotypes: from structure to effector functions\n. Front Immunol (2014 ) 5 :520. 10.3389/fimmu.2014.00520 \n25368619 \n29 \nUeda H Howson JM Esposito L Heward J Snook H Chamberlain G \nAssociation of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease\n. Nature (2003 ) 423 :506–11. 10.1038/nature01621 \n\n30 \nHertz DL Rae J \nPharmacogenetics of cancer drugs\n. Annu Rev Med (2015 ) 66 :65 –81\n. 10.1146/annurev-med-053013-053944 \n25386932 \n31 \nUdagawa C Zembutsu H \nPharmacogenetics for severe adverse drug reactions induced by molecular-targeted therapy\n. Cancer Sci (2020 ) 111 :3445–57. 10.1111/cas.14609 \n\n32 \nRefae S Gal J Ebran N Otto J Borchiellini D Peyrade F \nGerminal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors\n. Invest New Drugs (2020 ) 38 :160–71. 10.1007/s10637-019-00845-w \n\n33 \nBins S Basak EA El Bouazzaoui S Koolen SLW Oomen-de Hoop E van der Leest CH \nAssociation between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients\n. Br J Cancer (2018 ) 118 :1296–301. 10.1038/s41416-018-0074-1\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "diabetes insipidus; hypophysitis; immune checkpoint inhibitors; ipilimumab; panhypophysitis",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "582394",
"pmc": null,
"pmid": "33335854",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29695768;24001893;29511565;29442540;25368619;11754330;25386932;19628625;32780457;30184160;23779068;32239475;22437870;22614989;32297436;30547288;29220526;23471977;12724780;27750046;25099440;32244049;31621445;15634713;31863360;24695685;19639414;32267349;31402427;29313945",
"title": "Case Report: Ipilimumab-Induced Panhypophysitis: An Infrequent Occurrence and Literature Review.",
"title_normalized": "case report ipilimumab induced panhypophysitis an infrequent occurrence and literature review"
} | [
{
"companynumb": "IT-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-113327",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nMany studies investigated the association between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) but none focused on the association between ADHD and nonmedical prescription opioids such as tramadol. The objective of this study was to assess the prevalence, correlates, and consequences of co-occurrence of ADHD and tramadol use among adults.\n\n\nMETHODS\nThis study included 122 Egyptian adults with opioid use disorders attributed to tramadol (N = 122). Participants were recruited from the psychiatric outpatient clinic and inpatient unit of Zagazig University Hospital, Egypt. ADHD and SUDs were assessed by using the Adult ADHD Self-Report Scale (ASRS-v 1.1) and SCID-I criteria of DSM-5, respectively. All participants were screened for drugs by urinalysis.\n\n\nRESULTS\nForty percent of the participants used tramadol alone, whereas the remaining used it with other substances, such as alcohol (51.6%) and cannabis (48.4%). Thirty-eight cases (31%) had adult ADHD and most of them had inattentive or mixed types. Adults with tramadol use and ADHD were more likely to have a younger age of onset of tramadol use, use a higher dose of tramadol, and use it for a longer duration than those with tramadol use without ADHD.\n\n\nCONCLUSIONS\nADHD in adults with tramadol use is common and is associated with early-onset, high dose, and long duration of tramadol use.\n\n\nCONCLUSIONS\nThis is the first study to investigate the co-occurrence of ADHD and tramadol misuse among adults.",
"affiliations": "Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig, Egypt.;Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig, Egypt.;Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig, Egypt.;Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig, Egypt.",
"authors": "Bassiony|Medhat M|MM|http://orcid.org/0000-0001-9754-1847;Salah El-Deen|Ghada M|GM|;Ameen|Noha|N|;Mahdy|Rehab S|RS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ajad.13231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1055-0496",
"issue": null,
"journal": "The American journal on addictions",
"keywords": null,
"medline_ta": "Am J Addict",
"mesh_terms": null,
"nlm_unique_id": "9208821",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34608707",
"pubdate": "2021-10-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prevalence, correlates, and consequences of attention-deficit/hyperactivity disorder in a clinical sample of adults with tramadol use in Egypt.",
"title_normalized": "prevalence correlates and consequences of attention deficit hyperactivity disorder in a clinical sample of adults with tramadol use in egypt"
} | [
{
"companynumb": "EG-AMNEAL PHARMACEUTICALS-2021-AMRX-04260",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"d... |
{
"abstract": "OBJECTIVE\nTo describe a case of retinal occlusive vasculopathy associated with intravitreal administration of rituximab.\n\n\nMETHODS\nA single case report from a tertiary referral center.\n\n\nRESULTS\nThe patient described in the following case report developed a diffuse retinal occlusive vasculopathy following intravitreal rituximab for intraocular lymphoma. He required panretinal photocoagulation, avastin, and cyclophotocoagulation to control his intraocular pressure from ocular ischemia resulting in neovascular glaucoma.\n\n\nCONCLUSIONS\nThis is the first reported case of occlusive retinal vasculopathy subsequent to intravitreal administration of rituximab. Whereas hypersensitivity reactions to intravenous infusion of rituximab have been noted in the literature, no such reports exist in response to intravitreal therapy.",
"affiliations": "Department of Ophthalmology, John A. Moran Eye Center, University of Utah , Salt Lake City, UT, USA.;Department of Ophthalmology, John A. Moran Eye Center, University of Utah , Salt Lake City, UT, USA.",
"authors": "Conrady|Christopher D|CD|;Shakoor|Akbar|A|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2019.1611874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "28(4)",
"journal": "Ocular immunology and inflammation",
"keywords": "Ischemia; lymphoma; rituximab; vascular; vasculopathy",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000369:Aged, 80 and over; D005134:Eye Neoplasms; D006801:Humans; D007155:Immunologic Factors; D058449:Intravitreal Injections; D008223:Lymphoma; D008297:Male; D031300:Retinal Vasculitis; D012171:Retinal Vessels; D000069283:Rituximab; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "622-625",
"pmc": null,
"pmid": "31314626",
"pubdate": "2020-05-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rituximab-Associated Retinal Occlusive Vasculopathy: A Case Report and Literature Review.",
"title_normalized": "rituximab associated retinal occlusive vasculopathy a case report and literature review"
} | [
{
"companynumb": "US-ROCHE-2363796",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "The present study (ClinicalTrials.gov Identifier: NCT02221492) was conducted to assess the efficacy and safety of plerixafor for the mobilization and collection of haematopoietic stem cells (HSCs) for autologous transplantation in Japanese non-Hodgkin lymphoma (NHL) patients. In this randomized phase 2 study, patients received granulocyte-colony stimulating factor (G-CSF, filgrastim) 400 µg/m²/day for up to 8 days. Starting on the evening of day 4, patients received, for up to 4 days, either plerixafor (240 µg/kg/day) in the G-CSF+ plerixafor arm (GP arm) or G-CSF alone arm (G arm). On day 5, daily apheresis started and was continued for up to 4 days, or until ≥ 5 × 106 CD34+ cells/kg was collected. A total of 32 patients were randomized to either the GP or G arm. In the GP arm, 9/16 patients (56.3%) achieved collection of ≥ 5 × 106 CD34+ cells/kg in ≤ 4 days of apheresis, while 1/16 patient (6.3%) achieved this target in the G arm. The most common treatment-emergent adverse events in the GP arm were back pain (56.3%), platelet count decreased (25.0%), headache, diarrhoea, and nausea (18.8% each). We found that plerixafor was well tolerated and effective for the mobilization and collection of peripheral HSCs for autologous transplantation in Japanese NHL patients.",
"affiliations": "Department of Hematology and Oncology, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba, 296-8602, Japan. koseimatsue@gmail.com.;Division of Hematology and Oncology, Chiba Cancer Center, Chiba, Japan.;Department of Hematology & Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan.;Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.;Hematology/Oncology, Gunma Cancer Center, Ota, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University Hospital, Sapporo, Japan.;Hematology and Oncology, Japanese Red Cross Society Suwa Hospital, Suwa, Japan.;Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Haematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan.;Department of Hematology, Chugoku Central Hospital, Fukuyama, Japan.;Sanofi K.K., Tokyo, Japan.;Sanofi K.K., Tokyo, Japan.;Department of Hematology, Mitsui Memorial Hospital, Tokyo, Japan.",
"authors": "Matsue|Kosei|K|http://orcid.org/0000-0002-8669-9865;Kumagai|Kyoya|K|;Sugiura|Isamu|I|;Ishikawa|Takayuki|T|;Igarashi|Tadahiko|T|;Sato|Tsutomu|T|;Uchiyama|Michihiro|M|;Miyamoto|Toshihiro|T|;Ono|Takaaki|T|;Ueda|Yasunori|Y|;Kiguchi|Toru|T|;Sunaga|Yoshinori|Y|;Sasaki|Toru|T|;Suzuki|Kenshi|K|",
"chemical_list": "D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; C088327:plerixafor",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-018-2505-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "108(5)",
"journal": "International journal of hematology",
"keywords": "Apheresis; G-CSF; Non-Hodgkin’s lymphoma (NHL); Plerixafor; Stem cell",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D064592:Autografts; D001596:Benzylamines; D000080027:Cyclams; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells; D006571:Heterocyclic Compounds; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "524-534",
"pmc": null,
"pmid": "30043330",
"pubdate": "2018-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "19720922;26969772;14990978;8807097;23170195;19167685;23749109;18940680;20411999;24141007;18628138;29255168;9763111;28527129;20636438;15009065;24686988;19363221;15147376",
"title": "Plerixafor for mobilization and collection of haematopoietic stem cells for autologous transplantation in Japanese patients with non-Hodgkin lymphoma: a randomized phase 2 study.",
"title_normalized": "plerixafor for mobilization and collection of haematopoietic stem cells for autologous transplantation in japanese patients with non hodgkin lymphoma a randomized phase 2 study"
} | [
{
"companynumb": "PHHY2018JP153423",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS"
},
"drugadd... |
{
"abstract": "The patient was a 41-year-old, premenopausal woman with a chief complaint of well-circumscribed palpable, right breast mass without nipple discharge. Although she noticed the lump 3 months previously, the size of the tumor (1.1 × 0.9 cm(2)) had been stable. The patient's mother suffered from gastric cancer. Her previous history of the triple different malignancies was as follows: (1) left osteosarcoma [amputation of left lower leg at 15 years old (y/o)]. After the operation, she was treated with various kinds of anticancer drugs including a total of 45 g ifosphamide and 342 g methotrexate; (2) tongue cancer (right radical neck resection; 23 y/o); and (3) thyroid cancer (right lobectomy; 40 y/o). There was no evidence of recurrence of these malignancies at the present consultation. At the time of tongue cancer operation, chromosome abnormality was investigated, but the results were normal. Physical examination showed a well-delimited, elastic-firm, mobile tumor in the central outer right breast. Regional lymph nodes were not palpable. Mammography showed a focal asymmetry in the right upper breast on the mediolateral oblique view. Ultrasonography revealed a hypoechoic mass with irregular margins. Distant metastases could not be detected by whole-body computed tomography scan. The histology of the Mammotome(®) (vacuum-assisted core needle biopsy) specimen revealed that this tumor was low-grade ductal carcinoma in situ (DCIS). She underwent breast-conserving surgery with sentinel lymph node biopsy. On permanent histopathological examination, the diagnosis of the tumor was intracystic papilloma with low-grade DCIS. Surgical margin was negative, and sentinel lymph node metastases could not be observed. Estrogen and progesterone receptor (ER/PR) were strongly positive, but human epidermal growth factor receptor-2 (HER-2) overexpression was not tested because the lesion was DCIS. She has received no adjuvant therapy and is currently disease free 3 months after surgery.",
"affiliations": "Division of Breast and Endocrine Surgery, Department of Surgery, Aichi Medical University, 21 Yasago-Karimata, Nagakute, Aichi-gun, 480-1195, Japan.",
"authors": "Kousaka|Junko|J|;Fujii|Kimihito|K|;Yorozuya|Kyoko|K|;Mouri|Yukako|Y|;Yoshida|Miwa|M|;Nakano|Shogo|S|;Fukutomi|Takashi|T|;Takahashi|Emiko|E|;Yokoi|Toyoharu|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12282-011-0271-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1340-6868",
"issue": "21(4)",
"journal": "Breast cancer (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Breast Cancer",
"mesh_terms": "D000328:Adult; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D002285:Carcinoma, Intraductal, Noninfiltrating; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007621:Karyotyping; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary; D012516:Osteosarcoma; D011379:Prognosis; D013964:Thyroid Neoplasms; D014062:Tongue Neoplasms",
"nlm_unique_id": "100888201",
"other_id": null,
"pages": "500-3",
"pmc": null,
"pmid": "21562838",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of quadruple primary malignancies including breast, tongue, and thyroid cancers and osteosarcoma in a young female without karyotype abnormality.",
"title_normalized": "a case of quadruple primary malignancies including breast tongue and thyroid cancers and osteosarcoma in a young female without karyotype abnormality"
} | [
{
"companynumb": "JP-JNJFOC-20140803581",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nVocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.\nWe report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.\nRight vocal fold paralysis was diagnosed with flexible laryngoscopy.\n\n\nMETHODS\nPatient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.\n\n\nRESULTS\nPostoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.\n\n\nCONCLUSIONS\nThe case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.",
"affiliations": "Department of Orthopedics, Zhangqiu People's Hospital, Jinan.;Department of Orthopedic Surgery, Liaocheng People's Hospital, No.67 Dongchang West Road, Liaocheng, Shandong, PR China.;Department of Orthopedics, Zhangqiu People's Hospital, Jinan.;Department of Orthopedics, Zhangqiu People's Hospital, Jinan.;Department of Orthopedics, Zhangqiu People's Hospital, Jinan.",
"authors": "Xiang|Yuanling|Y|;Wang|Weifeng|W|;Jing|Shenfeng|S|;Zhang|Zhong|Z|;Wang|Dezhang|D|0000-0002-9925-6959",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000024374",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-20-00246\n10.1097/MD.0000000000024374\n24374\n7100\nResearch Article\nClinical Case Report\nVocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia\nA case reportXiang Yuanling MDa Wang Weifeng MDb Jing Shenfeng MDa Zhang Zhong MDa Wang Dezhang MDa∗ Saranathan. Maya a Department of Orthopedics, Zhangqiu People's Hospital, Jinan\nb Department of Orthopedic Surgery, Liaocheng People's Hospital, No.67 Dongchang West Road, Liaocheng, Shandong, PR China.\n∗ Correspondence: Dezhang Wang, Department of Orthopedics, Zhangqiu People's Hospital, Jinan, Shandong 250200, PR China (e-mail: dezhangwang2@outlook.com).\n22 1 2021 \n22 1 2021 \n100 3 e2437410 1 2020 23 12 2020 29 12 2020 Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.2021This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nVocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.\n\nPatient concerns:\nWe report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.\n\nDiagnoses:\nRight vocal fold paralysis was diagnosed with flexible laryngoscopy.\n\nInterventions:\nPatient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.\n\nOutcomes:\nPostoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.\n\nLessons:\nThe case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.\n\nKeywords\ncauda equina syndromeepidural aesthesiahallux valgusspinalvocal fold paralysisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nRegional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.\n\n2 Case presentation\nA previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.\n\nAfter surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.\n\nThe patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.\n\n3 Discussion and conclusions\nThe patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.\n\nVarious possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.\n\nCauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.\n\nIn summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.\n\nAuthor contributions\nConceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nData curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nFormal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nInvestigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nMethodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nProject administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nResources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nSoftware: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nSupervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nValidation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nVisualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nWriting – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nWriting – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.\n\nAbbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.\n\nHow to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).\n\nWritten consent was obtained from the patient for the purpose of publication of case details and images.\n\nThe authors have no conflicts of interests to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Traore M Diallo A Coulibaly Y \nCauda equina syndrome and profound hearing loss after spinal anesthesia with isobaric bupivacaine\n. Anesth Analg \n2006 ;102 :1863 –4\n.16717339 \n[2] Guardiani E Sulica L \nVocal fold paralysis following spinal anesthesia\n. JAMA Otolaryngol Head Neck Surg \n2014 ;140 :662 –3\n.24831755 \n[3] Aytuluk HG Aktas O \nVocal fold paralysis due to intracranial hypotension following spinal anesthesia\n. Anaesthesist \n2018 ;67 :868 –70\n.30315318 \n[4] Saeks J Reynolds SB Alexander JS \nBilateral vocal fold paralysis after epidural anesthesia\n. Cureus \n2019 ;11 :e4212 .31114731 \n[5] Long B Koyfman A Gottlieb M \nEvaluation and management of cauda equina syndrome in the emergency department\n. Am J Emerg Med \n2020 ;38 :143 –8\n.31471075 \n[6] Sakura S \nResearch on local anesthetic neurotoxicity using intrathecal and epidural rat models\n. J Anesth \n2007 ;21 :533 –4\n.18008132 \n[7] Arai T Hoka S \nNeurotoxicity of intrathecal local anesthetics\n. J Anesth \n2007 ;21 :540 –1\n.18008135 \n[8] Hofer JE Scavone BM \nCranial nerve VI palsy after dural-arachnoid puncture\n. Anesth Analg \n2015 ;120 :644 –6\n.25695579 \n[9] Vial F Bouaziz H Adam A \nParalysie oculomotrice et rachianesthésie [Oculomotor paralysis and spinal anesthesia]\n. Ann Fr Anesth Reanim \n2001 ;20 :32 –5\n.11234575 \n[10] Day CJ Shutt LE \nAuditory, ocular, and facial complications of central neural block. A review of possible mechanisms\n. Reg Anesth \n1996 ;21 :197 –201\n.8744660 \n[11] Whiting AS Johnson LN Martin DE \nCranial nerve paresis following epidural and spinal anesthesia\n. Trans Pa Acad Ophthalmol Otolaryngol \n1990 ;42 :972 –3\n.2084996 \n[12] King RA Calhoun JH \nFourth cranial nerve palsy following spinal anesthesia. A case report\n. J Clin Neuroophthalmol \n1987 ;7 :20 –2\n.2952674 \n[13] Fang JY Lin JW Li Q \nTrigeminal nerve and facial nerve palsy after combined spinal-epidural anesthesia for cesarean section\n. J Clin Anesth \n2010 ;22 :56 –8\n.20206854 \n[14] Kirshblum S Snider B Rupp R \nRead MS; International Standards Committee of ASIA and ISCoS. Updates of the international standards for neurologic classification of spinal cord injury: 2015 and 2019\n. Phys Med Rehabil Clin N Am \n2020 ;31 :319 –30\n.32624097 \n[15] ASIA and ISCoS International Standards Committee . The 2019 revision of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI)-what's new?\n\nSpinal Cord \n2019 ;57 :815 –7\n.31530900 \n[16] Schroeder GD Kwon BK Eck JC \nSurvey of cervical spine research society members on the use of high-dose steroids for acute spinal cord injuries\n. Spine (Phila Pa 1976) \n2014 ;39 :971 –7\n.24583739 \n[17] Amrhein TJ Kranz PG \nSpontaneous intracranial hypotension: imaging in diagnosis and treatment\n. Radiol Clin North Am \n2019 ;57 :439 –51\n.30709479 \n[18] Del-Rio-Vellosillo M Garcia-Medina JJ Pinazo-Duran MD \nOcular motor palsy after spinal puncture\n. Reg Anesth Pain Med \n2017 ;42 :1 –9\n.27846186 \n[19] Merino-Urrutia W Villagrán-Schmidt M Ulloa-Vásquez P \nCauda equina syndrome following an uneventful spinal anesthesia in a patient undergoing drainage of the Bartholin abscess: a case report\n. Medicine (Baltimore) \n2018 ;97 :e0693 .29742719 \n[20] Tseng WC Wu ZF Liaw WJ \nA patient with postpolio syndrome developed cauda equina syndrome after neuraxial anesthesia: a case report\n. J Clin Anesth \n2017 ;37 :49 –51\n.28235527 \n[21] Greenhalgh S Finucane L Mercer C \nAssessment and management of cauda equina syndrome\n. Musculoskelet Sci Pract \n2018 ;37 :69 –74\n.29935940 \n[22] Faccenda KA Finucane BT \nComplications of regional anaesthesia Incidence and prevention\n. Drug Saf \n2001 ;24 :413 –42\n.11368250 \n[23] Sarifakioglu AB Yemisci OU Yalbuzdag SA \nCauda equina syndrome after cesarean section\n. Am J Phys Med Rehabil \n2013 ;92 :179 –82\n.23044703 \n[24] Yorozu T Matsumoto M Hayashi S \nDibucaine for spinal anesthesia is a probable risk for cauda equina syndrome\n. Masui \n2002 ;51 :1151 –4\n.12428328 \n[25] Kozody R Palahniuk RJ Wade JG \nThe effect of subarachnoid epinephrine and phenylephrine on spinal cord blood flow\n. Can Anaesth Soc J \n1984 ;31 :503 –8\n.6498566 \n[26] Chen X Xu Z Lin R \nPersistent cauda equina syndrome after cesarean section under combined spinal-epidural anesthesia: a case report\n. J Clin Anesth \n2015 ;27 :520 –3\n.26111666 \n[27] Rigler ML Drasner K Krejcie TC \nCauda equina syndrome after continuous spinal anesthesia\n. Anesth Analg \n1991 ;72 :275 –81\n.1994754 \n[28] Kato J Konishi J Yoshida H \nCauda equina syndrome following combined spinal and epidural anesthesia: a case report\n. Can J Anaesth \n2011 ;58 :638 –41\n.21519981 \n[29] Chabbouh T Lentschener C Zuber M \nPersistent cauda equina syndrome with no identifiable facilitating condition after an uneventful single spinal administration of 0.5% hyperbaric bupivacaine\n. Anesth Analg \n2005 ;101 :1847 –8\n.16301272\n\n",
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"title": "Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.",
"title_normalized": "vocal fold paralysis and cauda equina syndrome following spinal epidural anesthesia a case report"
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"abstract": "There is no known recommended chemotherapy after radical surgery for gastric cancer for patients who have non-curative disease. We defined positive peritoneal cytology(CY1), resection margin involvement, pathological peritoneal metastasis (pP1)and pN3b as clinical non-curative factors and administered adjuvant chemotherapy with S-1 and docetaxel(DOC) (80 mg/m2 day 1-14 of S-1 for 2 weeks with 40 mg/m2 of DOC on day 1, every 3 weeks). This regimen lasted for 1 year; however, if chemotherapy could be continued after this period, we used S-1 only. We reported the results of 11 cases who received this treatment.\n\n\nMETHODS\nThere were 6 total gastrectomies and 5 distal gastrectomies. Clinical non-curative factors were 5 pP1, 5 pN3b, 3 CY1 and 1 resection margin involvement.\n\n\nRESULTS\nAt the end of adjuvant therapy there were 6 completions, 4 recurrences, and 1 patient with side effects. The main adverse event of Grade 3 or greater was neutropenia (46%). The recurrence rate was 63.6%. Types of relapse included 6 disseminations and 1 patient with lymph node involvement. One-, 3-, and 5-year survival rates were 100%, 72.7% and 72.7%, respectively, and the RFS was 64.0 months.\n\n\nCONCLUSIONS\nS-1 and DOC adjuvant chemotherapy produced good results and may serve as a therapy of choice for patients with advanced gastric cancer with non-curative factors after a relatively curative resection.",
"affiliations": "Dept. of Gastroenterological and General Surgery, Showa University Fujigaoka Hospital.",
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"title": "Long-Term Follow-Up of Patients Who Received Chemotherapy with S-1 and Docetaxel after Relatively Curative Surgery for Advanced Gastric Cancer Including Non-Curative Factors.",
"title_normalized": "long term follow up of patients who received chemotherapy with s 1 and docetaxel after relatively curative surgery for advanced gastric cancer including non curative factors"
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{
"abstract": "In COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.",
"affiliations": "Manuel Piti Fajardo University Hospital, Ciudad Escolar Abel Santamaría. U/M 9958, Santa Clara city, Villa Clara, Cuba.;Manuel Piti Fajardo University Hospital, Ciudad Escolar Abel Santamaría. U/M 9958, Santa Clara city, Villa Clara, Cuba.;Manuel Piti Fajardo University Hospital, Ciudad Escolar Abel Santamaría. U/M 9958, Santa Clara city, Villa Clara, Cuba.;Arnaldo Milián University Hospital, Santa Clara St., Santa Clara city, Villa Clara, Cuba.;Manuel Piti Fajardo University Hospital, Ciudad Escolar Abel Santamaría. U/M 9958, Santa Clara city, Villa Clara, Cuba.;Arnaldo Milián University Hospital, Santa Clara St., Santa Clara city, Villa Clara, Cuba.;Manuel Piti Fajardo University Hospital, Ciudad Escolar Abel Santamaría. U/M 9958, Santa Clara city, Villa Clara, Cuba.;Manuel Piti Fajardo University Hospital, Ciudad Escolar Abel Santamaría. U/M 9958, Santa Clara city, Villa Clara, Cuba.;Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba.;Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba.;Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba.;Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba.;Superior Institute of Basic & Preclinical Sciences of Havana \"Victoria de Girón\", Street 25, Playa, Havana, Cuba.;Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba.;Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba.;Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba.;Arnaldo Milián University Hospital, Santa Clara St., Santa Clara city, Villa Clara, Cuba.",
"authors": "Filgueira|Lázaro Manuel|LM|0000-0003-2156-0456;Cervantes|Julio Betancourt|JB|0000-0001-8515-8226;Lovelle|Orlando Adolfo|OA|0000-0003-3944-3514;Herrera|Carlos|C|0000-0002-3072-4275;Figueredo|Carlos|C|;Caballero|Jorge Alain|JA|0000-0002-3090-2457;Sánchez|Naivy|N|0000-0003-4129-460X;Berrio|Jorge|J|;Lorenzo|Geidy|G|0000-0002-5959-5665;Cepeda|Meylan|M|0000-0002-7408-9939;Ramos|Mayra|M|0000-0002-9058-3224;Saavedra|Danay|D|0000-0002-6614-3819;Añe-Kouri|Ana Laura|AL|0000-0003-1426-3162;Mazorra|Zaima|Z|0000-0003-3812-1767;Leon|Kalet|K|0000-0002-3709-7091;Crombet|Tania|T|0000-0002-3103-6925;Caballero|Armando|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; C062279:CD6 antigen; D015850:Interleukin-6; C000597346:itolizumab",
"country": "England",
"delete": false,
"doi": "10.2217/imt-2020-0235",
"fulltext": "\n==== Front\nImmunotherapy\nImmunotherapy\nIMT\nImmunotherapy\n1750-743X 1750-7448 Future Medicine Ltd London, UK \n\n10.2217/imt-2020-0235\nCase Series\nAn anti-CD6 antibody for the treatment of COVID-19 patients with cytokine-release syndrome: report of three cases\nhttps://orcid.org/0000-0003-2156-0456Filgueira Lázaro Manuel 1 https://orcid.org/0000-0001-8515-8226Cervantes Julio Betancourt 1 https://orcid.org/0000-0003-3944-3514Lovelle Orlando Adolfo 1 https://orcid.org/0000-0002-3072-4275Herrera Carlos 2 Figueredo Carlos 1 https://orcid.org/0000-0002-3090-2457Caballero Jorge Alain 2 https://orcid.org/0000-0003-4129-460XSánchez Naivy 1 Berrio Jorge 1 https://orcid.org/0000-0002-5959-5665Lorenzo Geidy 3 https://orcid.org/0000-0002-7408-9939Cepeda Meylan 3 https://orcid.org/0000-0002-9058-3224Ramos Mayra 3 https://orcid.org/0000-0002-6614-3819Saavedra Danay 3 https://orcid.org/0000-0003-1426-3162Añe-Kouri Ana Laura 4 https://orcid.org/0000-0003-3812-1767Mazorra Zaima *3 https://orcid.org/0000-0002-3709-7091Leon Kalet 3 https://orcid.org/0000-0002-3103-6925Crombet Tania 3 Caballero Armando 2 1Manuel Piti Fajardo University Hospital, Ciudad Escolar Abel Santamaría. U/M 9958, Santa Clara city, Villa Clara, Cuba\n2Arnaldo Milián University Hospital, Santa Clara St., Santa Clara city, Villa Clara, Cuba\n3Center of Molecular Immunology, 216 St, corner 15, Atabey, Havana, Cuba\n4Superior Institute of Basic & Preclinical Sciences of Havana “Victoria de Girón”, Street 25, Playa, Havana, Cuba\n* Author for correspondence: Tel.: +537 2143 143; zaima1972@gmail.com\n05 1 2021 \n3 2021 \n05 1 2021 \n10.2217/imt-2020-023527 8 2020 09 12 2020 05 1 2021 © 2021 Future Medicine Ltd2021This work is licensed under the Creative Commons Attribution 4.0 LicenseIn COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.\n\nLay abstract\nIn COVID-19 patients, inflammation is associated with the progression of the disease. This inflammation comes from immune system activation in response to SARS-COV-2. Itolizumab is an antibody that recognizes a protein expressed in immune cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of inflammation and immune system activation. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access clinical protocol. Itolizumab was able to reduce inflammation in all patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.\n\nKeywords: \nCD6 moleculecoronavirus 2COVID-19cytokine-release syndromeIL-6itolizumabmonoclonal antibodySARS-CoV-2Center of Molecular Immunology\n==== Body\nA group of COVID-19 patients develops severe or critical disease accompanied by the cytokine storm syndrome. Cytokines are essential to the pathophysiology of disease and IL-6, IL-1 and TNF-α appear to be harmful, particularly in the context of the cytokine-release syndrome (CRS) [1,2].\n\nCD6 is a membrane glycoprotein expressed primarily in mature, activated T cells. Ligand binding of CD6, increases events such as adhesion, activation, proliferation, differentiation and survival [3–6]. In addition, CD6 mediates interaction between T cells and antigen-presenting cells, contributing to the maturation of immune synapses [6]. CD6-mediated costimulation contributes to the maturation of a Th1 pattern in human T cells and preferentially promotes a pro-inflammatory response characterized by the secretion of TNF-α, IL-6 and IFN γ [7].\n\nThe activated leukocyte-cell adhesion molecule (ALCAM), also known as CD166, has been identified as the CD6 ligand [8,9]. ALCAM interaction with CD6 stabilizes the formation of the immune synapse between the lymphocytes and the antigen-presenting cells [5].\n\nItolizumab is a humanized monoclonal antibody developed at the Center of Molecular Immunology, in Cuba, that recognizes a region in the distal domain of the human CD6 [10,11]. The antibody reduces the expression of the intracellular proteins involved in activation and inhibits the proliferation of T cells, even in the presence of the ALCAM and IL-2 [10–12]. The effect is associated with the reduction of the secretion of pro-inflammatory cytokines including IFN-γ, IL-6 and TNF-α [13,14]. The antibody has demonstrated to be safe and efficacious in patients with moderate to severe psoriasis [15,16]. Studies from blood and tissue samples from patients with severe psoriasis showed that itolizumab reduces the proliferation of T cells and serum concentration of IL-6, TNF-α and IFN-γ [13–16]. A significant reduction of the inflammatory pattern was also observed in the tissue. On account of its well proven effect on T-cell activation and proinflammatory cytokines production, itolizumab was included as part of a Cuban expanded access protocol in critical, severe and moderate COVID-19 patients with high risk of aggravation. The study will be published soon (manuscript accepted) and here we describe in detail the outcome of three initial patients receiving the antibody.\n\nCases description\nPatient 1: A 53-year old woman with a personal history of essential hypertension and Type 2 diabetes mellitus presented with symptoms of polypnea of more than 40 rpm, use of respiratory ancillary musculature and dry cough. She arrived from a foreign country where COVID-19 was spreading. Symptoms started on 23 March and COVID-19 was diagnosed on 26 March on the basis of positive real time PCR (RT-PCR) for SARS-CoV-2. Initial gasometry showed moderate hypoxemia and respiratory alkalosis with a partial pressure of oxygen/fraction of inspired oxygen (PO2/FiO2) ratio of 191. Chest x-rays showed interstitial lesions in both lung fields. She started therapy with lopinavir/ritonavir, chloroquine, recombinant IFN α-2b and rocephin. In spite of treatment, the illness subsequently progressed to hypoxemic respiratory failure warranting the initiation of invasive mechanical ventilation. At day 13 of her admission in the ICU, she showed radiologic worsening of the interstitial multifocal pneumonia, with elevation of ALP, LDH, erythrocyte sedimentation rate and D-dimer. Physicians administered itolizumab at a dose of 200 mg. After 48 h of the first itolizumab dose, PO2/FiO2 improved and there were evidences of radiological improvement (Figure 1A & B). Patient was extubated after the first dose of the antibody and her status changed from critical to severe. She received a second dose of the antibody (200 mg), 48 h after the first infusion. 3 days after the first administration, patient was hemodynamically stable and has spontaneous ventilation. IL-6 levels were evaluated before itolizumab administration and after 2 and 7 days of the first administration. IL-6 levels reduced overtime from 172 pg/ml to 60 pg/ml (day 7) as depicted in Figure 2A. IL-1 was evaluated at the same time intervals, but it was undetectable. In addition, aspartate amino transferase (AST) concentrations were evaluated at different time points showing a reduction from 43 U/l to 24 U/l after 7 days (Figure 2B). No adverse events related with itolizumab were reported.\n\nFigure 1. Radiological images before and after one dose of itolizumab.\nPatient 1\n(A) Before itolizumab (D0): diffuse Interstitial-alveolar infiltrate in both lung fields, predominantly in the bases. Minor left pleural effusion. (B) After itolizumab (48 h): radiological improvement with decreased diffuse infiltrate and radio-opacity at the top of both lungs and in both lung bases, in less proportion. The minor pleural effusion persists. Patient 3\n(C) Before itolizumab (D0): alveolar interstitial inflammatory infiltrate in both lung fields, predominantly on the right side. (D) After itolizumab (48 h): radiological improvement with significant decrease of the alveolar interstitial infiltrate of both lungs.\n\nFigure 2. Circulating biomarkers in patient's sera.\nIL-6 and AST concentrations kinetics (A & B, respectively) measured in patients during itolizumab treatment.\n\nPatient 2: An 89-year old man with a personal history of chronic ischemic cardiopathy, permanent atrial fibrillation, hypertension and hypothyroidism. He has a previous history of alcoholism and several hospital admissions in the last 3 months on account of infectious respiratory diseases. He came to the hospital on 2 April after 7 days of shortness of breath, fever, asthenia and dry cough. He was in contact with a person who returned from a foreign country, where COVID-19 was extending. Physical examination shows signs of respiratory failure characterized by tachycardia, polypnea, intercostal and supraclavicular muscle retraction, high blood pressure, oxygen saturation of 82%, poor diuresis and drowsiness. Chest x-rays showed bilateral pulmonary inflammatory infiltrates, predominantly in the right lung. Admission ECG showed an atrial fibrillation with rapid ventricular response and the initial gasometry showed severe hypoxemia and respiratory alkalosis. Patient also had leukocytosis, altered globular sedimentation rate as well as elevated values of AST, LDH, D-dimer and positive C-reactive protein. He was admitted into the ICU requiring invasive mechanical ventilation. Treatment with lopinavir–ritonavir, chloroquine, IFN α-2b, meropenem and linezolid was initiated. 3 days after his admission into the ICU, itolizumab was prescribed, due to worsening of the bilateral pulmonary infiltrates together with a deterioration of the ventilatory function (PO2/FiO2 = 173). After the first antibody infusion, PO2/FiO2 significantly increased (PO2/FiO2 = 320) and there were evidences of radiological improvement. 3 days after, patient showed radiological worsening of the left lung, characterized by alveolar hypoventilation and atelectasis; then, a 70% pneumothorax was established. Treatment of the pneumothorax with minimal pleurotomy was very demanding and required 3 days for the resolution. The patient received a second infusion of the monoclonal antibody 72 h after the first, while a third dose was administered at the discretion of the treating physicians, 2 days after the second. In total, patient received three doses of itolizumab (200 mg) without any related adverse event. IL-6 levels were evaluated before itolizumab administration and after 2, 4 and 7 days of the first administration. IL-6 was extremely high at baseline (623 pg/ml) and even though cytokine levels reduced roughly 50%, the lowest value remained above 300 pg/ml after 7 days. IL-6 kinetics is shown in Figure 2A. Apart from IL-6, IL-1 was undetectable at this time point of the disease. Interesting, in the case of AST, a significant reduction is detecting at day 7 (pretreatment: 156 U/l, D7: 40 U/l) as is showed in Figure 2B. After 10 days of admission into the ICU, patient presented a myocardial dysfunction and shock that required vasoactive support with norepinephrine. On day 13, he finally died, on account of a mixed cardiovascular and respiratory failure.\n\nPatient 3: An 81-year old female, who is COVID-19 positive contact was not identified at the moment of hospitalization. She started symptoms on 2 April and entered the ICU on 5 April. Patient has a previous history of hypertension, diabetes mellitus, glaucoma and smoking habit. She was admitted with frequent cough, wheezing and diarrhea. The diagnosis of viral pneumonia by COVID-19 was confirmed by RT-PCR on 7 April. Oxygen support at 5 l/min and treatment with ceftriaxone, lopinavir–ritonavir, chloroquine and IFN α-2b was indicated. Chest images showed bilateral interstitial infiltration in both lungs. Patient condition was classified as severe, although she did not require invasive mechanical ventilation. A dose of itolizumab (200 mg) was given the day after her admission into the ICU. Two days after the antibody administration, together with the rest of the therapy, there was an improvement of the respiratory distress while the chest image showed a decrease of the alveolar interstitial infiltrate of both lungs (Figure 1C & D). Patient left the ICU after a favorable clinical and radiological evolution. IL-6 concentration was measured prior and after the antibody administration. IL-6 level at baseline was lower than in previous cases (30 pg/ml), but also decreased 48 h and 168 h after itolizumab infusion, in parallel with patient recovery (Figure 2A). IL-1 and TNF-α were untraceable before and 48 h after the antibody administration. Regarding to AST concentration, the values were in the normal range during the treatment period (Figure 2B).\n\nMaterials & methods\nThree patients with diagnosis of COVID-19 classified as critically ill (two) and severely ill (one) were included in an expanded access trial to receive itolizumab in addition to standard treatment (http://rpcec.sld.cu/trials/RPCEC00000311-En). The study was approved by a central ethical review board, created especially for COVID-19 and by the Cuban Regulatory Agency (CECMED). Before the treatment, informed consent was obtained from enrolled patient.\n\nLaboratory results included blood routine, leucocyte subsets and blood biochemical parameters were collected. The level of inflammatory cytokines was measured using human validated commercially available kit from R&D Systems (MN, USA): human IL-6 Quantikine ELISA Kit (Cat# S6050), human IL-1 beta/IL-1F2 Quantikine ELISA Kit (Cat# SLB50) and human TNF-α Quantikine ELISA Kit (Cat# STA00D). In the case of IL-6, the normal range of this cytokine in sera is between 0 and 7 pg/ml [17]. We used intra-assay precision and inter-assay precision methods to evaluate precision in this study.\n\nFor intra-assay precision (precision within an assay), three samples of known concentration were tested on one plate to assess intra-assay precision.\n\nFor inter-assay precision (precision between assays), three samples of known concentration were tested in separate assays to assess inter-assay precision.\n\nDiscussion\nCRS is characterized by high levels of inflammatory cytokines. Among them, IL-6 is considered a major mediator of this hyperinflammation [18,19]. Most of the COVID-19 patients-related papers showed the CRS as one of the main hallmark of the disease [20]. Additionally, IL-6 levels predict severity in COVID-19 patients [21]. There is high heterogeneity of IL-6 values among papers for classifying severe and nonsevere patients. In a large meta-analysis of 52 manuscripts, Elshazli and coworkers found that the IL-6 level associated with COVID-19 severity was 22.9 pg/ml [22]. In a series of patients treated with itolizumab a cutoff of 28 pg/ml discriminates severe patients from nonsevere (manuscript just accepted in Immunity and Aging). In the present study, the IL-6 concentration of the three patients was above this cutoff. It confirms the classification of these patients as severe and that the CRS is probably occurring.\n\nSeveral anticytokine therapies have been tried for treating the hyperinflammatory phase of COVID-19 [20,23–25]. Here, we report the use of a well-known anti-inflammatory antibody targeting CD6 to treat the CRS arising in COVID-19 patients. Using an anti-CD6 antibody could reduce the concentration of several pro-inflammatory cytokines, including IL-6, IFN-γ, TNF-α and IL-17, among others, representing an advantage as compared with single-cytokine targeting antibodies. The antibody would not exacerbate lymphopenia since it does not induce complement or antibody dependent cytotoxicity [10,11].\n\nThese three SARS-CoV2 patients developed severe respiratory distress together with multifocal interstitial pneumonia. Two patients required invasive mechanical ventilation while the third patient only needed oxygen supply. They all received the anti-CD6 antibody itolizumab in combination with other drugs incorporated into the Cuban national protocol, including lopinavir/ritonavir, chloroquine and IFNα-2b. Regarding to laboratory parameters, AST is strongly associated with mortality risk compared with other parameters, reflecting liver and kidney injury [26,27]. In our cases, critically ill patients showed a significant reduction of AST concentration after the treatment suggesting an improvement in the function of these organs.\n\nItolizumab was very safe and did not seem to exacerbate opportunistic secondary infections. Unfortunately, we did no measure neither the frequency nor the total amount of circulating T cells in these initial patients. The impact of itolizumab on circulating T cells are being implementing in new recruited patients.\n\nOur preliminary findings support that IL-6 levels correlated with the severity of the disease and that the antibody was capable of reducing IL-6 concentration in all three subjects. One patient died after subsequent respiratory and cardiovascular complications. In this particular case, IL-6 concentration was extremely elevated at the moment of itolizumab infusion. Although, the levels of IL-6 decreased during treatment, the values at 7 days kept still very high (above 300 pg/ml). There was a transient improvement of respiratory function but it was not enough. Presumably, the consequences of the hyperinflammatory syndrome (thrombosis, alveolar damage and severe tissue hypoxia) were irreversible at the moment of treatment and patient died as consequence of these factors.\n\nConclusion\nIn summary, in these severe and critically ill patients, itolizumab was able to reduce IL-6 concentrations. Notably, itolizumab-related adverse events were not reported. Patients with baseline IL-6 levels below 200 pg/ml, showed prompt clinical and radiological recovery. We anticipate that the timely use of this anti-inflammatory antibody in combination with the appropriate antiviral and anticoagulant therapy could reduce the mortality associated with COVID-19. The analysis of the complete-series will be published shortly.\n\nSummary points\nInflammatory cytokine-release syndrome is associated with the progression of the coronavirus disease (COVID-19).\n\nNo current therapy has proven effective for the management of this syndrome so far.\n\nItolizumab is a humanized monoclonal antibody that recognizes human CD6 and its effect is associated with the reduction of pro-inflammatory cytokines release.\n\nWe present three COVID-19 cases who developed severe respiratory distress together with multifocal interstitial pneumonia.\n\nThe patients were treated with itolizumab combined with antiviral therapies.\n\nItolizumab reduced circulating IL-6 concentrations in the three COVID-19 patients.\n\nTwo patients showed rapid ventilatory and radiological improvement and were fully recovered.\n\nItolizumab-related adverse events were not reported.\n\nThese cases show that the timely use of this anti-inflammatory antibody in combination with the appropriate antiviral and anticoagulant therapy could reduce the mortality associated with COVID-19.\n\nAuthor contributions\nStudy design and data interpretation: G Lorenzo, M Cepeda, M Ramos, D Saavedra, Z Mazorra, K Leon and T Crombet; clinical investigators (recruited and treated patients): LM Filgueira, JB Cervantes, OA Lovelle, C Herrera, C Figueredo, JA Caballero, N Sánchez, J Berrio, A Caballero; immunological assessments: D Saavedra, AL Añe-Kouri, Z Mazorra; writing and or/revision of the manuscript: T Crombet and A Caballero.\n\nAcknowledgments\nWe are extremely grateful to all ICU physicians, nurses and general staff working with severe and critically ill COVID-19 patients.\n\nFinancial & competing interests disclosure\nSeven authors (G Lorenzo, M Cepeda, M Ramos, D Saavedra, Z Mazorra, K Leon and T Crombet) currently work for the Center of Molecular Immunology, the institution that generated and originally patented itolizumab. The remaining authors do not have any commercial or financial relationships that could be taken as a potential conflict of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nEthical conduct of research\nThe authors state that they have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. The study was approved by a central ethical review board, created especially for COVID-19 and by the Cuban Regulatory Agency (CECMED). Before the treatment, informed consent was obtained from enrolled patient.\n\nData sharing statement\nThe authors certify that this manuscript reports original clinical trial data on three patients, RPCEC00000311. Individual participant data that underlies the results reported in the article, after de-identification (text, tables, figures and supplement) are available along with the study protocol. The data will be available 9 months after article publication and will end 36 months following article publication. The information will be shared with investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose and for individual participant data meta-analysis. Proposals may be submitted up to 36 months following article publication. After this date the data will be available in our data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposal and accessing data may be found at http://rpcec.sld.cu/trials/RPCEC00000311-En\n==== Refs\nReferences\nPapers of special note have been highlighted as: • of interest; •• of considerable interest\n\n1. 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Xu X , Han M , Li T \n\nEffective treatment of severe COVID-19 patients with tocilizumab\n. Proc. Natl Acad. Sci. USA \n117 (20 ), 10970 –10975\n (2020 ).32350134 \n18. McGonagle D , Sharif K , O'Regan A , Bridgewood C \nThe role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease\n. Autoimmun. Rev. \n19 (6 ), 102537 (2020 ). 32251717 • Demonstrates the role of IL-6 as major mediator of hyperinflammation.\n\n\n19. Giamarellos-Bourboulis EJ , Netea MG , Rovina N \n\nComplex immune dysregulation in COVID-19 patients with severe respiratory failure\n. Cell Host Microbe. \n27 (6 ), 992 –1000\n\ne1003 (2020 ).32320677 \n20. Saha A , Sharma AR , Bhattacharya M , Sharma G , Lee SS , Chakraborty C \nTocilizumab: a therapeutic option for the treatment of cytokine storm syndrome in COVID-19\n. Arch. Med. Res. \n51 (6 ), 595 –597\n (2020 ).32482373 \n21. Chen X , Zhao B , Qu Y \n\nDetectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019\n. Clin. Infect. Dis. \n71 (8 ), 1937 –1942\n (2020 ). 32301997 • Shows the IL-6 levels as predictor of severity in COVID-19 patients.\n\n\n22. Elshazli RM , Toraih EA , Elgaml A \n\nDiagnostic and prognostic value of hematological and immunological markers in COVID-19 infection: a meta-analysis of 6320 patients\n. PLoS ONE \n15 (8 ), e0238160 (2020 ).32822430 \n23. Mehta P , McAuley DF , Brown M \n\nCOVID-19: consider cytokine storm syndromes and immunosuppression\n. Lancet \n395 (10229 ), 1033 –1034\n (2020 ). 32192578 • Suggests cytokine-mediated inflammation as a mechanism of COVID-19 pneumonia.\n\n\n24. Calabrese C , Rajendram P , Sacha G , Calabrese L \nPractical aspects of targeting IL-6 in COVID-19 disease\n. Cleve. Clin. J. Med. (2020 ) (Epub ahead of print ).\n25. Chakraborty C , Sharma AR , Bhattacharya M , Sharma G , Lee SS , Agoramoorthy G \nCOVID-19: consider IL-6 receptor antagonist for the therapy of cytokine storm syndrome in SARS-CoV-2 infected patients\n. J. Med. Virol. \n92 (11 ), 2260 –2262\n (2020 ).32462717 \n26. Lei F , Liu YM , Zhou F \n\nLongitudinal association between markers of liver injury and mortality in COVID-19 in China\n. Hepatology \n72 (2 ), 389 –398\n (2020 ).32359177 \n27. Henry BM , de Oliveira MHS , Benoit S , Plebani M , Lippi G \nHematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis\n. Clin. Chem. Lab. Med. \n58 (7 ), 1021 –1028\n (2020 ). 32286245 • Identifies potential biomarkers for predicting severe and fatal COVID-19.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1750-743X",
"issue": "13(4)",
"journal": "Immunotherapy",
"keywords": "CD6 molecule; COVID-19; IL-6; SARS-CoV-2; coronavirus 2; cytokine-release syndrome; itolizumab; monoclonal antibody",
"medline_ta": "Immunotherapy",
"mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D000086382:COVID-19; D016638:Critical Illness; D000080424:Cytokine Release Syndrome; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015850:Interleukin-6; D008297:Male; D008875:Middle Aged; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "289-295",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "An anti-CD6 antibody for the treatment of COVID-19 patients with cytokine-release syndrome: report of three cases.",
"title_normalized": "an anti cd6 antibody for the treatment of covid 19 patients with cytokine release syndrome report of three cases"
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"companynumb": "CU-ABBVIE-21K-040-3781038-00",
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"abstract": "Status cataplecticus is a rare manifestation of narcolepsy with cataplexy episodes recurring for hours or days, without a refractory period, in the absence of emotional triggers. This case highlights a narcoleptic patient who developed status cataplecticus after abrupt withdrawal of venlafaxine.",
"affiliations": "Division of Pulmonary, Critical Care and Sleep Medicine, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, NY 11040, USA. janiceywang@gmail.com",
"authors": "Wang|Janice|J|;Greenberg|Harly|H|",
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"keywords": "Status cataplecticus; cataplexy; narcolepsy; venlafaxine withdrawal",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000368:Aged; D002385:Cataplexy; D003511:Cyclohexanols; D004569:Electroencephalography; D005260:Female; D006801:Humans; D006973:Hypertension; D009290:Narcolepsy; D017367:Serotonin Uptake Inhibitors; D013375:Substance Withdrawal Syndrome; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "715-6",
"pmc": null,
"pmid": "23853567",
"pubdate": "2013-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18175082;18753005;15033130;3704444;22205591;2740697",
"title": "Status cataplecticus precipitated by abrupt withdrawal of venlafaxine.",
"title_normalized": "status cataplecticus precipitated by abrupt withdrawal of venlafaxine"
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"companynumb": "PHHY2013US092189",
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"occurcountry": "US",
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"activesubstancename": "LISINOPRIL"
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"abstract": "Amiodarone-induced SIADH is a rare but serious side effect of this drug. We report two cases of mild hyponatremia, observed in the last five years, and discuss the role played by age, sex and dose of amiodarone as well as the influence that this molecule may have on aquaporin-2 water channel expression in the renal collecting ducts.",
"affiliations": "Endocrinology and Metabolic Diseases, Eboli Hospital, Salerno, Italy. micheleiovino06@tin.it.",
"authors": "Iovino|Michele|M|;Iovine|Nicola|N|;Petrosino|Antonio|A|;Licchelli|Brunella|B|;Giagulli|Vito A|VA|;Iacoviello|Massimo|M|;Guastamacchia|Edoardo|E|;Triggiani|Vincenzo|V|",
"chemical_list": "D000638:Amiodarone",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1871530314666140407111410",
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"issue": "14(2)",
"journal": "Endocrine, metabolic & immune disorders drug targets",
"keywords": null,
"medline_ta": "Endocr Metab Immune Disord Drug Targets",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D001145:Arrhythmias, Cardiac; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007177:Inappropriate ADH Syndrome; D008297:Male",
"nlm_unique_id": "101269157",
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"pages": "123-5",
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"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amiodarone-induced SIADH: two cases report.",
"title_normalized": "amiodarone induced siadh two cases report"
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"abstract": "Lung transplant (LuTx) recipients represent a population at risk of nontuberculous mycobacterial pulmonary disease (NTM-PD). Yet the risk factors, the timing of NTM-PD after transplantation, and the association with allograft dysfunction all remain poorly defined. We report 2 cases of early-onset NTM-PD and review the literature, focusing on NTM-PD in LuTx recipients not colonized with NTM prior to transplantation. In addition, we summarize the main characteristics and differences between early- and late-onset disease.",
"affiliations": "Department for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.;Department for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.;Department for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.;Department for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.;National Reference Laboratory for Mycobacteria, National Institute of Health, Zagreb, Croatia.;Department for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.;Department for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.;School of Medicine, University of Zagreb, Zagreb, Croatia.;Department of Surgery, Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.;Department of Surgery, Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.;Department for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.",
"authors": "Jankovic Makek|M|M|;Pavlisa|G|G|;Jakopovic|M|M|;Redzepi|G|G|;Zmak|L|L|;Vukic Dugac|A|A|;Hecimovic|A|A|;Mazuranic|I|I|;Jaksch|P|P|;Klepetko|W|W|;Samarzija|M|M|",
"chemical_list": null,
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"doi": "10.1111/tid.12481",
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"issn_linking": "1398-2273",
"issue": "18(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "lethal outcome; lung transplantation; nontuberculous mycobacteria; nontuberculous mycobacterial pulmonary disease",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008168:Lung; D008171:Lung Diseases; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "112-9",
"pmc": null,
"pmid": "26556693",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Early onset of nontuberculous mycobacterial pulmonary disease contributes to the lethal outcome in lung transplant recipients: report of two cases and review of the literature.",
"title_normalized": "early onset of nontuberculous mycobacterial pulmonary disease contributes to the lethal outcome in lung transplant recipients report of two cases and review of the literature"
} | [
{
"companynumb": "HR-MYLANLABS-2016M1015537",
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"activesubstancename": "CLARITHROMYCIN"
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{
"abstract": "Human adenoviruses (HAdV) are well-known opportunistic pathogens of immunocompromised adult and pediatric patients but specific associations between HAdV species or individual HAdV types and disease are poorly understood. In this study we report the isolation of a novel HAdV-B2 genotype from two unrelated immunocompromised patients, both recipients of a hematopoietic cell transplant. In both patients, the course of HAdV infection is consistent with a scenario of reactivation of a latent virus rather than a primary opportunistic infection. Archived HAdV PCR-positive plasma, urine, and stool specimens were processed for virus isolation and detailed molecular characterization. Virus isolates were recovered from patient 1 from PCR-positive urine specimens obtained at days 103 and 116 after transplant in association with gross hematuria, and from a stool specimen obtained 138 days after transplant in association with diarrhea. An isolate was recovered from patient 2 from a PCR-positive urine specimen. Hexon and fiber gene amplification and sequencing were carried out for initial molecular typing, identifying the isolates as an intertypic recombinant with a HAdV-11-like hexon gene and a HAdV-77-like fiber gene. Comprehensive restriction fragment length polymorphism (RFLP) analysis was performed on viral DNA purified from urine and stool isolates, and next generation whole genome sequencing was carried out on purified viral genomic DNA. The genomes of the two isolated strains are 99.5% identical and represent the same RFLP genomic variant. The identified virus is a novel HAdV-B2 genotype designated HAdV-78 exhibiting a HAdV-11-like penton base, a HAdV-11-like hexon and a HAdV-77-like fiber (P11H11F77).",
"affiliations": "Lovelace Respiratory Research Institute (LRRI), Albuquerque, NM, USA.;Virology Laboratory, Wadsworth Center, New York State Department of Health, Albany, NY, USA.;Division of Infectious Diseases, The Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Infectious Disease Diagnostics Laboratory, Children's Hospital of Philadelphia, Philadelphia, PA.;Department of Laboratory Medicine and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Division of Infectious Diseases, The Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Virology Laboratory, Wadsworth Center, New York State Department of Health, Albany, NY, USA.",
"authors": "Kajon|A E|AE|;Lamson|D M|DM|;Spiridakis|E|E|;Cardenas|A M|AM|;Babady|N E|NE|;Fisher|B T|BT|;St George|K|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.nmni.2020.100677",
"fulltext": "\n==== Front\nNew Microbes New Infect\nNew Microbes New Infect\nNew Microbes and New Infections\n2052-2975 Elsevier \n\nS2052-2975(20)30029-9\n10.1016/j.nmni.2020.100677\n100677\nOriginal Article\nIsolation of a novel intertypic recombinant human mastadenovirus B2 from two unrelated bone marrow transplant recipients\nKajon A.E. akajon@lrri.org1∗ Lamson D.M. 2 Spiridakis E. 3 Cardenas A.M. 4 Babady N.E. 5 Fisher B.T. 3 St George K. 2 1) Lovelace Respiratory Research Institute (LRRI), Albuquerque, NM, USA\n2) Virology Laboratory, Wadsworth Center, New York State Department of Health, Albany, NY, USA\n3) Division of Infectious Diseases, The Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA, USA\n4) Infectious Disease Diagnostics Laboratory, Children's Hospital of Philadelphia, Philadelphia, PA\n5) Department of Laboratory Medicine and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA\n∗ Corresponding author: A. Kajon, Lovelace respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA. akajon@lrri.org\n09 4 2020 \n5 2020 \n09 4 2020 \n35 10067710 2 2020 19 3 2020 3 4 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Human adenoviruses (HAdV) are well-known opportunistic pathogens of immunocompromised adult and pediatric patients but specific associations between HAdV species or individual HAdV types and disease are poorly understood.\n\nIn this study we report the isolation of a novel HAdV-B2 genotype from two unrelated immunocompromised patients, both recipients of a hematopoietic cell transplant. In both patients, the course of HAdV infection is consistent with a scenario of reactivation of a latent virus rather than a primary opportunistic infection.\n\nArchived HAdV PCR-positive plasma, urine, and stool specimens were processed for virus isolation and detailed molecular characterization. Virus isolates were recovered from patient 1 from PCR-positive urine specimens obtained at days 103 and 116 after transplant in association with gross hematuria, and from a stool specimen obtained 138 days after transplant in association with diarrhea. An isolate was recovered from patient 2 from a PCR-positive urine specimen. Hexon and fiber gene amplification and sequencing were carried out for initial molecular typing, identifying the isolates as an intertypic recombinant with a HAdV-11-like hexon gene and a HAdV-77-like fiber gene. Comprehensive restriction fragment length polymorphism (RFLP) analysis was performed on viral DNA purified from urine and stool isolates, and next generation whole genome sequencing was carried out on purified viral genomic DNA. The genomes of the two isolated strains are 99.5% identical and represent the same RFLP genomic variant. The identified virus is a novel HAdV-B2 genotype designated HAdV-78 exhibiting a HAdV-11-like penton base, a HAdV-11-like hexon and a HAdV-77-like fiber (P11H11F77).\n\nHighlights\n• A novel HAdV-B2 type was isolated from 2 unrelated stem cell transplant recipients.\n\n• The two isolated strains are 99.5% identical and represent the same genomic variant.\n\n• The virus is an intertypic recombinant P11H11F77 designated HAdV-78.\n\n• Genotype HAdV-78 is closely related to HAdV-77 with a 99% sequence similarity.\n\n\n\nKeywords\nAdenovirusGenotype HAdV-78Species HAdV-BWhole-genome sequencing\n==== Body\nBackground\nHuman adenoviruses (HAdV) currently constitute a group of 51 antigenic (sero) types and over 90 genotypes defined on the basis of their genomic characteristics, classified into seven species designated human mastadenovirus A to G (HAdV-A to HAdV-G) [[1], [2], [3]]. HAdVs are frequently detected as opportunistic pathogens in paediatric and adult patients undergoing iatrogenic immunosuppression for bone marrow or solid organ transplantation, as well as in patients receiving chemotherapy, or with other immunocompromising conditions such as acquired immunodeficiency syndrome [[4], [5], [6], [7], [8], [9], [10]]. Paediatric allogeneic haematopoietic stem cell transplant recipients with an active HAdV infection resulting from either virus reactivation from a latent infection or a primary exposure are at particularly high risk of developing severe disease involving one or more organ systems [[11], [12], [13], [14], [15], [16]].\n\nThe natural history, epidemiology and pathobiology of HAdV infections detected in immunocompromised individuals are still poorly understood. Opportunities to study specific virus–host interactions and aspects of viral pathogenesis in this complex context where multiple opportunistic infections are often detected are very limited.\n\nObjectives\nTo describe the clinical and virological findings associated with the isolation of a novel intertypic recombinant human adenovirus of species HAdV-B from a paediatric and an unrelated adult haematopoietic cell transplant (HCT) recipient. This work is part of an ongoing collaborative effort to establish more comprehensive data on the impact of HAdV infections in paediatric patients undergoing HCT and to contribute to the characterization of the still poorly defined molecular epidemiology of HAdV infections in HCT recipients and other immunocompromised patient populations.\n\nStudy design\nCase identification and clinical data abstraction\nPatient 1 was originally investigated as part of a cohort of HAdV-positive transplant recipients assembled for an observational retrospective study performed at the Children's Hospital of Philadelphia (CHOP) in partnership with the Lovelace Respiratory Research Institute (LRRI). Patient 2 was originally investigated based on the clinical interest it elicited and the initial virological findings. The medical charts of these two individuals were retrospectively reviewed at CHOP (patient 1) and Memorial Sloan Kettering Cancer Center (MSKCC) (patient 2), respectively.\n\nAdenovirus detection in clinical specimens\nAt CHOP, the DNA was extracted from 200 μL of each clinical specimen for real-time TaqMan® quantitative PCR-based detection of adenovirus using an automated MagNAPure LC instrument and a total nucleic acid isolation kit from Roche Diagnostics (Indianapolis, IN, USA). A laboratory-developed quantitative real-time TaqMan® PCR was performed in 50-μL volumes based on the primers and probe targeting the hexon gene developed by Heim et al. [17].\n\nFor adenovirus testing, MSKCC submitted clinical specimens to a reference laboratory (Viracore, Lee Summit, MO, USA) where they were processed for a proprietary laboratory-developed quantitative PCR assay that targets two conserved regions of the HAdV hexon gene (Test code 7500, https://www.viracor-eurofins.com/test-menu/7500-adenovirus-real-time-qpcr).\n\nVirus isolation and initial rounds of molecular typing\nAll HAdV PCR-positive clinical specimens available for patient 1 (plasma, urine and stool) and the only specimen (urine) available for patient 2 were inoculated into conventional virus-culture tubes of A549 cells (ATCC® CCL-185) for virus isolation. Infected monolayers were monitored for the development of cytopathic effect for 1 week and harvested when extensive cytopathic effect was observed. Isolates were recovered only from the stool and urine specimens from patient 1 and from the urine specimen from patient 2. Intracellular viral DNA was isolated from infected A549 cell monolayers in 75-cm2 flasks for restriction enzyme analysis as previously described [18]. Briefly, ∼1 μg of viral genomic DNA was digested with 10 units of each endonuclease following the manufacturer's recommendations (New England Biolabs, Ipswich, MA, USA) and digests were analysed by horizontal 1% agarose gel electrophoresis. Initial typing at the species level was accomplished by analysis of BamHI digestion profiles. A more detailed characterization was subsequently performed by digestion with BclI, BglII, BstEII, HindIII, HpaI, PstI, SmaI and XbaI, the panel of endonucleases described by Li et al. [19] for the analysis of subspecies HAdV-B2 types. Molecular typing was initially carried out by PCR amplification and sequencing of hypervariable regions 1–7 of the hexon gene and the complete fibre gene followed by BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) analysis [20]. Molecular type identities were assigned based on the identity of the closest match. For initial molecular typing of patient 2's specimen, total DNA was extracted from 200 μL of the sample using a NUCLISENS easyMAG (bioMérieux, Durham, NC, USA) and processed for PCR amplification of hexon gene hypervariable regions 1–6 using the primers and cycling conditions developed by Okada et al. [21]. Sanger sequencing of the amplicon was performed on a 3130 analyser (ThermoFisher Scientific Inc., Waltham, MA, USA) using the amplification primers. The resulting sequences were assigned a hexon type identity by BLAST analysis.\n\nComplete genomic sequencing of adenovirus genomes\nViral DNA purified from a urine isolate from patient 1 (2146-13-VT10810), and from the urine isolate obtained from patient 2 were further processed for whole-genome sequencing. Next-generation whole-genome sequencing was performed on an Illumina MiSeq using the standard protocol recommended by the manufacturer (Illumina Inc., San Diego, CA, USA). In brief, barcoded libraries were prepared with the Nextera XT DNA Library Prep kit (Illumina Inc.) and quantified using the Qubit dsDNA HS assay (ThermoFisher Scientific Inc.). The library size was determined using the Agilent Bio-analyser (Agilent Technologies, Santa Clara, CA, USA). Paired-end sequencing with the 2 × 250 bp kit was performed using the MiSeq 500 cycle v2 kit. Contiguous sequences (contigs) were de novo assembled using the SPAdes 3.5 application in BaseSpace (Illumina Inc.), and the resulting contigs from each of the samples were used in all further genetic analyses.\n\nGenomic sequence data analysis\nThe complete genomic sequences of the prototype strains of HAdV-7 (Gomen/GenBank AY594255), HAdV-11 (Slobitski/GenBank AF32578), HAdV-34 (Compton/GenBank AY737797), HAdV-35 (Holden/GenBank AY271307), and that of a recently described intertypic recombinant P35H34F7 (HAdV-77, strain DEU/HEIM_00092/1985/GenBank KF268328) were included in the analysis. These genomic sequences and those obtained in this study for strains CHOP2146/10810 and NY12/12146 were aligned using MAFFT in Geneious R11 (Biomatters Inc., Auckland, New Zealand, www.geneious.com). Multiple alignments were further analysed with SimPlot [22] using the genome of urine isolate 2146-13-VT10810 as a query sequence. SimPlot settings were set at a window of 200 bp with a step of 20 bp. The neighbour-joining phylogenetic tree was constructed based on the Kimura two-parameter model [23,24] using MEGA X software (https://www.megasoftware.net) with 500 bootstrap replicates.\n\nIn silico restriction enzyme analysis of viral genomes was carried out using Geneious R11.\n\nResults\nCase reports\nPatient 1 was a 17-year-old male who received a matched unrelated B- and T-cell-depleted peripheral haematopoietic cell transplant for high-risk acute lymphoblastic leukaemia with induction failure. He was conditioned with total body irradiation, cyclophosphamide and thiotepa and received cyclosporine for prophylaxis against graft-versus-host disease (GVHD). His initial post-transplant course was complicated by mucositis, Capnocytophaga sp. bacteraemia, and stage III skin GVHD, that was controlled with prednisone and tacrolimus. The patient was discharged home 29 days after transplant (day +29) but had to be readmitted on day +33 for gross haematuria, urinary frequency, urgency and dysuria. At that time, his urine and blood were both PCR-positive for BK virus but negative for HAdV. He was given cidofovir at a dose of 0.25 mg/kg for presumed BK virus haemorrhagic cystitis and his haematuria resolved on day +40. Bone marrow studies showed absence of minimal residual disease and 100% donor engraftment by day +35, and he was eventually discharged to home on day +47. One week later he presented at the emergency department complaining of fever, nausea, vomiting, diarrhoea, weight loss and poor oral intake. His initial work-up including blood cultures, stool cultures and Clostridium difficile was negative. Viral PCR tests of his blood for cytomegalovirus (CMV), Epstein–Barr virus (EBV) and HAdV were negative. A viral gastrointestinal PCR panel that includes HAdV-40 and HAdV-41 was also negative. A lumbar puncture was negative for leukaemia and negative for CMV, EBV, human herpesvirus-6, HAdV, enterovirus and parechovirus by PCR. Upper gastrointestinal endoscopy revealed oesophagitis caused by Candida albicans and Candida tropicalis and the patient was started on fluconazole. After 21 days of hospitalization, the patient was discharged to home but was readmitted on day +99 for poor nutrition and skin and liver GVHD. His GVHD was treated with tacrolimus and methylprednisolone followed by prednisone. On day +103 he had recurrence of gross haematuria and this time, both his urine and blood tested positive for HAdV (Ct 22.4 and Ct 39.66, respectively) and BK virus. Cidofovir was restarted at a dose of 0.25 mg/kg and then increased up to 2 mg/kg administered weekly for a total of six doses. Despite this therapy his presentation progressed to kidney failure requiring dialysis. At this time (day +138) a plasma specimen, a nasopharyngeal aspirate and a stool specimen tested positive for HAdV by PCR with Ct values of 28.88, 41.99 and 25.39, respectively. These PCR test results were obtained in the setting of radiographic evidence of pneumonitis and diarrhoea, raising concern for disseminated adenoviral disease. His hospitalization was further complicated by Staphylococcus epidermidis bacteraemia, and by CMV and EBV reactivation that were managed with valganciclovir and rituximab, respectively. Unfortunately, on day +150 the patient died. His death was considered possibly attributable to disseminated HAdV disease.\n\nPatient 2 was a 50-year-old male with chronic lymphocytic leukaemia and small lymphocytic lymphoma treated with pentostatin, rituximab, fludarabine and bendamustine who was admitted to MSKCC for a double umbilical cord HCT. His medical history was significant for an episode, 3 years previously, of HAdV-associated haemorrhagic cystitis treated with intravenous cidofovir, and for a viscus perforation requiring an ileocolectomy. His post-transplant course was significant for fever close to the time of engraftment, rhinorrhoea, watery eyes and cough. At day +12 a nasopharyngeal specimen tested negative with the FilmArray RVP version 1.6 respiratory virus panel (Idaho Technology, Salt Lake City, UT, USA). At day +19 a plasma specimen tested positive for HAdV (1200 copies/mL) but negative for CMV and EBV. At day +32, in the context of dysuria and haematuria, a urine specimen tested positive for HAdV (8.1 × 106 copies/mL) and HAdV viraemia was still positive and elevated (43 200 copies/mL). He also tested positive for human herpesvirus-6. Over the following 3 weeks, to address his persistent HAdV viruria and viraemia, the patient was treated with nitravenous cidofovir at a dose of 3–5 mg/kg. Urine samples were tested multiple times for BK virus during the course of his hospitalization and were always negative. His condition worsened in the context of significant HAdV viraemia and viruria, further complicated by CMV reactivation, fatigue and weakness on walking and recurrent fevers, even under broad-spectrum antibiotic treatment. At day +45 in the context of diarrhoea, a stool specimen tested positive for HAdV. Renal failure limited cidofovir use. At day +124 the HAdV load in urine was 11 × 106 copies/mL and at day +132 the patient died.\n\nMolecular typing of virus isolates\nThe initial molecular typing for patient 1 isolates was carried out by PCR amplification and sequencing of hexon and fibre genes, and by restriction fragment length polymorphism (RFLP) analysis of viral DNA purified from a stool isolate from a specimen collected 138 days after the transplant (+138), and from two urine isolates from specimens collected at days +103 and + 116. The three isolates exhibited identical HAdV-11-like partial hexon gene sequences and identical HAdV-7-like fibre gene sequences (data not shown). The urine isolate from patient 2 was initially typed as HAdV-11-like based on PCR amplification and sequencing of hypervariable regions 1–6 of the hexon gene.\n\nRFLP analysis with a panel of nine endonucleases showed the three clinical isolates from patient 1 and the urine isolate from patient 2 to correspond to subspecies HAdV-B2, to be identical to one another (data not shown), and also to be highly similar to paediatric respiratory isolate Arg10817/00, an interypic recombinant with an HAdV-11-like hexon and an HAdV-7-like fibre gene originally typed as RFLP variant 11c4 [20].\n\nComplete genomic sequences were generated for urine isolate 2146-13-VT10810 from patient 1, and for urine isolate NYS12/12146 from patient 2. Sequences were deposited in GenBank under accession numbers KT970441 and KT970442. The sequences corresponded to a novel subspecies HAdV-B2 genotype and were 99.5% identical, with only 19 nucleotide differences scattered along the entire genome as described in Table 1. Simplot analysis (Fig. 1) identified the virus as an intertypic recombinant with a type 11-like penton base gene, a type 11-like hexon gene and a type 77-like fibre gene (P11H11F77). A detailed comparison of nucleotide and amino acid sequence similarities with other species HAdV-B types included in the analysis is presented in Table 2, Table 3.Table 1 Nucleotide and predicted amino acid differences between HAdV-78 strains 2146-13-VT10870 (KT970441) and NYS12/12146 (KT970442)\n\nTable 1Nucleotide position\tGene\tCDS\tNucleic acid change\tAmino acid change\t\nKT970442\tKT970441\tKT970442\tKT970441\t\n120\tITR\tNCR\tT\tC\tNCR\tNRC\t\n3036\tE1B\tE1B large T antigen\tT\tC\tSYN\tSYN\t\n4903\tIVa2\tIVa2\tA\tG\tIle\tMet\t\n6254\tE2B\tDNA polymerase\tT\tC\tSer\tPro\t\n16335–16637\tpTP/E2B/L1\tNCR\t—\tTTT\tNCR\tNCR\t\n17205\tL2\tx core\tG\tA\tSYN\tSYN\t\n17320–17323\tNCR\tNCR\t—\tAAAA\tNCR\tNCR\t\n23204\tE2A\tssDNA binding protein\tA\tC\tGlu\tAsp\t\n29867\tE3\tE3 RID-β\tT\tC\tLeu\tSer\t\n30170\tE3\tE3 RID-beta\tC\tA\tSYN\tSYN\t\n32486\tE4\tE4 control protein (34 KDa)\tA\tT\tSYN\tSYN\t\n33852\tE4\tE4 control protein ORF2\tC\tT\tSYN\tSYN\t\n34260\tE4\tE4 control protein ORF1\tG\tA\tArg\tLys\t\n34680\tITR\tNCR\tA\tG\tNTR\tNTR\t\nITR, inverted terminal repeat; NCR, non-coding region; SYN, synonymous.\n\nNon-synonymous mutations and their corresponding locations and resulting amino acid changes are presented in bold font.\n\nFig. 1 Analysis of sequence similarities between isolate 2146-13-VT10810 and closely related human adenovirus B (HAdV-B) types HAdV-7, HAdV-11, HAdV-34, HAdV-35 and HAdV-77. Plots of similarity were generated by SimPlot [22]. Each curve is a comparison between the genome being analysed and the genome of urine isolate 2146-13-VT10810 as a query sequence. Each point plotted is the percentage identity within a 200 bp wide sliding window centred on the position plotted, with a step size between points of 20 bp (GapSrip:On, J-C Correction: On). The horizontal bars above the curves are a cartoon of the coding regions of the HAdV-B genome. The colours indicate the type to which that part of the genome is most similar, based on the plot below.\n\nFig. 1Table 2 Analysis of sequence similarities between clinical isolates 2146-13-VT18017 and NY12/12146, and closely related viruses of species HAdV-B\n\nTable 2Gene\tNucleotide or amino acid\tStrain ID\tHAdV-7p (Gomen) AY594255\tHAdV-11p (Slobitski) AF32578\tHAdV-34p (Compton) AY737797\tHAdV-35p (Holden) AY271307\tHAdV-77 (Heim-00092) KF268328\t\nPenton base\tNt\t2146-13-VT10810\t80.4%\t97.3%\t94.2%\t97.3%\t100%\t\nNt\tNY12/12146\t80.4%\t97.3%\t94.2%\t97.3%\t100%\t\nAA\t2146-13-VT10810\t84.4%\t98%\t95.4%\t97.9%\t100%\t\nAA\tNY12/12146\t84.8%\t98%\t95.4%\t97.9%\t100%\t\nHexon\tNt\t2146-13-VT10810\t78.9%\t98.8%\t92%\t95.3%\t91.7%\t\nNt\tNY12/12146\t78.9%\t98.8%\t92%\t95.5%\t91.7%\t\nAA\t2146-13-VT10810\t85.7%\t99.3%\t92.2%\t95.1%\t92.3%\t\nAA\tNY12/12146\t86%\t99.3%\t92.2%\t95.1%\t92.3%\t\nFibre\tNt\t2146-13-VT10810\t96.2%\t94.8%\t67.5%\t67.7%\t100%\t\nNt\tNY12/12146\t96.2%\t94.8%\t67.5%\t67.7%\t100%\t\nAA\t2146-13-VT10810\t95.1%\t94.5%\t61.8%\t61.8%\t100%\t\nAA\tNY12/12146\t95.1%\t94.5%\t61.8%\t61.8%\t100%\t\n\n\n\t\nWhole-genome sequence\t2146-13-VT10810\t83.7%\t98.4%\t96.9%\t97.4%\t99%\t\nNY12/12146\t83.6%\t98.3%\t96.9%\t97.3%\t99%\t\nAA, amino acid, Nt, nucleotide.\n\nTable 3 Analysis of sequence similarities between clinical isolate 2146-13-18017 and closely related viruses of the same molecular type identity (P11H11F7)\n\nTable 3Strain ID\tCDS\tNucleotide or amino acid\tNYS12/12146\tArg/18017/2000\t\n2146-13-VT10810\tPenton\tNt\t100%\tNA\t\nAA\t100%\tNA\t\nHexon\tNt\t100%\t99.9% (X034750) a\t\nAA\t100%\t100%\t\nFibre\tNt\t100%\t99.8% (X034751) a\t\nAA\t100%\t100%\t\nWGS\tNt\t99.5%\t99.4%\t\nAA, amino acid; CDS, coding sequence; NA, sequence not available; Nt, nucleotide; WGS, whole-genome sequence.\n\na Described in Kajon et al. 2013 [20].\n\n\n\nThe Human Adenovirus Working Group (http://hadvwg.gmu.edu) assigned number 78 to designate the novel genotype reported in this paper. Phylogenetic analysis (Fig. 2) revealed HAdV-78 to be most closely related to genotype HAdV-77, which was recently described by bioinformatics analysis of the whole-genome sequence of a German isolate from 1985 (KF268328).Fig. 2 Phylogenetic analysis of whole-genome sequences of subgroup B human adenoviruses (HAdV). Eight whole-genome sequences including those of HAdV-7p (AY594255), HAdV-11p (AF532578), HAdV-34p (AY737797), HAdV-35p (AY271307), HAdV-55 (FJ597732), HAdV-77 (KF268328), and those obtained in this study for the newly identified HAdV-78 strains 2146-13-VT10810 and NYS12/12146 were aligned using MAAFT in Geneious R11 (Biomatters, Auckland, New Zealand; www.geneious.com). The phylogenetic tree was reconstructed in MEGAX using the neighbour-joining method based on the Kimura two-parameter model with 500 bootstrap replicates. Support values <70 not shown.\n\nFig. 2\n\nThe restriction profiles obtained in silico for the genomes of the two isolated strains of HAdV-78 together with those of other closely related genotypes of species HAdV-B are shown in Fig. 3. Consistent with the results of our initial gel-based RFLP analysis, strains 2146-13-VT10810 and NYS12/12146 yielded identical profiles with nine different endonucleases. The analysis of in silico-generated profiles also confirmed the close resemblance between the genomes of the HAdV-78 isolates and HAdV-77 demonstrated by our phylogenetic analysis.Fig. 3 In silico restriction enzyme analysis of HAdV-78 and closely related genotypes of species human adenovirus B (HAdV-B). Virtual restriction enzyme analysis of viral genomic DNAs of urine isolates in comparison with those of genomic DNA of HAdV-11(JN226748), HAdV-34 (JN226749) and HAdV-35 (JN226761), and HAdV-77. M: virtual 1 kb Plus™ ladder (100–12 000 bp, Life Technologies, Carldbad, CA, USA).\n\nFig. 3\n\nDiscussion\nA number of novel HAdV genotypes representing examples of intertypic recombination have been recently described through the molecular characterization of clinical isolates or by direct next-generation whole-genome sequencing of viral DNA recovered from patient specimens [[25], [26], [27], [28]]. HAdV-78 is a novel subspecies HAdV-B2 genotype, closely related phylogenetically to other members of the subspecies and in particular to HAdV-77, an intertypic recombinant (P35H34F7) isolated in Germany in 1985 from an unreported source and described in the GenBank accession as corresponding to serotype 34 (KF268328).\n\nThe high similarity of the restriction profiles and the identical predicted amino acid sequences of hexon and fibre proteins suggest that the virus reported in association with a paediatric case of acute respiratory infection sampled in 2000 in Argentina [20] may represent a genomic variant of HAdV-78. The identical hexon and fibre genes also support the hypothesis that HAdV-78 may neutralize as serotype 11 based on the serology data reported for Argentina strain 18017/2000 [20]. Although no sequence or RFLP analysis data are available for the HAdV-B detected in a blood specimen of a neonatal case of severe disseminated HAdV following water delivery, the reported description of a recombinant virus possessing an HAdV-11-like hexon gene and an HAdV-7-like fibre gene with comparable percentage similarities to reference strains [29] is strongly suggestive of a closely related genome.\n\nTaken together, the clinical and virology diagnostic test data available for the two unrelated individuals presented in this study, and the information available for the above mentioned unrelated cases described in the cited publications, support the hypothesis that infection by HAdV-78 is initially acquired through the respiratory tract and that the virus has the ability to persist in the gut and possibly also in the renal epithelium or vasculature, from where it can reactivate and be shed under certain immunocompromising or stressful conditions.\n\nThe detection of other HAdV-B2 types—including serologically ‘intermediate’ strains—has been reported in the allograft tissue and in the urine of renal transplant recipients, and also in the urine of HCT recipients and other immunocompromised patients presenting with symptoms of haemorrhagic cystitis, fever, renal dysfunction, or systemic disseminated disease [[30], [31], [32], [33], [34]]. These findings support the hypothesis that this subgroup of HAdV-B features the distinct ability to establish a latent infection in the kidney and become active again as a consequence of immunological impairment. Interestingly, the isolation from urine specimens of intertypic recombinants with restriction enzyme digestion profiles similar to those of HAdV-77 and HAdV-78 was actually reported in the USA in the 1980s [35,36]. Unfortunately, the lack of available sequence data for these strains prevented their inclusion in our phylogenetic analysis.\n\nAlthough molecular typing data were not retrievable for the HAdV genome detected by PCR in the nasopharyngeal aspirate obtained from patient 1 on day +138 concomitantly with radiographic evidence for pneumonitis, or from the stool specimen obtained from patient 2 at day +45, the clinical evidence interpreted in conjunction with available virology data is strongly indicative of a disseminated HAdV infection in both individuals.\n\nEthical approval\nThe study was approved by the Institutional Ethics and Review Committees of the Children's Hospital of Philadelphia and Memorial Sloan Kettering Cancer Center. Because the examined clinical specimens were de-identified before the study, the protocol was exempt from IRB review at the Lovelace Respiratory Research Institute and Wadsworth Center.\n\nAuthor contributions\nAEK contributed to funding acquisition, supervision, conceptualization, investigation, data curation, writing and original draft preparation. DL contributed to methodology, investigation, analysis and data curation. ES contributed to original case report draft preparation; NEB contributed to original draft preparation, diagnostic test data curation, reviewing and editing. AMC contributed to supervision and diagnostic test data curation. BF contributed to funding acquisition, supervision, reviewing and editing; and KSG contributed to funding acquisition, reviewing and editing.\n\nFunding\nThis work was supported in part by 10.13039/100000002NIH/NIAID contract HHSN2722011000040C.\n\nConflicts of interest\nThe authors have no competing interests or conflicts to declare.\n\nAcknowledgements\nThe authors thank Susan Core and Ulrike Galasinski at LRRI for their technical assistance with viral isolation and molecular typing. AEK is a member of the Center for Infectious Disease and Immunity, University of New Mexico.\n==== Refs\nReferences\n1 Wold W.S.M. Ison M.G. Adenovirus Knipe D.M. Howley P.M. Fields virology 6th ed. 2013 Lippincott, Williams & Wilkins Philadelphia 1732 1767 \n2 Houldcroft C.J. Beale M.A. Sayeed M.A. Qadri F. Dougan G. Mutreja A. Identification of novel adenovirus genotype 90 in children from Bangladesh Microb Genom 4 10 2018 10.1099/mgen.0.000221 \n3 Dhingra A. Hage E. Ganzenmueller T. Böttcher S. Hofmann J. Hamprecht K. Molecular evolution of human adenovirus (HAdV) species C Sci Rep 9 2019 1039 30705303 \n4 Hale G.A. Heslop H.E. Krance R.A. Brenner M.A. Jayawardene D. Srivastava D.K. Adenovirus infection after pediatric bone marrow transplantation Bone Marrow Transplant 23 1999 277 282 10084260 \n5 de Mezerville M.H. Tellier R. Richardson S. Hébert D. Doyle J. Allen U. Adenoviral infections in pediatric transplant recipients: a hospital-based study Pediatr Infect Dis J 25 2006 815 818 16940840 \n6 Echavarria M. Adenoviruses in immunocompromised hosts Clin Microbiol Rev 21 2008 704 715 18854488 \n7 Tebruegge M. Curtis N. Adenovirus infection in the immunocompromised host Adv Exp Med Biol 659 2010 153 174 20204763 \n8 Lion T. Adenovirus infections in immunocompetent and immunocompromised patients Clin Microbiol Rev 27 2014 441 462 24982316 \n9 Lynch J.P. Kajon A.E. Adenovirus: epidemiology, global spread of novel serotypes, and advances in treatment and prevention Semin Respir Crit Care Med 37 2016 586 602 27486739 \n10 Ison M.G. Hirsch H.H. Community-acquired respiratory viruses in transplant patients: diversity, impact, unmet clinical needs Clin Microbiol Rev 32 2019 pii: e00042-19 \n11 Morfin F. Boucher A. Najioullah F. Bertrand Y. Bleyzac N. Poitevin-Later F. Cytomegalovirus and adenovirus infections and disease among 75 pediatric unrelated allogeneic bone marrow transplant recipients J Med Virol 72 2004 257 262 14695667 \n12 Mynarek M. Ganzenmueller T. Mueller-Heine A. Mielke C. Gonnermann A. Beier R. Patient, virus, and treatment-related risk factors in pediatric adenovirus infection after stem cell transplantation: results of a routine monitoring program Biol Blood Marrow Transplant 20 2014 250 256 24269896 \n13 Kosulin K. Geiger E. Vécsei A. Huber W.D. Rauch M. Brenner E. Persistence and reactivation of human adenoviruses in the gastrointestinal tract Clin Microbiol Infect 22 2016 381 e1–8 \n14 Boge C.L.K. Fisher B.T. Petersen H. Seif A.E. Purdy D.R. Galetaki D.M. Outcomes of human adenovirus infection and disease in a retrospective cohort of pediatric solid organ transplant recipients Pediatr Transplant 23 2019 e13510 \n15 Dailey Garnes N.J.M. Ragoonanan D. Aboulhosn A. Adenovirus infection and disease in recipients of hematopoietic cell transplantation Curr Opin Infect Dis 32 2019 591 600 31567568 \n16 Lion T. Adenovirus persistence, reactivation, and clinical management FEBS Lett 2019 Aug 14 10.1002/1873-3468.13576 \n17 Heim A. Ebnet C. Harste G. Pring-Akerblom P. Rapid and quantitative detection of human adenovirus DNA by real-time PCR J Med Virol 70 2003 228 239 12696109 \n18 Kajon A.E. Erdman D.D. Assessment of genetic variability among subspecies B1 human adenoviruses for molecular epidemiology studies Methods Mol Med 131 2007 335 355 17656793 \n19 Li Q.G. Hambraeus J. Wadell G. Genetic relationship between thirteen genome types of adenovirus 11, 34, and 35 with different tropisms Intervirology 32 1991 338 350 1657824 \n20 Kajon A.E. de Jong J.C. Dickson L.M. Arron G. Murtagh P. Viale D. Molecular and serological characterization of species B2 adenovirus strains isolated from children hospitalized with acute respiratory disease in Buenos Aires, Argentina J Clin Virol 58 2013 4 10 23886503 \n21 Okada M. Ogawa T. Kubonoya H. Yoshizumi H. Shinozaki K. Detection and sequence-based typing of human adenoviruses using sensitive universal primer sets for the hexon gene Arch Virol 152 2007 1 9 16957827 \n22 Lole K.S. Bollinger R.C. Paranjape R.S. Gadkari D. Kulkarni S.S. Novak N.G. Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination J Virol 73 1999 152 160 9847317 \n23 Kimura M. A simple method for estimating evolutionary rate of base substitutions through comparative studies of nucleotide sequences J Mol Evol 16 1980 111 120 7463489 \n24 Kumar S. Stecher G. Li M. Knyaz C. Tamura K. Mega X. Molecular evolutionary genetics analysis across computing platforms Mol Biol Evol 35 2018 1547 1549 29722887 \n25 Kajon A.E. Dickson L.M. Murtagh P. Viale D. Carballal G. Echavarria M. Molecular characterization of an adenovirus 3-16 intertypic recombinant isolated in Argentina from an infant hospitalized with acute respiratory infection J Clin Microbiol 48 2010 1494 1496 20129962 \n26 Kajon A.E. Lamson D. Shudt M. Oikonomopoulou Z. Fisher B. Klieger S. Identification of a novel intertypic recombinant species D human adenovirus in a pediatric stem cell transplant recipient J Clin Virol 61 2014 496 502 25449172 \n27 Hage E. Gerd Liebert U. Bergs S. Ganzenmueller T. Heim A. Human mastadenovirus type 70: a novel, multiple recombinant species D mastadenovirus isolated from diarrhoeal faeces of a haematopoietic stem cell transplantation recipient J Gen Virol 96 2015 2734 2742 26002300 \n28 Hashimoto S. Gonzalez G. Harada S. Oosako H. Hanaoka N. Hinokuma R. Recombinant type Human mastadenovirus D85 associated with epidemic keratoconjunctivitis since 2015 in Japan J Med Virol 90 2018 881 889 29396992 \n29 Soileau S.L. Schneider E. Erdman D.D. Lu X. Ryan W.D. McAdams R.M. Case report: severe disseminated adenovirus infection in a neonate following water birth delivery J Med Virol 85 2013 667 669 23417617 \n30 Harnett G.B. Bucens M.R. Clay S.J. Saker B.M. 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Probable donor-derived human adenovirus type 34 infection in 2 kidney transplant recipients from the same donor Open Forum Infect Dis 6 2018 ofy354 30882008 \n35 de Jong P.J. Valderrama G. Spigland I. Horwitz M.S. Adenovirus isolates from urine of patients with acquired immunodeficiency syndrome Lancet 1 8337 1983 1293 1296 6134092 \n36 Flomenberg P.R. Chen M. Munk G. Horwitz M.S. Molecular epidemiology of adenovirus type 35 infections in immunocompromised hosts J Infect Dis 155 1987 1127 1134 3033089\n\n",
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"title": "Isolation of a novel intertypic recombinant human mastadenovirus B2 from two unrelated bone marrow transplant recipients.",
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"abstract": "Drug interactions are an important avoidable cause of illness. With an increasing array of medications available to treat human disease and an increasing number of patients taking many medications, the risk of clinically significant drug interactions increases. This review describes some examples of common drug interactions in gastroenterology. The underlying mechanisms are discussed, and strategies are proposed to avoid drug interactions in clinical practice.",
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"abstract": "Crohn's disease (CD) is a systemic illness with a constellation of extraintestinal manifestations affecting various organs. Of these extraintestinal manifestations of CD, those involving the lung are relatively rare. However, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases. The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. Bronchoalveolar lavage findings show an increased percentage of neutrophils. Drug-related pulmonary abnormalities include disorders which are directly induced by sulfasalazine, mesalamine and methotrexate, and opportunistic lung infections due to immunosuppressive treatment. In most patients, the development of pulmonary disease parallels that of intestinal disease activity. Although infrequent, clinicians dealing with CD must be aware of these, sometimes life-threatening, conditions to avoid further impairment of health status and to alleviate patient symptoms by prompt recognition and treatment. The treatment of CD-related respiratory disorders depends on the specific pattern of involvement, and in most patients, steroids are required in the initial management.",
"affiliations": "De-Gan Lu, Xiao-Qing Ji, Hong-Jia Li, Cai-Qing Zhang, Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.;De-Gan Lu, Xiao-Qing Ji, Hong-Jia Li, Cai-Qing Zhang, Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.;De-Gan Lu, Xiao-Qing Ji, Hong-Jia Li, Cai-Qing Zhang, Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.;De-Gan Lu, Xiao-Qing Ji, Hong-Jia Li, Cai-Qing Zhang, Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.;De-Gan Lu, Xiao-Qing Ji, Hong-Jia Li, Cai-Qing Zhang, Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.",
"authors": "Lu|De-Gan|DG|;Ji|Xiao-Qing|XQ|;Liu|Xun|X|;Li|Hong-Jia|HJ|;Zhang|Cai-Qing|CQ|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v20.i1.133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "20(1)",
"journal": "World journal of gastroenterology",
"keywords": "Crohn’s disease; Extracolonic involvement; Inflammatory bowel disease; Lung",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D003424:Crohn Disease; D005765:Gastrointestinal Agents; D006801:Humans; D008171:Lung Diseases; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "133-41",
"pmc": null,
"pmid": "24415866",
"pubdate": "2014-01-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "22040226;15565210;957997;11742200;11922200;8777981;23128233;10430329;7899671;18723019;7789480;2623217;19418577;20974510;5091808;18416645;21560645;22958334;11418451;16055885;6136183;17491318;3015749;14699483;5146188;10712362;1267553;11033846;23576654;16331316;16585347;11979139;17632266;19237838;22907164;12915753;11866276;17667053;19628819;15785830;21122509;2492786;21695953;4811676;21686567;14506385;9713458;6849612;6134089;11734067;7086730;16756646;7267968;14555914;1960905;7977257;18241628;3971763;15911023;15168813;9692115;19249397;7146309;2247378;21122534;18294633;10639206;16622902;742502;10940806;2521438;17560419;23291352;8502168;21935713;23695484;17713885;2731973;22896987;16511933;19705414;20709507;6380265;3940500;7892068;20107759;16937463;9030994;10706507;8902486;10710066;15223876;19687602;3428695;10678648;11596589;2802419;9101017;15669643;16625374;15290924;9431906;22230422;12772229;14716424;20954282;21980664;16636526;2248544;17965080;5467054;2090485;17429728;9817724;16143122;12122740;11515853;12548168;21805420;21969926;20062691;11687867;8633548;9053978;16670533;19212215;1344040",
"title": "Pulmonary manifestations of Crohn's disease.",
"title_normalized": "pulmonary manifestations of crohn s disease"
} | [
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"companynumb": "US-PFIZER INC-2019440672",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "METHOTREXATE SODIUM"
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"abstract": "The aim of our study is to determine characteristics and outcomes of kidney cancer in renal transplant recipients. MEDLINE® database was searched in June 2015 to identify cases of kidney cancer in renal transplant recipients. We include also a new case. Descriptive statistics were used for analysis. Forty-eight (48) recipients reported in 25 papers met the eligibility criteria. The median age was 47 years (range 9-66); 27% were females. Chronic glomerulonephritis, cystic kidney disease and hypertension were common indications for renal transplant. Among donors 24% were females and the median age was 52.5 years (17-73); 62% of kidney cancers were donor-derived. The median interval between transplant and cancer diagnosis was shorter for cancer of recipient versus donor origin (150 vs. 210 days). Clear cell carcinoma was diagnosed in 17%. 25% had metastasis at diagnosis. Kidney explantation or excision was done in 90% and 84% of cases with and without metastasis respectively. The median survival was 72 months. Actuarial 1-year and 5-year survival rates were 73.4% and 55.1% respectively. Among the recipients from 7 donors who subsequently developed malignancy, 57% were dead within a year. Kidney transplant recipients have a small risk of kidney cancer, which affects younger patients and occurs within a year of transplant, likely due to immunosuppression. Whether the use of older donors may increase the likelihood needs further investigation. The presence of metastasis, explantation or excision of affected kidney and development of cancer in donors predict outcomes. The results may guide patient education and informed decision-making.",
"affiliations": "Michigan State University, East Lansing, MI.;The Yale New Haven Hospital, New Haven, CT.;University of Tennessee, Memphis, TN.;Michigan State University, East Lansing, MI.;University of Nebraska Medical Center, Omaha, NE, USA.",
"authors": "Dhakal|Prajwal|P|;Giri|Smith|S|;Siwakoti|Krishmita|K|;Rayamajhi|Supratik|S|;Bhatt|Vijaya Raj|VR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.4081/rt.2017.6550",
"fulltext": "\n==== Front\nRare TumorsRare TumorsRTRare Tumors2036-36052036-3613PAGEPress Publications, Pavia, Italy 10.4081/rt.2017.6550ReviewRenal Cancer in Recipients of Kidney Transplant Dhakal Prajwal 1Giri Smith 2Siwakoti Krishmita 3Rayamajhi Supratik 1Bhatt Vijaya Raj 41 Michigan State University, East Lansing, MI2 The Yale New Haven Hospital, New Haven, CT3 University of Tennessee, Memphis, TN4 University of Nebraska Medical Center, Omaha, NE, USAMichigan State University, Department of Internal Medicine, 788 Service Road, B301 Clinical Center, East Lansing, MI, 48824, USA. +1.517.353.5100 - +1.517.432.2759. prazwal@gmail.comContributions: VRB, concept; PD, SG, VRB, literature search; PD, SG, KS, SR, VRB, data analysis, manuscript writing and final approval.\n\nConference presentation: this paper was presented as a poster in American College of Physicians-Michigan Chapter Abstract Competition 2015-16.\n\n24 3 2017 24 3 2017 9 1 655020 4 2016 29 12 2016 14 2 2017 ©Copyright P. Dhakal et al., 20172017Licensee PAGEPress, ItalyThis 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The aim of our study is to determine characteristics and outcomes of kidney cancer in renal transplant recipients. MEDLINE® database was searched in June 2015 to identify cases of kidney cancer in renal transplant recipients. We include also a new case. Descriptive statistics were used for analysis. Forty-eight (48) recipients reported in 25 papers met the eligibility criteria. The median age was 47 years (range 9-66); 27% were females. Chronic glomerulonephritis, cystic kidney disease and hypertension were common indications for renal transplant. Among donors 24% were females and the median age was 52.5 years (17-73); 62% of kidney cancers were donor-derived. The median interval between transplant and cancer diagnosis was shorter for cancer of recipient versus donor origin (150 vs. 210 days). Clear cell carcinoma was diagnosed in 17%. 25% had metastasis at diagnosis. Kidney explantation or excision was done in 90% and 84% of cases with and without metastasis respectively. The median survival was 72 months. Actuarial 1-year and 5-year survival rates were 73.4% and 55.1% respectively. Among the recipients from 7 donors who subsequently developed malignancy, 57% were dead within a year. Kidney transplant recipients have a small risk of kidney cancer, which affects younger patients and occurs within a year of transplant, likely due to immunosuppression. Whether the use of older donors may increase the likelihood needs further investigation. The presence of metastasis, explantation or excision of affected kidney and development of cancer in donors predict outcomes. The results may guide patient education and informed decision-making.\n\nKey words\nKidney cancertransplantkidney transplantrecipients\n==== Body\nCompeting interest statement\nConflict of interest: the authors declare no potential conflict of interest.\n\nIntroduction\nTransmission of malignancy from organ donor to recipient, well-recognized complication of transplantation,1 is rare but frequently unavoidable.2 About 17,000 of kidney transplants are performed in the US yearly and malignancy is the second most common cause of death (after cardiovascular events and infection) in these cases.3 In patients with transplants, the incidence of kidney cancer is estimated to be approximately 5%; 10% of these kidney cancers arise in renal grafts.4,5 The rarity of kidney cancers in kidney transplant recipients precludes understanding of the demographics, characteristics, treatment methods and outcomes of this entity. Most of these cancers are treated with explantation or excision of the graft. Chemotherapy and radiotherapy are used mostly as an adjunct. Here we present a case which was treated with explantation, followed by radiation therapy for recurrent disease. We have also reviewed cases of renal malignancy in renal transplant recipients.\n\nMaterials and Methods\nA systematic search of MEDLINE database (via PubMed) was conducted in July 2015 to identify articles describing a new diagnosis of kidney cancer following kidney transplant. The following terms were utilized for selecting the articles: (Kidney Transplantation OR Renal Transplantation OR Organ Transplantation) AND (malignant OR cancer OR tumor) AND (transmission). The bibliography of each article was hand-searched for additional reports. Only reports published in English language were included. Of a total of 420 searches, 24 articles met the eligibility criteria (Figure 1). Additionally, we also describe an original case report.\n\nDuring analysis, details of the patient, transplant history, diagnosis of kidney cancer, therapy, complications and outcomes were obtained until the last follow-up of the patient.\n\nResults\nA 55-year-old male presented to emergency department complaining of abdominal pain, distention, as well as nausea and vomiting of 2 days’ duration. He had a bilateral kidney transplant one year ago for end stage renal disease secondary to chronic hypertension. His post-transplant course was complicated by ureteral strictures, enterocutaneous fistula and recurrent small bowel obstructions. The patient was on mycophenolate mofetil, prednisone and tacrolimus to avoid graft rejection. He had a history of heavy smoking, alcohol consumption and cocaine use, but had quit one year ago. Physical examination revealed heart rate of 109 beats/min, blood pressure of 134/96 mm Hg, respiratory rate of 20/min and temperature of 36.6°C. On abdominal examination, there was diffuse tenderness and high-pitched bowel sounds. Rest of the examination was normal.\n\nLaboratory studies included white blood cell count of 10,200/μL with 78% granulocytes, hemoglobin of 16.6 g/dL and platelet count of 155,000/μL. He had a creatinine of 1.04 mg/dL, blood urea nitrogen of 13 mg/dL, sodium of 138 mmol/L, potassium of 3.3 mmol/L, and chloride of 100 mmol/L. Ultrasonography (USG) of right kidney demonstrated a transplanted kidney with a heterogeneous hyperechoic mass measuring 5.5*4.9X5.6 cm. Computed tomography (CT) scan of abdomen revealed right lower quadrant transplanted kidney with a new complex enhancing mass involving the lower pole measuring 5.4×73×6.5 cm, which was highly concerning for malignancy. CT scan also demonstrated new gastric distention, dilated loops of small bowel, fecal material in distal small bowel loops, and air and stool throughout colon, which was concerning for small bowel obstruction. Whole body positron emission tomography (PET) scan depicted a 73×6.4×6.2 cm inferior pole mass within right lower quadrant kidney transplant with a maximum SUV of 9.6, suspicious for primary renal cell carcinoma versus lymphoma. Biopsy of the mass showed sarcomatoid carcinoma with squamous differentiation, possibly of the uroepithelial origin.\n\nThe patient underwent nephrectomy of the right transplanted kidney. Pathology revealed high-grade carcinoma with squamous differentiation and sarcomatoid areas (sarcomatoid carcinoma/carcinosarcoma) with a tumor size of 6.7 cm in the greatest dimension. Tumor appeared to be arising in the setting of keratinizing squamous metaplasia involving the right renal pelvis and calyceal system with invasion into renal parenchyma and peripelvic adipose tissue (pT3). Margins were positive in areas where capsule was stripped but there was no lymphovascular invasion. Periureteral tissue was also involved with invasive carcinoma with squamous differentiation. Cytogenetics report showed: 68-77, XXY,+1, add (1)(p11),i(1)(p10)x2,-3,+6, add(7)(p15),add(7)(p21),add(7)(q32),add(8 )(p22),-9, i(9)(q10)x2,add(11)(q14),-13,-13,add(16)(q24), add(17)(p13),+add (19)(q133),+21,add(21)(p11.1)x2,-22,+7-12 mar,0-3dmin[cp 17]/129,slx2[1]//46,XX[2].\n\nA repeat PET/CT scan in a month revealed 2.1×53 cm soft tissue fullness in the right pelvis at the site of prior mass resection/nephrectomy. This lesion was markedly hypermetabolic with maximum standardized uptake value (SUV) of 13.0 compatible with recurrent local malignancy. Retroperitoneal and inguinal lymph nodes were not enlarged or PET-avid. The patient refused chemotherapy and therefore, was treated with a course of radiotherapy to 4230 cGy in 16 fractions. A follow-up PET scan showed a 1.9×1.7 cm minimally hyper metabolic focus of activity in the right pelvis with a SUV of 3.6. At 18 months’ follow-up, the patient is alive without any recurrence of cancer.\n\nReview of reported cases\nA total of 48 patients reported in 25 articles (along with our case report) met the eligibility criteria (Table 1). The median age of recipients was 47 years (range 9-66), and 27% were females. The cause for renal transplant were: chronic glomerulonephritis (22%, n=6),6-10 polycystic kidney disease (11%, n=3),8,11,12 hypertension (11%, n=3),13,14 IgA nephropathy (8%, n=2),10 renal pelvis carcinoma with left nephrectomy (4%, n=1),15 nephronopthisis (4%, n=1),16 congenital nephrotic syndrome (4%, n=1),10 amyloid disease (4%, n=1),17 diabetes mellitus (4%, n=1),6 interstitial nephritis (4%, n=1),18 Henoch-Schonlen purpura (4%, n=1),19 Alport syndrome (4%, n=1),18 neurogenic bladder (4%, n=1), obstructive uropathy (4%, n=1) and ESRD of unknown origin (8%, n=2).20,21\n\nThe median age of donors was 52.5 years (range 17-73) with 24% of them being females. Where data was available, 60% (n=22) of the donors were cadaver,6-8,12-15,17,18,21-28 while the rest (n=15, 40%) were living.2,11,16,19,20,28,29 Six of the living donors were related to the recipients.16,19,20,28,29\n\nSeven donors were subsequently found to have malignancy including clear cell carcinoma,20 hypernephroma,11 anaplastic tumor on nephrostomy scar,29 metastatic adenocarcinoma with unknown primary,13 primary hepatocellular carcinoma,9 metastatic giant and spindle cell carcinoma of thyroid,15 and a lung tumor.30 Out of seven, 2 donors were diagnosed with malignancy after 8 months and 10 months of transplantation.28,29 One donor had a renal cyst which was excised during the transplantation, and subsequently found to be a renal cell carcinoma.20 Three donors had history of malignancy in other organs with no identified metastasis to kidney at the time of donation.9,13,15 Tunner et al. described a case in which a kidney with resected renal cell carcinoma was transplanted to a man in desperate need of functioning kidney.11\n\nThe median time interval from transplantation to presentation or diagnosis of the malignancy in recipients was 210 days. The latency period between transplant and cancer diagnosis was 272 days in cancer of recipient origin in comparison to 210 days in those with cancer of donor origin.\n\nBiopsy was done for the diagnosis of cancer in 100% (n=48) of recipients, and 69% (n=33) of the cancers had RCC. The most common type of RCC was clear cell carcinoma (27%, n=9)7,10,12-14,20,21,31 while the other types were: sarcomatoid (15%, n=5),2,8 angiosarcoma (6%, n=2),18 renal papillary tumor (6%, n=2),28,31 anaplastic (6%, n=2),25,29 chromophobe (3%, n=1),16 cystic adenocarcinoma (3%, n=1),31 anaplastic adenocarcinoma (3%, n=1),29 giant and spindle cell carcinoma (3%, n=1),15 and undifferentiated (6%, n=2).17,22 The type of renal cell carcinoma was not mentioned in the rest (22%, n=7),2,6,19,31 Other tumors (31%, n=15) comprised 31% of the cases which included: undifferentiated cancer (20%, n=3),6 invasive urothelial carcinoma (7%, n=1),24 papillary transitional cell carcinoma of bladder (7%, n=1).31 Thirty-three percent of the tumors were subsequently found to be benign and the type of cancer was not mentioned in the rest (33%, n=5).\n\nFifty-five percent (n=31) of the tumors were donor in origin, while 39% (n=22) originated from the recipient. The rest (6%, n=3) were determined to be derived from both donor and recipient. For example, one of the tumors in Pedotti et al.31 had 60% recipient and 40% donor DNA material indicative origin from both donor and recipient cell.\n\nExplantation of the graft or excision of the tumor or a part of the graft, and discontinuation of immunosuppressants along with supportive treatment were used for management in most cases. Explantation or excision was done in 90% of the nonmetastatic malignancies, while 84% of metastatic malignancies underwent explantation or excision. Chemotherapy,6,7,12,24,28 radiotherapy,13,18,29 or both18 were also used in 9 cases. While 64% (n=7) of the 9 cases had metastasis,7,12,13,17,18,24,32 18% (n=2),29 had no metastasis, and the status of metastasis was not mentioned in the rest, (18%, n=2).6 In one case treated with local irradiation, distant metastasis was diagnosed at autopsy.29 Local irradiation was administered to treat recurrent local malignancy in our case after initial explantation.\n\nThe median survival was estimated to be approximately 72 months. Actuarial 1-year and 5-year survival rates were 73.4% and 55.1% respectively. Out of eleven recipients, who died after transplant, 9 were due to malignancy-related causes,6,8,11,15,17,18,24,26,29 while 2 were due to other causes.2 The recipient in Llamas et al.8 died 9 months post-transplant due to peritonitis secondary to sarcomatoid neoplasm of renal graft. Metastasis of the cancer was the cause of death in four recipients,15,17,18,29 while two recipients died due to intracerebral hemorrhage.6,24 Death due to invasion of renal cell carcinoma (RCC) aggressively into adjacent tissue accounted for the death in the patient reported by Tunner et al.11 Among the recipients from 7 donors who subsequently developed malignancy, 57% (n=4),9,11,15,29 were dead within a year. The cause of death in all these recipients was malignancy-related.\n\nDiscussion\nOur review revealed post renal transplant malignancy in a total of 48 recipients. RCC, the most common type of kidney cancer in adults, was diagnosed in the majority of our cases. Twenty-seven percent of the renal cell carcinoma were clear cell carcinoma which is the most common RCC type. RCC is also known to be the most frequently reported non-central nervous system (CNS) tumor transmitted by transplantation, followed by melanoma and choriocarcinoma.33 Twelve percent of the cases in our review, including our case, had a sarcomatoid differentiation. The incidence of tumors with sarcomatoid differentiation in general population is estimated as 1-8%, although as high as 32% has been reported.34-37\n\nIn our review, the median age of recipients at diagnosis was 49 years while the median age of donors was 52.5 years. The median age at diagnosis for RCC is 64 in normal population, and is unusual in patients under 40 years of age and rare in children.38-40 Immunosuppression in recipients may be one of the factors behind the development of malignancy at an early age. In addition, RCC may also occur in children receiving renal allografts from adults.16\n\nChronic glomerulonephritis, hypertension and cystic diseases of kidney were the common factors leading to end stage renal disease in our review. Our case also had a history of chronic hypertension and heavy smoking. In fact, hypertension, smoking, obesity and polycystic kidney disease have been well-recognized risk factors for the development of RCC in normal adults.41-45\n\nThe malignancy in post-transplant cases might be due to de novo occurrence, recurrence of malignancy or donor-related malignancy. Compared to 3% in general population, RCC occurs de novo in 4.6% of cancers in organ allograft recipients.46 Transmission of malignancy in an immunosuppressed recipient usually occurs when the tumor is undetected before the organ donation or it may be misdiagnosed as a benign condition such as cyst.24 This incidence of tumor transmission may also have risen in recent years with the increased donor age.8 In our review, more than half of the tumors were donor in origin-including both donor-derived and donor-transmitted malignancies. Thirty-nine percent of the tumors in our review were recipient in origin. Nineteen out of the twenty cases were recipient in origin in Pedotti et al.,31 thus, suggesting that donor transmission of solid cancer was an unlikely event in their study. Microchimerism, a phenomenon of harboring small numbers of cells that originated in a genetically different individual, has been described in previous post-transplant cases. Three cases in our review demonstrated microchimerism.10,31 In a case review by Mengel et al., two metanephric adenomas demonstrated microchimerism comprising both donor-and recipient-derived tumor cells, however, four other tumors were all of donor origin without chimerism.10 Thus, they concluded that tumors arising in renal transplants originate completely from graft cells except for metanephric adenomas. One of the cases in Pedotti et al.31 was also analyzed to be 60% recipient and 40% donor in origin. However, the cancer was considered to be a recipient origin because of greater percentage of recipient DNA.\n\nDifferent factors such as type, level and extent of immunosuppression, the use of drugs such as cyclosporine and azathioprine, carcinogenic factors such as sun exposure, genetic predisposition to cancer, pretransplantation dialysis, and the presence of particular viral infections are associated with development of de novo neoplasia in transplant recipients.47,48 The overall level and extent of immunosuppression, as illustrated by more malignancies after cardiac transplant in comparison to renal transplant, appears to be the principal factor that increases the risk of post-transplant malignancy.49 This is probably related to decreased immunosurveillance of neoplastic cells and depressed antiviral immune activity. A total of 7 donors in our review had a history of or were diagnosed after transplant with malignancy. Previous studies have shown that about 45% of recipients of kidney transplant from donors with known or incidentally discovered malignancy develop the malignancy.24 The risk of cancer transmission from donor to recipient is largely similar for all solid organ recipients.50 The median time interval from transplantation to presentation or diagnosis of the malignancy in recipients was 270 days in our review. In a study published by Buell et al., the mean time was approximately 2 months.50 The short latency period may indicate a possibility of undetected cancer at the time of transplantation or rapidity of tumorigenesis in immunosuppressant transplant recipients. Almost two-thirds of the cases underwent explantation of the graft. Eleven percent underwent excision of the tumor of a part of the graft. In our case, explantation was done initially and then local irradiation was performed later to treat local recurrent malignancy. The patient refused chemotherapy but was doing well till last follow-up at 18 months. In one case treated with local irradiation, distant metastasis was diagnosed at autopsy.29 Radiation therapy was used after explantation in 2 prior cases out of which one died,18 while the other remained in good clinical condition waiting for another kidney.13 Although guidelines are lacking, most cases with transplant related renal malignancy are treated primarily with explantation of the graft with chemotherapy and radiation therapy as adjunct in selected cases. Ribal et al.46 have reported successful conservative surgery of renal tumors (nephron sparing) with preservation of graft function, but this is only recommended for single carcinoma less than 4 cm in size.\n\nThe outcome for transplant recipients with neoplastic complications is unclear. We calculated the median survival to be 72 months. Actuarial 1-year and 5-year survival rates were 73.4% and 55.1% respectively. In our review, 25% of deaths were related to malignancy. In a review of data from different sources by Briggs et al.,51 malignancy was thought to account for 9-16% of all deaths in renal transplant recipients. Various factors affect the prognosis of RCC in general. The survival difference is largely due to differences in stage in particular and grade, although cytogenetics also play a role.52-54 Cytogenetic abnormalities such as del(8p)/-8, +12, and +20, p53, and gain of 5q31 have prognostic implications.52,55,56 The prognostic value of cytogenetic changes in RCC in transplant recipients has not been studied. The patient reported here had complex cytogenetic changes and was alive at 18-month follow-up.\n\nConclusions\nKidney transplant recipients have a small but definite risk of kidney cancer. It affects younger patients and usually occurs within a year of transplant, likely due to immunosuppression. Whether the use of older donors may increase the likelihood needs further investigation. Explantation or excision of the graft is the most important treatment for localized disease, while radiotherapy and chemotherapy may be used as adjunct in select cases. The presence of metastasis, explantation or excision of affected kidney and development of cancer in donors may predict outcomes. The results may guide patient education and informed decision-making.\n\nAcknowledgement\nVijaya Bhatt is supported by the 2015-2016 Physician-Scientist Training Program Grant from the College of Medicine, University of Nebraska Medical Center.\n\nFigure 1. Flow diagram for selection of the articles.\n\nTable 1. Kidney cancer in recipients of kidney transplant.\n\nVariables\tNon-metastatic kidney cancer\tMetastatic kidney cancer\t\nAge in years, median (range)\t47 (12-64)\t48 (27-66)\t\nFemale\t40%\t29%\t\nDonor type\tLiving 55%; Cadaver 45%\tLiving 0%; Cadaver 100%\t\nDonor age in years\t54 (22-73)\t52 (17-68)\t\nConcomitant cancer in the donor\t13%\t20%\t\nLatency period since kidney transplant (days)\tMedian 120 (0-6780)\tMedian- 210 (90-2190)\t\nHistology (%RCC)\t66\t80\t\nExplantation or excision\t90%\t84%\n==== Refs\nReferences\n1. Murray J Gleason R Bartholomay A. \nFourth report of the human kidney transplant registry: 16 September 1964 to 15 March 19651 . Transplantation \n1965 ;3 :684 .\n2. Desai R Collett D Watson CJ \nCancer transmission from organ donors-unavoidable but low risk . Transplantation \n2012 ;94 :1200 -7 .23269448 \n3. Xu J Murphy SL Kochanek KD Arias E. \nMortality in the United States, 2015 . NCHS data brief \n2016 :1 -8 .\n4. Penn I \nPrimary kidney tumors before and after renal transplantation . Transplantation \n1995 ;59 :480 -5 .7878750 \n5. Penn I \nOccurrence of cancers in immunosuppressed organ transplant recipients . Clin Transpl \n1998 :147 -58 .10503093 \n6. Bentdal OH Brekke IB Lien B \nRapid development of cancer in both kidney grafts after transplantation from a donor with undiagnosed malignant disease . Transplantation Proc \n1994 ;26 :1763 .\n7. Kunisch-Hoppe M Hoppe M Bohle RM \nMetastatic RCC arising in a transplant kidney . Eur Radiol \n1998 ;8 : 1441 -3 .9853232 \n8. Llamas F Gallego E Salinas A \nSarcomatoid renal cell carcinoma in a renal transplant recipient . Transplant Proc \n2009 ;41 :4422 -4 .20005414 \n9. Zukoski CF Killen DA Ginn E \nTransplanted carcinoma in an immunosuppressed patient . Transplantation \n1970 ;9 :71 -4 .4904755 \n10. Mengel M Jonigk D Wilkens L \nChimerism of metanephric adenoma but not of carcinoma in kidney transplants . Am J Pathol \n2004 ;165 :2079 -85 .15579450 \n11. Tunner WS Goldsmith EI Whitsell JC 2nd \nHuman homotransplantation of normal and neoplastic tissue from the same organ . J Urol \n1971 ;105 :18 -20 .5100867 \n12. Yaich S El’Aoud N Zaghdane S \nPrimary adenocarcinoma in a kidney allograft: a case report and review of the literature . Transplant Proc \n2011 ;43 :660 -2 .21440788 \n13. Homburg A Kindler J Hofstadter F \nRegression of an adenocarcinoma transmitted by a cadaver kidney graft . Transplantation \n1988 ;46 :777 -9 .3057702 \n14. McCanty TC Jonsson J Khawand N \nTransferral of a malignancy with a transplanted kidney . Transplantation \n1989 ;48 :877 -9 .2815261 \n15. Muiznieks HW Berg JW Lawrence W Jr.Randall HT \nSuitability of donor kidneys from patients with cancer . Surgery \n1968 ;64 :871 -7 .4879937 \n16. Greco AJ Baluarte JH Meyers KE \nChromophobe renal cell carcinoma in a pediatric living-related kidney transplant recipient . Am J Kidney Dis \n2005 ;45 :e105 -8 .15957121 \n17. Beckingham IJ O’Rourke JS Bishop MC \nThe use of DNA typing to clarify the origin of metastatic carcinoma after renal transplantation. A clinical and medico-legal problem . Transpl Int \n1994 ;7 :379 -81 .7993576 \n18. Thoning J Liu Y Bistrup C \nTransmission of angiosarcomas from a common multiorgan donor to four transplant recipients . Am J Transplant \n2013 ;13 :167 -73 .23094759 \n19. Lamb GW Baxter GM Rodger RS Aitchison M. \nPartial nephrectomy used to treat renal cell carcinoma arising in a live donor transplant kidney . Urol Res \n2004 ;32 :89 -92 .15250100 \n20. Neipp M Schwarz A Pertschy S \nAccidental transplantation of a kidney with a cystic renal cell carcinoma following living donation: management and 1 yr follow-up . Clin Transplant \n2006 ;20 :147 -50 .16640518 \n21. Heinz-Peer G Helbich T Nottling B \nRenal cell carcinoma in an allograft kidney transplant . Transplantation \n1994 ;57 :475 -8 .8108890 \n22. Barrou B Bitker MO Delcourt A \nFate of a renal tubulopapillary adenoma transmitted by an organ donor . Transplantation \n2001 ;72 :540 -1 .11502993 \n23. Detry O De Roover A de Leval L \nTransmission of an undiagnosed sarcoma to recipients of kidney and liver grafts procured in a non-heart beating donor . Liver Transpl \n2005 ;11 : 696 -9 .15915495 \n24. Ferreira GF de Oliveira RA Jorge LB \nUrothelial carcinoma transmission via kidney transplantation . Nephrol Dial Transplant \n2010 ;25 :641 -3 .20007757 \n25. Lotan D Laufer J. \nMetastatic renal carcinoma in a pediatric recipient of an adult cadaveric donor kidney . Am J Kidney Dis \n1995 ;26 :960 -2 .7503073 \n26. Matter B Zukoski CF Killen DA Ginn E. \nTransplanted carcinoma in an immunosuppressed patient . Transplantation \n1970 ;9 :71 -4 .4904755 \n27. Detroz B Detry O D’Silva M \nOrgan transplantation with undetected donor neoplasm . Transplant Proc \n1991 ;23 :2657 .1926521 \n28. Myron Kauffman H McBride MA Cherikh WS \nTransplant tumor registry: donor related malignancies . Transplantation \n2002 ;74 :358 -62 .12177614 \n29. Mocelin AJ \nLetter: inadvertent transplant of a malignancy . Transplantation \n1975 ;19 :430 .1154487 \n30. Kauffman HM \nMalignancies in organ transplant recipients . J Surg Oncol \n2006 ;94 :431 -3 .16967458 \n31. Pedotti P Poli F Longhi E \nEpidemiologic study on the origin of cancer after kidney transplantation . Transplantation \n2004 ;77 :426 -8 .14966419 \n32. Myron Kauffman H McBride MA Cherikh WS \nTransplant tumor registry: donor related malignancies . Transplantation \n2002 ;74 :358 -62 .12177614 \n33. Penn I \nTransmission of cancer from organ donors . Ann Transplant \n1997 ;2 :7 -12 .9869872 \n34. de Peralta-Venturina M Moch H Amin M \nSarcomatoid differentiation in renal cell carcinoma: a study of 101 cases . Am J Surg Pathol \n2001 ;25 :275 -84 .11224597 \n35. Shuch B Said J La Rochelle JC \nCytoreductive nephrectomy for kidney cancer with sarcomatoid histology: is up-front resection indicated and, if not, is it avoidable? \nJ Urol \n2009 ;182 :2164 -71 .19758641 \n36. Cheville JC Lohse CM Zincke H \nSarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome . Am J Surg Pathol \n2004 ;28 :435 -41 .15087662 \n37. Tomera KM Farrow GM Lieber MM \nSarcomatoid renal carcinoma . J Urol \n1983 ;130 :657 -9 .6887392 \n38. Siemer S Hack M Lehmann J \nOutcome of renal tumors in young adults . J Urol \n2006 ;175 :1240 -4 .16515969 \n39. Thompson RH Ordonez MA Iasonos A \nRenal cell carcinoma in young and old patients: is there a difference? \nJ Urol \n2008 ;180 :1262 -6 .18707708 \n40. Cook A Lorenzo AJ Salle JL \nPediatric renal cell carcinoma: single institution 25-year case series and initial experience with partial nephrectomy . J Urol \n2006 ;175 :1456 -60 .16516019 \n41. Cumberbatch MG Rota M Catto JW La Vecchia C. \nThe role of tobacco smoke in bladder and kidney carcinogenesis: a comparison of exposures and meta-analysis of incidence and mortality risks . Eur Urol \n2016 ;70 :458 -66 .26149669 \n42. Adams KF Leitzmann MF Albanes D \nBody size and renal cell cancer incidence in a large US cohort study . Am J Epidemiol \n2008 ;168 :268 -77 .18544571 \n43. Ljungberg B Campbell SC Choi HY \nThe epidemiology of renal cell carcinoma . Eur Urol \n2011 ;60 :615 -21 .21741761 \n44. Brennan JF Stilmant MM Babayan RK Siroky MB \nAcquired renal cystic disease: implications for the urologist . Br J Urol \n1991 ;67 :342 -8 .2032071 \n45. Wetmore JB Calvet JP Yu ASL \nPolycystic kidney disease and cancer after renal transplantation . J Am Soc Nephrol \n2014 ;25 :2335 -41 .24854270 \n46. Ribal MJ Rodriguez F Musquera M \nNephron-sparing surgery for renal tumor: a choice of treatment in an allograft kidney . Transplant Proc \n2006 ;38 :1359 -62 .16797303 \n47. Miao Y Everly JJ Gross TG \nDe novo cancers arising in organ transplant recipients are associated with adverse outcomes compared with the general population . Transplantation \n2009 ;87 :1347 -59 .19424035 \n48. Morath C Mueller M Goldschmidt H \nMalignancy in renal transplantation . J of Am Soc Nephrol \n2004 ;15 :1582 -8 .15153569 \n49. Buell JF Gross TG Woodle ES \nMalignancy after transplantation . Transplantation \n2005 ;80 :S254 -64 .16251858 \n50. Buell JF Beebe TM Trofe J \nDonor transmitted malignancies . Ann Transplant \n2004 ;9 :53 -6 .15478892 \n51. Briggs JD \nCauses of death after renal transplantation . Nephrol Dialysis Transplant \n2001 ;16 :1545 -9 .\n52. Gudbjartsson T Hardarson S Petursdottir V \nHistological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients . Eur Urol \n2005 ;48 :593 -600 .15964127 \n53. Tsui KH Shvarts O Smith RB \nPrognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria . J Urol \n2000 ;163 : 1090 -5 .10737472 \n54. Elfving P Mandahl N Lundgren R \nPrognostic implications of cytogenetic findings in kidney cancer . Br J Urol \n1997 ;80 :698 -706 .9393289 \n55. Gunawan B Huber W Holtrup M \nPrognostic impacts of cytogenetic findings in clear cell renal cell carcinoma: gain of 5q31-qter predicts a distinct clinical phenotype with favorable prognosis . Cancer Res \n2001 ; 61 :7731 -8 .11691785 \n56. Ljungberg B Bozoky B Kovacs G \np53 expression in correlation to clinical outcome in patients with renal cell carcinoma . Scand J Urol Nephrol \n2001 ;35 :15 -20 .11291681\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-3605",
"issue": "9(1)",
"journal": "Rare tumors",
"keywords": "Kidney cancer; kidney transplant; recipients; transplant",
"medline_ta": "Rare Tumors",
"mesh_terms": null,
"nlm_unique_id": "101526926",
"other_id": null,
"pages": "6550",
"pmc": null,
"pmid": "28458790",
"pubdate": "2017-03-24",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "10503093;10737472;11224597;11291681;11477152;11502993;1154487;11691785;12177614;14966419;15087662;15153569;15250100;15478892;15579450;15915495;15957121;15964127;16251858;16515969;16516019;16640518;16797303;16967458;18544571;18707708;1926521;19424035;19758641;20005414;20007757;2032071;21440788;21741761;23094759;23269448;24854270;26149669;27930283;2815261;3057702;4879937;4904755;5100867;6887392;7503073;7878750;7993576;8030123;8108890;9393289;9853232;9869872",
"title": "Renal Cancer in Recipients of Kidney Transplant.",
"title_normalized": "renal cancer in recipients of kidney transplant"
} | [
{
"companynumb": "US-ACCORD-051411",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Experience with zinc in treating symptomatic hepatic Wilson's disease (WD) is limited.\n\n\n\nTo study the efficacy of Penicillamine followed by zinc in treating symptomatic hepatic Wilson's disease.\n\n\n\nWe retrospectively analyzed case records of 31 symptomatic hepatic WD patients for whom disease severity scores (Child's, model for end-stage liver disease (MELD), Nazer's, and New Wilson Index (NWI) score) and 24-h urinary copper were compared at 3-time points-baseline at presentation, at transition from penicillamine to zinc and at end of follow up.\n\n\n\nThirty-one patients (median age 11 [5-24] years) with symptomatic hepatic WD were studied; ten had associated neuropsychiatric manifestations of WD. Penicillamine was changed to zinc sulfate either due to financial constraints (28 patients) or due to adverse effects of penicillamine (3 patients). At presentation (baseline), six patients belonged to Child's class A, five to Child's B, and 17 to Child's C. Duration of initial penicillamine chelation therapy was 134 (2-320) weeks, and of subsequent zinc therapy was 363 (35-728) weeks. There was a significant improvement in liver function tests and disease severity scores (Child's, MELD, Nazer's, and NWI score) at the transition from penicillamine to zinc compared to baseline. This improvement was maintained until the end of study period with 90% survival at 10 (2-20) years. Fifteen of the 17 Child's C cirrhotic patients showed significant improvement in disease severity scores from baseline until end of follow up.\n\n\n\nPenicillamine followed by zinc may be a safe and effective treatment in resource-constrained setting for symptomatic hepatic WD patients in all grades of baseline disease severity. Some patients with decompensated cirrhosis due to WD may be managed with medical treatment, avoiding liver transplantation.",
"affiliations": "Department of Hepatology, Christian Medical College, Vellore, 632 004, India. docpiyushgupta@gmail.com.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.;Department of Biostatistics, Christian Medical College, Vellore, 632 004, India.;Department of Hepatology, Christian Medical College, Vellore, 632 004, India.",
"authors": "Gupta|Piyush|P|http://orcid.org/0000-0002-3670-2800;Choksi|Mehul|M|;Goel|Ashish|A|;Zachariah|Uday|U|;Sajith|Kattiparambil Gangadharan|KG|;Ramachandran|Jeyamani|J|;Chandy|George|G|;Kurian|George|G|;Rebekah|Grace|G|;Eapen|Chundamannil Eapen|CE|",
"chemical_list": "D002614:Chelating Agents; D019287:Zinc Sulfate; D003300:Copper; D010396:Penicillamine",
"country": "India",
"delete": false,
"doi": "10.1007/s12664-018-0829-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0254-8860",
"issue": "37(1)",
"journal": "Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology",
"keywords": "Hepatic Wilson’s disease; Penicillamine; Symptomatic Wilson’s; Wilson’s disease; Zinc",
"medline_ta": "Indian J Gastroenterol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002614:Chelating Agents; D002648:Child; D002675:Child, Preschool; D003300:Copper; D017046:Cost Savings; D057915:Drug Substitution; D005260:Female; D005500:Follow-Up Studies; D006527:Hepatolenticular Degeneration; D006801:Humans; D008297:Male; D010396:Penicillamine; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D019287:Zinc Sulfate",
"nlm_unique_id": "8409436",
"other_id": null,
"pages": "31-38",
"pmc": null,
"pmid": "29457214",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16793346;3792921;15776453;8936358;11172350;17276780;15871305;14713890;21078496;9794697;19211426;8534043;17460493;18506894;19731238;14723607;24661374;23760378;16466879;17765927;21970993;3819764;22340672",
"title": "Maintenance zinc therapy after initial penicillamine chelation to treat symptomatic hepatic Wilson's disease in resource constrained setting.",
"title_normalized": "maintenance zinc therapy after initial penicillamine chelation to treat symptomatic hepatic wilson s disease in resource constrained setting"
} | [
{
"companynumb": "IN-BAUSCH-BL-2018-013087",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PENICILLAMINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo assess the psychiatric side effects of ketamine when administered in subanesthetic doses to hospitalized patients. It is hypothesized that such effects occur frequently.\n\n\nMETHODS\nIn this retrospective study, the medical records of 50 patients hospitalized on medical and surgical units at our facility who had continuous intravenous infusions of ketamine for pain or mild sedation were reviewed. Patient progress in the days following the start of ketamine infusion was reviewed and response to ketamine was noted.\n\n\nRESULTS\nTwenty-two percent of the patients were noted to have some type of psychiatric reaction to ketamine, including agitation, confusion, and hallucinations. These reactions were relatively short lived, namely, occurring during or shortly after the infusions. No association was found between patient response to ketamine and gender, age, or infusion rate.\n\n\nCONCLUSIONS\nAwareness of the psychiatric side effects of ketamine is an important consideration for clinicians administering this medication either for pain control or for depressive illness.",
"affiliations": "Department of Psychiatry and Psychology,Mayo Clinic,Rochester,Minnesota,MN,USA.",
"authors": "Rasmussen|Keith G|KG|",
"chemical_list": "D000700:Analgesics; D007649:Ketamine",
"country": "England",
"delete": false,
"doi": "10.1017/neu.2013.61",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-2708",
"issue": "26(4)",
"journal": "Acta neuropsychiatrica",
"keywords": null,
"medline_ta": "Acta Neuropsychiatr",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000700:Analgesics; D005260:Female; D006760:Hospitalization; D006801:Humans; D007649:Ketamine; D008297:Male; D008875:Middle Aged; D010146:Pain; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9612501",
"other_id": null,
"pages": "230-3",
"pmc": null,
"pmid": "25142291",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Psychiatric side effects of ketamine in hospitalized medical patients administered subanesthetic doses for pain control.",
"title_normalized": "psychiatric side effects of ketamine in hospitalized medical patients administered subanesthetic doses for pain control"
} | [
{
"companynumb": "US-MYLAN-2014M1001570",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Progressive multifocal leukoencephalopathy (PML) is a rare but devastating neurological disease caused by reactivation of the JC virus in susceptible individuals. The illness has classically been associated with the human immunodeficiency virus (HIV) and multiple sclerosis (MS) patients who are treated with natalizumab. It is also associated with haematological malignancies, organ transplantation, autoimmune disease and immunodeficiency. Aside from natalizumab, a range of other immunomodulators including obinutuzumab and rituximab have been associated with PML. The nature of these associations is unclear due to the overall low incidence of PML associated with these drugs and the fact that most patients will have other confounding risk factors for developing the disease. There is no known effective treatment available for PML in the non-HIV, non-MS cohort. Recent case studies and series have proposed that pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, may be a potentially efficacious option for these patients. We present two cases of non-HIV, non-MS patients with PML who were treated with pembrolizumab with little clinical benefit. The literature surrounding pembrolizumab use in PML is discussed, with a focus on potential indicators of successful outcomes for patients who receive this therapy.",
"affiliations": "Department of Neurology, Tallaght University Hospital, Dublin 24, Ireland. sarah.darcy@ucdconnect.ie.;Department of Neurophysiology, Tallaght University Hospital, Dublin 24, Ireland.;Department of Neurology, Tallaght University Hospital, Dublin 24, Ireland.;Department of Neurology, Tallaght University Hospital, Dublin 24, Ireland.",
"authors": "Darcy|Sarah|S|http://orcid.org/0000-0002-5926-8816;Alexander|Michael|M|;McCarthy|Allan|A|;O'Dowd|Seán|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-021-01028-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-0284",
"issue": null,
"journal": "Journal of neurovirology",
"keywords": "Anti-CD20 monoclonal antibodies; Immune checkpoint inhibitors; JC virus; Progressive multifocal leukoencephalopathy",
"medline_ta": "J Neurovirol",
"mesh_terms": null,
"nlm_unique_id": "9508123",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34874539",
"pubdate": "2021-12-07",
"publication_types": "D016428:Journal Article",
"references": "28975841;21555606;30864100;31597693;31597692",
"title": "Pembrolizumab treatment of inflammatory progressive multifocal leukoencephalopathy: a report of two cases.",
"title_normalized": "pembrolizumab treatment of inflammatory progressive multifocal leukoencephalopathy a report of two cases"
} | [
{
"companynumb": "IE-ROCHE-2980253",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "In 2010, the American College of Medical Toxicology (ACMT) established its Case Registry, the Toxicology Investigators Consortium (ToxIC). All cases are entered prospectively and include only suspected and confirmed toxic exposures cared for at the bedside by board-certified or board-eligible medical toxicologists at its participating sites. The primary aims of establishing this Registry include the development of a realtime toxico-surveillance system in order to identify and describe current or evolving trends in poisoning and to develop a research tool in toxicology. ToxIC allows for extraction of data from medical records from multiple sites across a national and international network. All cases seen by medical toxicologists at participating institutions were entered into the database. Information characterizing patients entered in 2012 was tabulated and data from the previous years including 2010 and 2011 were included so that cumulative numbers and trends could be described as well. The current report includes data through December 31st, 2012. During 2012, 38 sites with 68 specific institutions contributed a total of 7,269 cases to the Registry. The total number of cases entered into the Registry at the end of 2012 was 17,681. Emergency departments remained the most common source of consultation in 2012, accounting for 61 % of cases. The most common reason for consultation was for pharmaceutical overdose, which occurred in 52 % of patients including intentional (41 %) and unintentional (11 %) exposures. The most common classes of agents were sedative-hypnotics (1,422 entries in 13 % of cases) non-opioid analgesics (1,295 entries in 12 % of cases), opioids (1,086 entries in 10 % of cases) and antidepressants (1,039 entries in 10 % of cases). N-acetylcysteine (NAC) was the most common antidote administered in 2012, as it was in previous years, followed by the opioid antagonist naloxone, sodium bicarbonate, physostigmine and flumazenil. Anti-crotalid Fab fragments were administered in 109 cases or 82 % of cases in which a snake envenomation occurred. There were 57 deaths reported in the Registry in 2012. The most common associated agent alone or in combination was the non-opioid analgesic acetaminophen, being reported in 10 different cases. Other common agents and agent classes involved in death cases included ethanol, opioids, the anti-diabetic agent metformin, sedatives-hypnotics and cardiovascular agents, in particular amlodipine. There were significant trends identified during 2012. Abuse of over-the-counter medications such as dextromethorphan remains prevalent. Cases involving dextromethorphan continued to be reported at frequencies higher than other commonly abused drugs including many stimulants, phencyclidine, synthetic cannabinoids and designer amphetamines such as bath salts. And, while cases involving synthetic cannabinoids and psychoactive bath salts remained relatively constant from 2011 to 2012 several designer amphetamines and novel psychoactive substances were first reported in the Registry in 2012 including the NBOME compounds or \"N-bomb\" agents. LSD cases also spiked dramatically in 2012 with an 18-fold increase from 2011 although many of these cases are thought to be ultra-potent designer amphetamines misrepresented as \"synthetic\" LSD. The 2012 Registry included over 400 Adverse Drug Reactions (ADRs) involving 4 % of all Registry cases with 106 agents causing at least 2 ADRs. Additional data including supportive cares, decontamination, and chelating agent use are also included in the 2012 annual report. The Registry remains a valuable toxico-surveillance and research tool. The ToxIC Registry is a unique tool for identifying and characterizing confirmed cases of significant or potential toxicity or complexity to require bedside care by a medical toxicologist.",
"affiliations": "The University of Rochester Medical Center and Strong Memorial Hospital, Rochester, USA, Timothy_Wiegand@URMC.Rochester.edu.",
"authors": "Wiegand|Timothy|T|;Wax|Paul|P|;Smith|Eric|E|;Hart|Katherine|K|;Brent|Jeffrey|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-013-0352-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "9(4)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002170:Canada; D002648:Child; D002675:Child, Preschool; D003299:Cooperative Behavior; D057225:Data Mining; D005260:Female; D006801:Humans; D007223:Infant; D007391:International Cooperation; D007557:Israel; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D012042:Registries; D012307:Risk Factors; D012955:Societies, Medical; D013997:Time Factors; D014116:Toxicology; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "380-404",
"pmc": null,
"pmid": "24178902",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21956161;22068919;22528591;23055123",
"title": "The Toxicology Investigators Consortium Case Registry--the 2012 experience.",
"title_normalized": "the toxicology investigators consortium case registry the 2012 experience"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-RO-01034RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"... |
{
"abstract": "Chronic lymphocytic leukemia (CLL) typically pursues a prolonged course. Its transformation into a more aggressive lymphoma occurs in 2-8% of all patients. Most commonly, diffuse large B-cell lymphoma develops. Transformation into a classical Hodgkin's lymphoma (cHL) occurs in <1%. Plasmablastic transformation has been only rarely reported. Cases of synchronous divergent transformation of CLL into a composite lymphoma are exceedingly rare. We describe the unique occurrence of the transformation of a long-standing CLL into a synchronous clonally related cHL as well as plasmablastic lymphoma (PBL) in an 85-year-old female patient. After 10 years of asymptomatic CLL, our patient was treated with a rituximab-chlorambucil scheme in combination with pegfilgrastim for recurrent infections and the development of B symptoms. Five cycles (of six planned) were administrated with no adverse effects. After the fifth cycle, lymphadenopathy with pronounced B symptoms appeared. Histology showed the presence of cHL in the lymph node, while the bone marrow was infiltrated by PBL. Our patient died in sepsis not receiving further specific oncologic treatment due to her poor general condition. Additional cytogenetic and molecular studies showed that this was a case of mutated CLL with trisomies of chromosomes 12, 3, and 18 (a rare specific +12 plus other-non+19 CLL subgroup). The presence of trisomy 12 has also been proved in plasmablasts and in cHL cells.",
"affiliations": "Department of Pathology, Institute of Oncology, Ljubljana, Slovenia.;Department of Hematology, General Hospital Celje, Celje, Slovenia.;Department of Cytology, Institute of Oncology, Ljubljana, Slovenia.;Department of Pathology, Institute of Oncology, Ljubljana, Slovenia.;Department of Pathology, Institute of Oncology, Ljubljana, Slovenia.;Clinical Institute of Medical Genetics, University Medical Center Ljubljana, Ljubljana, Slovenia.;Department of Hematology, University Medical Center Ljubljana, Ljubljana, Slovenia.",
"authors": "Gasljevic|Gorana|G|;Grat|Mateja|M|;Kloboves Prevodnik|Veronika|V|;Grcar Kuzmanov|Biljana|B|;Gazic|Barbara|B|;Lovrecic|Luca|L|;Podgornik|Helena|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000505683",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Chronic lymphocytic leukemia; Classical Hodgkin's lymphoma; Plasmablastic lymphoma; Richter's transformation; Trisomy 12",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "120-129",
"pmc": null,
"pmid": "32231533",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "12149227;21266718;22207691;10835534;23923114;18720210;19074125;20869749;22432520;17593029;17895764;20956983;27102498;23282972;23791008",
"title": "Chronic Lymphocytic Leukemia with Divergent Richter's Transformation into a Clonally Related Classical Hodgkin's and Plasmablastic Lymphoma: A Case Report.",
"title_normalized": "chronic lymphocytic leukemia with divergent richter s transformation into a clonally related classical hodgkin s and plasmablastic lymphoma a case report"
} | [
{
"companynumb": "SI-AMGEN-SVNSP2020054511",
"fulfillexpeditecriteria": "2",
"occurcountry": "SI",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHeparin-induced thrombocytopenia (HIT) is immune-mediated thrombotic thrombocytopenia following the use of heparin, which contributes to a high limb-amputation rate and mortality if not appropriately handled. There is growing evidence suggesting that novel oral anticoagulants (NOACs) may be effective for treating HIT.\n\n\nMETHODS\nWe described five rare cases of patients with HIT associated with deep vein thrombosis treated with dabigatran, a member of NOACs. We also reviewed representative cases and literature investigating the use of NOACs to treat patients with HIT to further discuss the efficacy and safety.\n\n\nCONCLUSIONS\nFollowing the treatment of dabigatran after argatroban, the platelet count of patients with HIT gradually elevated and reached the normal range eventually. There was no incidence of new symptomatic, objectively-confirmed arteriovenous thromboembolism observed within the 90-day-period follow up. The patient in case 3 presented with gastric bleeding after dabigatran treatment and died in the end. The results suggested that dabigatran use after argatroban may be effective in the treatment of patients with HIT. However, safety should be reconsidered since severe complications were observed in case 3.",
"affiliations": "Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.; Department of Cardiac Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.;Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.;Department of Vascular Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.;Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.;Department of Vascular Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.. Electronic address: lawson4001@zju.edu.cn.",
"authors": "Wang|Yue|Y|;Zhang|Kaijie|K|;Yin|Li|L|;Fu|Guosheng|G|;Liu|Zhenjie|Z|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2021.08.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": null,
"journal": "Annals of vascular surgery",
"keywords": "Dabigatran; Efficacy; Heparin-induced thrombocytopenia; Novel oral anticoagulants; Safety",
"medline_ta": "Ann Vasc Surg",
"mesh_terms": null,
"nlm_unique_id": "8703941",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34656708",
"pubdate": "2021-10-14",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Dabigatran Use after Argatroban for Heparin-induced Thrombocytopenia with Thrombosis: A Case Series and Literature Review.",
"title_normalized": "dabigatran use after argatroban for heparin induced thrombocytopenia with thrombosis a case series and literature review"
} | [
{
"companynumb": "CN-ALKEM LABORATORIES LIMITED-CN-ALKEM-2022-02215",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "A 92-year-old woman with previous total hip replacement presented with sudden onset of atraumatic hip pain and inability to weight bear. In the absence of radiographic signs of fracture, loosening or biochemical evidence of infection a CT scan of the pelvis and hips was performed, which showed psoas thickening. MRI identified two separate collections related to the psoas and greater trochanteric regions. Ultrasound-guided aspiration was performed to rule out infection and demonstrated a haematoma. In contrast to previously reported cases caused by anticoagulant therapy or inherited coagulopathy, this case was secondary to single antiplatelet agent treatment alone. In the increasingly co-morbid ageing population with associated polypharmacy, aspirin is a common primary and secondary prevention treatment. In patients with atraumatic hip pain, spontaneous psoas haematoma due to antiplatelet therapy should be considered and investigated appropriately.",
"affiliations": "Department of Orthopaedics, Royal Glamorgan Hospital, Llantrisant, UK.;Department of Orthopaedics, Royal Glamorgan Hospital, Llantrisant, UK.;Medical School, Cardiff University, Cardiff, UK.;Department of Orthopaedics, Royal Glamorgan Hospital, Llantrisant, UK.",
"authors": "Key|Thomas|T|;Kimberley|Charles|C|;Rietz|Robert|R|;Roy|Stuart William|SW|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(4)",
"journal": "BMJ case reports",
"keywords": "orthopaedic and trauma surgery; orthopaedics; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D001241:Aspirin; D000072700:Conservative Treatment; D004322:Drainage; D005260:Female; D006406:Hematoma; D006801:Humans; D010146:Pain; D010975:Platelet Aggregation Inhibitors; D016658:Psoas Muscles",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30962214",
"pubdate": "2019-04-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20541888;27353057;21722393;30147925;11172167;11880914;26217580;11478557;26669607",
"title": "Spontaneous psoas haematoma secondary to antiplatelet therapy: a rare cause of atraumatic hip pain.",
"title_normalized": "spontaneous psoas haematoma secondary to antiplatelet therapy a rare cause of atraumatic hip pain"
} | [
{
"companynumb": "GB-GENUS_LIFESCIENCES-USA-POI0580201900283",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN\\OMEPRAZOLE"
},
"dr... |
{
"abstract": "Midazolam, a benzodiazepine, is commonly used for intravenous sedation for dental procedures and, together with other benzodiazepines, can cause anterograde amnesia. Retrograde amnesia, however, is rare. It is defined as a loss of access to memory of events that occurred, or information that was learned, before the injury or event that caused the amnesia. We know of no reports of this occurring after the intravenous use of midazolam alone and few after general anaesthesia. We present two cases of retrograde amnesia: one after intravenous sedation and one after general anaesthesia.",
"affiliations": "Oral Surgery Department, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: gsaulakh90@gmail.com.;Oral Surgery Department, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: bizhan.shokouhi@gstt.nhs.uk.;Oral Surgery Department, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address: kiran.beneng@kcl.ac.uk.",
"authors": "Aulakh|G|G|;Shokouhi|B|B|;Beneng|K|K|",
"chemical_list": "D006993:Hypnotics and Sedatives; D008874:Midazolam",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.bjoms.2018.06.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0266-4356",
"issue": "56(7)",
"journal": "The British journal of oral & maxillofacial surgery",
"keywords": "cognitive dysfunction; general anaesthesia; intravenous sedation; retrograde amnesia",
"medline_ta": "Br J Oral Maxillofac Surg",
"mesh_terms": "D000328:Adult; D000648:Amnesia, Retrograde; D000768:Anesthesia, General; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D007262:Infusions, Intravenous; D008874:Midazolam; D008964:Molar, Third; D014081:Tooth Extraction",
"nlm_unique_id": "8405235",
"other_id": null,
"pages": "632-635",
"pmc": null,
"pmid": "30029983",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Retrograde amnesia after intravenous sedation and general anaesthesia in a dental hospital.",
"title_normalized": "retrograde amnesia after intravenous sedation and general anaesthesia in a dental hospital"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201809598",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": null,
... |
{
"abstract": "Fifty-seven patients with advanced cancer (52 with squamous cell carcinoma of the head and neck) were treated with short-course, multiple drug chemotherapy using schedules that were similar to those proposed by Price et al. Chemotherapy consisted of vincristine, methotrexate and folinic acid rescue, bleomycin, and FU, with or without Adriamycin and hydroxyurea. Most patients had received radiation therapy. There were only six objective responses (one CR, five PR) and except for one patient who is alive without disease following subsequent radiation the remissions were of short duration. Most patients tolerated treatment well but there was one toxic death, two sudden deaths of unknown cause, and renal impairment, mucositis, myelosuppression, or bleomycin skin toxicity in 14 others. Our results differ from those of Price et al. and do not support a role for this type of chemotherapy in the treatment of recurrent or metastatic head and neck cancer.",
"affiliations": null,
"authors": "Tannock|I|I|;Sutherland|D|D|;Osoba|D|D|",
"chemical_list": "D000970:Antineoplastic Agents; D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(19820401)49:7<1358::aid-cncr2820490709>3.0.co;2-k",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "49(7)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D003404:Creatinine; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006258:Head and Neck Neoplasms; D006801:Humans; D007970:Leukopenia; D009364:Neoplasm Recurrence, Local; D013997:Time Factors",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "1358-61",
"pmc": null,
"pmid": "7059951",
"pubdate": "1982-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Failure of short-course multiple drug chemotherapy to benefit patients with recurrent or metastatic head and neck cancer.",
"title_normalized": "failure of short course multiple drug chemotherapy to benefit patients with recurrent or metastatic head and neck cancer"
} | [
{
"companynumb": "CA-PFIZER INC-2019400544",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Saprophytic fungi are being increasingly recognized as etiologic agents of mycoses in immunosuppressed patients. We report a case of subcutaneous infiltration by Aureobasidium pullulans, likely due to traumatic inoculation, in a neutropenic patient during chemotherapy for chronic lymphocytic leukemia. The patient was treated with amphotericin B deoxycholate but was subsequently switched to itraconazole, which improved the lesion. This case highlights the importance of considering unusual fungal infections in critically ill patients such as those who are immunosuppressed due to chemotherapy. Diagnostic techniques and effective antifungal therapy have improved the prognosis of these cases.",
"affiliations": "Serviço de Hematologia, Universidade Federal do Triângulo Mineiro, UberabaMG.",
"authors": "Oliveira|Leonardo Rodrigues de|LR|;Moraes-Souza|Helio|H|;Maltos|André Luiz|AL|;Santos|Keila Cristina dos|KC|;Molina|Rodrigo Juliano|RJ|;Barata|Cristina Hueb|CH|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0037-8682",
"issue": "46(5)",
"journal": "Revista da Sociedade Brasileira de Medicina Tropical",
"keywords": null,
"medline_ta": "Rev Soc Bras Med Trop",
"mesh_terms": "D000368:Aged; D001203:Ascomycota; D017809:Fatal Outcome; D064147:Febrile Neutropenia; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D009181:Mycoses",
"nlm_unique_id": "7507456",
"other_id": null,
"pages": "660-2",
"pmc": null,
"pmid": "24270260",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aureobasidium pullulans infection in a patient with chronic lymphocytic leukemia.",
"title_normalized": "aureobasidium pullulans infection in a patient with chronic lymphocytic leukemia"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2014R1-86154",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"druga... |
{
"abstract": "Recent clinical trials have demonstrated that anti-PD-1 blocking antibodies showed remarkable clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Clinical trials usually exclude patients with renal dysfunction who are receiving hemodialysis (HD). Therefore, it is unclear whether these patients can be safely and effectively treated with pembrolizumab. Here, we present a non-small cell lung cancer patient on HD who achieved complete remission after one dose of pembrolizumab without severe adverse events. We assessed pembrolizumab binding to peripheral blood T cells in this patient using a method that we recently developed. This is the first report to visualize pembrolizumab binding to T cells in a patient on HD during and after pembrolizumab treatment. The pharmacokinetics of pembrolizumab in this case were similar to those in patients with normal renal function, suggesting that severe renal dysfunction has little influence on the metabolism of pembrolizumab, and is not a contraindication for anti-PD-1 treatment. Immune checkpoint inhibitors, including pembrolizumab, may be a vital therapeutic option for lung cancer patients on HD.",
"affiliations": "Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.",
"authors": "Osa|Akio|A|;Uenami|Takeshi|T|;Naito|Yujiro|Y|;Hirata|Haruhiko|H|;Koyama|Shohei|S|0000-0002-6897-9417;Takimoto|Takayuki|T|;Shiroyama|Takayuki|T|;Futami|Shinji|S|;Nakatsubo|Saeko|S|;Sawa|Nobuhiko|N|;Yano|Yukihiro|Y|;Nagatomo|Izumi|I|;Takeda|Yoshito|Y|;Mori|Masahide|M|;Kida|Hiroshi|H|;Kumanogoh|Atsushi|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582435:pembrolizumab",
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.13197",
"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.13197TCA13197Case ReportCase ReportsMonitoring antibody binding to T cells in a pembrolizumab‐treated patient with lung adenocarcinoma on hemodialysis Pembrolizumab binding to T cellsA. Osa et al.Osa Akio \n1\n\n2\n\n3\nUenami Takeshi \n4\nNaito Yujiro \n1\n\n2\nHirata Haruhiko \n1\nKoyama Shohei https://orcid.org/0000-0002-6897-9417\n1\n\n2\nkoyama@imed3.med.osaka-u.ac.jp Takimoto Takayuki \n1\nShiroyama Takayuki \n1\nFutami Shinji \n1\nNakatsubo Saeko \n1\nSawa Nobuhiko \n4\nYano Yukihiro \n4\nNagatomo Izumi \n1\nTakeda Yoshito \n1\nMori Masahide \n4\nKida Hiroshi \n1\n\n4\nKumanogoh Atsushi \n1\n\n2\n\n5\n\n1 \nDepartment of Respiratory Medicine and Clinical Immunology\nOsaka University Graduate School of Medicine\nSuita\nJapan\n\n2 \nLaboratory of Immunopathology, WPI Immunology Frontier Research Center (iFReC)\nOsaka University\nSuita\nJapan\n\n3 \nDepartment of Respiratory Medicine\nKinki Central Hospital\nItami\nJapan\n\n4 \nDepartment of Thoracic Oncology\nNational Hospital Organization Osaka Toneyama Medical Center\nToyonaka\nJapan\n\n5 \nIntegrated Frontier Research for Medical Science Division, The Institute for Open and Transdisciplinary Research Initiatives\nOsaka University\nSuita\nJapan\n* Correspondence\n\nShohei Koyama, Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Laboratory of Immunopathology, WPI Immunology Frontier Research Center (iFReC), Osaka University, Osaka 565‐0871, Japan.\n\nTel: +81 6 6879 3833\n\nFax: +81 6 6879 3839\n\nEmail: koyama@imed3.med.osaka-u.ac.jp\n14 9 2019 11 2019 10 11 10.1111/tca.v10.112183 2187 22 7 2019 27 8 2019 27 8 2019 © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis 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.Recent clinical trials have demonstrated that anti‐PD‐1 blocking antibodies showed remarkable clinical efficacy in a subset of non‐small cell lung cancer (NSCLC) patients. Clinical trials usually exclude patients with renal dysfunction who are receiving hemodialysis (HD). Therefore, it is unclear whether these patients can be safely and effectively treated with pembrolizumab. Here, we present a non‐small cell lung cancer patient on HD who achieved complete remission after one dose of pembrolizumab without severe adverse events. We assessed pembrolizumab binding to peripheral blood T cells in this patient using a method that we recently developed. This is the first report to visualize pembrolizumab binding to T cells in a patient on HD during and after pembrolizumab treatment. The pharmacokinetics of pembrolizumab in this case were similar to those in patients with normal renal function, suggesting that severe renal dysfunction has little influence on the metabolism of pembrolizumab, and is not a contraindication for anti‐PD‐1 treatment. Immune checkpoint inhibitors, including pembrolizumab, may be a vital therapeutic option for lung cancer patients on HD.\n\nHemodialysismonitoringPD‐1 blocking antibodypembrolizumab Japan Society for the Promotion of ScienceKAKENHI JP17K16045Japan Agency for Medical Research and DevelopmentJP18cm0106335JP19cm0106310 source-schema-version-number2.0component-idtca13197cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:03.11.2019\n==== Body\nIntroduction\nRecent clinical trials demonstrated that PD‐1 blockade showed high clinical efficacy in patients with non‐small cell lung cancer (NSCLC) who had a high PD‐L1 tumor proportion score.1, 2, 3, 4 Clinical trials generally exclude patients with renal dysfunction who are receiving hemodialysis (HD), and it is therefore unclear whether these patients can be safely and effectively treated with anti‐PD‐1 therapy.\n\nIn this article we describe a NSCLC patient on HD who was treated with pembrolizumab. An obvious clinical response was obtained after only one treatment. The therapeutic effect was maintained and no recurrence had occurred at 50 weeks after discontinuation of treatment.\n\nWe have previously developed and reported a method to monitor binding of the anti‐PD‐1 antibody nivolumab to T cells in NSCLC patients.5 The same method could be used to detect pembrolizumab since both anti‐PD‐1 antibodies comprise fully humanized IgG4 and interfere with recognition by the PD‐1‐detecting antibody EH12.1.6, 7 In this study, we monitored pembrolizumab binding to peripheral blood T cells in a patient on HD, and found that the immunokinetics of pembrolizumab were similar to those in control patients with normal renal function.\n\nCase report\nA 72‐year‐old male patient was diagnosed with stage IIIB lung adenocarcinoma harboring neither EGFR mutation nor ALK rearrangement. Positron emission tomography (PET) showed a primary lesion in the right lower lobe and metastases to multiple lymph nodes, including the right supraclavicular lymph node (Fig 1). Although this patient was ineligible for cytotoxic chemotherapy due to anemia and HD,8 and could not undergo radiotherapy due to the large irradiated area in the lung, he was eligible to receive anti‐tumor treatment. PD‐L1 evaluation was performed by immunohistochemistry using the 22C3 antibody, and a biopsy sample showed a PD‐L1 tumor proportion score of 80%. Based on this clinical background, intravenous pembrolizumab 200 mg was administered as first‐line therapy. Three weeks after the first injection, he developed mild ileus and aspiration pneumonia which resolved with conservative treatment. The treatment was discontinued because immune‐related adverse events9 could not completely be ruled out as a cause of his condition. Despite the fact that the patient received only a single dose of pembrolizumab, his clinical response was maintained and follow‐up positron emission tomography/computed tomography revealed complete metabolic remission10 at 50 weeks after the dose (Fig 1). During his clinical course, peripheral blood was analyzed at three time points: at pretreatment, eight and 24 weeks after the injection. We previously developed a method to monitor nivolumab binding to T cells after discontinuation of treatment.5 This method was available for monitoring pembrolizumab binding in this patient. Briefly, we prepared two types of antibodies for the analysis: the first, EH12.1, binds to PD‐1 expressed on T cells, and the second, HP6025, is an anti‐IgG4 antibody identifying the PD‐1‐blocking antibodies consisted of humanized IgG4, nivolumab and pembrolizumab. EH12.1 recognizes a similar epitope as nivolumab and pembrolizumab. After treatment, EH12.1 does not detect PD‐1 expressed on T cells if PD‐1 is completely blocked by therapeutic antibodies, whereas HP6025 detects nivolumab and pembrolizumab is bound to T cells. This method simply identified the status of pembrolizumab binding to T cells in this patient. The binding status was classified as complete binding (CB), partial binding (PB), or no binding (NB).5 In this patient, T cells at eight and 24 weeks after injection showed CB and NB, respectively (Fig 2). We compared the immunokinetics of pembrolizumab binding in the current patient with that in a control group consisting of five lung adenocarcinoma patients with normal renal function who were treated with one to four doses of pembrolizumab (Fig 3a). Follow‐up in controls was performed between nine and 25 weeks after pembrolizumab discontinuation. One representative control patient showed decreased CB (red) and an absolute loss of CB at 25 weeks after the final dose (Fig 3b). The other four patients showed a similar trend in decreased CB, with an absolute CB loss at around 20–25 weeks (Fig 3c).\n\nFigure 1 Axial computed tomography (CT) (upper lane) and positron emission tomography/CT images (lower lane) at indicated time points.\n\nFigure 2 Staining of PD‐1 and IgG4 in blood CD8 and CD4 T cells from the patient on hemodialysis. Flow cytometry analysis was performed at pretreatment (pre) and at eight weeks and 24 weeks after discontinuation of pembrolizumab. CB, complete binding (red); NB, no binding (green); PB, partial binding (blue).\n\nFigure 3 (a) Characteristics of control lung adenocarcinoma patients with normal renal function. (b) Representative staining results examining time‐dependent changes in pembrolizumab binding to T cells after drug discontinuation. Flow cytometry analysis was performed to evaluate PD‐1 and IgG4 staining in blood CD8 and CD4 T cells from patient 1 (Pt. 1). (c) The percent of complete binding of pembrolizumab in CD8 and CD4 T cells was followed up in five NSCLC patients (*follow‐up discontinued due to hospital change or death). () CD8 T cells and () CD4 T cells.\n\nDiscussion\nFew case reports have reported the successful administration of anti‐PD‐1 antibodies in cancer patients receiving HD.11, 12, 13 Here, we present a patient on HD who achieved complete remission after one dose of the anti‐PD‐1 antibody pembrolizumab, without severe adverse events. Renal impairment reportedly has little effect on the pharmacokinetics of pembrolizumab.14 However, no studies have visualized anti‐PD‐1 antibody binding to T cells after anti‐PD‐1 antibody discontinuation in patients on HD. Monitoring of antibody binding to T cells in the patient in this case revealed that CB was maintained at eight weeks and binding was completely lost at 24 weeks after a single pembrolizumab injection. Similar immunokinetics were confirmed in control patients treated with a small number of pembrolizumab doses, suggesting that HD had little effect on pembrolizumab metabolism, though the time points of sample collection could not be standardized among individuals. Importantly, clinical efficacy in this case was maintained independently of pembrolizumab binding at ≥24 weeks after one dose,15 suggesting that either T cell immune surveillance began to function efficiently after treatment or viable cancer cells were cleared before pembrolizumab binding was lost.\n\nPembrolizumab may be a vital treatment option for lung cancer patients on HD who have no contraindications. Moreover, our monitoring strategy for anti‐PD‐1 antibody binding in patients on HD could be useful for understanding the metabolism of anti‐PD‐1 antibodies and the maintenance of anti‐tumor T cell immunity after complete loss of antibody binding.\n\nDisclosure\nThe authors do not report any conflict of interest.\n==== Refs\nReferences\n1 \n\nTopalian \nSL \n, \nHodi \nFS \n, \nBrahmer \nJR \n\net al\nSafety, activity, and immune correlates of anti‐PD‐1 antibody in cancer . N Engl J Med \n2012 ; 366 : 2443 –54 .22658127 \n2 \n\nReck \nM \n, \nRodriguez‐Abreu \nD \n, \nRobinson \nAG \n\net al\nPembrolizumab versus chemotherapy for PD‐L1‐positive non‐small‐cell lung cancer . N Engl J Med \n2016 ; 375 : 1823 –33 .27718847 \n3 \n\nReck \nM \n, \nRodriguez‐Abreu \nD \n, \nRobinson \nAG \n\net al\nUpdated analysis of KEYNOTE‐024: Pembrolizumab versus platinum‐based chemotherapy for advanced non‐small‐cell lung cancer with PD‐L1 tumor proportion score of 50% or greater . J Clin Oncol \n2019 ; 37 : 537 –46 .30620668 \n4 \n\nMok \nTSK \n, \nWu \nYL \n, \nKudaba \nI \n\net al\nPembrolizumab versus chemotherapy for previously untreated, PD‐L1‐expressing, locally advanced or metastatic non‐small‐cell lung cancer (KEYNOTE‐042): A randomised, open‐label, controlled, phase 3 trial . Lancet \n2019 ; 393 : 1819 –30 .30955977 \n5 \n\nOsa \nA \n, \nUenami \nT \n, \nKoyama \nS \n\net al\nClinical implications of monitoring nivolumab immunokinetics in non‐small celllung cancer patients . JCI Insight \n2018 ; 3 : 59125 .30282824 \n6 \n\nKamphorst \nAO \n, \nPillai \nRN \n, \nYang \nS e a \n. Proliferation of PD‐1+ CD8 T cells in peripheral blood after PD‐1‐targeted therapy in lung cancer patients . Proc Natl Acad Sci U S A \n2017 ; 114 : 4993 –8 .28446615 \n7 \n\nZelba \nH \n, \nBochem \nJ \n, \nPawelec \nG \n, \nGarbe \nC \n, \nWistuba‐Hamprecht \nK \n, \nWeide \nB \n. Accurate quantification of T‐cells expressing PD‐1 in patients on anti‐PD‐1 immunotherapy . Cancer Immunol Immunother \n2018 ; 67 : 1845 –51 .30218171 \n8 \n\nFunakoshi \nT \n, \nHorimatsu \nT \n, \nNakamura \nM \n\net al\nChemotherapy in cancer patients undergoing haemodialysis: A nationwide study in Japan . ESMO Open \n2018 ; 3 : e000301.29531838 \n9 \n\nNishijima \nTF \n, \nShachar \nSS \n, \nNyrop \nKA \n, \nMuss \nHB \n. Safety and tolerability of PD‐1/PD‐L1 inhibitors compared with chemotherapy in patients with advanced cancer: A meta‐analysis . Oncologist \n2017 ; 22 : 470 –9 .28275115 \n10 \n\nHicks \nRJ \n. The role of PET in monitoring therapy . Cancer Imaging \n2005 ; 5 : 51 –7 .16154820 \n11 \n\nAnsari \nJ \n, \nAli \nM \n, \nFarrag \nA \n, \nAli \nAM \n, \nAlhamad \nA \n. Efficacy of nivolumab in a patient with metastatic renal cell carcinoma and end‐stage renal disease on dialysis: Case report and literature review . Case Reports Immunol \n2018 ; 2018 : 1623957 .30009063 \n12 \n\nCarlo \nMI \n, \nFeldman \nDR \n. Response to nivolumab in a patient with metastatic clear cell renal cell carcinoma and end‐stage renal disease on dialysis . Eur Urol \n2016 ; 70 : 1082 –3 .27311362 \n13 \n\nChang \nR \n, \nShirai \nK \n. Safety and efficacy of pembrolizumab in a patient with advanced melanoma on haemodialysis . BMJ Case Rep \n2016 ; bcr2016216426 .\n14 \n\nAhamadi \nM \n, \nFreshwater \nT \n, \nProhn \nM e a \n. Model‐based characterization of the pharmacokinetics of pembrolizumab: A humanized anti‐PD‐1 monoclonal antibody in advanced solid tumors . CPT Pharmacometrics Syst Pharmacol \n2017 ; 6 : 49 –57 .27863186 \n15 \n\nGaron \nEB \n, \nHellmann \nMD \n, \nRizvi \nNA \n\net al\nFive‐year overall survival for patients with advanced nonsmall‐cell lung cancer treated with pembrolizumab: Results from the phase I KEYNOTE‐001 study . J Clin Oncol \n2019 ; Jco1900934 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1759-7706",
"issue": "10(11)",
"journal": "Thoracic cancer",
"keywords": "Hemodialysis; PD-1 blocking antibody; monitoring; pembrolizumab",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D006435:Renal Dialysis; D013601:T-Lymphocytes; D016896:Treatment Outcome",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "2183-2187",
"pmc": null,
"pmid": "31520515",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports",
"references": "27863186;30218171;29531838;22658127;27718847;27659911;28275115;30620668;16154820;30009063;27311362;30282824;31154919;30955977;28446615",
"title": "Monitoring antibody binding to T cells in a pembrolizumab-treated patient with lung adenocarcinoma on hemodialysis.",
"title_normalized": "monitoring antibody binding to t cells in a pembrolizumab treated patient with lung adenocarcinoma on hemodialysis"
} | [
{
"companynumb": "JP-009507513-1712JPN002268J",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CODEINE PHOSPHATE"
},
"drugadditional": "1"... |
{
"abstract": "To describe the prevalence, clinical presentation, and management of rheumatic immune-related adverse effects (Rh-irAEs) from immune checkpoint inhibitor (ICI) therapy.\n\n\n\nFrom a database of all patients who received any ICI at the Mayo Clinic Rochester, Minnesota campus between January 1, 2011 and March 1, 2018, we retrospectively identified those with Rh-irAEs, using diagnostic codes, search terms, and manual chart review.\n\n\n\nOf the 1,293 patients who received any ICI, Rh-irAEs were clinically diagnosed in 43. Eighteen patients with Rh-irAEs who received ICI therapy elsewhere were also analyzed. Clinical syndromes included inflammatory arthritis (n = 34 [prevalence 2%]), myopathy (n = 10), and other rheumatic syndromes (n = 17). Inflammatory arthritis was most commonly polyarticular, and glucocorticoid treatment was required in 26 patients (76%). The mean ± SD duration of treatment was 18 ± 18 weeks. Five patients (15%) also received disease-modifying antirheumatic drugs, and ICI therapy had to be discontinued in 3 patients (9%). Myopathy was treated with glucocorticoids in all cases (mean ± SD treatment duration 15 ± 17 weeks) and led to 2 deaths and permanent ICI discontinuation in 9 patients (90%). Other syndromes included connective tissue diseases, vasculitis, polymyalgia rheumatica-like syndrome, and flare of preexisting rheumatic disease. Most (71%) were treated with immunosuppression, with 12% requiring ICI discontinuation.\n\n\n\nThis study represents the largest cohort of patients with Rh-irAEs reported to date. Most patients received long courses of immunosuppressive treatment, although discontinuation of ICI therapy was required in only a minority.",
"affiliations": "Mayo Clinic, Rochester, Minnesota.;Mayo Clinic, Rochester, Minnesota.;Mayo Clinic, Rochester, Minnesota.;Mayo Clinic, Rochester, Minnesota.;Mayo Clinic, Rochester, Minnesota.;Mayo Clinic, Rochester, Minnesota.",
"authors": "Richter|Michael D|MD|;Crowson|Cynthia|C|;Kottschade|Lisa A|LA|;Finnes|Heidi D|HD|;Markovic|Svetomir N|SN|;Thanarajasingam|Uma|U|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/art.40745",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-5191",
"issue": "71(3)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D016208:Databases, Factual; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D012216:Rheumatic Diseases; D013577:Syndrome",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "468-475",
"pmc": null,
"pmid": "30281202",
"pubdate": "2019-03",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Rheumatic Syndromes Associated With Immune Checkpoint Inhibitors: A Single-Center Cohort of Sixty-One Patients.",
"title_normalized": "rheumatic syndromes associated with immune checkpoint inhibitors a single center cohort of sixty one patients"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-041224",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). All-trans retinoic acid (ATRA) is the first-choice therapy for the treatment of this disease, but has been associated with side effects, the most serious of which is retinoic acid syndrome (RAS). RAS is characterized by unexplained fever, dyspnea, pulmonary infiltrate, leukocytosis and nephropathy. Genital ulcers have been described in some cases, but only two cases of oral ulcers related to this syndrome have been described in the literature. This paper describes the third case of oral ulceration related to ATRA in a 32-year-old white man with diagnosis of APL. Clinicians should know the side effects of ATRA and identify oral ulcers resulting from this therapy. The prompt identification of these ulcers enables the institution of appropriate treatment and can therefore contribute to continuation of the patient's cancer treatment.",
"affiliations": "University Hospital, Federal University of Santa Maria, Roraima Avenue, 1000, Building 20; CEP: 97105-900, Santa Maria, RS, Brazil.;University Hospital, Federal University of Santa Maria, Roraima Avenue, 1000, Building 20; CEP: 97105-900, Santa Maria, RS, Brazil.;University Hospital, Federal University of Santa Maria, Roraima Avenue, 1000, Building 20; CEP: 97105-900, Santa Maria, RS, Brazil.;Department of Pathology, School of Dentistry, Federal University of Santa Maria, Roraima Avenue, 1000, Building 20; CEP: 97105-900, Santa Maria, RS, Brazil.",
"authors": "Buligon|M P|MP|;Mielke|J C|JC|;Chiesa|J|J|;Ferrazzo|K L|KL|",
"chemical_list": "D000970:Antineoplastic Agents; D014212:Tretinoin",
"country": "United States",
"delete": false,
"doi": "10.1111/scd.12293",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-1879",
"issue": "38(4)",
"journal": "Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry",
"keywords": "case report; leukemia; oral ulcer; tretinoin",
"medline_ta": "Spec Care Dentist",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008047:Lip Diseases; D008297:Male; D014212:Tretinoin; D014456:Ulcer",
"nlm_unique_id": "8103755",
"other_id": null,
"pages": "234-238",
"pmc": null,
"pmid": "29786869",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Rare labial ulcer related to the use of all-trans retinoic acid in a patient with acute promyelocytic leukemia.",
"title_normalized": "rare labial ulcer related to the use of all trans retinoic acid in a patient with acute promyelocytic leukemia"
} | [
{
"companynumb": "BR-ZO SKIN HEALTH-2019ZOS00001",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": null... |
{
"abstract": "Incidence of malignant tumors in kidney transplant recipients is higher than nontransplanted population due to many factors, such as immunosuppression therapy and complex donor-recipient interaction. Genitourinary malignancies have been reported as the second most common malignancy in kidney transplant recipients. In this regard, prostate cancer is the most common neoplasm. Herein, we describe a rare case of prostate cancer recurrence after 15 years in a patient who underwent kidney transplant after radical prostatectomy.",
"affiliations": "Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy. Electronic address: dsforza@gmail.com.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.;Urology Unit, Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy.;Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy Unit, Tor Vergata University of Rome, Rome, Italy.;Department of Hepatobiliary Surgery and Transplant Unit, Tor Vergata University of Rome, Italy.",
"authors": "Sforza|Daniele|D|;Parente|Alessandro|A|;Pellicciaro|Marco|M|;Morabito|Marika|M|;Iaria|Giuseppe|G|;Anselmo|Alessandro|A|;Lindfors|Elisa Rossi|ER|;Corrado|Federica|F|;Cacciatore|Chiara|C|;Del Fabbro|Dario|D|;Ingrosso|Gianluca|G|;Tisone|Giuseppe|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.04.098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D009364:Neoplasm Recurrence, Local; D011468:Prostatectomy; D011471:Prostatic Neoplasms",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2995-2997",
"pmc": null,
"pmid": "31607619",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prostate Cancer Recurrence in Kidney Transplant Recipient 15 Years After Radical Prostatectomy: A Case Report.",
"title_normalized": "prostate cancer recurrence in kidney transplant recipient 15 years after radical prostatectomy a case report"
} | [
{
"companynumb": "NVSC2019IT051924",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The α1-adrenergic antagonist prazosin has showed good effect against posttraumatic stress disorder-related nightmares in several randomized controlled trials. The α1-adrenergic antagonist doxazosin, which has a longer half-live than prazosin, has received far less attention in the treatment of such nightmares. Here, we report a case of a patient suffering from severe nightmares following an erroneous medical administration of adrenaline (causing severe physiological hyper-activation) who was treated with doxazosin. Over a period of 280 days, the patient kept a nightmare diary and took 0, 4, or 8 mg doxazosin. The analyses showed that 8 mg doxazosin (55.2% nightmare-free nights) worked better (odds ratio = 28.2; 95% confidence interval = 3.7-213.9) compared to nights without doxazosin (4.3% nightmare-free nights). Except dizziness, which was not regarded as particularly bothersome by the patient, doxazosin was well tolerated. It is concluded that doxazosin may be indicated as a pharmacological treatment for patients suffering from posttraumatic stress disorder-related nightmares.",
"affiliations": "Department of Psychosocial Science, University of Bergen, Bergen, Norway.;Diakonhjemmet Hospital, Oslo, Norway.;Diakonhjemmet Hospital, Oslo, Norway.;Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway.",
"authors": "Pallesen|Ståle|S|https://orcid.org/0000-0002-5831-0840;Hamre|Hilde Sofie|HS|;Lang|Nina|N|;Bjorvatn|Bjørn|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X20936079",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20936079\n10.1177_2050313X20936079\nCase Report\nDoxazosin for the treatment of nightmare disorder: A diary-based case study\nhttps://orcid.org/0000-0002-5831-0840Pallesen Ståle 12 Hamre Hilde Sofie 3 Lang Nina 3 Bjorvatn Bjørn 24 1 Department of Psychosocial Science, University of Bergen, Bergen, Norway\n2 Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway\n3 Diakonhjemmet Hospital, Oslo, Norway\n4 Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway\nStåle Pallesen, Department of Psychosocial Science, University of Bergen, Christies gate 12, Bergen 5015, Norway. Email: pklsp@uib.no\n29 6 2020 \n2020 \n8 2050313X209360793 7 2019 13 5 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).The α1-adrenergic antagonist prazosin has showed good effect against posttraumatic stress disorder–related nightmares in several randomized controlled trials. The α1-adrenergic antagonist doxazosin, which has a longer half-live than prazosin, has received far less attention in the treatment of such nightmares. Here, we report a case of a patient suffering from severe nightmares following an erroneous medical administration of adrenaline (causing severe physiological hyper-activation) who was treated with doxazosin. Over a period of 280 days, the patient kept a nightmare diary and took 0, 4, or 8 mg doxazosin. The analyses showed that 8 mg doxazosin (55.2% nightmare-free nights) worked better (odds ratio = 28.2; 95% confidence interval = 3.7–213.9) compared to nights without doxazosin (4.3% nightmare-free nights). Except dizziness, which was not regarded as particularly bothersome by the patient, doxazosin was well tolerated. It is concluded that doxazosin may be indicated as a pharmacological treatment for patients suffering from posttraumatic stress disorder–related nightmares.\n\nα1-adrenergic antagonistdoxazosinnightmare disordertreatmentcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nNightmare disorder is characterized by episodes of extended, very frightening, and well-remembered dreams. Usually, nightmares involve threats to survival, security, or physical integrity. When the person awakens from a nightmare, he or she swiftly regains full consciousness and thus becomes oriented and alert. The dream experience, or the dream disturbance, which is a consequence of awakening from it, causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The latter is indicated by the patients reporting at least one of the following: sleep resistance, mood disturbance, cognitive impairments, negative impact on caregiver or family functioning, behavioral problems, daytime sleepiness, fatigue or low energy, impaired occupational or educational function, or impaired interpersonal/social function.1 It has been argued that a distinction between idiopathic nightmares and posttraumatic stress disorder (PTSD)-related nightmares is warranted. PTSD-related nightmares seem, among others, to be characterized by more awakenings than idiopathic nightmares2 and by higher sympathetic activation during rapid eye movement (REM) sleep than in normal controls.3\n\nIn regard of pharmacological treatment, the α1-adrenergic antagonist prazosin has in several randomized controlled trials showed clinical effect for PTSD-related nightmares;4–6 however, in a recent study with military veterans suffering from PTSD, prazosin did not improve posttraumatic stress symptoms, nightmares, and sleep problems in general compared to placebo.7 A retrospective chart review concluded that prazosin is effective for pediatric PTSD-associated nightmares and sleep disturbances.8 For adults, dosages are normally titrated up to 12 mg for women and 25 mg for men,5 whereas the dosages for youth seem to vary between 1 and 15 mg.8 α1-receptors are located in locus coeruleus, cerebral cortex, and limbic regions such as hippocampus and amygdala. It has been reported that α1-receptor stimulation disturbs REM sleep and increases non-REM sleep. Furthermore, stimulation of α1-receptors causes release of corticotropin-releasing hormone, which triggers the cortisol stress response.9\n\nIn a conditioning study, prazosin was shown not to affect threat conditioning, but augmented stimulus discrimination between safe and threatening stimuli during extinction and reextinction, hence prazosin may facilitate discrimination between the safe and threatening stimuli.10 Prazosin crosses the blood–brain barrier, antagonizes the α1-receptors in the central nervous system (CNS) and by this blocks the stress responses by which prazosin improves sleep and reduces PTSD-related nightmares.9 In some countries, including Norway, prazosin is however not available as a regular prescription drug. Other α1-adrenergic antagonists may, however, have similar therapeutic properties. In one uncontrolled study, the α1-adrenergic antagonist doxazosin, titrated up to 8 mg daily, was shown to be effective against nightmares.11 This was also supported by a more recent case study.12 In a crossover trial with eight patients suffering from PTSD, doxazosin was titrated from 4 to 16 mg daily over 12 days. On some PTSD-outcome measures, doxazosin improved PTSD symptoms, but not on a subscale assessing problematic dreams.13 A chart review concluded, however, that doxazosin might improve nightmares associated with trauma as well as sleep parameters in general in patients with PTSD and borderline personality disorder.14 Prazosin has a half-life of only 2–3 h and has thus to be taken twice daily, whereas doxazosin has a considerably longer half-life, approximately 22 h.15 This implies that the effects of prazosin may subside during the night which may increase the risk of nightmares in the latter half of sleep in contrast to doxazosin.16 Hence, more studies on doxazosin as a treatment for PTSD-related nightmares are warranted.\n\nCase\nHere, we describe a diary-based case study of a 56-year-old woman strongly affected by PTSD-related nightmares. The nightmares were triggered by an incident where the patient during hospitalization became the victim of a grossly erroneous medical treatment as racemic adrenaline, which should be delivered by aerosol, instead was administered through a peripheral intravenous catheter. The patient got seizures, severe tachycardia, and hypertension. The black hair of a nurse bending over the patient during the incident became associated with an eagle, which appeared in subsequent dreams, attacking the patient. The patient experienced that sleeping following a nightmare became difficult. Furthermore, the nightmares caused tiredness/sleepiness, lack of ability to concentrate, nervousness during daytime, and acted as a reminder of the trauma. The patient also became afraid of sleeping in new contexts as this often provoked nightmares. The patient was not bothered with nightmares before the incident. All nightmares she experienced were related to the incident. The symptoms triggered by the incident made her fulfill the criteria for PTSD found in the ICD-10 Classification of Mental and Behavioural Disorders.17 The patient had been suffering from nightmares for 11 months before she started treatment with doxazosin in December 2012.\n\nShe kept a diary with information about dosage (0, 4, and 8 mg of doxazosin) and nightmare occurrence (occurred or not occurred) for 280 consecutive days. The dosage varied due to factors such as hospitalization and deliberate experimentation on behalf of the patient. The patient was instructed by her medical doctor to take doxazosin in doses up to 8 mg per day. The dosage varied between 4 and 8 mg (one or two tablets) due to dizziness as a side effect, typically lowering the dosage when dizziness became somewhat conspicuous. During periods of hospitalization, doxazosin was normally not administered.\n\nA logistic regression analysis was conducted in which day was entered as a control variable in order to control for time as a confounding factor. The dosage of doxazosin was dummy coded and 0 mg of doxazosin constituted the reference category. Nightmare occurrence (0 = present, 1 = absent) comprised the dependent variable. In the crude analysis, the two predictors (day and dosage) were entered/analyzed separately, whereas in the adjusted analysis they were entered simultaneously. The result is considered significant when the 95% confidence interval does not include 1.00. In total, there were 23 days when the patient did not take any medication (0 mg doxazosin), 74 days when the patient took 4 mg of doxazosin, and 183 days when the patient took 8 mg of doxazosin. Of the 280 days, nightmares occurred on 162 nights and were absent on 118 nights. Cross-tabulation of dosage and nightmare frequency showed that only one of the 23 days (4.3%) without medication was nightmare free. Nightmare was absent in 16 of the 74 days (21.6%) with 4 mg of doxazosin, whereas nightmares was absent in 101 of the 183 days (55.2%) with 8 mg of doxazosin. The results are presented in Table 1. The adjusted model was statistically significant (χ2 = 45.7, df = 3, p < 0.001) and explained between 15.1% (Cox and Snell R2) and 20.2% (Nagelkerke R2) of the variance in nightmare occurrence and correctly classified 62.5% of the nights. The results showed that doxazosin 8 mg had a better effect on nightmare occurrence than no medication. Doxazosin 4 mg had a near significantly better effect on nightmare occurrence than no medication. Hypotension is a potential side effect of α1-adrenergic antagonists18 and the patient experienced some dizziness in hot weather when taking 8 mg doxazosin and rising quickly from lying positions. The patient did, however, not regard this as bothersome. At one occasion when she had taken 8 mg of doxazosin, the patient fainted. Besides dizziness, no other side effects were noted by the patient. The patient went to regular check-ups of the blood pressure during the doxazosin treatment, and blood pressure was not abnormal at any point. Although a daily dose of 8 mg of doxazosin did not eliminate nightmares completely, the reduction in nightmare frequency was experienced as a clinical significant improvement by the patient.\n\nTable 1. Logistic regression analysis where time and dosage of doxazosin were regressed on nightmare occurrence (0 = nightmare present, 1 = nightmare absent).\n\nPredictor\tCrude\tAdjusted\t\n\tOR\t95% CI\tOR\t95% CI\t\nDay\t1.01\t1.00–1.01**\t1.00\t1.00–1.01\t\nDoxazosina\t\n 4 mg\t6.07\t0.76–48.53\t8.06\t0.96–67.5\t\n 8 mg\t27.10\t3.58–205.31**\t28.15\t3.71–213.89**\t\nOR: odds ratio; CI: confidence interval.\n\na 0 mg doxazosin comprised the reference category.\n\n** p < 0.01.\n\nDiscussion\nThis case study suggests that doxazosin seems to alleviate PTSD nightmares at least when taken in dosages of 8 mg or more. As this study suggests a dose-dependent effect, it is possible that higher doses would have produced even better outcome, and studies have shown that dosages up to 16 mg per day seem to be tolerated well.13 This study lasted for 280 days and the effects of doxazosin did not seem to wear off by time, indicating no development of tolerance. It should be noted that no placebo was used in this study and that the patient partly experimented with different dosages by herself, hence the results may have been influenced by expectations on behalf of the patient. Still, as the study lasted for 280 days and consistently showed effects of 8 mg of doxazosin, it is concluded, in line with other studies,11,12,14 that doxazosin may be indicated as a pharmacological treatment for patients suffering from nightmares. Doxazosin also seems to be well tolerated. We strongly recommend a large randomized controlled trial of the effectiveness of doxazosin against nightmares to be conducted. A comparative study between doxazosin and prazosin also seems warranted.\n\nConclusion\nA doxazosin dose of 8 mg seemed to alleviate PTSD-related nightmares, was well tolerated, and did not lead to tolerance during the 280-day study period.\n\nAuthor’s note: Ståle Pallesen is also affiliated with Optentia, the Vaal Triangle Campus of the North-West University, Vanderbijlpark, South-Africa\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\nEthical approval: Our institutions do not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Verbal and written informed consent was obtained from the patient(s) for their anonymized information to be published in this article. The patient had completed college education and was not suffering from psychosis or any other delusional disorder. Thus, she was deemed to have the decisional capacity to provide informed consent.\n\nORCID iD: Ståle Pallesen \nhttps://orcid.org/0000-0002-5831-0840\n==== Refs\nReferences\n1 \nAmerican Academy of Sleep Medicine . International classification of sleep disorders . 3rd ed. \nDarien, IL : American Academy of Sleep Medicine , 2014 .\n2 \nGermain A Nielsen TA. \nSleep pathophysiology in posttraumatic stress disorder and idiopathic nightmare sufferers\n. Biol Psychiatry \n2003 ; 54 (10 ): 1092 –1098\n.14625152 \n3 \nMellman TA Knorr BR Pigeon WR , et al\nHeart rate variability during sleep and the early development of posttraumatic stress disorder\n. Biol Psychiatry \n2004 ; 55 (9 ): 953 –956\n.15110740 \n4 \nRaskind MA Peskind ER Hoff DJ , et al\nA parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder\n. Biol Psychiatry \n2007 ; 61 (8 ): 928 –934\n.17069768 \n5 \nRaskind MA Peterson K Williams T , et al\nA trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan\n. Am J Psychiatry \n2013 ; 170 (9 ): 1003 –1010\n.23846759 \n6 \nTaylor FB Martin P Thompson C , et al\nPrazosin effects on objective sleep measures and clinical symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study\n. Biol Psychiatry \n2008 ; 63 (6 ): 629 –632\n.17868655 \n7 \nRaskind MA Peskind ER Chow B , et al\nTrial of prazosin for post-traumatic stress disorder in military veterans\n. N Engl J Med \n2018 ; 378 (6 ): 508 –518\n.\n8 \nKeeshin BR Ding Q Presson AP , et al\nUse of prazosin for pediatric PTSD-associated nightmares and sleep disturbances: a retrospective chart review\n. Neurol Ther \n2017 ; 6 (2 ): 247 –257\n.28755207 \n9 \nHudson SM Whiteside TE Lorenz RA , et al\nPrazosin for the treatment of nightmares related to posttraumatic stress disorder: a review of the literature\n. Prim Care Companion CNS Disord \n2012 ; 14 (2 ): PCC.11r01222 .22943034 \n10 \nHoman P Lin Q Murrough JW , et al\nPrazosin during threat discrimination boosts memory of the safe stimulus\n. Learn Mem \n2017 ; 24 (11 ): 597 –601\n.29038221 \n11 \nDe Jong J Wauben P Huijbrechts I , et al\nDoxazosin treatment for posttraumatic stress disorder\n. J Clin Psychopharmacol \n2010 ; 30 (1 ): 84 –85\n.20075659 \n12 \nSethi R Vasudeva S. \nDoxazosin for the treatment of nightmares: does it really work? A case report\n. Prim Care Companion CNS Disord \n2012 ; 14 (5 ): PCC.12l01356 .23469321 \n13 \nRodgman C Verrico CD Holst M , et al\nDoxazosin XL reduces symptoms of posttraumatic stress disorder in veterans with PTSD: a pilot clinical trial\n. J Clin Psychiatry \n2016 ; 77 (5 ): e561 –e565\n.27249080 \n14 \nRoepke S Danker-Hopfe H Repantis D , et al\nDoxazosin, an alpha-1-adrenergic-receptor antagonist, for nightmares in patients with posttraumatic stress disorder and/or borderline personality disorder: a chart review\n. Pharmacopsychiatry \n2017 ; 50 (1 ): 26 –31\n.27276365 \n15 \nChung M Vashi V Puente J , et al\nClinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation\n. Br J Clin Pharmacol \n1999 ; 48 (5 ): 678 –687\n.10594469 \n16 \nSmith C Koola MM. \nEvidence for using doxazosin in the treatment of posttraumatic stress disorder\n. Psychiatr Ann \n2016 ; 46 (9 ): 553 –555\n.27667865 \n17 \nWorld Health Organization . The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines . 10th ed. \nGeneva : World Health Organization , 1992 .\n18 \nCarruthers SG. \nAdverse effects of alpha 1-adrenergic blocking drugs\n. Drug Saf \n1994 ; 11 (1 ): 12 –20\n.7917078\n\n",
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"title": "Doxazosin for the treatment of nightmare disorder: A diary-based case study.",
"title_normalized": "doxazosin for the treatment of nightmare disorder a diary based case study"
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"abstract": "First-line anti-tubercular therapy (ATT) is very effective in management of tuberculosis and is usually well tolerated. Varied spectrum of cutaneous adverse drug reactions is associated with ATT, of which lichenoid drug eruption (LDR) constitutes approximately 10% of the cases. However, LDR presenting as erythroderma is very rare. Here, we report a case of exfoliative dermatitis secondary to LDR which developed after 5 months of ATT.",
"affiliations": "Department of Dermatology, PGIMER Dr RML Hospital, New Delhi, India.;Department of Dermatology, PGIMER Dr RML Hospital, New Delhi, India.;Department of Dermatology, PGIMER Dr RML Hospital, New Delhi, India.;Department of Pathology, PGIMER Dr RML Hospital, New Delhi, India.",
"authors": "Katare|Anusha|A|0000-0002-4997-5306;Arora|Pooja|P|0000-0002-0718-6990;Sardana|Kabir|K|;Malhotra|Purnima|P|",
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"mesh_terms": "D000995:Antitubercular Agents; D003873:Dermatitis, Exfoliative; D006801:Humans; D017512:Lichenoid Eruptions; D008297:Male; D008875:Middle Aged; D014388:Tuberculosis, Lymph Node",
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"title": "Lichenoid drug reaction due to anti-tubercular therapy presenting as erythroderma.",
"title_normalized": "lichenoid drug reaction due to anti tubercular therapy presenting as erythroderma"
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"abstract": "Second cancers in survivors of hereditary retinoblastoma occur much more commonly than in the general population. This can be attributed both to the germline mutation of the RB gene and chemoradiation used for treatment of this paediatric cancer. Medulloepithelioma is an uncommon tumor of neuroectodermal origin, seen largely in the paediatric population and rarely reported in adults. Though the incidence of second malignancies is common in retinoblastoma, medulloepithelioma as a second malignancy in retinoblastoma survivors is rare, with only one case reported so far. Herein, we present a case of a 29-year-old patient presenting with medulloepithelioma of the right orbit, arising in the radiation field of previously treated retinoblastoma. This case was also peculiar in that though the origin of tumor was in the eyeball it had a very aggressive clinical course.",
"affiliations": "a Department of Radiation Oncology , All India Institute of Medical Sciences , New Delhi , India.;a Department of Radiation Oncology , All India Institute of Medical Sciences , New Delhi , India.;b Department of Ocular Pathology , All India Institute of Medical Sciences , New Delhi , India.;a Department of Radiation Oncology , All India Institute of Medical Sciences , New Delhi , India.;a Department of Radiation Oncology , All India Institute of Medical Sciences , New Delhi , India.;a Department of Radiation Oncology , All India Institute of Medical Sciences , New Delhi , India.;a Department of Radiation Oncology , All India Institute of Medical Sciences , New Delhi , India.",
"authors": "Thottian|Antony George Francis|AG|;Benson|Rony|R|;Kashyap|Seema|S|;Haresh|K P|KP|;Gupta|Subhash|S|;Sharma|Dayanand|D|;Rath|Goura Kishor|GK|",
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"keywords": "Medulloepithelioma; retinoblastoma; second malignancy",
"medline_ta": "Orbit",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009381:Neoplasms, Radiation-Induced; D018242:Neuroectodermal Tumors, Primitive; D009918:Orbital Neoplasms; D061766:Proton Therapy; D011880:Radiotherapy Planning, Computer-Assisted; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8301221",
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"pages": "313-316",
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"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Orbital medulloepithelioma in an adult patient: Radiation-induced second neoplasia?",
"title_normalized": "orbital medulloepithelioma in an adult patient radiation induced second neoplasia"
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"abstract": "Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.",
"affiliations": "Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece; Department of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece.;Department of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece.;Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece; Genetic and Epigenetic Alterations of Genomes, de Duve Institute, Catholic University of Louvain, Brussels, 1200, Belgium.;Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece.;Department of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece.;Second Department of Obstetrics & Gynaecology, Athens University Medical School, 11528 Athens, Greece.;Second Department of Obstetrics & Gynaecology, Athens University Medical School, 11528 Athens, Greece.;Department of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece.;First Department of Propedeutic Medicine, Athens University Medical School, 11527 Athens, Greece.;Department of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece.;Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece.",
"authors": "Stefanou|Dimitra T|DT|;Bamias|Aristotelis|A|;Episkopou|Hara|H|;Kyrtopoulos|Soterios A|SA|;Likka|Maria|M|;Kalampokas|Theodore|T|;Photiou|Stylianos|S|;Gavalas|Nikos|N|;Sfikakis|Petros P|PP|;Dimopoulos|Meletios A|MA|;Souliotis|Vassilis L|VL|",
"chemical_list": "D000970:Antineoplastic Agents; D010984:Platinum; D016190:Carboplatin",
"country": "United States",
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"doi": "10.1371/journal.pone.0117654",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2565911410.1371/journal.pone.0117654PONE-D-14-31418Research ArticleAberrant DNA Damage Response Pathways May Predict the Outcome of Platinum Chemotherapy in Ovarian Cancer DNA Damage Response in Ovarian Cancer ChemotherapyStefanou Dimitra T. \n1\n\n2\nBamias Aristotelis \n2\nEpiskopou Hara \n1\n\n3\nKyrtopoulos Soterios A. \n1\nLikka Maria \n2\nKalampokas Theodore \n4\nPhotiou Stylianos \n4\nGavalas Nikos \n2\nSfikakis Petros P. \n5\nDimopoulos Meletios A. \n2\nSouliotis Vassilis L. \n1\n*\n1 \nInstitute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece\n\n2 \nDepartment of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece\n\n3 \nGenetic and Epigenetic Alterations of Genomes, de Duve Institute, Catholic University of Louvain, Brussels, 1200, Belgium\n\n4 \nSecond Department of Obstetrics & Gynaecology, Athens University Medical School, 11528 Athens, Greece\n\n5 \nFirst Department of Propedeutic Medicine, Athens University Medical School, 11527 Athens, Greece\nSamimi Goli Academic Editor\nGarvan Institute of Medical Research, AUSTRALIA\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: AB VLS. Performed the experiments: DTS HE VLS. Analyzed the data: DTS SAK PPS MAD VLS. Contributed reagents/materials/analysis tools: ML TK SP NG. Wrote the paper: DTS SAK VLS.\n\n* E-mail: vls@eie.gr6 2 2015 2015 10 2 e011765416 7 2014 12 11 2014 © 2015 Stefanou et al2015Stefanou et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.\n\nThis work was supported in part by the Athens University Medical School grant ELKE 097, and by the ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityData are available from the Helios Digital Repository: http://helios-eie.ekt.gr/EIE/handle/10442/14421.Data Availability\nData are available from the Helios Digital Repository: http://helios-eie.ekt.gr/EIE/handle/10442/14421.\n==== Body\nIntroduction\nOvarian cancer (OC) is the fifth most common type of cancer in females and the leading cause of mortality for gynecological malignancies, with epithelial carcinoma being the most frequent variety [1,2]. OC is typically diagnosed in advanced stages and often carries a dismal prognosis, even though current treatment strategies including aggressive surgical cytoreduction and platinum-paclitaxel chemotherapy seem to have significantly improved the relative survival of these patients to a 5-year survival rate of over 40% [3]. Established prognostic factors for OC include stage, histologic subtype, tumor grade and volume of residual disease after cytoreductive surgery [4,5].\n\nThree different platinum compounds, namely cisplatin, carboplatin and oxaliplatin, are currently used in the clinical practice, with numerous indications, which cover a broad spectrum of solid tumors [6]. Their cytotoxic action is exerted through reaction with DNA and the development of DNA damage by the formation of cross-links, Pt-d[GpG] (1,2-intrastrand cross-links, 65%), Pt-d[ApG] (1,2-intrastrand cross-links, 25%) and in smaller extent Pt-d[GpNgG] (1,3-intrastrand cross-links), interstrand cross-links (ICLs, the most cytotoxic) and single-nucleotide damage of guanine [7]. Nucleotide excision repair (NER) is the main process by which platinum intrastrand crosslinks and single-nucleotide damage of guanine are repaired [8,9]. On the other hand, ICL repair is complex and requires a combination of NER, Fanconi Anemia repair pathway, translesion synthesis and homologous recombination [10–12]. Interestingly, ICLs repair proceeds via the formation of DNA double-strand breaks (DSBs) that represent the most lethal form of DNA damage [13]. The formation of DSBs is always followed by the phosphorylation of the histone H2AX, a variant of the H2A protein family, which is a component of the histone octamer in nucleosomes. The histone H2AX is phosphorylated by kinases such as ataxia telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) in the PI3K pathway [14]. This newly phosphorylated protein, γH2AX, is the first step in recruiting and localizing DNA repair proteins.\n\nThe mammalian genome is protected against genotoxic insults by a network of DNA damage response (DDR) pathways, which are triggered by the detection of DNA lesions through specific sensors [15]. The subsequent step is the initiation of a signal transduction cascade, which activates various genome-protection pathways. Since DDR is a comprehensive signaling process that determines the cell fate either by repairing DNA damage or undergoing apoptosis, its role has been implicated in the disease process and in the success of chemotherapy. Indeed, it has been shown that abnormalities in the DNA repair pathways play an important role in the malignant transformation of OC [16]. Also, expression of DNA repair proteins, such as Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1) have correlated with poor survival in advanced OC and were found to be markers of resistance to platinum-based drugs [17–19]. In addition, our previous studies focused on the levels of DNA damage in peripheral blood mononuclear cells (PBMCs) from multiple myeloma patients have shown that DNA damage could prospectively distinguish between patients with different degrees of therapeutic response, providing the basis for pre-screening and selection of those patients more likely to benefit from this treatment [20–24].\n\nHerein, we conducted a study to test the hypothesis that DDR, a crucial mechanism for cell survival, is involved in resistance to platinum chemotherapy. We found that OC patients are characterized by higher intrinsic DNA damage compared to healthy volunteers, and that the efficiency of DNA repair as measured in PBMCs from OC patients correlates with the drug sensitivity of these cells and reflects the individualized response to platinum-based chemotherapy.\n\nMaterials and Methods\nPatients\nAll patients included in this analysis were managed in a single institution (Alexandra Hospital, Athens, Greece). Blood samples were obtained from eighteen (n = 18) patients undergoing surgery for suspected ovarian cancer (mean age 62 years, range 34–77) (Table 1) prior to any therapeutic treatment. Nine (n = 9) healthy individuals, age- and gender-matched to patients (all females, mean age 60 years, range 29–73) were served as controls. All patients were staged according to FIGO staging system. Chemotherapy was initiated within one month from surgery. Paclitaxel at 175mg/m2 over 3 hours immediately followed by carboplatin 5–6 AUC over 60 minutes were administered every 3 weeks. Six cycles of chemotherapy were administered. Seven patients did not receive post surgery chemotherapy: 3 had borderline tumors, 1 patient died in the postoperative period, while 3 patients refused any treatment after surgery. Platinum sensitivity for the 11 patients who received first line chemotherapy was assessed according to the Gynecologic Cancer Intergroup Committee (GCIC) criteria [25]. By these criteria, there were 4 platinum-resistant and 7 platinum-sensitive patients. Surviving patients should have a minimum follow-up of 2 years. All participants gave written informed consent according to the Declaration of Helsinki Principles, and the study was approved by the Institutional Review Board of Alexandra Hospital.\n\n10.1371/journal.pone.0117654.t001Table 1 Baseline characteristics of 18 patients with epithelial ovarian cancer included in this analysis.\nCharacteristic\tNo\t% of total\t\nAge (years)\tMedian (range)\t62 (34–77)\t\t\nCA125 (U/ml)\tMedian (range)\t304 (105–1295)\t\t\nPS\t0\t7\t46.7\t\n\t1\t5\t33.3\t\n\t2\t3\t20\t\nHistology\tSerous\t9\t50\t\n\tClear cell\t6\t33.3\t\n\tBorderline tumors\t3\t16.7\t\nGrade\tII\t3\t20\t\n\tIII\t12\t80\t\nChemotherapy\tCarboplatin/paclitaxel\t11\t61.1\t\nStage\tI\t1\t6.7\t\n\tIII\t8\t53.3\t\n\tIV\t6\t40\t\nSurgical procedure\tAscites cytology only\t1\t6.7\t\n\tTAH\n1\n+BSO/USO\n2\n+Omentectomy\t10\t66.6\t\n\tBiopsy only\t3\t20\t\n\tPelvic exenteration\t1\t6.7\t\nResidual disease\t0\t2\t13.3\t\n\t<2 cm\t2\t13.3\t\n\t2–5 cm\t3\t20\t\n\t>5 cm\t5\t33.4\t\n\tUnknown\t3\t20\t\n\n1TAH: Total Abdominal Hysterectomy\n\n\n2BSO/USO: Bilateral (or Unilateral) Salpingo-Oophorectomy\n\nCell treatment\nThe platinum-sensitive A2780 and the platinum-resistant A2780/C30 cell lines [26] were kindly provided by Dr. George Koukos (Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA). Cells were cultured in monolayer by using RPMI 1640 containing 10% fetal calf serum, 100μg/ml streptomycin, 100units/ml penicillin, 0.3mg/ml glutamine and 0.3unit/ml insulin in a 37°C incubator continuously gassed with 5% CO2. Cells were treated with cisplatin (0–100μg/ml for 0–24h), followed by incubation in drug-free medium for 0–24h or carboplatin (0–300μg/ml for 0–24h), followed by post-incubation in drug-free medium for 0–24h.\n\nPBMCs were isolated from freshly drawn peripheral blood using standard methods [23]. Then, cells were stimulated into proliferation using 10μg/ml phytohemagglutinin (PHA) for 48h at 37°C in RPMI 1640 supplemented with 10% FCS, 50mg/l penicillin, 50.000lU/l streptomycin and subsequently treated with cisplatin (0–300μg/ml for up to 3h), followed by incubation in drug-free medium for 0–24h or carboplatin (0–1800μg/ml for up to 24h), followed by post-incubation in drug-free medium for 0–24h.\n\nCytotoxicity assay\nFollowing drug treatment, viable cells were counted by trypan blue dye-exclusion [27]. Briefly, following incubation with the drug, cells were washed and resuspended in complete medium. An equal volume of 0.4% trypan blue reagent was added to the cell suspension and the percentage of viable cells was evaluated. Assays were performed in triplicate.\n\nSingle-cell gel electrophoresis (Comet assay)\nThe single-cell gel electrophoresis assay was performed under alkaline conditions as described previously [28]. Briefly, aliquots of 5x104 untreated or platinum drug treated cells were suspended in low melting point agarose (1%) in PBS (135mmol/l NaCl, 2.5mmol/l KCl, pH 10) at 37°C, and spread onto fully frosted microscope slides precoated with a thin layer of 1% normal melting agarose (Biozyme, Hameln, Germany). The cell suspension was immediately covered with a coverglass and the slides were kept at 4°C for 1h to allow solidification of the agarose. After removing the coverglass, cells were exposed to lysis buffer (2.5M NaCl, 100mM EDTA, 10mM Tris-HCI, pH 10, 1% Triton X-100) at 4°C for 1h. Then, the slides were placed in a horizontal gel electrophoresis chamber. The chamber was filled with cold electrophoresis buffer (1mM EDTA, 300mM NaOH, pH 13) and slides were kept at 4°C for 40min to allow the DNA to unwind. Electrophoresis was performed for 40min (1V/cm, 255mA). After electrophoresis, the slides were washed with neutralisation buffer (0.4M Tris-HCI, pH 7.5) for 10min and then with H2O for 10min. All preparative steps were conducted in dark to prevent additional DNA damage. The slides were stained with 20μl of 1μg/ml DAPI and analysed with a fluorescence microscope (NIKON Eclipse 400) equipped with a CCD-4230A video camera. Digital images were acquired using an image analysis system (Kinetic Analysis, Wirral, UK). Olive Tail Moments [OTM = (Tail Mean—Head Mean) x (% of DNA) / 100] of 100 cells/treatment condition were evaluated.\n\nImmunofluorescence antigen staining and confocal laser scanning microscope analysis\nAliquots of 2x104 untreated or platinum drug treated cells were adhered to coverslip coated with 1M HCI and 50mg/ml poly-D-lysine prior to use, fixed by adding a 4% paraformaldehyde solution for 6min at room temperature and stored at -70°C until the analysis of pATM (serine-1981, Santa Cruz), pATR (serine-428, Cell Signaling), pChk1 (serine-345, Santa Cruz), pChk2 (threonine-68, Abcam) and γH2AX (serine-139, Cell Signaling) [29]. Cells were washed with cold PBS and blocked with 0.5ml per well blocking buffer (0.1% Triton X-100, 0.2% skimmed dry milk in PBS) for 1h at room temperature in a humidified box. Blocked cells were incubated with antibodies against pATM, pATR, pChk1, pChk2 or γH2AX in blocking buffer at 4°C overnight. After washing with blocking buffer, cells were incubated with goat anti-mouse antibody, FITC labeled, paired with goat anti-rabbit, TRITC labeled, for double labeling (Invitrogen) at a dilution of 1:4000 in blocking buffer for 1h at room temperature in the dark. Coverslips were applied, and the edges were sealed with clear nail polish. Images were visualized with a Leica TCS SP-1 confocal laser scanning microscope. Foci were manually counted in 200 cells/treatment condition and results are expressed as the % of γH2AX positive cells (mean±SD) from three independent experiments; positive cells are defined as cells with more than 5 foci per cell.\n\nApoptosis assay\nApoptosis was evaluated by using the Cell Death Detection ELISA-PLUS kit (Roche Applied Sciences), according to manufacturer’s instructions. In brief, cells were treated with various doses of carboplatin (cell lines, 0–300μg/ml; PBMCs, 0–1800μg/ml) for 24h followed by incubation in drug-free medium for 24h. Then, cells were collected to prepare the cytosolic fractions that contained fragments of DNA. Equal volumes of these cytosolic fractions were incubated in anti-histone antibody-coated wells (96-well plates), and the histones of the DNA fragments were allowed to bind to the anti-histone antibodies. The peroxidase-labeled mouse monoclonal DNA antibodies were used to localize and detect the bound fragmented DNA using photometric detection with 2,29-azino-di-(3-ethylbenzthiazoline sulfonate) as the substrate. The test quantifies apoptosis as the fold increase (expressed as Enrichment Factor, EF) in the level of apoptosis in treated samples to untreated samples. We calculated the specific enrichment of mono- and oligo-nucleosomes released into the cytoplasm using the following formula: (EF) = [(absorbance of the treated cells) / (absorbance of the cells without drug treatment)]. Finally, the individual apoptosis rate was expressed as the carboplatin dose sufficient to trigger the induction of a certain Enrichment Factor (EF = 3).\n\nStatistical analysis\nThe efficiency of DNA repair and the induction of apoptosis were compared between groups of individuals using non-parametric tests. Specifically, Kruskal Wallis analysis was used for comparisons across all three groups, and Wilcoxon rank sum test for the pair wise comparisons. Correlations between the values of the various DDR-related parameters within the cell lines or PBMCs of the different OC patients were assessed by the Spearman correlation coefficient (all groups combined). To assess the linear association between DNA damage and platinum drug dose, apoptosis and DNA damage, as well as apoptosis and pan-nuclear staining, linear regression of these parameters was performed. A P-value less than 0.05 was considered statistically significant. To account for multiple comparisons the Bonferonni correction was used.\n\nResults\nDNA repair of platinum-induced damage in ovarian carcinoma cell lines correlates with the drug sensitivity of these cells\nTo examine the molecular mechanisms implicated in the drug sensitivity of platinum chemotherapy, changes in key molecules of the cellular DDR pathway (pATM, pATR, pChk1, pChk2, γH2AX) were evaluated in two ovarian carcinoma cell lines: one platinum-sensitive (A2780) and one platinum-resistant (A2780/C30) [26]. Cells were treated with various doses of cisplatin (0–100μg/ml) for 0–24h followed by incubation in drug-free medium for 0–24h. Both cell lines showed a dose-dependent increase in the formation of all key molecules under study (Fig. 1A, D). Maximal levels of these molecules were observed at 6h post-treatment, remaining stable or slightly decreasing thereafter (Fig. 1B). Interestingly, γH2AX showed the highest induction rates among the key molecules examined. The lowest cisplatin concentration at which γH2AX induction could be detected was 2.5μg/ml for 1h (Fig. 1C). Moreover, cells were treated with carboplatin (0–300μg/ml) for 0–24h followed by post-incubation in drug-free medium for 0–24h. Similar results to those obtained from the cisplatin experiments were found. That is, in both cell lines a dose-dependent increase in the formation of all key molecules was observed (Fig. 1E, F). Also, maximal levels of these molecules were observed at the end of the 24h treatment, decreasing thereafter. Again, the γH2AX showed the highest induction rates among the key molecules examined. Taken together, these results indicate that immunofluorescence quantification of γH2AX foci is a powerful approach to measure DNA damage induced by platinum drugs.\n\n10.1371/journal.pone.0117654.g001Fig 1 Changes in key molecules of the DDR pathways in ovarian carcinoma cell lines.\nA2780/C30 cells (representative of the two OC cell lines) were treated (A) with cisplatin (0–100μg/ml) for 3h, or (B) with 100μg/ml cisplatin, subsequently incubated in drug-free medium for various time-periods (0–24h), or (C) with relatively small doses (0–15μg/ml) of cisplatin for up to 3h, and analyzed at the end of the treatment using confocal microscopy. Positive cells: cells with more than 5 foci per cell. The error bars represent standard deviation. In (D) typical images showing the key molecules under study using microscope analysis of A2780/C30 cells treated with 100μg/ml of cisplatin for 3h; upper images, immunofluorescence antigen staining; bottom images, cell nuclei labeled with DAPI. (E) A2780/C30 cells were treated with carboplatin (0–300μg/ml) for 24h or (F) with 100μg/ml carboplatin for various time-periods (0–24h) and analyzed using confocal microscopy. The error bars represent standard deviation. All assays were performed in triplicate.\n\nThe levels of platinum-induced DNA damage in both cell lines were also evaluated using alkaline comet assay. This version of the comet assay detects DNA migration caused by strand breaks, alkaline labile sites, and transient repair sites [30]. Following treatment of cells with 0–150μg/ml cisplatin for 3h (Fig. 2A, C) or 0–300μg/ml carboplatin for 24h (Fig. 2B, C), a linear dose-dependent increase of DNA damage levels was obtained in both cell lines, indicating that the method has the sensitivity and accuracy to detect and quantify platinum-induced DNA damage.\n\n10.1371/journal.pone.0117654.g002Fig 2 Measurement of DNA damage in ovarian carcinoma cell lines using alkaline comet assay.\nA2780/C30 cells (representative of the two OC cell lines) were treated with (A) cisplatin (0–150μg/ml) for 3h or (B) carboplatin (0–300μg/ml) for 24h, and analyzed at the end of the treatment using comet assay. The error bars represent standard deviation. In (C) typical comet assay images of A2780/C30 cells non-treated (NT), treated with 50μg/ml cisplatin (cis-50), 100μg/ml cisplatin (cis-100), 150μg/ml carboplatin (carbo-150) or 300μg/ml carboplatin (carbo-300). All assays were performed in triplicate.\n\nFurthermore, using the two powerful approaches validated above, the levels of the intrinsic DNA damage were assessed in untreated cell lines. Both immunofluorescence γH2AX staining and alkaline comet assay showed significant differences between the two cell lines, with the intrinsic DNA damage being higher in A2780 than in A2780/C30 cells. Particularly, using γH2AX immunofluorescence staining, A2780 cells exhibited 28.8±3.4% positive cells (i.e. cells with more than 5 foci per cell) and A2780/C30 17.4±3.4% positive cells (P = 0.01; Table 2). Moreover, by using comet assay, A2780 cells showed OTM values of 33.9±5.5 arbitrary units, while A2780/C30 cells showed 14.4±2.9 units (P<0.001; Table 2).\n\n10.1371/journal.pone.0117654.t002Table 2 DNA damage response-related parameters and associated Wilcoxon rank-sum tests in platinum-sensitive (A2780) and platinum-resistant (A2780/C30) cell lines.\nParameter measured\tMethod\tMean(SD)\t\nP-values\n9\n\n\t\n\t\tA2780\tA2780/C30\tA2780 vs A2780/C30\t\nIntrinsic DNA damage\tγH2Ax\t28.8(4.7)\n1\n\n\t17.4(3.4)\t0.01\t\n\tComet assay\t33.9(5.5)\n2\n\n\t14.4(2.9)\t<0.001\t\nInduced DNA damage\tγH2Ax\t17200(3650)\n3\n\n\t12400(2140)\t0.01\t\n\tComet assay\t14900(3280)\n4\n\n\t9400(1150)\t0.01\t\nDNA repair efficiency\tγH2Ax\t11.7(2.6)\n5\n\n\t5.2(0.7)\t<0.01\t\n\tComet assay\t16.7(3.4)\n6\n\n\t9.9(1.3)\t<0.01\t\nApoptosis\tELISA\t43.8(5.6)\n7\n\n\t78.5(9.2)\t0.001\t\nPan-nuclear staining\tγH2Ax\t13400(2850)\n8\n\n\t7500(1760)\t0.001\t\n\n1cells that are defined as having more than 5 foci per cell, expressed as a fraction of 100\n\n\n2Olive Tail Moment (OTM) values, arbitrary units\n\n\n3AUC values, expressed as (% of γH2AX positive staining cells) x (carboplatin dose)\n\n\n4AUC values (expressed as OTM x carboplatin dose)\n\n\n5t1/2 for γH2AX foci removal, in h\n\n\n6t1/2 values for carboplatin-induced damage repair, in h\n\n\n7apoptosis rates expressed as doses of carboplatin inducing apoptosis (as defined in the Materials and Methods section)\n\n\n8AUC values, expressed as (% of pan-nuclear staining cells) x (carboplatin dose)\n\n\n9Wilcoxon rank-sum tests.\n\nTo exhibit the DNA repair efficiency in these two cell lines, cells were treated with carboplatin (0–300μg/ml) for 24h followed by post-incubation in drug-free medium for 0–24h and the induced DNA damage (i.e. total DNA damage normalized by the intrinsic DNA damage) was analyzed at the end of drug treatment. Both immunofluorescence γH2AX staining and comet assay showed significant differences between the two cell lines. That is, in both cell lines DNA damage reached highest levels at the end of the drug treatment, with DNA damage being significantly higher in A2780 than in A2780/C30 cells (data not shown). Thereafter, carboplatin-induced DNA damage levels were reduced and the extent of repair was significantly lower in A2780 than in A2780/C30 cells (P<0.03). Particularly, using confocal microscopy the γH2AX foci were removed with t1/2 = 5.2±0.7h in A2780/C30 cells and 11.7±2.6h in A2780 cells. By using comet assay, the t1/2 values for carboplatin-induced damage repair in A2780/C30 and A2780 cells were 9.9±1.3h and 16.7±3.4h, respectively.\n\nMoreover, the Area Under the Curve (AUC) for carboplatin-induced DNA damage, a parameter that reflects the overall DNA damage burden resulting from initial damage formation and DNA repair was calculated (Table 2). By using γH2AX immunofluorescence staining, A2780 cells showed AUC values [expressed as (% of γH2AX positive staining cells) x (carboplatin dose)] of 17200±3650, and A2780/C30 cells 12400±2140 (P = 0.01). Furthermore, comet assay confirmed the above findings with A2780 cells showing AUC values [expressed as (OTM x carboplatin dose)] of 14900±3280 while A2780/C30 cells showed AUC values of 9400±1150 (P = 0.01).\n\nIn addition, both cell types were treated with various doses of carboplatin (0–300μg/ml) for 24h and the induction of apoptosis was measured 24h post-treatment. We found that apoptosis rates were higher in the A2780 cells than in A2780/C30 cells (P = 0.001; Table 2). In particular, A2780 cells showed evidence of apoptosis at carboplatin doses as low as 43.8±5.6μg/ml, while A2780/C30 cells required a dose of 78.5±9.2μg/ml, indicating that the drug sensitivity of cells inversely correlated with their DNA repair capacity (Table 2).\n\nA noteworthy finding was that following carboplatin treatment, a fraction of cells showed diffuse, bright pan-nuclear γH2AX staining. Previous studies have shown that pan-nuclear γH2AX staining represents a pre-apoptotic signal associated with ATM- and JNK-dependent apoptosis during replication [31]. In line with the results from the DNA repair efficiency experiments, we observed higher levels of pan-nuclear γH2AX staining [expressed as AUC (% of pan-nuclear staining cells) x (carboplatin dose)] in A2780 cells (13400±2850) than in A2780/C30 cells (7500±1760) (P = 0.001, Table 2).\n\nDeficient DNA repair of platinum-induced damage in PBMCs of OC patients correlates with better clinical outcome\nTurning to PBMCs, in agreement with previous studies [32], we found that following treatment of non-dividing PBMCs with platinum drugs, very low or null induction rates of the key molecules under study were observed. Therefore, we first treated PBMCs from nine healthy volunteers with various doses of PHA for up to 72h to induce proliferation of the cells. Optimal results were obtained following 48h incubation of PBMCs with 10μg/ml PHA (data not shown). Then, PBMCs were treated with cisplatin (0–300μg/ml for up to 3h) followed by incubation in drug-free medium for 0–24h or with carboplatin (0–1800μg/ml for up to 24h) followed by post-incubation in drug-free medium for 0–24h. In accordance to the results from the cell lines experiments, by either of the platinum drugs, a dose-dependent induction of all key molecules was observed (Fig. 3A, C), with the γH2AX again showing the highest induction rates (Fig. 3B, D). Moreover, the levels of platinum-induced DNA damage in PBMCs from the same nine healthy volunteers were measured using alkaline comet assay. We also found that the ex vivo treatment of PBMCs with cisplatin (Fig. 3E) or carboplatin (Fig. 3F) showed a dose-dependent increase of DNA damage levels. Taken together, the results from both cell lines and PBMCs experiments indicate that immunofluorescence quantification of γH2AX foci and alkaline comet assay are two powerful approaches for the quantification of platinum-induced DNA damage in clinical samples.\n\n10.1371/journal.pone.0117654.g003Fig 3 Changes in key molecules of the DDR pathways and comet assay in PBMCs from healthy volunteers.\nPBMCs from nine healthy volunteers were ex vivo treated (A) with cisplatin (0–300μg/ml) for 3h or (B) with 150μg/ml cisplatin, subsequently incubated in drug-free medium for various time-periods (0–24h), and analyzed thereafter using confocal microscopy. Also, PBMCs from the same healthy volunteers were treated (C) with carboplatin (0–1800μg/ml) for 24h or (D) with 1400μg/ml carboplatin for various times (0–24h) and analyzed at the end of the treatment using confocal microscopy. The error bars represent standard deviation. Finally, PBMCs were treated with (E) cisplatin (0–150μg/ml) for 3h or (F) carboplatin (0–1800μg/ml) for 24h and analyzed thereafter using comet assay. Box plots show statistical distribution of the levels of DNA damage. The horizontal lines within the boxes represent the median values and the vertical lines extending above and below the box indicate maximum and minimum values, respectively. All assays were performed in triplicate.\n\nThereafter, using these assays we examined the intrinsic levels of DNA damage in untreated PBMCs from the three groups of individuals (healthy volunteers, patients sensitive and patients resistant to platinum chemotherapy). Both γH2AX immunofluorescence staining and comet assay showed significant differences among the three groups of individuals (all P<0.05; Table 3), with the intrinsic DNA damage being higher in OC patients than in healthy volunteers. Interestingly, in line with the results from the ovarian carcinoma cell lines experiments, higher levels of intrinsic DNA damage were observed in PBMCs from patients sensitive compared to those resistant to subsequent platinum chemotherapy (γH2AX, P = 0.05; comet assay, P = 0.003; Table 3; Fig. 4A-D). Particularly, using γH2AX immunofluorescence staining, platinum-sensitive patients exhibited 16.8±2.3% positive cells, platinum-resistant patients 8.9±2.4%, while healthy volunteers showed 3.9±1.2% positive cells (Table 3; Fig. 4A). By using comet assay, patients sensitive to platinum chemotherapy showed OTM values of 20.1±5.5 arbitrary units, platinum-resistant 7.8±2.5, while healthy volunteers showed 2.4±1.1 units (Table 3; Fig. 4C). Interestingly, to confirm that the differences in the DDR signals are really reflective of platinum sensitivity rather than tumor type, patients bearing the same histotype were divided into sensitive and resistant to platinum therapy and the intrinsic DNA damage levels were compared. Although each subgroup contains a small number of samples, the results showed that differences in the intrinsic DNA damage levels are reflective of platinum sensitivity. For example, in serous tumors only, using γH2AX staining, sensitive patients (n = 6) showed higher levels of intrinsic DNA damage (mean value, 16.6% positive cells; range, 13.1–23.2%) than resistant patient (n = 1; 7.5%). In addition, in clear cell ovarian cancer only, sensitive patient (n = 1) exhibited 18.5% positive cells, while resistant patients (n = 3) only 9.4% (range, 6.3–13.7%). Similar results were obtained using comet assay.\n\n10.1371/journal.pone.0117654.g004Fig 4 Intrinsic and carboplatin-induced DNA damage in PBMCs from healthy volunteers and OC patients.\n(A) Box plots showing statistical distribution of the levels of the intrinsic DNA damage in untreated PBMCs using immunofluorescence quantification of γH2AX. HV, healthy volunteers; Sens: OC patients sensitive to subsequent platinum therapy; Res: OC patients resistant to subsequent platinum therapy. (B) Typical images from confocal laser scanning microscope analysis of PBMCs from the three groups; upper images, γH2AX staining; bottom images, cell nuclei labeled with DAPI. (C) Box plots showing statistical distribution of the levels of the intrinsic DNA damage in untreated PBMCs using alkaline comet assay. (D) Typical comet images from untreated PBMCs of the three groups of individuals. Box plots showing statistical distribution of the levels of DNA damage in PBMCs stimulated into proliferation using PHA and treated with carboplatin (0–1800μg/ml) for 24h, using (E) immunofluorescence quantification of γH2AX and (F) alkaline comet assay. The horizontal lines within the boxes represent the median values and the vertical lines extending above and below the box indicate maximum and minimum values, respectively. All assays were performed in triplicate.\n\n10.1371/journal.pone.0117654.t003Table 3 DNA damage response-related parameters and associated Wilcoxon rank-sum tests in PBMCs from healthy volunteers and OC patients, sensitive or resistant to platinum therapy.\nParameter measured\tMethod\tMean (range)\t\nP-values\n12\n\n\t\n\t\tHV\n1\n (n = 9)\tPS\n2\n (n = 7)\tPR\n3\n (n = 4)\tHV vs PS\tHV vs PR\tPS vs PR\t\nIntrinsic DNA damage\tγH2Ax\t3.9\n4\n\n\t16.8\t8.9\t<0.01\t0.04\t0.05\t\n\t\t2.1–6.5\t13.1–23.2\t6.3–13.7\t\t\t\t\n\tComet assay\t2.4\n5\n\n\t20.1\t7.8\t<0.001\t<0.01\t0.003\t\n\t\t1.1–5.8\t16.7–31.1\t3.7–16.1\t\t\t\t\nInduced DNA damage\tγH2Ax\t10300\n6\n\n\t28500\t17700\t0.02\t0.01\t0.03\t\n\t\t7500–18700\t25100–34400\t13700–23500\t\t\t\t\n\tComet assay\t9850\n7\n\n\t22700\t16240\t<0.01\t<0.01\t0.05\t\n\t\t1050–14930\t14990–29640\t6840–21870\t\t\t\t\nDNA repair efficiency\tγH2Ax\t2.7\n8\n\n\t15.4\t8.8\t0.03\t0.03\t<0.01\t\n\t\t1.5–3.2\t12.8–18.2\t6.1–10.6\t\t\t\t\n\tComet assay\t4.8\n9\n\n\t21.4\t12.9\t0.02\t0.01\t<0.01\t\n\t\t2.3–6.7\t17.3–26.0\t8.5–15.2\t\t\t\t\nApoptosis\tELISA\t1597\n10\n\n\t605\t1020\t<0.01\t<0.05\t<0.01\t\n\t\t1350–2000\t390–1050\t800–1370\t\t\t\t\nPan-nuclear staining\tγH2Ax\t4600\n11\n\n\t20700\t11100\t<0.001\t<0.005\t<0.01\t\n\t\t850–9500\t15900–27000\t7300–19400\t\t\t\t\n\n1HV, Healthy volunteers\n\n\n2PS, Platinum-sensitive patients\n\n\n3PR, Platinum-resistant patients\n\n\n4PBMCs that are defined as having more than 5 foci per cell, expressed as a fraction of 100\n\n\n5Olive Tail Moment (OTM) values, arbitrary units\n\n\n6AUC values, expressed as (% of γH2AX positive staining cells) x (carboplatin dose)\n\n\n7AUC values (expressed as OTM x carboplatin dose)\n\n\n8t1/2 for γH2AX foci removal, in h\n\n\n9t1/2 values for carboplatin-induced damage repair, in h\n\n\n10apoptosis rates expressed as doses of carboplatin inducing apoptosis (as defined in the Materials and Methods section)\n\n\n11AUC values, expressed as (% of pan-nuclear staining cells) x (carboplatin dose)\n\n\n12Wilcoxon rank-sum tests\n\nTo examine the DNA repair efficiency in the three groups of individuals, following 48h incubation of PBMCs with 10μg/ml PHA, cells were treated with carboplatin (0–1800μg/ml) for 24h, post-incubated in drug-free medium for 0–24h and the induced DNA damage was analyzed. Both γH2AX immunofluorescence staining and comet assay showed similar results. That is, in all individuals analyzed DNA damage reached highest levels at the end of the drug treatment, with DNA damage being higher in OC patients than in healthy volunteers; platinum-sensitive patients showed higher levels of DNA damage than platinum-resistant ones (data not shown). Thereafter, DNA damage levels were eliminated and the extent of repair was higher in healthy volunteers than in patients. Interestingly, in line with the results from the cell lines experiments, platinum-sensitive patients showed significantly lower repair efficiency than platinum-resistant ones (P<0.03). Particularly, using confocal microscopy the γH2AX foci were removed with t1/2 = 2.7±0.5h in healthy controls, 8.8±1.9h in platinum-resistant and 15.4±3.2h in platinum-sensitive patients. By using comet assay, the t1/2 values for carboplatin-induced DNA damage repair were 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively. Notably, in serous tumors only, the γH2AX foci were removed with t1/2 = 15.4h in sensitive patients (n = 6; range, 12.8–18.2h) and t1/2 = 8.4h in the resistant one (n = 1). In addition, in clear cell ovarian cancer only, sensitive patient (n = 1) showed t1/2 = 17.1h, while resistant patients t1/2 = 8.9h (n = 3; range, 6.1–10.6h). Similar results were obtained using comet assay.\n\nThe AUC levels for carboplatin-induced DNA damage were also calculated. By using confocal microscopy, platinum-sensitive patients showed AUC values of 28500±2323, platinum-resistant patients 17700±1138, while healthy volunteers showed values of 10300±810 (Table 3, all P<0.05) (Fig. 4E). Comet assay showed similar results. That is, patients sensitive to chemotherapy showed AUC values of 22700±540, platinum-resistant patients 16240±2417, while healthy volunteers showed AUC values of 9850±540 (Table 3; Fig. 4F). Interestingly, in serous tumors only, sensitive patients showed AUC values of 28400 (n = 6; range, 25100–34400), while the platinum-resistant patient 15200 (n = 1). In addition, in clear cell ovarian cancer only, sensitive patient (n = 1) exhibited AUC values of 29000, while resistant patients (n = 3) only 18500 (range, 13700–23500). Similar results were obtained using comet assay.\n\nMoreover, following 48h incubation of PBMCs from the three groups of individuals with 10μg/ml PHA, cells were treated ex vivo with various doses of carboplatin (0–1800μg/ml) for 24h and the induction of apoptosis was measured 24h after the end of the treatment. In accordance with the results from the cell lines experiments, we found that apoptosis rates were higher in platinum-sensitive patients than in platinum-resistant ones, with healthy volunteers showing the lowest rates (all P<0.05; Fig. 5A). In particular, PBMCs from platinum-sensitive patients showed evidence of apoptosis at carboplatin doses of 605±36μg/ml, platinum-resistant patients at 1020±158μg/ml, while healthy volunteers at 1597±254μg/ml. Interestingly, an inverse correlation was observed between the apoptosis rates and the DNA repair efficiencies of the same individuals (linear regression analysis; microscope analysis: r2 = 0.94, P<0.001, Fig. 5B; comet assay: r2 = 0.83, P<0.001, Fig. 5C). Notably, in serous tumors only, sensitive patients (n = 6) showed evidence of apoptosis at carboplatin doses of 636μg/ml (range, 390–1050μg/ml) and the platinum-resistant patient at 1370μg/ml (n = 1). In addition, in clear cell ovarian cancer only, the corresponding values were 420μg/ml for the sensitive patient (n = 1) and 877μg/ml (n = 3; range, 800–940μg/ml) for the resistant ones.\n\n10.1371/journal.pone.0117654.g005Fig 5 The induction of the apoptotic pathway in carboplatin-treated PBMCs.\n(A) Box plots showing statistical distribution of the individual apoptosis rates, expressed as doses of carboplatin inducing apoptosis in the three groups of individuals. HV, healthy volunteers; Sens: OC patients sensitive to subsequent platinum therapy; Res: OC patients resistant to subsequent platinum therapy. The correlations between the individual apoptosis rates and the DNA damage in PBMCs from the same individuals using γH2AX immunofluorescence staining (B) and comet assay (C) are presented. (D) Box plots showing statistical distribution of the levels of the pan-nuclear immunofluorescence γH2AX staining in the three groups of individuals. The horizontal lines within the boxes represent the median values and the vertical lines extending above and below the box indicate maximum and minimum values, respectively. (E) Correlation between pan-nuclear γH2AX staining and the individual apoptosis rates in the same samples. (F) Typical images showing pan-nuclear immunofluorescence γH2AX staining; upper images, γH2AX staining; bottom images, cell nuclei labeled with DAPI. All assays were performed in triplicate.\n\nFinally, using confocal microscope analysis, in agreement with the results from the apoptosis experiments we observed higher levels of pan-nuclear γH2AX staining in OC patients than in healthy volunteers (Fig. 5D, F). Particularly, patients sensitive to platinum chemotherapy showed higher levels of pan-nuclear staining expressed as AUC (20700±3143), than platinum-resistant patients (11100±1012; P<0.01; Table 3). Healthy volunteers showed the lowest levels of pan-nuclear staining (4600±477).\n\nDiscussion\nMammalian cells have evolved a sophisticated signal transduction network to sense DNA damage and to mount an appropriate DDR pathway. Dysregulation of the DDR pathway has been involved into both malignant transformation and response to chemotherapy with DNA damaging drugs. Therefore, we conducted a study to shed light on the DDR signaling in OC patients, sensitive or resistant to platinum chemotherapy. We found that OC patients are characterized by higher intrinsic DNA damage compared to healthy volunteers, and that the efficiency of DNA repair as measured in PBMCs from OC patients inversely correlates with the response of individual patients to platinum-based chemotherapy.\n\nPlatinum-based drug cytotoxicity is mainly mediated by the introduction of ICLs into the DNA of treated cells. ICLs involve the covalent linking of the two strands of DNA which prevents their separation and consequently blocks transcription, segregation and replication. Repair of ICLs caused by platinum drugs involves the generation of DSBs as an intermediate step followed by the phosphorylation of the histone H2AX [33–35]. In the present study, by using confocal microscope analysis we first investigated changes in the expression of key molecules of the DDR pathways (pATM, pATR, pChk1, pChk2, γH2AX) after treatment of ovarian carcinoma cell lines and PBMCs from healthy volunteers with platinum-based drugs. In all cell types analyzed, a dose-dependent induction of all molecules under study was observed, with γH2AX showing the highest induction rates. Moreover, using ovarian carcinoma cell lines and PBMCs from healthy volunteers, we validated the comet assay, a technically simple and fast method that detects genotoxicity in virtually any mammalian cell type [36,37]. Thereafter, using these two powerful approaches the levels of the DNA damage were assessed in clinical samples.\n\nPrevious reports have shown a link between ovarian carcinogenesis and the repair efficiency of DNA damage [16]. In fact, defects in genes involved in DSBs repair, such as ERCC1, BRCA1 and BRCA2 are implicated in familial OC [17–19]. Also, a strong association between the MGMT (O6-methylguanine-DNA methyltransferase) activity and OC risk has been described [38]. In addition, the repair efficiency of the DNA damage induced by the alkylating agent MNNG (N-methyl-N-nitro-N-nitrosoguanidine) decreased with progression of the cervical cancer in a stepwise manner [39]. In the present study, we found that the intrinsic DNA damage was higher in OC patients than in healthy volunteers. Moreover, in line with the findings from the two OC cell lines, the intrinsic DNA damage was significantly higher in platinum-sensitive than in platinum-resistant patients. High intrinsic damage could be the outcome of increased formation of DNA damage and/or a delay in the repair of these lesions. Increased DNA damage formation can be generated by pathological or physiological agents or processes. These agents or processes can be exogenous such as ionizing radiation or endogenous such as oxidative free radicals, replication across a nick, inadvertent enzyme action at fragile sites, mechanical shearing at anaphase bridges, metabolic byproducts, and so forth [40–42]. Physiological processes such as V(D)J recombination, class switch recombination (CSR) and meiosis also induce DNA damage in the genome [43–45].\n\nSince the higher intrinsic DNA damage gives no information about the repair capacity of the cells, we analyzed the repair efficiency of the carboplatin-induced DNA damage in both PBMCs and OC cell lines. In agreement with the results from the intrinsic DNA damage experiments, we found higher DNA repair efficiency in healthy volunteers than in OC patients, suggesting that malignant transformation correlates with a reduction of DNA repair efficiency. Whether reduced DNA repair is the cause or effect of carcinogenesis is still unclear. In any case, since failure to repair DNA damage can lead to genomic instability, the accumulation of DNA damage in OC patients may be involved in the pathogenesis of the disease.\n\nInterestingly, the OC cell line sensitive to platinum treatment showed higher levels of DNA damage than the platinum-resistant one. In line with this finding, the levels of the ex vivo platinum-induced DNA damage in PBMCs were higher in platinum-sensitive than in platinum-resistant patients, reflecting the clinical response of OC patients to the subsequent chemotherapy (Table 3). Moreover, in agreement with the results from the DNA repair experiments, following treatment of the two OC cell lines with carboplatin, the apoptosis rates inversely correlated with the repair capacity of these cells, being higher in the sensitive than in the resistant cells. In line with this finding, following treatment of PBMCs with carboplatin, an inverse correlation was observed between the apoptosis rates and the DNA repair efficiencies of the same individuals, with the apoptosis rates being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.01; Table 3). Moreover, in accordance to previous studies [31,46], the correlation between apoptosis and pan-nuclear γH2AX staining in PBMCs from the same patients confirm that pan-nuclear γH2AX staining represents a pre-apoptotic signal (linear regression analysis; r2 = 0.72, P<0.001, Fig. 5E).\n\nIt is generally accepted that ovarian cancer is not a single disease but is made up of several different distinct histotypes. The main histotypes are epithelial in origin and include high-grade serous carcinoma, clear cell carcinoma, endometrioid carcinoma, low-grade serous carcinoma, and mucinous carcinoma [47]. Also, there are several rare types of non-epithelial ovarian cancers including germ cell tumors, stromal tumors such as granulosa cell tumor and Sertoli Leydig cell tumor [48]. On the other hand, cell lines derived from tumors are the most frequently utilized models in in vitro drug sensitivity studies. In the present study, the cisplatin-sensitive A2780 cell line (the second most commonly used ovarian cancer cell line) [49], and the cisplatin-resistant cell line A2780/C30 (derived from A2780 following continuous exposure to increasing concentrations of cisplatin) [26] were examined. Owing to the molecular heterogeneity of the various histotypes of epithelial ovarian cancer, we recognize that a single pair of cell lines may not accurately reflect the broad spectrum of phenotypes and that use of patient-derived cells would enhance the study.\n\nThe results presented in the present study showed that the disease-associated nature of the defects in DDR pathways reflected in cells of the peripheral blood of OC patients. In agreement with these results, previous reports have shown that biomarkers (e.g. transcriptomic and epigenetic profiles, chromosomal aberrations, telomere length, DNA damage response signals) measured in peripheral blood leukocytes (a) can distinguish between healthy controls and subjects with a variety of diseases including various types of cancer [50–56] and (b) can predict clinical response to therapeutic treatment [20–23,57–59]. Although one cannot rule out the possibility that these findings may be caused by the presence in blood of circulating tumor cells [60,61], the very small numbers of such cells make such an explanation unlikely. Therefore, it seems possible that the regulation at the individual level of cellular responses to various influences is partly controlled by genetically or environmentally determined systemic factors and that, as regards response to the highly toxic effects of cytotoxic drugs, such systemic factors remain predominant despite any disease-related perturbations occurring in cancer cells.\n\nTaken together, the results reported here demonstrate the critical importance of cellular responses to DNA damage in determining the cytotoxicity of platinum-based drugs, as measured in in vitro cellular systems, as well as their therapeutic efficiency in OC patients. In particular, we have found that the efficiency of DNA repair as measured in PBMCs from OC patients correlates with the drug sensitivity of these cells and reflects the response of individual patients to platinum-based chemotherapy. 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Proc Natl Acad Sci U S A \n84 : 5024 –5028 .\n3110781 \n59 \nWang LE , Yin M , Dong Q , Stewart DJ , Merriman KW , et al (2011 ) DNA repair capacity in peripheral lymphocytes predicts survival of patients with non-small-cell lung cancer treated with first-line platinum-based chemotherapy . J Clin Oncol \n29 : 4121 –4128 . 10.1200/JCO.2010.34.3616 \n21947825 \n60 \nLiu JF , Kindelberger D , Doyle C , Lowe A , Barry WT , et al (2013 ) Predictive value of circulating tumor cells (CTCs) in newly-diagnosed and recurrent ovarian cancer patients . Gynecol Oncol \n131 : 352 –356 . 10.1016/j.ygyno.2013.08.006 \n23954902 \n61 \nKim JH , Chung HH , Jeong MS , Song MR , Kang KW , et al (2013 ) One-step detection of circulating tumor cells in ovarian cancer using enhanced fluorescent silica nanoparticles . Int J Nanomedicine \n8 : 2247 –2257 . 10.2147/IJN.S45059 \n23818781\n\n",
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"abstract": "A ketogenic diet (KD) may have a role in treating patients in super-refractory status epilepticus (SRSE). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have a risk of ketoacidosis that could facilitate induction of KD.\nA 42-year-old with a history of drug resistant epilepsy developed SRSE requiring several pharmacological interventions during her hospital course including the initiation of KD that failed. SGLT2 inhibitor therapy was initiated in a successful attempt to augment ketone production.\nSGLT2 inhibitors may have a therapeutic value in SRSE patients who cannot achieve ketosis with KD alone.",
"affiliations": "Saint Luke's Hospital, 4401 Wornall Rd., 64111 Kansas City, MO, United States of America.;Saint Luke's Hospital, 4401 Wornall Rd., 64111 Kansas City, MO, United States of America.;Saint Luke's Hospital, 4401 Wornall Rd., 64111 Kansas City, MO, United States of America.;Saint Luke's Hospital, 4401 Wornall Rd., 64111 Kansas City, MO, United States of America.",
"authors": "Blunck|Joseph R|JR|;Newman|Joseph W|JW|;Fields|Ronald K|RK|;Croom|John E|JE|",
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"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(18)30052-510.1016/j.ebcr.2018.05.002ArticleTherapeutic augmentation of ketogenic diet with a sodium-glucose cotransporter 2 inhibitor in a super-refractory status epilepticus patient Blunck Joseph R. Newman Joseph W. jnewman@saint-lukes.org⁎Fields Ronald K. Croom John E. Saint Luke's Hospital, 4401 Wornall Rd., 64111 Kansas City, MO, United States of America⁎ Corresponding author. jnewman@saint-lukes.org20 6 2018 2018 20 6 2018 10 61 64 26 4 2018 18 5 2018 29 5 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nA ketogenic diet (KD) may have a role in treating patients in super-refractory status epilepticus (SRSE). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have a risk of ketoacidosis that could facilitate induction of KD.\n\nCase summary\nA 42-year-old with a history of drug resistant epilepsy developed SRSE requiring several pharmacological interventions during her hospital course including the initiation of KD that failed. SGLT2 inhibitor therapy was initiated in a successful attempt to augment ketone production.\n\nConclusion\nSGLT2 inhibitors may have a therapeutic value in SRSE patients who cannot achieve ketosis with KD alone.\n\nHighlights\n• Super-refractory status epilepticus (SRSE) carries a high risk of morbidity and mortality despite both pharmacologic and non-pharmacologic interventions.\n\n• The ketogenic diet can play an important role as an adjunct treatment for these patients, but delaying ketosis could negate those benefits.\n\n• Sodium-glucose cotransporter 2 inhibitors can carry an increased risk of ketoacidosis that may benefit patients in SRSE who do not achieve ketosis on the ketogenic diet alone.\n\n\n\nKeywords\nKetogenic dietKetosisKetoacidosisStatus epilepticusRefractory status epilepticusSuper-refractory status epilepticusSodium-glucose cotransporter 2 inhibitorEpilepsySeizurePentobarbital\n==== Body\n1 Introduction\nSuper-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues for more than 24 h despite general anesthetic agents, including recurrent SE upon reduction or withdrawal of anesthesia [1]. SRSE carries a high risk of morbidity and a high mortality rate ranging from 23 to 57% [2], [3]. Current SE guidelines only offer pharmacological recommendations likely due to the lack of evidence for initiating other therapies for refractory status epilepticus [4]. The optimal management of SRSE is unknown, but a growing body of evidence suggests that initiating a KD in these patients may be effective in terminating SE [5], [6], [7], [8], [9], [10], [11], [12]. The KD is a high fat, low carbohydrate, sufficient protein diet that mimics a starvation state provoking fat metabolism for energy and ketone body production. Diet modification therapies including KD and Modified Atkins Diet can be effective and safe when used as an adjunct therapy for patients with epilepsy, regardless of their age [13].\n\nSodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively novel class of oral glucose-lowering therapies for managing type 2 diabetes. SGLT2 inhibitors control glucose levels by preventing reabsorption of glucose at the proximal renal tubules thereby enhancing urinary glucose excretion. This insulin-independent mechanism of glycemic control creates a reduction in circulating insulin and increased glucagon levels. As a result, a metabolic shift towards lipolysis and hepatic ketogenesis may occur leading to ketoacidosis that is often euglycemic in nature [14]. One of several risk factors for SGLT2 inhibitor related ketoacidosis is low carbohydrate intake [14], [15], [16], [17], [18]. We present a case with a patient in SRSE who experienced an inability to sustain ketosis with KD alone, but after the addition of an SGLT2 inhibitor, consistent ketosis was achieved.\n\n2 Case\nA 42-year-old female with a long standing history of drug resistant epilepsy in the setting of cerebral palsy. Based on previous records, her seizures were only described as her waking up with tongue trauma and bladder or bowel incontinence, but were overall controlled with phenytoin monotherapy. Previous work-ups have included an MRI of her brain with and without contrast which was reportedly negative in her early to mid-thirties. A routine EEG was abnormal due to continuous background and generalized theta slowing and the occurrence of frequent, nearly continuous atypical absence seizures.\n\nShe developed refractory SE after transitioning from phenytoin to a combination of levetiracetam and lamotrigine because of concern of phenytoin associated long-term side effects. She presented to an outside hospital with clusters of breakthrough seizures in the setting of hyponatremia, hypoglycemia, and subtherapeutic serum levetiracetam levels. Intravenous levetiracetam was loaded and her outpatient dosage was continued with the addition of intravenous lacosamide. The patient's seizures initially improved for several days before reverting back to refractory SE. She was intubated, sedated with propofol, and loaded with fosphenytoin. A bedside electroencephalograph (EEG) was performed off propofol and interpreted as an onset of rhythmic 1–2 Hz sharp activity emanating from the right fronto-temporal region synchronous with observed rhythmic left jaw twitching, then limb twitching, and finally lower extremity twitching. This soon became bilateral synchronous polyspike-like discharges confirming refractory SE at which time propofol was restarted. She was transferred to our level 4 Comprehensive Epilepsy Center for further evaluation and treatment.\n\nWhile monitored with continuous video-EEG, the patient was maintained on scheduled fosphenytoin, lacosamide, levetiracetam, and continuous propofol. An MRI of her brain reported advanced, diffuse cerebellar atrophy, but no acute intracranial process. After four days of maintaining burst-suppression, attempts to wean propofol led to recurrent SE associated with facial twitching. This was associated with electrographic changes over the vertex and posterior head regions. Despite increasing lacosamide and maintaining optimized serum phenytoin levels, she failed to wean from propofol over the next week prompting the addition of a continuous midazolam infusion to maintain burst-suppression.\n\nOver the next month, multiple anti-seizure drugs, including a trial of ketamine, were added without significant improvement. Despite these interventions, SRSE returned with every propofol or midazolam wean attempt. As a result of propofol-induced hypertriglyceridemia and midazolam tachyphylaxis, a pentobarbital infusion was started to replace the latter two infusions. Moreover, failure to wean off these tertiary SRSE therapies lead to an enrollment in a phase II trial evaluating allopregnanolone for SRSE treatment. However, the patient never received, nor was exposed to allopregnanolone as it was later halted and not initiated due to study closure [19].\n\nApproximately 12 weeks after unsuccessful attempts to control the patient's SRSE without infusions of anesthetic agents, the ketogenic diet was initiated with daily monitoring of serum beta hydroxybutyrate (BHB) and serum glucose levels (Fig. 1). The patient was placed in a fasting state for 24 h prior to starting KD. KetoCal® 4:1 was started with a goal of 1780 kcals per day which consisted of 175.5 g (g) of fat, 36.5 g of protein, and 20.5 g of carbohydrates. All dextrose containing intravenous admixtures were changed to normal saline and enteral solutions were adjusted to minimize carbohydrate intake.Fig. 1 Serum beta hydroxybutyrate and glucose levels recorded over time (days) during KD. Serum glucose plotted from the left y-axis values with 70 mg/dL (hypoglycemia threshold) represented with black dotted line. Serum beta hydroxybutyrate levels plotted from right y-axis values with 0.6 mmol/L (upper limit of normal) represented with grey dashed line. SGLT2 inhibitor introduced on day 16 post KD represented by the black diamond with ketosis occuring in 7 days. Initiation of lorazepam infusion (propylene glycol source) is represented by a black square on day 33 post KD with subsequent normalization of beta hydroxybutyrate.\n\nFig. 1\n\nAfter about a week without consistent ketosis, her macronutrient intake was adjusted to account for the metabolic impact of 40% propylene glycol additive in pentobarbital [20]. KetoCal® 4:1 was reduced to 1068 kcals per day and the remaining nutritional goal was corrected with enteral medium chain triglyceride (MCT) oil. Over the next week, intermittent elevation in serum BHB occurred, but sustained ketosis was not achieved.\n\n16 days after starting KD, dapagliflozin (SGLT2 inhibitor) 10 mg daily via nasal gastric tube was added in attempt to augment ketone production while maintaining euglycemia. After one week, the patient entered a consistent state of ketosis which allowed the pentobarbital infusion to be weaned off for the first time in 65 days. With the absence of propylene glycol, the MCT oil was discontinued and the original KD formula was resumed.\n\nDespite undetectable serum pentobarbital levels 72 h after its discontinuation, the patient remained severely encephalopathic. Ten days after pentobarbital discontinuation, SRSE returned prompting reintroduction of propofol, lorazepam, and eventually pentobarbital infusions. This occurred despite maintaining ketosis during this time. Shortly after lorazepam infusion began, ketosis was lost likely due its high propylene glycol content. A multidisciplinary discussion took place resulting in a final decision of comfort care. The patient expired after 120 days of SRSE management summarized in Fig. 2.Fig. 2 Representation of SRSE interventions over 121 day course in the neuroscience intensive care unit. Tertiary anesthetic agents were used including pentobarbital titrated for burst suppression starting on day 40. Several pentobarbital weaning attempts are noted with black diamonds with eventual discontinuation on day 105 following consistent ketosis obtainment. Pentobarbital was resumed on day 119 due to relapse of SRSE.\n\nFig. 2\n\n3 Discussion\nKD for seizure control was first described in the literature in 1921 yet the exact mechanism is unknown and seems to be complex [21], [22]. Although KD is more commonly used for drug resistant epilepsy primarily in children, it is emerging as an adjunctive treatment option for adult patients in SRSE. One challenge for treating patients in SRSE who do not respond to pharmacological therapy is that there are no current guidelines that recommend the use or specify the timing of KD.\n\nThe ability of KD to control SRSE has been reported in several case reports, small case series, and a small prospective multicenter trial [5], [6], [7], [8], [9], [10], [11], [12]. A retrospective case review of 10 patients from 4 medical centers utilizing KD for SRSE described a 90% ketosis obtainment with SE resolution [11] The median time to KD initiation was 21.5 days and the time to ketosis ranged from one to seven days (median of three days). Minimal side effects were reported including increased triglycerides in two patients and acidosis in one patient. More recently, Cervenka and colleagues performed a prospective multicenter observational trial to investigate the feasibility, safety, and efficacy of KD for SRSE [12]. Fifteen patients were enrolled and all patients achieved ketosis. The median time to KD initiation was ten days and the time to ketosis ranged from 0 to 16 days (median of two days). SRSE resolved in 73% of patients with minimal side effects. The authors concluded that this study provided preliminary evidence that KD is a feasible, safe, and effective adjunctive treatment for SRSE management with the need for comparative randomized placebo-controlled trials to assess outcomes. Combining the two previously described studies, the median time to initiate KD after SRSE onset was only 17 days with a range of 2–60 days [11], [12]. The one patient who failed to achieve ketosis in these studies did not undergo KD initiation until day 60.\n\nOur case was challenging in that consistent ketosis was not achieved after more than two weeks of KD despite multidisciplinary efforts to limit carbohydrate intake. It is unknown why this patient was resistant to KD, but several exogenous factors may have contributed. One possibility is that delaying initiation of KD may allow metabolic changes that delay induction of ketosis. For our patient, KD was not initiated until 82 days after admission. This delay may have allowed for accumulation of glycogen storage postponing fat-dependent metabolism.\n\nAnother potential factor for delayed ketosis involves propylene glycol which is typically used as a solvent for several intravenous medications including benzodiazepines and pentobarbital. The patient described above underwent a prolonged pentobarbital infusion with significant amounts of propylene glycol which may have provided an energy source contributing to delayed ketosis. This significant exposure to a propylene glycol energy source may have factored into delayed ketosis. Additionally, there remains the possibility that unrecognized additives were given that may have negatively impacted induction of ketosis. Despite the lack of human studies investigating propylene glycol on delaying ketosis, there is a wide array of literature within the cattle industry outlining the successful use of propylene glycol as a treatment for ketosis. For example, Jenkins and colleagues demonstrated that cows with subclinical ketosis were likely to be cured after treatment with propylene glycol [24].\n\nAfter exhausting multiple treatment modalities and considering the patient's severity of illness, we decided to initiate an SGLT2 inhibitor in an attempt to augment ketogenesis given that we were not able to achieve sustained ketosis with the KD alone. SGLT2 inhibitors have the potential to induce significant ketosis as demonstrated by a large claims database analysis concluding about a two-fold risk of developing ketoacidosis with a rate of 4.9 vs 2.3 events per 1000 person years [15]. In 2015 the Food and Drug Administration released a drug safety communication regarding the potential risk for ketosis with SGLT2 inhibitors and reports have highlighted increased risk when combined with a low carbohydrate diet [14], [15], [16], [17], [18], [23]. In a small (N = 23) randomized open-label exploratory study, Yabe and colleagues evaluated ketone production in Japanese diabetic patients receiving luseogliflozin (SGLT2 inhibitor) 2.5 mg while consuming 55% of total energy source from carbohydrates compared to 40% (low carbohydrate arm) [18]. Participants were started on their protocol diet for 14 days with SGLT2 inhibitor initiation on days 8–15. Blood samples were drawn on day 1, 8 and 15 to assess ketone production. Ketone bodies on day 15 (7 days after SGLT2 inhibitor initiation) were significantly higher in the low carbohydrate group. The authors concluded that strict low carbohydrate consumption while on SGLT2 inhibitors should be avoided due to increased risk for ketoacidosis.\n\nTo our knowledge, this is the first SRSE patient that achieved consistent ketosis within 7 days post SGLT2 initiation while on KD without hypoglycemic events (Fig. 1). Although SGLT2 inhibitors do not directly induce hypoglycemia, serum glucose should be monitored closely as KD alone can lead to hypoglycemia [14]. An obvious limitation in this report is the lack of any control group and therefore, it is uncertain whether the addition of an SGLT2 inhibitor augmented ketone production or if consistent ketosis was from KD and more time alone. As such, use of SGLT2 inhibitors for this indication should be reserved for patients who do not readily achieve ketosis with KD alone. If data continues to support KD initiation for adjunctive treatment of SRSE, then there may be clinical utility in formally evaluating the safety and efficacy of SGLT2 inhibitor augmentation of KD and whether it leads to faster ketosis and potentially faster SRSE resolution.\n\n4 Conclusion\nDespite recommendations to avoid low carbohydrate diets when taking a SGLT2 inhibitors due to risk of ketoacidosis in normal circumstances, there could be therapeutic value in SRSE patients that are unable to achieve consistent ketosis with KD alone. Our case suggests that initiation of a SGLT2 inhibitor is a safe adjunct that may augment the production of ketones in patients on a KD. It remains to be shown whether such intervention conclusively enhances ketone production compared to KD alone and whether this impact has any effect on morbidity or mortality in this critically ill population. In addition, the consideration of early KD initiation should be contemplated when unable to wean from general anesthetic therapies. By doing so, potential factors that may delay ketosis can be identified and corrected in order to attain the best outcome.\n\nEthical statement\nThe following article is of original work and complies with all submission instructions to the best of our knowledge. All authorship requirements have been met and the final manuscript was approved by all authors. This article has not been published elsewhere and is not under consideration for publication elsewhere. No source funding took place and there were no conflicts of interest or ethical dilemmas involved with any of the following authors.\n\nConflict of interest statement\nThe authors involved declare no conflict of interest.\n==== Refs\nReferences\n1 Hocker S.E. Britton J.W. Mandrekar J.N. Wijdicks E.F. Rabinstein A.A. Predictors of outcome in refractory status epilepticus JAMA Neurol 70 2013 72 77 23318514 \n2 Ferlisi M. Shorvon S. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy Brain 135 2012 2314 2328 22577217 \n3 Hocker S. Tatum W.O. LaRoche S. Freeman W.D. Refractory and super-refractory status epilepticus: an update Curr Neurol Neurosci Rep 14 2014 452 24760477 \n4 Brophy G.M. Bell R. Claassen J. Alldredger B. Bleck T.P. Glauser T. Guidelines for the evaluation and management of status epilepticus Neurocrit Care 17 2012 3 23 22528274 \n5 Bodenant M. Moreau C. Sejourne C. Auvin S. Delval A. Cuisset J.M. Interest of the ketogenic diet in a refractory status epilepticus in adults Rev Neurol 164 2008 194 199 18358881 \n6 Cervenka M.C. Hartman A.L. Venkatesan A. Geocadin R.G. Kossoff E.H. The ketogenic diet for medically and surgically refractory status epilepticus in the neurocritical care unit Neurocrit Care 15 2011 519 524 21523523 \n7 Nabbout R. Mazzuca M. Hubert P. Peudennier S. Allaire C. Flurin V. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES) Epilepsia 51 2010 2033 2037 20813015 \n8 Nam S.H. Lee B.L. Lee C.G. Yu H.J. Joo E.Y. Lee J. The role of ketogenic diet in the treatment of refractory status epilepticus Epilepsia 52 2011 e181 e184 22003821 \n9 Wusthoff C.J. Kranick S.M. Morley J.F. Christina Bergqvist A.G. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus Epilepsia 51 2010 1083 1085 19845731 \n10 Strzelczyk A. Reif P.S. Bauer S. Belke M. Oertel W.H. Knake S. Intravenous initiation and maintenance of ketogenic diet: proof of concept in super-refractory status epilepticus Seizure 22 2013 581 583 23597842 \n11 Thakur K.T. Probasco J.C. Hocker S.E. Roehl K. Henry B. Kossoff E.H. Ketogenic diet for adults in super-refractory status epilepticus Neurology 82 2014 665 670 24453083 \n12 Cervenka M.C. Hocker S. Koenig M. Bar B. Henry-Barron B. Kossoff E.H. Phase I/II multicenter ketogenic diet study for adult superrefractory staus epilepticus Neurology 88 2017 938 943 28179470 \n13 Kossoff E.H. Zupec-Kania B.A. Amark P.E. Ballaban-Gil K.R. Christina Bergqvist A.G. Blackford R. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group Epilepsia 50 2 Feb 2009 304 317 18823325 \n14 Ogawa W. Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors J Diabetes Investig 7 2016 135 138 \n15 Fralick M. Schneeweiss S. Patorno E. Risk of diabetic ketoacidosis after initiation on an SGLT2 inhibitor N Engl J Med 376 2017 2300 2302 28591538 \n16 Handelsman Y. Henry R.R. Bloomgarden Z.T. Dagogo-Jack S. DeFronzo R.A. Einhorn D. American association of clinical endocrinologists and American college of endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis Endocr Pract 22 2016 753 762 27082665 \n17 Hayami T. Kato Y. Kamiya H. Kodo M. Naito E. Sugiura Y. Case of ketoacidosis by sodium-glucose cotransporter 2 inhibitor in a diabetic patient with low carbohydrate diet J Diabetes Investig 6 2015 587 590 \n18 Yabe D. Iwasaki M. Kuwata H. Haraguchi T. Hamamoto Y. Kurose T. Sodium-glucose cotransporter 2 inhibitor use and dietary carbohydrate intake in Japanese individuals with type 2 diabetes: a randomized, open-label, 3-arm parallel comparative, exploratory study Diabetes Obes Metab 19 2017 739 743 27990776 \n19 Rosenthal E.S. Claassen J. Wainwright M.S. Husain A.M. Vaitkevicius H. Raines S. Brexanolone as adjunctive therapy in super-refractory status epilepticus Ann Neurol 82 2017 342 352 28779545 \n20 Nembutal (pentobarbital) [prescribing information]. Lake Forest, IL Oak Pharmaceuticals November 2013 \n21 Masino S.A. Rho J.M. Mechanisms of ketogenic diet action Noebels J.L. Avoli M. Rogawski M.A. Jasper's basic mechanisms of the epilepsies [internet] 4th ed. 2012 National Center for biotechnology information (US) Bethesda (MD) \n22 Geyelin H. Fasting as a method for treating epilepsy Med Rec 99 1921 1037 1039 \n23 FDA/CEDR Resources Page Food and drug administration web site https://www.fda.gov/drugs/drugsafety/ucm475463.htm \n24 Jenkins N.T. Pena G. Risco C. Barbosa C.C. Vieira-Neto A. Galvao K.N. Utility of inline milk fat and protein ratio to diagnose subclinical ketosis and to assign propylene glycol treatment in lactating dairy cows Can Vet J 56 2015 850 854 26246632\n\n",
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"keywords": "Epilepsy; Ketoacidosis; Ketogenic diet; Ketosis; Pentobarbital; Refractory status epilepticus; Seizure; Sodium-glucose cotransporter 2 inhibitor; Status epilepticus; Super-refractory status epilepticus",
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"abstract": "BACKGROUND\nTo compare the steady state plasma concentrations (Css) of three antiretroviral drugs in both normal and overweight patients, and to determine the relationship between Css and fat mass (FM) or lean body mass.\n\n\nMETHODS\nPatients treated for more than 6 months once daily with one of the antiretroviral drugs: efavirenz (EFV) 600mg, atazanavir boosted with ritonavir (ATV-r) 300mg/100mg, or darunavir boosted with ritonavir (DRV-r) 800mg/100mg, combined with two nucleoside analogues, were enrolled prospectively. One at steady state, plasma samples for the assessment of drug concentration were taken and body composition was assessed by bioelectrical impedance.\n\n\nRESULTS\nOne hundred and thirty-nine patients were enrolled (46, 45 and 48 in the groups EFV, ATV-r and DRV-r respectively). Their mean age was 46.2±10.4 years, 58% were male, 55.4% were from Sub Sahara African (SSA); body mass index (BMI) was 25.4±4.4kg/m2. Mean drug plasma Css of the three drugs did not differ according to BMI group. DRV-r Css tended to be higher in patients with BMI≥25kg/m2 (2896.7±1689 versus 2091.9±1038, P=0.09) and was significantly correlated with FM (r=0.3, P=0.02). In subgroup analysis, the effect of FM on DRV-r Css was significant in patients from SSA (r=0.4, P=0.04).\n\n\nCONCLUSIONS\nCss result from many factors and body composition has been shown to only weakly influence interindividual variability but should be investigated in morbidly obese patients treated with DRV-r.",
"affiliations": "Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France. Electronic address: celialloret@yahoo.fr.;Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.;Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.;Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.;Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.;Yorkleigh surgery, Cheltenham GL50 3ED, Gloucestershire, United Kingdom.;Department of toxicology, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 75010 Paris, France.;Biological pharmacology, Saint Louis hospital, 75010 Paris, France.;Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.;Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.;Unit of therapeutic research, department of internal medicine, hôpital Lariboisière, Assistance publique-Hôpitaux de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.",
"authors": "Lloret-Linares|Célia|C|;Rahmoun|Yasmin|Y|;Lopes|Amanda|A|;Chopin|Dorothée|D|;Simoneau|Guy|G|;Green|Andrew|A|;Delhotal|Brigitte|B|;Sauvageon|Hélène|H|;Mouly|Stéphane|S|;Bergmann|Jean-François|JF|;Sellier|Pierre-Olivier|PO|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000069446:Atazanavir Sulfate; C098320:efavirenz; D000069454:Darunavir",
"country": "France",
"delete": false,
"doi": "10.1016/j.therap.2017.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "73(3)",
"journal": "Therapie",
"keywords": "Antiretroviral drugs; Atazanavir; Body composition; Darunavir; Drug monitoring; Efavirenz; Overweight",
"medline_ta": "Therapie",
"mesh_terms": "D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D048588:Benzoxazines; D001823:Body Composition; D001835:Body Weight; D003521:Cyclopropanes; D000069454:Darunavir; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D050177:Overweight",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "185-191",
"pmc": null,
"pmid": "29395300",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of body weight and composition on efavirenz, atazanavir or darunavir concentration.",
"title_normalized": "effect of body weight and composition on efavirenz atazanavir or darunavir concentration"
} | [
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"companynumb": "FR-MYLANLABS-2018M1094061",
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"activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
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{
"abstract": "The selective inhibitors of COX-2, coxibs, are nonsteroidal anti-inflammatory drugs (NSAIDs) that have much better gastrointestinal safety profile as compared with non-selective NSAIDs. In this review, we analyze both the epidemiological features of coxib-induced hepatotoxicity and the clinical impact of coxib-associated liver damage, based on literature data. Areas covered: We carried out a search of the databases MEDLINE (PubMed), LILACS and SCIELO, from December 1999 to January 2016, to retrieve studies exploring the real impact of coxibs in liver toxicity as compared to non-selective COX-2 inhibitor NSAIDs. Expert opinion: Although reliable data on the incidence of celecoxib- and etoricoxib-induced hepatotoxicity are lacking, because of cohort studies have been generally underpowered to detect hepatic events, coxibs have been scarcely related to hepatotoxicity. Hence, coxib-induced liver injury seems to be an uncommon event, yet exhibits a wide spectrum of damage. Increasing COX-2 drug selectivity, as for rofecoxib, valdecoxib, parecoxib, and lumiracoxib, has been associated with higher cardiovascular risk, as well as dermatological and serious hepatic reactions. The actual risk of liver toxicity from the currently approved coxibs compared with non-selective NSAIDs will be discussed. Finally, classical and novel molecular mechanisms of coxib-induced hepatotoxicity are also described.",
"affiliations": "a Hospital Provincial del Centenario, University of Rosario School of Medicine , Gastroenterology & Hepatology Department , Rosario , Argentina.;b Hospital de Clínicas, Facultad de Medicina , Universidad de la República , Montevideo , Uruguay.;c Instituto de Fisiología Experimental (CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmaceúticas , Universidad de Rosario , Rosario , Argentina.;d Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno 'CEMIC' , Medicine Department, Hepatology Section , Ciudad Autónoma de Buenos Aires , Argentina.;e Hospital Universitario Austral , Herpatology & Liver Transplant Unit , Buenos Aires , Argentina.;f UGC de Ap Digestivo y Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria , Universidad de Málaga, CIBERehd , Málaga , Spain.;f UGC de Ap Digestivo y Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria , Universidad de Málaga, CIBERehd , Málaga , Spain.;f UGC de Ap Digestivo y Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria , Universidad de Málaga, CIBERehd , Málaga , Spain.;f UGC de Ap Digestivo y Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria , Universidad de Málaga, CIBERehd , Málaga , Spain.",
"authors": "Bessone|Fernando|F|;Hernandez|Nelia|N|;Roma|Marcelo Gabriel|MG|;Ridruejo|Ezequiel|E|;Mendizabal|Manuel|M|;Medina-Cáliz|Inmaculada|I|;Robles-Díaz|Mercedes|M|;Lucena|M Isabel|MI|;Andrade|Raúl J|RJ|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2016.1225719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "15(11)",
"journal": "Expert opinion on drug safety",
"keywords": "Selective COX-2 inhibitors; acute liver failure; cholestasis; coxibs; hepatitis; hepatotoxicity",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D056486:Chemical and Drug Induced Liver Injury; D052246:Cyclooxygenase 2 Inhibitors; D006801:Humans",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "1463-1475",
"pmc": null,
"pmid": "27537326",
"pubdate": "2016-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hepatotoxicity induced by coxibs: how concerned should we be?",
"title_normalized": "hepatotoxicity induced by coxibs how concerned should we be"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US17982",
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"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "CELECOXIB"
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"drugadditional": "3",
... |
{
"abstract": "Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. Lung transplantation is the only available therapy that deals definitively with the end-stage pulmonary disease and has become the treatment of choice for some of these patients. As patients with CF are living longer, extrapulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency and CF-related diabetes (CFRD). Both of these can be managed through pancreas transplantation. We have previously reported our series of three simultaneous lung and pancreas transplants in patients with CF, which were complicated by surgical issues for both the thoracic and abdominal portions, rejection and resistant infections with disappointing long-term survival. Based on these results, a sequential approach was adopted: first, the thoracic transplant; and second, once the patient has recovered, the abdominal transplants. This is the first reported case of pancreas and kidney transplantation performed after a lung transplant in a patient with CF. It demonstrates a successful approach to treating CF with a lung transplant, and in an effort to improve the patient's long-term outcome, treating CFRD and pancreatic enzyme insufficiency, with a subsequent pancreas transplant.",
"affiliations": "Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Surgery, Division of Abdominal Transplant Surgery, Indiana University School of Medicine, Indianapolis, Indiana.",
"authors": "Fridell|Jonathan A|JA|0000-0002-8708-1506;Lutz|Andrew J|AJ|;Powelson|John A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16597",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(9)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research / practice; diabetes; lung disease: congenital; lung transplantation / pulmonology; pancreas / simultaneous pancreas-kidney transplantation",
"medline_ta": "Am J Transplant",
"mesh_terms": "D003550:Cystic Fibrosis; D006801:Humans; D016030:Kidney Transplantation; D016040:Lung Transplantation; D010179:Pancreas; D016896:Treatment Outcome",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3180-3183",
"pmc": null,
"pmid": "33811791",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Simultaneous pancreas and kidney transplant after bilateral lung transplant for a recipient with cystic fibrosis.",
"title_normalized": "simultaneous pancreas and kidney transplant after bilateral lung transplant for a recipient with cystic fibrosis"
} | [
{
"companynumb": "US-ASTELLAS-2021US041981",
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
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... |
{
"abstract": "Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder accounting for about 2% of all leukemias. The clinical course is indolent, however HCL patients are particularly susceptible to infections. Here we report two cases of Q-fever as first manifestation of disease in two patients affected by HCL. Both patients described in this report showed an unusually sluggish clinical response to the antibiotic treatment with ciprofloxacin probably because of the marked immunodeficiency. However, treatment of HCL with cladribine administered soon after the resolution of QF pneumonitis was uneventful and led to a complete remission in both cases. Most probably the association of Coxiella burnetii (CB) infection and HCL that we observed in two patients is due to chance. However, a hairy cell resembling transformation of freshly isolated human peripheral blood lymphocytes upon CB has been showed. We think that the possibility of CB infection in febrile HCL patient should be always taken in mind, especially in endemic areas. In addition the potential for such infections to become chronic in HCL patients should not be overlooked and the reporting of further cases should be encouraged.",
"affiliations": "Department of Hematology, Erasmus University Medical Centre, Daniel den Hoed, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.;Department of Oncology, Haematology Unit, University of Palermo School of Medicine, Palermo, Italy.;Department of Internal Medicine, Maxima Medical Centre, The Netherlands.;Laboratory for Medical Microbiology, PAMM Foundation, Veldhoven, The Netherlands.;Department of Clinical Chemistry, Máxima Medical Centre, Veldhoven, The Netherlands.;Department of Internal Medicine, Maxima Medical Centre, The Netherlands.",
"authors": "Ammatuna|Emanuele|E|0000-0001-8247-4901;Iannitto|Emilio|E|;Tick|Lidwine W|LW|;Arents|Nicolaas L A|NL|;Kuijper|Philip H|PH|;Nijziel|Marten R|MR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/863932",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2014/863932Case ReportTwo Cases of Q-Fever in Hairy Cell Leukemia http://orcid.org/0000-0001-8247-4901Ammatuna Emanuele \n1\n*Iannitto Emilio \n2\nTick Lidwine W. \n3\nArents Nicolaas L. A. \n4\nKuijper Philip H. \n5\nNijziel Marten R. \n3\n1Department of Hematology, Erasmus University Medical Centre, Daniel den Hoed, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands2Department of Oncology, Haematology Unit, University of Palermo School of Medicine, Palermo, Italy3Department of Internal Medicine, Maxima Medical Centre, The Netherlands4Laboratory for Medical Microbiology, PAMM Foundation, Veldhoven, The Netherlands5Department of Clinical Chemistry, Máxima Medical Centre, Veldhoven, The Netherlands*Emanuele Ammatuna: ammatuna@gmail.comAcademic Editor: Kazunori Nakase\n\n2014 12 8 2014 2014 86393223 6 2014 25 7 2014 Copyright © 2014 Emanuele Ammatuna et al.2014This 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.Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder accounting for about 2% of all leukemias. The clinical course is indolent, however HCL patients are particularly susceptible to infections. Here we report two cases of Q-fever as first manifestation of disease in two patients affected by HCL. Both patients described in this report showed an unusually sluggish clinical response to the antibiotic treatment with ciprofloxacin probably because of the marked immunodeficiency. However, treatment of HCL with cladribine administered soon after the resolution of QF pneumonitis was uneventful and led to a complete remission in both cases. Most probably the association of Coxiella burnetii (CB) infection and HCL that we observed in two patients is due to chance. However, a hairy cell resembling transformation of freshly isolated human peripheral blood lymphocytes upon CB has been showed. We think that the possibility of CB infection in febrile HCL patient should be always taken in mind, especially in endemic areas. In addition the potential for such infections to become chronic in HCL patients should not be overlooked and the reporting of further cases should be encouraged.\n==== Body\n1. Introduction\nHairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder accounting for about 2% of all leukemias [1]. The median age of diagnosis is 56 years, and it affects mainly elderly men, with a male to female ratio of 4 : 1 [2]. The neoplastic clone usually grows slowly and homes preferentially in bone marrow and spleen with a subtle spill-over in the peripheral blood resulting in a clinical picture characterized mostly by splenomegaly and pancytopenia. The clinical course is quite indolent; however, the peculiar clinical characteristic of patients affected by HCL is the susceptibility to develop severe life threatening infections. Approximately 25% present with infection and 70% have either documented or suspected infection during the course of the disease. The susceptibility to infection is higher in those patients with active disease and high tumor burden, while it is markedly reduced in those in complete remission after effective treatment. Fifty percent of these infections comprise those typically seen in a neutropenic host. The rest of reported cases include atypical mycobacterial infections, Listeria, Pneumocystis, Legionella, viral infections, Aspergillus, and other fungal infections [3, 4].\n\nQ-fever (QF) is a worldwide zoonosis caused by Coxiella burnetii (CB). CB is a gram-negative and obligate intracellular bacterium that tends to infect mononuclear phagocytes but can infect other cell types as well. The course of human infection ranges from asymptomatic to severe but typically results in a mild, self-limiting, influenza-like disease making the diagnosis challenging and probably under reported [5, 6]. To date, only one case of QF in HCL patient has been described [7]. Here we report two patients with severe Q-fever as an initial manifestation of HCL.\n\n2. Cases Presentation\n2.1. Case 1\nIn March 2009, a 48-year-old man was admitted to the ward following one week of high fever, chills, cough, dyspnea, and disorientation. His past medical history was unremarkable and he did not report any contact with animals such as cattle or parrots but he was used to taking a daily walk passing a petting zoo. Physical examination revealed a temperature of 39.6°C, a respiratory rate of 32/minute, and rhonchi and crackling sounds at right lung base. The spleen was felt 2 cm under the costal margin and no enlarged superficial lymph nodes were detected. Blood and sputum culture were negative for growth of fungi and gram+ or gram− bacteria. Hemoglobin level was 7.2 mmol/L, platelet count was 83 × 109/L, and the total WBC count was 1.1 × 109/L. The differential leukocyte count showed neutropenia (0.5 × 109/L) and lymphopenia (0.6 × 109/L). A chest X-ray showed a consolidation in the right basal lobe. The patient was empirically treated with intravenous penicillin 6 million international units/day and oral ciprofloxacin 500 mg b.i.d. for 7 days. However, after a week of antibiotic treatment neither the clinical picture nor the marked pancytopenia showed any improvement. Bone marrow trephine biopsy and bronchoscopy with bronchus brushing were performed. The bone marrow histological analysis revealed a heavy interstitial infiltration of lymphoid cells with a typical fried egg pattern. Immunophenotypic analysis of the bone marrow aspirate showed the following: CD20++ CD22+, CD103+ CD25+/− CD11c+/− CD10−CD23−CD5− and the diagnosis of HCL was made. The bronchoscopy with bronchus brushing (BAL) revealed a positive CB PCR which led to the diagnosis of QF and prompted an antibiotic switch to doxycycline monotherapy. Because of an allergic reaction characterized by diffuse rash covering the entire body surface, he was further treated with oral ciprofloxacin monotherapy. Clinical conditions slowly ameliorated and all signs and symptoms of pneumonitis regressed except for the fever and the marked pancytopenia. After an extensive search for other infective causes, the persistent febrile status was interpreted as tumor related and 3 weeks after the admission the patient was treated with cladribine 0.15 mg/kg for 5 consecutive days for his primary hematological disease. The clinical course was uneventful and the patient achieved a complete remission (CR) and resolution of all symptoms. At the 4-year follow-up the patient is still in CR and the CB DNA in the peripheral blood is undetectable.\n\n2.2. Case 2\nIn May 2009, a 56-year-old man was seen in the emergency room because of fever, chest pain, and dyspnoea accompanying atrial fibrillation. Prior to admission he was prescribed amoxicillin/clavulanic acid t.i.d. during 4 days because of a pneumonic process in the medium lobe. His past medical history was unremarkable and he did not report any recent travel outside of The Netherlands nor contact with animals. At admission, physical examination revealed a body temperature of 40.0°C, respiratory rate of 36/min, and crackling sounds at medium and lower right lung lobe. The spleen was felt 4 cm under the costal margin but no enlarged superficial lymph nodes were identified. Laboratory analysis showed a severe pancytopenia (hemoglobin: 4.6 mmol/L, leukocytes 1.1 × 109/L, and thrombocytes 23 × 109/L). Blood and sputum culture were negative for growth of fungi and/or gram+ or gram− bacteria. The patient was empirically treated with penicillin 6 million international units/day and oral ciprofloxacin 500 mg b.i.d. Five days after admission, the clinical condition worsened and the patient developed respiratory failure that necessitated mechanical ventilation at the intensive care unit. At this point antibiotics were switched to intravenous ceftazidime 1500 mg t.i.d. and vancomycin 1 gr b.i.d. A peripheral blood immunophenotype assay was performed to investigate a possible underlying blood disease. This revealed a monoclonal B-cell population CD20++ CD22+, CD25+ CD103+− CD11c+ CD10−CD23−CD5− compatible with the diagnosis of HCL. Clinical conditions and fever did not improve and the patient underwent a BAL and successively a wedge excision of the medium lobe. Both procedures did not show any fungal or bacterial infection. Subsequently, an acute renal failure due to acute tubular necrosis requiring dialysis developed. At that point, a rising phase 2 antibody titre against CB was detected and the diagnosis of QF was made. Treatment with doxycycline was started but because of liver toxicity was switched to ciprofloxacin. Moreover, chemotherapy with cladribine 0.15 mg/kg for 5 consecutive days for the treatment of the HCL was delivered. After a few weeks, clinical conditions ameliorated and the patient was discharged from the intensive care unit following complete recovery from pneumonia and renal failure. While asymptomatic, for the persistent positive CB PCR in the peripheral blood, treatment with daily moxifloxacin 400 mg and plaquenil 200 mg t.i.d. for 18 months was carried out. During this period the CB PCR assay became negative and the phase 2 IgG antibody titer reduced consistently. Four years after cladribine treatment, the patient is still in complete remission from his HCL.\n\n3. Discussion and Conclusion\nThe most common clinical manifestation of acute QF is a nonspecific febrile illness followed by pneumonia and hepatitis. However, asymptomatic infections have been reported in up to 60% of cases identified during outbreak investigations. This fact indicates that other factors than CB exposure are responsible for the severity of this disease. Our patients suffered from a severe form of acute QF leading to a respiratory insufficiency. This can be explained by the severe immunocompromised status typical of patients affected by HCL. Indeed, poor granulocyte reserve and mobilization and several defects of innate and acquired immunity as well as the marked monocytopenia and functional abnormalities of monocytes and dendritic cells make HCL patients particularly vulnerable to infections caused by intracellular microorganisms [8–10]. The risk is particularly high at disease onset and during the early treatment period due to the neutropenia and immunosuppression caused by the purine analogues.\n\nThe first and most obvious consideration from the analysis of these cases is to consider the possibility of QF as a cause of pneumonitis in patients with HCL, particularly in an endemic area or in patients belonging to high occupational risk groups with the latter being workers in slaughterhouses, farms, and animal research facilities. We would also underscore that in both patients described in this report, QF showed an unusually sluggish clinical response to the antibiotic treatment with ciprofloxacin probably because of the marked immunodeficiency. However, treatment of HCL with cladribine administered soon after the resolution of QF pneumonitis was uneventful and led to a complete remission in both cases. Prior to this paper, only one case of CB infection associated with HCL has been reported in the literature. Most probably the association of CB infection and HCL that we observed in two patients is due to chance in an endemic area for CB such as the North Brabant province in The Netherlands. However, a very interesting observation was done by Lee and coworkers, who showed that a hairy cell resembling transformation of freshly isolated human peripheral blood lymphocytes (PBL) could be observed in vitro upon CB infection [11]. Moreover, in two-thirds of cases, the transformed PBL acquired tartrate resistant phosphates acid expression, a phenotype quite distinctive of HCL. We certainly acknowledge that these data, although fascinating, are insufficient to speculate on a possible role of CB in the developing of HCL. In conclusion, we think that the possibility of CB infection in a febrile HCL patient should be always taken in mind, especially in endemic areas. In addition the potential for such infections to become chronic in HCL patients should not be overlooked and the reporting of further cases should be encouraged.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n==== Refs\n1 Bouroncle BA Wiseman BK Doan CA Leukemic reticuloendotheliosis Blood 1958 13 7 609 630 2-s2.0-0001322730 13560561 \n2 Frassoldati A Lamparelli T Federico M Hairy cell leukemia: a clinical review based on 725 cases of the Italian Cooperative Group (ICGHCL) Leukemia and Lymphoma 1994 13 3-4 307 316 2-s2.0-0028344716 7519510 \n3 Rice L Shenkenberg T Lynch EC Wheeler TM Granulomatous infections complicating hairy cell leukemia Cancer 1982 49 9 1924 1928 2-s2.0-0020051401 7074589 \n4 Kraut EH Clinical manifestations and infectious complications of hairy-cell leukaemia Best Practice and Research: Clinical Haematology 2003 16 1 33 40 2-s2.0-0037250849 12670463 \n5 Dupont HT Raoult D Brouqui P Epidemiologic features and clinical presentation of acute Q fever in hospitalized patients: 323 French cases The American Journal of Medicine 1992 93 4 427 434 2-s2.0-0026672337 1415306 \n6 Caron F Meurice JC Ingrand P Acute Q fever pneumonia: a review of 80 hospitalized patients Chest 1998 114 3 808 813 2-s2.0-0031662922 9743171 \n7 Vuille C Delafontaine P Unusual association of Q fever and hairy cell leukemia Schweizerische Medizinische Wochenschrift 1989 119 6 187 191 2-s2.0-0024496845 2928742 \n8 Seshadri RS Brown EJ Zipursky A Leukemic reticuloendotheliosis—a failure of monocyte production The New England Journal of Medicine 1976 295 4 181 184 2-s2.0-0017187575 775335 \n9 Child JA Cawley JC Martin S Ghoneim ATM Microbicidal function of the neutrophils in hairy-cell leukemia Acta Haematologica 1979 62 4 191 198 2-s2.0-0018597520 119411 \n10 Hoffman MA Clinical presentations and complications of hairy cell leukemia Hematology/Oncology Clinics of North America 2006 20 5 1065 1073 2-s2.0-33748616255 16990107 \n11 Lee WY Hairy cell transformation of human peripheral blood lymphocytes by Coxiella burnetii. Yonsei Medical Journal 1993 34 1 11 21 2-s2.0-0027571131 8379181\n\n",
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"journal": "Case reports in hematology",
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"nlm_unique_id": "101576456",
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"pmid": "25180111",
"pubdate": "2014",
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"references": "2928742;13560561;1415306;16990107;12670463;9743171;8379181;7074589;775335;119411;7519510",
"title": "Two cases of q-Fever in hairy cell leukemia.",
"title_normalized": "two cases of q fever in hairy cell leukemia"
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... |
{
"abstract": "OBJECTIVE\nThe 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide (HEC) is superior to a lower dose of epirubicin, 60 mg/m(2) (EC), for event-free survival (EFS; 27% reduction), but is not superior to classical oral cyclophosphamide, methotrexate, and fluorouracil (CMF) in the adjuvant treatment of node-positive breast cancer. Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial.\n\n\nMETHODS\nBetween March 1988 and December 1996, 777 eligible patients were randomly assigned to six cycles of CMF, eight cycles of EC, or eight cycles HEC.\n\n\nRESULTS\nThe 15-year EFS was 45% for patients who received CMF, 39% for patients who received EC, and 50% for patients who received HEC. The hazard ratios (HR) were 0.77 for HEC versus EC (95% CI, 0.60 to 0.98; P = .03), 0.90 for HEC versus CMF (P = .39), and 0.86 for EC versus CMF (P = .21). No difference in overall survival (OS) was seen. Cardiac toxicity was more frequent with HEC than with CMF (11 patients v 1 patient; P = .006), but no more than with EC (P = .21).\n\n\nCONCLUSIONS\nTreatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin. However, we do not recommend the use of HEC regimen in daily clinical practice, mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study.",
"affiliations": "Institut Jules Bordet and Université Libre de Bruxelles, Brussels.",
"authors": "de Azambuja|Evandro|E|;Paesmans|Marianne|M|;Beauduin|Marc|M|;Vindevoghel|Anita|A|;Cornez|Nathalie|N|;Finet|Claude|C|;Ries|Fernand|F|;Closon-Dejardin|Marie Thérèse|MT|;Kerger|Joseph|J|;Gobert|Philippe|P|;Focan|Christian|C|;Tagnon|Alain|A|;Dolci|Stella|S|;Nogaret|Jean M|JM|;di Leo|Angelo|A|;Piccart-Gebhart|Martine J|MJ|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2008.17.2155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "27(5)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D001530:Belgium; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008198:Lymph Nodes; D008727:Methotrexate; D008875:Middle Aged",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "720-5",
"pmc": null,
"pmid": "19103732",
"pubdate": "2009-02-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study.",
"title_normalized": "long term benefit of high dose epirubicin in adjuvant chemotherapy for node positive breast cancer 15 year efficacy results of the belgian multicentre study"
} | [
{
"companynumb": "BE-PFIZER INC-2018173486",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Eribulin mesylate is a non-taxane microtubule inhibitor effective in the treatment of metastatic breast cancer refractory to anthracyclines and taxanes. In preclinical studies, additional mechanisms of eribulin included reversal of epithelial mesenchymal transition and tumor vascular remodeling. The present study compared the safety and efficacy of eribulin plus cyclophosphamide (ErC) to docetaxel plus cyclophosphamide (TC) as neoadjuvant therapy for operable HER2- breast cancer.\n\n\n\nWomen with invasive HER2- breast adenocarcinoma with no distant metastases were eligible. After a 10-patient safety lead-in, the patients were randomized 2:1 to receive either ErC (eribulin 1.4 mg/m2 on days 1 and 8 plus cyclophosphamide 600 mg/m2 on day 1) or TC (docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1) administered every 21 days for 6 cycles, followed by surgery. The pathologic complete response (pCR) rate was the primary endpoint. Tumor samples collected at baseline and at surgery were assayed for select epithelial mesenchymal transition and vascular density markers: E-cadherin, vimentin, and CD31 expression.\n\n\n\nA total of 76 patients were enrolled. Of the 76 patients, 10 received ErC in the lead-in phase and 66 were randomized to ErC (n = 44) or TC (n = 22). The pCR rates with ErC and TC were 13% and 9%, respectively. Both regimens produced frequent neutropenia and peripheral neuropathy. Both regimens increased vascular density as measured by CD31 staining.\n\n\n\nThe neoadjuvant regimens of ErC and TC resulted in relatively low pCR rates in this patient population. No unexpected toxicities were observed. Our results also provided no suggestion that ErC is a neoadjuvant treatment with greater efficacy than that of standard regimens.",
"affiliations": "Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN. Electronic address: dyardley@tnonc.com.;Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN.;Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN.;Sarah Cannon Research Institute, Nashville, TN; Florida Cancer Specialists, Hudson, FL.;Oncology Hematology Care, Cincinnati, OH.;Memorial Cancer Institute, Hollywood, FL.;Sarah Cannon Research Institute, Nashville, TN.;Sarah Cannon Research Institute, Nashville, TN.;Sarah Cannon Research Institute, Nashville, TN.;Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN.",
"authors": "Yardley|Denise A|DA|;Shipley|Dianna|D|;Zubkus|John|J|;Wright|Gail L|GL|;Ward|Patrick J|PJ|;Mani|Aruna|A|;Shastry|Mythili|M|;Finney|Lindsey|L|;DeBusk|Laura|L|;Hainsworth|John D|JD|",
"chemical_list": "D005663:Furans; D007659:Ketones; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077143:Docetaxel; D003520:Cyclophosphamide; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C490954:eribulin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2018.08.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "19(1)",
"journal": "Clinical breast cancer",
"keywords": "ErC; HER2(−); NAC; TC",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D018275:Carcinoma, Lobular; D003520:Cyclophosphamide; D000077143:Docetaxel; D005260:Female; D005500:Follow-Up Studies; D005663:Furans; D006801:Humans; D007659:Ketones; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015996:Survival Rate",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "30245148",
"pubdate": "2019-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Randomized Phase II Study of Eribulin/Cyclophosphamide or Docetaxel/Cyclophosphamide as Neoadjuvant Therapy in Operable HER2-negative Breast Cancer.",
"title_normalized": "a randomized phase ii study of eribulin cyclophosphamide or docetaxel cyclophosphamide as neoadjuvant therapy in operable her2 negative breast cancer"
} | [
{
"companynumb": "US-PFIZER INC-2019472922",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "A 29-year-old Caucasian woman presented to hospital with a 2-day history of diarrhoea, anorexia and rigors. Investigations showed abnormal liver function tests, hyponatremia, hypoalbuminaemia and lymphopenia. The initial chest radiograph was normal. A bone marrow trephine biopsy showed non-caseating granulomata and she subsequently developed miliary shadowing on the chest radiograph. A transjugular liver biopsy confirmed the presence of acid-alcohol fast bacilli. Despite starting triple therapy for miliary tuberculosis she remained febrile and developed massive hepatosplenomegaly, jaundice and pancytopenia. Standard triple therapy was substituted with ethambutol, streptomycin and oral prednisolone and the patient made a dramatic recovery. The clinical symptoms of miliary tuberculosis are frequently non-specific and the onset of the illness is often insidious. The liver is involved in almost all patients with miliary tuberculosis, but massive hepatosplenomegaly and jaundice are rare. Standard triple-therapy should be discontinued when there is significant liver dysfunction, and corticosteroids should be considered for patients with miliary tuberculosis who fail to respond to conventional therapy.",
"affiliations": "Department of Medicine & Infectious Diseases, University Hospital of Wales, Cardiff, UK.",
"authors": "Evans|R H|RH|;Evans|M|M|;Harrison|N K|NK|;Price|D E|DE|;Freedman|A R|AR|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000995:Antitubercular Agents",
"country": "England",
"delete": false,
"doi": "10.1016/s0163-4453(98)80025-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4453",
"issue": "36(2)",
"journal": "The Journal of infection",
"keywords": null,
"medline_ta": "J Infect",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000995:Antitubercular Agents; D004359:Drug Therapy, Combination; D005260:Female; D006529:Hepatomegaly; D006801:Humans; D007565:Jaundice; D008099:Liver; D010198:Pancytopenia; D013163:Splenomegaly; D014057:Tomography, X-Ray Computed; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "7908424",
"other_id": null,
"pages": "236-9",
"pmc": null,
"pmid": "9570666",
"pubdate": "1998-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Massive hepatosplenomegaly, jaundice and pancytopenia in miliary tuberculosis.",
"title_normalized": "massive hepatosplenomegaly jaundice and pancytopenia in miliary tuberculosis"
} | [
{
"companynumb": "GB-MYLANLABS-2018M1048763",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": "1",
... |
{
"abstract": "There is little data available on the use of new oral direct-acting antiviral (DAA) regimens to treat human immunodeficiency virus and hepatitis C virus (HIV/HCV) co-infected patients in real-life settings. Here, the efficacy and safety of all-oral DAA-based regimens in HIV/HCV-co-infected patients enrolled in the French nationwide ANRS CO13 HEPAVIH observational cohort are reported.\n\n\n\nHIV/HCV-co-infected patients enrolled in the ANRS CO13 HEPAVIH observational cohort were included if they began an all-oral DAA-based regimen before 1st May 2015 (12-week regimens) or 1st February 2015 (24-week regimens). Treatment success (SVR12) was defined by undetectable HCV-RNA 12weeks after treatment cessation. Exact logistic regression analysis was used to identify factors associated with SVR12.\n\n\n\nA total of 323 patients (74% men) with a median age of 53years were included, 99% of whom were on combination antiretroviral therapy (cART). HIV RNA load was <50 copies/ml in 88% of patients; median CD4 cell count was 540/mm3; 60% of patients were cirrhotic; 68% had previously received unsuccessful anti-HCV treatment. cART was protease inhibitor (PI)-based in 23%, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based in 15%, and integrase inhibitor (II)-based in 38%, while 24% of patients received other regimens. The SVR12 rate was 93.5% overall (95% confidence interval [CI]: 90.2-95.9), 93.3% (88.8-96.4) in patients with cirrhosis and 93.8% (88.1-97.3) in patients without cirrhosis. The SVR12 rates were 93.1% (84.5-97.7), 91.8% (80.4-97.7) and 95.8% (90.5-98.6) respectively, in patients receiving PI-based, NNRTI-based and II-based cART. In adjusted analysis, SVR12 was not associated with HIV RNA load, the cART regimen, cirrhosis, prior anti-HCV treatment, the duration of anti-HCV therapy, or ribavirin use. The most common adverse effects were fatigue and digestive disorders.\n\n\n\nNew all-oral DAA regimens were well-tolerated and yielded high SVR12 rates in HIV/HCV-co-infected patients.\n\n\n\nWe evaluated efficacy and safety of all-oral DAA regimens in a large French nationwide observational cohort study of HIV/HCV co-infected patients. Sustained virological response 12weeks after treatment cessation was 93.5% overall. The all-oral DAA regimens were well-tolerated and most common adverse effects were fatigue and digestive disorders.",
"affiliations": "Centre Hospitalier Universitaire de Dijon, Département d'Infectiologie, Dijon, France; Université de Bourgogne, Dijon, France.;Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, team MORPH3EUS, UMR 1219, CIC-EC 1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pole de sante publique, Service d'information medicale, F-33000 Bordeaux, France. Electronic address: Linda.Wittkop@isped.u-bordeaux2.fr.;Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Service Maladies infectieuses et tropicales, Paris, France; UMPC (Université Pierre et Marie Curie), UMR S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.;Centre Hospitalier Universitaire de Nice, Service de Médecine Interne, Hôpital l'Archet, Nice, France; Université de Nice-Sophia Antipolis, Nice, France.;Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, team MORPH3EUS, UMR 1219, CIC-EC 1401, F-33000 Bordeaux, France.;Service des Maladies Infectieuses et Tropicales, CHU Lyon, Hôpital de la Croix Rousse, Lyon, France.;Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Service Maladies infectieuses et tropicales, Paris, France.;Aix Marseille Univ, APHM Sainte-Marguerite, Service d'Immuno-hématologie clinique, Marseille, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Bichat Claude Bernard, Service des Maladies Infectieuses et tropicales, Paris, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Henri Mondor, Service Immunologie clinique et Maladies Infectieuses, Immunologie clinique, Créteil, France.;Centre Hospitalier Universitaire de Bordeaux, Service Maladies infectieuses et tropicales Bordeaux, Hôpital Pellegrin, Bordeaux, France.;Hôpital Foch, unité VIH, Suresnes, France.;Centre Hospitalier Universitaire de Nantes, Service Maladies infectieuses et tropicales, Nantes, France.;Centre Hospitalier Universitaire de Bordeaux, Service de Médecine Interne, hôpital Saint-André, Bordeaux, France.;Centre Hospitalier de Perpignan, Service Maladies infectieuses et tropicales, Perpignan, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Service Maladies infectieuses et tropicales, Paris, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Département de Médecine Interne et Immunologie Clinique, Paris, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Avicenne, Service Maladies infectieuses et tropicales, Bobigny, France; Université Paris 13 Nord, Bobigny, France.;Assistance Publique des Hôpitaux de Paris, GH Paris Sud : Service Médecine Interne et Immunologie clinique, Hôpital Bicêtre, Le Kremlin-Bicêtre; Centre Hépato-Biliaire, Hôpital Paul-Brousse,Villejuif, France.;Centre Hospitalier Universitaire de Reims, Service de Médecine Interne, Maladies Infectieuses et immunologie clinique, Reims, France; Université de Reims, Champagne-Ardenne, Reims, France.;Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, Service Médecine Interne-Pôle Digestif, Toulouse, France; UMR 152 IRD Université Toulouse III, Paul Sabatier, Toulouse, France.;Université Paris Sud, Le Kremlin-Bicêtre, France; Assistance Publique des Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux universitaires Paris Sud, Service Maladies infectieuses et tropicales, Le Kremlin-Bicêtre, France.;Université Paris Sud, Le Kremlin-Bicêtre, France; Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Paris Sud, Hôpital Antoine-Béclère, Service Médecine Interne et immunologie, Clamart, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Maladies Infectieuses et Tropicales, Centre d'infectiologie Necker-Pasteur, IHU Imagine, Paris, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Service Maladies infectieuses et tropicales, Paris, France.;Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, team MORPH3EUS, UMR 1219, CIC-EC 1401, F-33000 Bordeaux, France.;Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, team MORPH3EUS, UMR 1219, CIC-EC 1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pole de sante publique, Service d'information medicale, F-33000 Bordeaux, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Cochin, Service d'Hépatologie, Paris, France; INSERM U-1223 - Institut Pasteur, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Assistance Publique des Hôpitaux de Paris, Hôpital Cochin, Service Maladies infectieuses et tropicales, Paris, France.",
"authors": "Piroth|Lionel|L|;Wittkop|Linda|L|;Lacombe|Karine|K|;Rosenthal|Eric|E|;Gilbert|Camille|C|;Miailhes|Patrick|P|;Carrieri|Patrizia|P|;Chas|Julie|J|;Poizot-Martin|Isabelle|I|;Gervais|Anne|A|;Dominguez|Stéphanie|S|;Neau|Didier|D|;Zucman|David|D|;Billaud|Eric|E|;Morlat|Philippe|P|;Aumaitre|Hugues|H|;Lascoux-Combe|Caroline|C|;Simon|Anne|A|;Bouchaud|Olivier|O|;Teicher|Elina|E|;Bani-Sadr|Firouzé|F|;Alric|Laurent|L|;Vittecoq|Daniel|D|;Boué|François|F|;Duvivier|Claudine|C|;Valantin|Marc-Antoine|MA|;Esterle|Laure|L|;Dabis|François|F|;Sogni|Philippe|P|;Salmon|Dominique|D|;|||",
"chemical_list": "D000998:Antiviral Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhep.2017.02.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0168-8278",
"issue": "67(1)",
"journal": "Journal of hepatology",
"keywords": "All-oral DAA; HIV/HCV co-infection; Sustained virological response",
"medline_ta": "J Hepatol",
"mesh_terms": "D000998:Antiviral Agents; D015331:Cohort Studies; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8503886",
"other_id": null,
"pages": "23-31",
"pmc": null,
"pmid": "28235612",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of direct-acting antiviral regimens in HIV/HCV-co-infected patients - French ANRS CO13 HEPAVIH cohort.",
"title_normalized": "efficacy and safety of direct acting antiviral regimens in hiv hcv co infected patients french anrs co13 hepavih cohort"
} | [
{
"companynumb": "FR-JNJFOC-20170700950",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nTo evaluate the effects of ketoconazole, rifampicin and efavirenz on the pharmacokinetics of telaprevir in healthy volunteers.\n\n\nMETHODS\nResults from three clinical studies are described. (1) Volunteers received a single 750 mg dose telaprevir with and without a single 400 mg dose ketoconazole. (2) Volunteers received (a) 1250 mg telaprevir followed by three 750 mg doses given every 8 h and (b) four 1250 mg telaprevir doses given every 8 h, with a single 400 mg dose ketoconazole given with the fourth dose of telaprevir. (3) Volunteers received either a single 750 mg dose telaprevir with or without 600 mg once daily rifampicin, or 750 mg every 8 h telaprevir with and without 600 mg once daily efavirenz.\n\n\nRESULTS\nA single 400 mg dose of ketoconazole increased single dose telaprevir exposure: the geometric least-squares mean ratio (GLSMR, with 90% confidence limits) was 1.24 (1.10, 1.41) for C(max) and 1.62 (1.45, 1.81) for AUC(0,∞). However, after multiple doses of telaprevir, there was no discernible effect of ketoconazole on telaprevir exposure. Co-administration of rifampicin at steady-state markedly reduced single dose telaprevir exposure with GLSMRs of 0.14 (0.11, 0.18) for C(max) and 0.08 (0.07, 0.11) for AUC(0,∞), whereas efavirenz had a smaller effect on telaprevir exposure when both drugs were co-administered at steady-state, with GLSMRs of 0.91 (0.81, 1.02) for C(max) , 0.53 (0.44, 0.65) for C(min), and 0.74 (0.65, 0.84) for AUC(0,8 h).\n\n\nCONCLUSIONS\nCYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. The effect of ketoconazole as an inhibitor of telaprevir metabolism is more pronounced after a single dose of telaprevir than after repeated administration.",
"affiliations": "Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139-4242, USA. varun_garg@vrtx.com",
"authors": "Garg|Varun|V|;Chandorkar|Gurudatt|G|;Yang|Yijun|Y|;Adda|Nathalie|N|;McNair|Lindsay|L|;Alves|Katia|K|;Smith|Frances|F|;van Heeswijk|Rolf P G|RP|",
"chemical_list": "D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C486464:telaprevir; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz; D007654:Ketoconazole; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2125.2012.04345.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "75(2)",
"journal": "British journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D048588:Benzoxazines; D002986:Clinical Trials as Topic; D003521:Cyclopropanes; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007654:Ketoconazole; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D012293:Rifampin",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "431-9",
"pmc": null,
"pmid": "22642697",
"pubdate": "2013-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12882588;16787300;19403903;19403902;21696308;17148083;23685940;22039291;6322675;21696307;22162542;19246722;20375406;1559307;21916639",
"title": "The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers.",
"title_normalized": "the effect of cyp3a inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers"
} | [
{
"companynumb": "US-JNJFOC-20130208980",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TELAPREVIR"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLarge sessile/flat colonic polyps are traditionally removed by lift polypectomy. Underwater endoscopic mucosal resection (UEMR) is a novel technique where air is suctioned out and replaced by water to decompress the colon so that the flat lesions assumes a more polypoid shape facilitating its removal with the standard snare resection. We report the feasibility and safety in our series of patients utilizing this technique.\n\n\nMETHODS\nA retrospective, observational study of all patients who underwent removal of large colonic polyps (>10 mm) over a period of 3 years (January 2012 to January 2015) at a tertiary care center by UEMR were included in the study.\n\n\nRESULTS\nA total of 102 polyps were removed in 93 adult patients using UEMR. The mean age of patients was 64.7±9.7 years. The average number of polyps per patient was 1.84±1.3 with a range of 1-7. The range of the polyp size was 10 to 60 mm. The mean size of the polyp was 20.4±9.4 mm, median size 26.9±9.4 mm. Ninety-two (90.2%) were removed in piecemeal fashion and ten (9.8%) were removed en bloc. Delayed bleeding occurred in seven (9.7%) patients.\n\n\nCONCLUSIONS\nIn this largest series on UEMR, we report the feasibility and safety of this procedure. Future randomized trials comparing this technique versus standard lift polypectomy technique will further elucidate the benefit of one over other.",
"affiliations": "Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA - drdalbir@gmail.com.;Division of Gastroenterology and Hepatology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.;Division of Gastroenterology and Hepatology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.",
"authors": "Sandhu|Dalbir S|DS|;Lee|Ye J|YJ|;Gerke|Henning|H|",
"chemical_list": "D014867:Water",
"country": "Italy",
"delete": false,
"doi": "10.23736/S1121-421X.17.02444-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-421X",
"issue": "64(2)",
"journal": "Minerva gastroenterologica e dietologica",
"keywords": null,
"medline_ta": "Minerva Gastroenterol Dietol",
"mesh_terms": "D003111:Colonic Polyps; D000069916:Endoscopic Mucosal Resection; D005240:Feasibility Studies; D006801:Humans; D007417:Intestinal Polyps; D008875:Middle Aged; D012002:Rectal Diseases; D012189:Retrospective Studies; D014867:Water",
"nlm_unique_id": "9109791",
"other_id": null,
"pages": "106-110",
"pmc": null,
"pmid": "28994567",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Underwater endoscopic mucosal resection: an alternative treatment for large colorectal polyp removal.",
"title_normalized": "underwater endoscopic mucosal resection an alternative treatment for large colorectal polyp removal"
} | [
{
"companynumb": "US-BAYER-2018-097386",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "The goal of this pilot study was to measure patient satisfaction, pain scores associated with injection, and patient perceptions of a pharmacist-led specialty injection clinic.\n\n\n\nThe Medical University of South Carolina Specialty Pharmacy.\n\n\n\nThe specialty pharmacy comprises decentralized clinical pharmacy specialists who provide medication education to patients via phone. Many of the medications dispensed are self-administered injectables, but patients often request in-person assistance to learn the best way to use the drug. The investigators sought to provide an avenue for patients to receive teaching and drug administration from a pharmacist without scheduling a formal nurse visit or enrolling the patients in a manufacturer program.\n\n\n\nClinical pharmacy specialists offered every patient a referral to the Assistance with Injectable Medication clinic for in-person injection teaching during the initial clinical assessment. At the first clinic visit, the patients were provided with printed injection instructions, and a demo injector from the manufacturer was available for practice before the actual drug administration.\n\n\n\nThis was a prospective pilot study conducted from January 2019 to April 2019. Patient identification occurred directly through our clinical pharmacy specialists via referrals and informational flyers. The eligible patients were aged 18 years or older and had received a qualifying subcutaneous injection via the Medical University of South Carolina Specialty Pharmacy. The outcomes included pain score and patient satisfaction.\n\n\n\nAs of April 30, 2019, 17 patients had completed 24 clinic visits. The average reported pain and satisfaction scores (scale 0-10) were 2.5 and 9.6, respectively. The 2 most commonly administered medications in the clinic were alirocumab and adalimumab.\n\n\n\nA clinic to assist with specialty injectable medications resulted in high patient satisfaction scores and low pain scores associated with injection.",
"affiliations": null,
"authors": "Simerlein|Whitney M|WM|;Beeker|Kristin E|KE|;Cruse|David B|DB|;Brittain|Kristy L|KL|",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1016/j.japh.2020.02.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1086-5802",
"issue": "60(3S)",
"journal": "Journal of the American Pharmacists Association : JAPhA",
"keywords": null,
"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": "D006801:Humans; D004364:Pharmaceutical Preparations; D010595:Pharmacists; D010604:Pharmacy; D010865:Pilot Projects; D011446:Prospective Studies",
"nlm_unique_id": "101176252",
"other_id": null,
"pages": "S76-S79",
"pmc": null,
"pmid": "32249172",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Assistance with injectable medications: Implementation of a pharmacist-run specialty pharmacy injection clinic.",
"title_normalized": "assistance with injectable medications implementation of a pharmacist run specialty pharmacy injection clinic"
} | [
{
"companynumb": "US-AMGEN INC.-USASP2020130175",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERENUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrome, myopathy, and cardiomyopathy have been reported. Recent studies suggested that provision of exogenous L-cysteine or N-acetylcysteine may ameliorate the effects of disease-causing variants and improve the natural history of the disease. Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine. We highlight the first report of an affected patient undergoing orthotopic liver transplantation, the long-term effects of cysteine supplementation, and the ability of the initial presentation to mimic multiple inborn errors of metabolism. We propose that TRMU deficiency should be suspected in all children presenting with persistent lactic acidosis and hypoglycemia, and that combined N-acetylcysteine and L-cysteine supplementation should be considered prior to molecular diagnosis, as this is a low-risk approach that may increase survival and mitigate the severity of the disease course.",
"affiliations": "Division of Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America; Texas Children's Hospital, Houston, TX, United States of America.;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America; Texas Children's Hospital, Houston, TX, United States of America.;Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.;Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.;Naval Medical Center Portsmouth, Portsmouth, VA, United States of America.;University of the Philippines, Manila, Philippines.;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America; Texas Children's Hospital, Houston, TX, United States of America; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Shatin, Hong Kong.;Division of Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America. Electronic address: ganetzkyr@email.chop.edu.",
"authors": "Murali|Chaya N|CN|;Soler-Alfonso|Claudia|C|;Loomes|Kathleen M|KM|;Shah|Amit A|AA|;Monteil|Danielle|D|;Padilla|Carmencita D|CD|;Scaglia|Fernando|F|;Ganetzky|Rebecca|R|",
"chemical_list": "D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012343:RNA, Transfer; D012359:tRNA Methyltransferases; C496706:TRMU protein, human; D003545:Cysteine; D000111:Acetylcysteine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ymgme.2021.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1096-7192",
"issue": "132(2)",
"journal": "Molecular genetics and metabolism",
"keywords": "Cysteine; Liver failure; Mitochondrial disorder; Orthotopic liver transplant; TRMU",
"medline_ta": "Mol Genet Metab",
"mesh_terms": "D000111:Acetylcysteine; D000138:Acidosis; D003545:Cysteine; D004272:DNA, Mitochondrial; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D008928:Mitochondria; D024101:Mitochondrial Proteins; D014176:Protein Biosynthesis; D012343:RNA, Transfer; D012359:tRNA Methyltransferases",
"nlm_unique_id": "9805456",
"other_id": null,
"pages": "146-153",
"pmc": null,
"pmid": "33485800",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "25665837;25407320;27854233;25058219;29374875;23625533;25741868;7070878;28467362;23814040;16826519;21931168;30740308;19732863;21153446",
"title": "TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation.",
"title_normalized": "trmu deficiency a broad clinical spectrum responsive to cysteine supplementation"
} | [
{
"companynumb": "US-ROCHE-2822269",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nWe evaluate the incidence of complications associated with the use of nitrates in patients presenting with acute pulmonary edema and concomitant moderate or severe aortic stenosis compared with patients without aortic stenosis. Nitrates are contraindicated in severe aortic stenosis because of the theoretical yet unproven risk of precipitating profound hypotension.\n\n\nMETHODS\nA cohort design with retrospective chart review study was conducted at two Canadian hospitals. Patients with aortic stenosis (moderate or severe) and without aortic stenosis were included if they presented with acute cardiogenic pulmonary edema, received intravenous or sublingual nitroglycerin, and had an echocardiography report available. The primary outcome was clinically relevant hypotension, defined as hypotension leading to any of the following predefined events: nitroglycerin discontinuation, intravenous fluid bolus, vasopressor use, or cardiac arrest. The secondary outcome was sustained hypotension, defined as a systolic blood pressure less than 90 mm Hg and lasting greater than or equal to 30 minutes.\n\n\nRESULTS\nThe cohort consisted of 195 episodes of acute pulmonary edema, representing 65 episodes with severe aortic stenosis (N=65) and an equal number of matched episodes with moderate aortic stenosis (N=65) and no aortic stenosis (N=65). Nitroglycerin was administered intravenously only in 70% of cases, intravenously and sublingually in 25%, and sublingually only in the remaining 5%. After adjustment for sex, initial systolic blood pressure, furosemide dose, and use of noninvasive ventilation, moderate and severe aortic stenosis were not associated with clinically relevant hypotension after receipt of nitroglycerin (adjusted odds ratio [OR] 0.97, 95% confidence interval [CI] 0.40 to 2.37 for moderate aortic stenosis; adjusted OR 0.99, 95% CI 0.41 to 2.41 for severe aortic stenosis). The incidence of clinically relevant hypotension was 26.2% for moderate and severe aortic stenosis and 23.1% in the no aortic stenosis reference group. The secondary outcome of sustained hypotension occurred in 29.2% of patients with severe aortic stenosis, 16.9% with moderate aortic stenosis, and 13.8% in the no aortic stenosis group (adjusted OR for severe aortic stenosis 2.34; 95% CI 0.91 to 6.01).\n\n\nCONCLUSIONS\nIn this retrospective study, neither moderate nor severe aortic stenosis was associated with a greater risk of clinically relevant hypotension requiring intervention when nitroglycerin was used for acute pulmonary edema. Future studies should investigate safety and efficacy of nitroglycerin for patients with aortic stenosis because this study was limited by a small sample size and design limitations. Cautious use of nitroglycerin in patients with moderate or severe aortic stenosis and presenting with acute pulmonary edema may be a safer strategy than traditionally thought.",
"affiliations": "McGill Emergency Medicine Program, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Centre de Santé et de Services Sociaux de Trois-Rivières, site Centre hospitalier Régional, Trois-Rivières, Quebec, Canada. Electronic address: david.claveau@mail.mcgill.ca.;Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.;Faculty of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.;Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.;Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.",
"authors": "Claveau|David|D|;Piha-Gossack|Adam|A|;Friedland|Sayuri N|SN|;Afilalo|Jonathan|J|;Rudski|Lawrence|L|",
"chemical_list": "D014665:Vasodilator Agents; D005996:Nitroglycerin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "66(4)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D001024:Aortic Valve Stenosis; D002170:Canada; D005260:Female; D006801:Humans; D007022:Hypotension; D008297:Male; D005996:Nitroglycerin; D011654:Pulmonary Edema; D012189:Retrospective Studies; D016896:Treatment Outcome; D014463:Ultrasonography; D014665:Vasodilator Agents",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "355-362.e1",
"pmc": null,
"pmid": "26002298",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Complications Associated With Nitrate Use in Patients Presenting With Acute Pulmonary Edema and Concomitant Moderate or Severe Aortic Stenosis.",
"title_normalized": "complications associated with nitrate use in patients presenting with acute pulmonary edema and concomitant moderate or severe aortic stenosis"
} | [
{
"companynumb": "CA-BAXTER-2015BAX056223",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NITROGLYCERIN"
},
"drugadditional": null,
... |
{
"abstract": "Granulocyte colony-stimulating factor (G-CSF)-producing bladder cancer is a rare variant subtype of bladder cancer with a poor prognosis. Pembrolizumab has improved overall survival in bladder cancer and is widely used as a standard second-line treatment. However, no reports on G-CSF-producing cancer treated by pembrolizumab are available. We report a case of the pathologically evaluated antitumor effect of pembrolizumab, a programmed death-1 immune checkpoint inhibitor antibody, in G-CSF-producing bladder cancer. A 53-year-old male patient underwent 4 courses chemotherapy with a combination of gemcitabine and carboplatin before a radical cystectomy with ileal neobladder. Four months after the surgery, local recurrence was detected in the pelvis and therefore pembrolizumab was used. One week after its administration, the patient showed increased mucus in his urine. A computed tomography scan and cystoscopy revealed a fistula between the ileum and the neobladder. He subsequently underwent partial ileectomy and repair of the neobladder-ileum fistula. Pathology-diagnosed tumor response to pembrolizumab in the metastatic tumor showed predominant infiltration by lymphocytes, unlike that in the primary bladder cancer. The patient has shown complete response and no recurrence at 1 year after the beginning of treatment, and therapy is still continuing. Although many questions still remain regarding the treatment of G-CSF-producing bladder cancer, pathologic evaluation of the present case suggests that treatment with pembrolizumab may be one option for G-CSF-producing bladder cancer that has failed chemotherapy treatment, similar to non-G-CSF-producing bladder cancer.",
"affiliations": "Department of Urology, Gifu University Graduate School of Medicine.;Department of Urology, Gifu University Graduate School of Medicine.;Department of Urology, Gifu University Graduate School of Medicine.;Department of Urology, Gifu University Graduate School of Medicine.;Department of Urology, Gifu University Graduate School of Medicine.;Department of Urology, Gifu University Graduate School of Medicine.;Department of Pathology, Gifu University Hospital, Gifu, Japan.;Department of Urology, Gifu University Graduate School of Medicine.;Department of Urology, Gifu University Graduate School of Medicine.",
"authors": "Muramatsu-Maekawa|Yuka|Y|;Taniguchi|Tomoki|T|;Ito|Hiroki|H|;Nakane|Keita|K|;Kato|Taku|T|;Tsuchiya|Tomohiro|T|;Miyazaki|Tatsuhiko|T|;Koie|Takuya|T|;Mizutani|Kosuke|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016179:Granulocyte Colony-Stimulating Factor; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "43(4)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D061026:Programmed Cell Death 1 Receptor; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "134-138",
"pmc": null,
"pmid": "32080020",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pembrolizumab Treatment and Pathologic Therapeutic Evaluation for Granulocyte Colony-stimulating Factor-producing Bladder Cancer: A Case Report and Literature Review.",
"title_normalized": "pembrolizumab treatment and pathologic therapeutic evaluation for granulocyte colony stimulating factor producing bladder cancer a case report and literature review"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-241163",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "Severe oral mucositis as a complication of chemotherapy may lead to airway obstruction and require prolonged intubation. As its course is consistent with the course of neutropenia, airway management strategies should be determined individually.",
"affiliations": "Department of Critical Care Medicine National Center for Child Health and Development Tokyo Japan.;Department of Critical Care Medicine National Center for Child Health and Development Tokyo Japan.;Children's Cancer Center National Center for Child Health and Development Tokyo Japan.;Children's Cancer Center National Center for Child Health and Development Tokyo Japan.;Children's Cancer Center National Center for Child Health and Development Tokyo Japan.;Department of Critical Care Medicine National Center for Child Health and Development Tokyo Japan.;Department of Critical Care Medicine National Center for Child Health and Development Tokyo Japan.",
"authors": "Tsuboi|Kaoru|K|https://orcid.org/0000-0003-3633-3600;Tsuboi|Norihiko|N|;Sakamoto|Kenichi|K|;Takebayashi|Akira|A|;Tomizawa|Daisuke|D|;Nishimura|Nao|N|;Nakagawa|Satoshi|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4356",
"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/ccr3.4356\nCCR34356\nCase Report\nCase Reports\nLife‐threatening oral mucositis following chemotherapy in a pediatric patient\nTSUBOI et al.\nTsuboi Kaoru https://orcid.org/0000-0003-3633-3600\n1 shimizu-k@ncchd.go.jp\n\nTsuboi Norihiko 1\nSakamoto Kenichi 2\nTakebayashi Akira 2\nTomizawa Daisuke 2\nNishimura Nao 1\nNakagawa Satoshi 1\n1 Department of Critical Care Medicine National Center for Child Health and Development Tokyo Japan\n2 Children’s Cancer Center National Center for Child Health and Development Tokyo Japan\n* Correspondence\nKaoru Tsuboi, Department of Critical Care Medicine, National Center for Child Health and Development. 2‐10‐1 Okura, Setagaya‐ku, Tokyo, Japan.\nEmail: shimizu-k@ncchd.go.jp\n\n10 6 2021\n6 2021\n9 6 10.1002/ccr3.v9.6 e0435605 5 2021\n14 3 2021\n06 5 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\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\nAbstract\n\nSevere oral mucositis as a complication of chemotherapy may lead to airway obstruction and require prolonged intubation. As its course is consistent with the course of neutropenia, airway management strategies should be determined individually.\n\nSevere oral mucositis as a complication of chemotherapy may lead to airway obstruction and require prolonged intubation. As its course is consistent with the course of neutropenia, airway management strategies should be determined individually.\n\n\n\nchemotherapy\nMucositis\nneutropenia\npediatric\nupper airway obstruction\nsource-schema-version-number2.0\ncover-dateJune 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:10.06.2021\nTsuboi K , Tsuboi N , Sakamoto K , et al. Life‐threatening oral mucositis following chemotherapy in a pediatric patient. Clin Case Rep. 2021;9 :e04356. 10.1002/ccr3.4356\n==== Body\n1 INTRODUCTION\n\nMucositis is a common adverse event in pediatric patients receiving chemotherapy for hematological malignancies. 1 However, severe mucositis leading to upper airway obstruction is rare, and literature regarding this topic is scarce. It is an impending oncologic emergency and clinicians should be aware of the clinical course and management of this life‐threatening complication.\n\n2 CASE PRESENTATION\n\nA 10‐year‐old, 34 kg girl with no significant medical history was admitted with recently diagnosed acute myeloid leukemia. She was treated with etoposide 150 mg/m2/dose on days 1‐5, cytarabine 200 mg/m2/dose on days 6‐12, mitoxantrone 5 mg/m2/dose on days 6‐10, and triple intrathecal therapy on day 6 as induction therapy (JPLSG AML‐05 protocol 2 ). Following chemotherapy, her course was complicated by continued febrile neutropenia and oral mucositis.\n\nOn day 10, she started complaining of throat pain and dysphagia. Aphthous lesions covered with white coatings were found on her pharyngeal soft palate and buccal mucosa. On day 11, broad‐spectrum antibiotics including meropenem, teicoplanin, and caspofungin with granulocyte colony‐stimulating factor (G‐CSF) were initiated as she developed febrile neutropenia. As multiplex polymerase chain reaction proved positive for Herpes simplex viral infection, acyclovir was added. Continuous infusion of morphine was required for pain control, and total parenteral nutrition was initiated on day 13 as alimentation was significantly impaired. On day 18, stridor was heard on auscultation. The patient was unable to lie down because of dyspnea. On day 20, she was spitting out her sputum due to worsening throat pain and dysphagia. On day 24, the patient complained of further increasing throat pain and difficulty breathing. She was found sitting up in bed, leaning forward, drooling. Pan‐inspiratory stridor and mild effort of breathing were observed on physical examination. She was alert with her vital signs otherwise stable. Examination on nasolaryngoscopy revealed extensive desquamation of the oropharyngeal mucosa and multiple, confluent ulcerative lesions with significant edema extending down to the arytenoid cartilage (Figure 1). The patient was taken to the operating room for elective intubation with otolaryngology team on standby for tracheostomy placement. A size 5.0‐mm internal diameter endotracheal tube was successfully inserted by video laryngoscopy with anesthesia maintaining spontaneous ventilation.\n\nFIGURE 1 Nasolarygoscopy revealed significantly swollen, erythematous arytenoid cartilages with extensive desquamation\n\nThe patient was then transported to the pediatric intensive care unit. As infection being considered as an aggravating factor, antimicrobiotic agents and G‐CSF were continued, and granulocyte transfusion from paternal donor was attempted.\n\nOn day 28, she developed significant spontaneous bleeding from the gingiva and the oropharyngeal ulcers, resulting in hemorrhagic shock. Platelet transfusions and vasoconstrictors were warranted for resuscitation. Nasolaryngoscopy revealed further aggravation of the ulcerative lesions with active oozing and worsening edema of the oropharyngeal tissues showing complete obstruction of the retropharyngeal space. Packing of the oropharyngeal space was performed as electrocoagulation of bleeding vessels failed to control bleeding.\n\nSurgical tracheostomy was considered taking the above finding into account. After thorough discussion with the oncologists and the otolaryngologists, a decision was made to wait for resolution of neutropenia considering the elevated risk of procedure in the nadir phase and expected improvement of mucositis following recovery of neutrophil counts.\n\nOn day 29, absolute neutrophil count exceeded 500 /µL and G‐CSF was discontinued. Her bleeding was well controlled. On day 31, defervescence was achieved. On day 32, improvement of the ulcerative lesions and airway swelling was confirmed on nasolaryngoscopy. Adequate leakage around the endotracheal tube was verified. The patient was able to cough, swallow efficiently requiring minimum ventilatory support. Extubation was successful on first attempt. Repeated blood cultures obtained throughout her course were found to be negative. Her course after extubation was uneventful. The course of the patient's peripheral neutrophil cell counts, C‐reactive protein levels, and maximum body temperature is demonstrated in Figure 2.\n\nFIGURE 2 The course of peripheral neutrophil cell counts, C‐reactive protein, and maximum body temperature of the patient. Abbreviations are as follows. PNC: peripheral neutrophil cell, CRP: C‐reactive protein, BT: body temperature\n\n3 DISCUSSION\n\nOral mucositis (OM) is a common adverse event in patients receiving chemotherapy. Its clinical manifestation ranges from mild erythema and soreness to extreme pain and ulceration, significantly affecting patient's quality of life. It may also lead to treatment changes such as reduction of chemotherapy dosage, resulting in negative effect on treatment outcome. 3 Specific drug therapy has been associated with an increased risk of developing mucositis; etoposide is excreted in the saliva which increases its oral toxicity. 1 In rare cases, severe OM can result in significant edema of the upper airway leading to airway obstruction. 4\n\nPediatric patients are more prone to develop OM with increased severity. 5 Its prevalence is reported to exceed 90% among children under 12 years old receiving chemotherapy for hematological malignancies compared with 40% in the adult counterparts. 1 This has been attributed to the greater number of mitoses in the basal epithelium in younger patients, making the epithelial cells more vulnerable to cytotoxic effects. 6 The duration of OM in the pediatric population tends to be shorter reflecting their greater healing capacity. 6\n\nPediatric patients with severe OM are at greater risk of airway compromise due to their narrower airway. 6 The exact prevalence of upper airway complications in the pediatric patients following chemotherapy is unknown. One study reported that 10.5% of the pediatric patients following bone marrow transplantation required mechanical ventilation, of which upper airway obstruction due to mucositis accounted for 13%. 7\n\nTypically, OM develops 10‐14 days after initiation of chemotherapy and heals within 2‐4 weeks, consistent with the clinical course of neutropenia. 8 Neutropenia has been reported to play a key role in the development of OM. Severity of OM is associated with the degree of neutropenia, and resolution coincides with granulocyte recovery. 8 This is assumed to be a result of neutropenia leading to impaired mucosal defense and repair. 8\n\nManagement of OM is crucial as it provides a portal for potentially life‐threatening infection. 8 Previous studies have shown that the risk of infection increases with increasing grade of OM. 8 As most patients with OM develop neutropenic fever, broad‐spectrum beta‐lactam with combination of antifungal and antiviral agents is commonly used as a standard treatment to cover gram‐negative bacteria, Coagulase‐negative Streptococci, Streptococcus viridans, Candida albicans, and Herpes simplex. 6 , 9 , 10 However, fever remains unexplained in 30%‐50% of neutropenic patients with no evidence of infection. 11 Furthermore, fever persists for 4‐5 days or even longer in approximately 30% of cases despite adequate microbial treatment directed at bacteria and fungi. 11 In these cases, fever may not be necessarily related to infection and may be a manifestation of the inflammatory process contributed by the mucositis itself. 9 , 11 In a report examining patients receiving chemotherapy for treatment of acute leukemia, inflammation was shown to be correlated with the occurrence of mucositis. The inflammatory response is elicited by formation of reactive oxygen species due to DNA damage of the epithelial cells, followed by amplification of proinflammatory and inflammatory cytokine release triggered by various microbial motifs (Pathogen‐associated molecular patterns) released from invading microorganisms and damaged tissues (Damage‐associated molecular patterns) through the distorted mucosal barrier, manifesting systemic fever and further tissue damage. 11\n\nIn the current case, the patient remained febrile despite treatment with broad spectrum antibiotics, antifungal, and antiviral agents lacking evidence of infection. Regarding her prompt defervescence coinciding with recovery of mucositis, her fever may have been a manifestation of the inflammation of mucositis, irrelevant of infection. Currently, no guideline is provided regarding the use of G‐CSF on mucositis due to insufficient evidence. 12 Yet, the possibility of infection could not be discarded in this circumstance, and treatment with broad‐spectrum antimicrobials combined with G‐CSF was continued.\n\nRecently, several new strategies have been developed for the management of oral mucositis. The administration of palifermin, caphosol, and photobiomodulation (low‐level laser therapy) is reported to decrease the duration and severity of oral mucositis and seems to be a promising strategy though further studies are needed to confirm the results. 3\n\nIn the current case, the patient was successfully extubated following recovery of mucositis but required prolonged mechanical ventilation. Determination whether to perform tracheostomy in this case was difficult considering its reversible pathology.\n\nAirway management with intubation possesses a significant risk of complete airway obstruction and death in case of accidental extubation, mandating deep sedation (paralysis may be considered), and prolonged mechanical ventilation which significantly delays patient recovery.\n\nPlacement of a tracheostomy provides a secure airway and enables safe management of the patient with further advantages of improved patient comfort, reduced sedative requirements, and early patient recovery. Although surgical tracheostomy in the presence of severe immunosuppression and thrombocytopenia is not a contraindication, it may be associated with increased risk of surgical complications. Studies regarding this topic are scarce, especially in the pediatric population, and do not support a recommendation. 13 , 14 , 15\n\nThus, airway management in these patients must be determined prudently regarding the expected duration of neutropenia, weighting the risks and benefits on an individual case basis.\n\n4 CONCLUSION\n\nPediatric patients undergoing chemotherapy may require intubation and mechanical ventilation due to airway compromise as a complication. The clinical course of oral mucositis is consistent with the course of neutropenia and may require prolonged intubation. Determination of whether to perform tracheostomy in these circumstances is difficult due to the essentially reversible pathology of this complication. Thus, airway management of these patients should be determined on an individual case basis.\n\nCONFLICT OF INTEREST\n\nThe authors have no conflict of interest to declare.\n\nAUTHOR CONTRIBUTIONS\n\nKT: drafted and revised the initial manuscript. NT, KS, AT, DT, NN, and SN: critically revised the manuscript for important intellectual content. All authors: read and approved the final manuscript.\n\nETHICAL APPROVAL\n\nInformed consent was obtained from the patient and her parents for publication of this case report. Approval of the institutional ethics committee was obtained in advance to submission.\n\nACKNOWLEDGMENTS\n\nThe authors gratefully acknowledge the assistance of Dr Noriko Morimoto of the department of otolaryngology, National Center for Child Health and Development, for providing the laryngoscopy images. Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nResearch data are not shared.\n==== Refs\nREFERENCES\n\n1 Damascena LCL , de Lucena NNN , Ribeiro ILA , Pereira TL , Lima‐Filho LMA , Valença AMG . Severe oral mucositis in pediatric cancer patients: survival analysis and predictive factors. Int J Environ Res Public Health. 2020;17 :1235.\n2 Tomizawa D , Tawa A , Watanabe T , et al. Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children. Leukemia. 2013;27 :2413‐2416.23677335\n3 Kusiak A , Jereczek‐Fossa BA , Cichońska D , Alterio D . Oncological‐therapy related oral mucositis as an interdisciplinary problem‐literature review. Int J Environ Res Public Health. 2020;17 :2464.\n4 Chaimberg KH , Cravero JP . Mucositis and airway obstruction in a pediatric patient. Anesth Analg. 2004;99 :59‐61.15281504\n5 Walsh LJ . Clinical assessment and management of the oral environment in the oncology patient. Aust Dent J. 2010;55 :66‐77.20553247\n6 Raber‐Durlacher JE , Weijl NI , Abu Saris M , de Koning B , Zwinderman AH , Osanto S . Oral mucositis in patients treated with chemotherapy for solid tumors: a retrospective analysis of 150 cases. Support Care Cancer. 2000;8 :366‐371.10975685\n7 Drew B , Peters C , Rimell F . Upper airway complications in children after bone marrow transplantation. Laryngoscope. 2000;110 :1446‐1451.10983940\n8 McCann S , Schwenkglenks M , Bacon P , et al. The Prospective Oral Mucositis Audit: relationship of severe oral mucositis with clinical and medical resource use outcomes in patients receiving high‐dose melphalan or BEAM‐conditioning chemotherapy and autologous SCT. Bone Marrow Transplant. 2009;43 :141‐147.18776926\n9 Blijlevens NMA , Logan RM , Netea MG . Mucositis: from febrile neutropenia to febrile mucositis. J Antimicrob Chemother. 2009;63 :i36‐i40.19372181\n10 Blijlevens NM , Donnelly JP , de Pauw BE . Empirical therapy of febrile neutropenic patients with mucositis: challenge of risk‐based therapy. Clin Microbiol Infect. 2001;7 :47‐52.\n11 van der Velden WJ , Herbers AH , Netea MG , Blijlevens NM . Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol. 2014;167 :441‐452.25196917\n12 Raber‐Durlacher JE , von Bültzingslöwen I , Logan RM , et al. Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21 :343‐355.22987094\n13 Manna SS , Malik R , Douthwaite A , Vaidya S . Surgical tracheostomy in children with malignancy receiving intensive chemotherapy: A case series and review of literature. Pediatr Blood Cancer. 2020;67 :e28105.31876351\n14 Raimondi N , Vial MR , Calleja J , et al. Evidence‐based guidelines for the use of tracheostomy in critically ill patients. J Crit Care. 2017;38 :304‐318.28103536\n15 Blot F , Nitenberg G , Guiguet M , et al. Safety of tracheotomy in neutropenic patients: a retrospective study of 26 consecutive cases. Intensive Care Med. 1995;21 :687‐690.8522676\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(6)",
"journal": "Clinical case reports",
"keywords": "Mucositis; chemotherapy; neutropenia; pediatric; upper airway obstruction",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e04356",
"pmc": null,
"pmid": "34136255",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
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"title": "Life-threatening oral mucositis following chemotherapy in a pediatric patient.",
"title_normalized": "life threatening oral mucositis following chemotherapy in a pediatric patient"
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"abstract": "Pseudomyogenic hemangioendothelioma (PMH) is a rare neoplasm with vascular and sarcomatous elements, unpredictable course, and uncommon metastatic or fatal potential. Although systemic chemotherapy has been reported with variable success, generally accepted treatment is aggressive surgery with wide margins. Evidence-based treatment options are lacking, and lack of clear prognostic features poses a risk of undertreatment or overtreatment with associated morbidity and mortality. We report the use of initial systemic therapy with oral sirolimus (SIR) and IV zoledronic acid (ZA) to induce a sustained clinical response and avoidance of amputation in a 6-year-old boy. At 37 months after diagnosis, our patient remains in sustained clinical remission as documented by x-ray, MRI, and PET-CT with return of normal mobility/activity and resolution of swelling and pain. Literature review identified 20 cases of pediatric and young adult patients with PMH, of which 7 received some form of systemic therapy. To the best of our knowledge, our patient represents the youngest reported case of PMH and the first successful and limb-sparing utilization of systemic chemotherapy as primary treatment for PMH.",
"affiliations": "Family Medicine Residency Program, Samaritan Health Services, Corvalis, OR.;Rush University Medical Center.;Rush University Medical Center.;Morrissey College of Arts and Science, Boston College, Chestnut Hill, MA.;Departments of Pathology.;Radiology.;Diagnostic Radiology and Nuclear Medicine.;Radiology.;Pediatric Hematology-Oncology, Rush University Medical Center, Chicago, IL.",
"authors": "Danforth|Olivia M|OM|;Tamulonis|Karen|K|;Vavra|Kimberly|K|;Oh|Caleb|C|;Brickman|Arlen|A|;Ebersole|John|J|;Cameron|James|J|;Mahon|Brett|B|;Kent|Paul|P|",
"chemical_list": "D000077211:Zoledronic Acid; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001459",
"fulltext": null,
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"issn_linking": "1077-4114",
"issue": "41(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D001859:Bone Neoplasms; D002648:Child; D006390:Hemangioendothelioma; D006801:Humans; D008297:Male; D064847:Multimodal Imaging; D020123:Sirolimus; D000077211:Zoledronic Acid",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "382-387",
"pmc": null,
"pmid": "31094908",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effective Use of Sirolimus and Zoledronic Acid for Multiosteotic Pseudomyogenic Hemangioendothelioma of the Bone in a Child: Case Report and Review of Literature.",
"title_normalized": "effective use of sirolimus and zoledronic acid for multiosteotic pseudomyogenic hemangioendothelioma of the bone in a child case report and review of literature"
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"abstract": "BACKGROUND\nA serious complication of intravenous tissue plasminogen activator (tPA) in acute ischemic stroke is hemorrhage. Coagulation factors that may potentially increase the risk of bleeding after tPA are not well understood.\n\n\nMETHODS\nWe retrospectively reviewed 284 acute ischemic stroke patients who received tPA. Post-tPA coagulopathy was defined as a documented elevation of international normalized ration (INR) > 1.5 within 24 hours after IV tPA without a known cause.\n\n\nRESULTS\nWe identified 21 (7.4%) patients with an elevated INR post-thrombolysis. The mean age was 68.3 years (standard deviation ± 11.9) and 57% were male. The mean initial National Institutes of Health Stroke Scale (pre-tPA) was 15.8 (range, 4-35). Liver disease or alcohol abuse was noted in 19%. There were 2 tPA protocol violations who received more than 90 mg tPA. The mean post-tPA INR was 2.03 (range, 1.5-4.7) and the elevation in INR was documented within a mean 5.4 hours (range, 1-15) after tPA initiation. Repeat INR levels returned to normal during their hospital stay in 19 patients. Hypofibrinogenemia was noted in 10 of 12 patients who had fibrinogen levels drawn within 48 hours after tPA initiation and in all 7 patients with fibrinogen levels drawn the same time as the elevated INR. Among the 6 patients with bleeding complications, 2 patients had symptomatic intracerebral hemorrhage.\n\n\nCONCLUSIONS\nWe report an under-recognized early transient coagulopathy associated with elevated INR in stroke patients after treatment with tPA.",
"affiliations": "Department of Neurological Sciences, Section of Cerebrovascular Disease, Rush University Medical Center, Chicago, Illinois. Electronic address: Vivien_lee@rush.edu.;Department of Neurological Sciences, Section of Cerebrovascular Disease, Rush University Medical Center, Chicago, Illinois.;Department of Neurological Sciences, Section of Cerebrovascular Disease, Rush University Medical Center, Chicago, Illinois.;Department of Neurological Sciences, Section of Cerebrovascular Disease, Rush University Medical Center, Chicago, Illinois.;Department of Neurology, Northwestern University, Chicago, Illinois.;Department of Neurology, Northwestern University, Chicago, Illinois.",
"authors": "Lee|Vivien H|VH|;Conners|James J|JJ|;Cutting|Shawna|S|;Song|Sarah Y|SY|;Bernstein|Richard A|RA|;Prabhakaran|Shyam|S|",
"chemical_list": "D001779:Blood Coagulation Factors; D005343:Fibrinolytic Agents; D005340:Fibrinogen; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2014.03.021",
"fulltext": null,
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"issn_linking": "1052-3057",
"issue": "23(8)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Coagulopathy; acute stroke; tPA; thrombolysis",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001779:Blood Coagulation Factors; D002543:Cerebral Hemorrhage; D042241:Early Diagnosis; D005260:Female; D005340:Fibrinogen; D005343:Fibrinolytic Agents; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "9111633",
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"pmid": "25081309",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Elevated international normalized ratio as a manifestation of post-thrombolytic coagulopathy in acute ischemic stroke.",
"title_normalized": "elevated international normalized ratio as a manifestation of post thrombolytic coagulopathy in acute ischemic stroke"
} | [
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"abstract": "Our patient is a 67-year-old male with a past medical history significant for hypertension and hyperlipidemia came to a hospital with hemoptysis. He was also having cough and shortness of breath for the last 1 month. He said that his hemoptysis was about 1 cup per day mixed with yellowish sputum. He noticed around 20 pounds of weight loss in the last 1 month. He also complained of night sweats but had no fever. He had no history of travel outside the USA. He has never been incarcerated before, but he endorsed that his son has been to Jail before and he visited him twice a year in patient's home. But he also said that his son has never been diagnosed with TB. He smoked 1.5 packs per day for the last 50 years and quit smoking 2 months ago. His medication include hydrochlorothiazide, lisinopril, gabapentin, aspirin and trazodone. On examination, vital signs were within the normal range except a hearty rate of 106 beats/minute. He had slightly pale conjunctiva, non-icteric sclera and had wet tongue and buccal mucosa. There was decreased air entry with crepitations in the right side of the posterior chest but no wheezes or rales. No peripheral lymphadenopathy, no peripheral edema or sign of fluid collection in the abdomen. Chest x ray showed multiple cavitary lesion in the right upper lobe area. CT scan of the chest with PE protocol showed pulmonary venous partial thrombosis in the right upper lobe. Multiple cavitary lesions with hilar and mediastinal lymphadenopathy. There are also smaller nodular lesions in the left chest too. Small right pleural effusion with multiple calcified granulomata in the left upper lobe. QuantiFERON gold test was found to be positive. Sputum AFB smear was found to be strongly positive and it is sensitive to rifampin. Echocardiography showed no valvular lesions with preserved ejection fraction (>65%) and normal right ventricular size and normal right ventricular systolic pressure. Liver enzymes and renal function tests were found within the normal limit. HIV test was negative. Patient was started with intensive phase anti-tuberculosis treatment with rifampin, isoniazid, ethambutol, pyrazinamide with vitamin B6. He was also started with anticoagulation with heparin and warfarin considering the tuberculosis being the cause of the pulmonary vein thrombosis. Patient was also given supportive treatment and he made a gradual improvement and was discharged with anti-tuberculosis treatment and warfarin. Patient needed to be placed on a higher dose of warfarin as it was difficult to keep him therapeutic with lower doses. He was also advised to follow with infectious disease and anticoagulation clinic. Patient was found to have a significant increase in liver enzymes and bilirubin on follow up and the anti-TB medications were stopped to be restarted one by one with a follow up of his liver enzymes and liver function tests. He was also continued with warfarin.",
"affiliations": "Internal Medicine Resident, Marshall University School of Medicine, Huntington, WV, USA.;Internal Medicine Resident, Marshall University School of Medicine, Huntington, WV, USA.;Pulmonary and Critical Care Medicine, Marshall University School of Medicine, Huntington, WV, USA.;Department of Internal Medicine, Marshall University School of Medicine and Huntington VAMC, Huntington, WV, USA.",
"authors": "Raru|Yonas|Y|;Abouzid|Mahmoud|M|;Zeid|Fuad|F|;Teka|Samson|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2018.11.020",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30368-X10.1016/j.rmcr.2018.11.020Case ReportPulmonary vein thrombosis secondary to tuberculosis in a non-HIV infected patient Raru Yonas raru@marshall.edua∗Ballengee Jason aAbouzid Mahmoud aZeid Fuad bTeka Samson ca Internal Medicine Resident, Marshall University School of Medicine, Huntington, WV, USAb Pulmonary and Critical Care Medicine, Marshall University School of Medicine, Huntington, WV, USAc Department of Internal Medicine, Marshall University School of Medicine and Huntington VAMC, Huntington, WV, USA∗ Corresponding author. raru@marshall.edu05 12 2018 2019 05 12 2018 26 91 93 25 11 2018 28 11 2018 28 11 2018 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tuberculosis has been suggested as an independent risk factor for thromboembolism due to a hypercoagulable state induced by changes in clotting factors, protein C and vascular endothelium. Pulmonary vein thrombosis (PVT) is a rare, potentially serious and life-threatening condition that can be caused by tuberculosis. Its rare occurrence is due to a rich network of venous collateral vessels that drain the lung. PVT can also occur following lobectomy for malignancy, lung transplantation, radiofrequency catheter ablation for atrial fibrillation, sclerosing mediastinitis and following metastatic cancer, such as liposarcoma. Pulmonary vein thrombosis is difficult to diagnose clinically and requires a combination of conventional diagnostic modalities. Systemic anticoagulation, treatment of the predisposing pathology and monitoring of the thrombosis are parts of management of pulmonary vein thrombosis. We present a case of pulmonary vein thrombosis due to tuberculosis. Our patient is a 67-year-old Caucasian male with a past medical history significant for hypertension and hyperlipidemia who came to our hospital with hemoptysis, cough and shortness of breath 1-month duration. He also noticed around 20 pounds of weight loss and night sweats but had no fever. He had no history of travel outside the USA and has never been incarcerated before, but he endorsed that his son has been in Jail before but the son has never been diagnosed with TB. He quit smoking 2 months ago. He was tachycardic, tachypneic and had decreased air entry with crepitation in the right side of the posterior chest. Chest x ray showed multiple cavitary lesions in the right upper lobe area. CT scan of the chest with contrast showed pulmonary venous partial thrombosis in the right upper lobe with multiple cavitary lesions with hilar and mediastinal lymphadenopathy. Sputum AFB was positive for mycobacterium tuberculosis and was sensitive for rifampicin. Patient was treated with systemic anticoagulation and anti-tuberculosis medications. Patient’s hospital course was complicated by development of elevated liver enzymes at which time the anti-TB medications were stopped to be restarted one by one with a follow up of his liver enzymes and liver function tests. Our case shows that presentation of patients with PVT is non-specific and needs a very high index of suspicion for proper diagnosis and management to prevent further complications as it is associated with limb and life-threatening complications. It also illustrates the importance of considering PVT in a patient with tuberculosis.\n==== Body\n1 Introduction\nAbout 30 percent of the world population are estimated to be infected with mycobacterium tuberculosis [[1], [2], [3]]. Tuberculosis has been suggested as an independent risk factor for thromboembolism due to a hypercoagulable state induced by changes in clotting factors, protein C and vascular endothelium [4,5]. Pulmonary vein thrombosis (PVT) is a rare, potentially serious and life-threatening condition that can be caused by tuberculosis. Its rare occurrence is due to a rich network of venous collateral vessels that drain the lung [[6], [7], [8]]. PVT can also occur following lobectomy for malignancy, lung transplantation, radiofrequency catheter ablation for atrial fibrillation, sclerosing mediastinitis and following metastatic cancer, such as liposarcoma [[9], [10], [11]]. Pulmonary vein thrombosis is difficult to diagnose clinically and requires a combination of conventional diagnostic modalities. Systemic anticoagulation, treatment of the predisposing pathology and monitoring of the thrombosis are parts of management of pulmonary vein thrombosis [8]. We present a case of pulmonary vein thrombosis due to tuberculosis.\n\n2 Case presentation\nOur patient is a 67-year-old male with a past medical history significant for hypertension and hyperlipidemia who came to our hospital with hemoptysis. He was also having cough and shortness of breath for the last 1 month. He said that his hemoptysis was about 1 cup per day mixed with yellowish sputum. He noticed around 20 pounds of weight loss in the last 1 month. He also complained of night sweats but had no fever. He had no history of travel outside the USA. He has never been incarcerated before, but he endorsed that his son has been in Jail before and he visited him twice a year in patient's home. But he also said that his son has never been diagnosed with TB. He smoked 1.5 packs per day for the last 50 years and quit smoking 2 months ago. His medication includes hydrochlorothiazide, lisinopril, gabapentin, aspirin and trazodone. On examination, vital signs were within the normal range except a heart rate of 106 beats/minute. He had slightly pale conjunctiva, non-icteric sclera and had wet tongue and buccal mucosa. There was decreased air entry with crepitations in the right side of the posterior chest but no wheezes or rales. No peripheral lymphadenopathy, no peripheral edema or sign of fluid collection in the abdomen.\n\nChest x ray (Fig. 1) showed multiple cavitary lesion in the right upper lobe area. CT scan of the chest with contrast (Fig. 2, Fig. 3) showed pulmonary venous partial thrombosis in the right upper lobe. Multiple cavitary lesions with hilar and mediastinal lymphadenopathy. There are also smaller nodular lesions in the left chest too. Small right pleural effusion with multiple calcified granulomata in the left upper lobe. QuantiFERON gold test was found to be positive. Sputum AFB smear was found to be strongly positive and it is sensitive to rifampin. Echocardiography showed no valvular lesions with preserved ejection fraction (>65%) and normal right ventricular size and normal right ventricular systolic pressure. Liver enzymes and renal function tests were found within the normal limit. HIV test was negative. Patient was started with intensive phase anti-tuberculosis treatment with rifampin, isoniazid, ethambutol, pyrazinamide with vitamin B6. He was also started with anticoagulation with heparin and warfarin considering the tuberculosis being the cause of the pulmonary vein thrombosis. Patient was also given supportive treatment and he made a gradual improvement and was discharged with anti-tuberculosis treatment and warfarin. Patient needed to be placed on a higher dose of warfarin as it was difficult to keep him therapeutic with lower doses. He was also advised to follow with infectious disease and anticoagulation clinic. Patient was found to have a significant increase in liver enzymes and bilirubin on follow up and the anti-TB medications were stopped to be restarted one by one with a follow up of his liver enzymes and liver function tests. He was also continued with warfarin.Fig. 1 Chest X ray.\n\nFig. 1Fig. 2 CT scan showing the pulmonary vein thrombosis.\n\nFig. 2Fig. 3 CT scan picture showing the TB lesions and pulmonary vein thrombosis.\n\nFig. 3\n\n3 Discussion\nMore than two billion people, about 30 percent of the world population, are estimated to be infected with mycobacterium tuberculosis. The global incidence of tuberculosis (TB) peaked around 2003 and appears to be declining slowly. According to the World Health Organization (WHO), in 2016, 10.4 million individuals became ill with TB and 1.7 million died [1]. Poverty, human immunodeficiency virus (HIV), and drug resistance are major contributors to the resurging global TB epidemic. Approximately 95 percent of TB cases occur in developing countries (2). Around 70% of TB cases in the United States now occurs in foreign-born individuals emigrating from countries with high rates of endemic TB [3]. Tuberculosis, both pulmonary and extrapulmonary, has been suggested as an independent risk factor for venous thromboembolism (VTE), perhaps due to a hypercoagulable state.\n\nIn one retrospective study including 3485 cases of active TB, the prevalence of VTE was approximately 2 percent, which is similar to the rate associated with malignancy and approximately 100 times higher than the incidence of VTE among hospitalized patients in general [4,5]. Previous studies have shown that there is high level of plasma fibrinogen with impaired fibrinolysis, low level of antithrombin III and protein C which induce a hypercoagulable state and thus more thrombosis. It has also been shown that there is significant decrease of prothrombin levels in one third of tuberculosis patients which also further exposes TB patients to thrombosis [8,9]. The other theory suggested in literature as to the cause of thrombosis in TB is the cytokine theory where cytokines are proinflammatory and activate the vascular intima and make the endothelium more thrombogenic [9]. Some authors have postulated that various local factors may lead to thrombosis such as from venous compression by lymph nodes, as mediastinal and retroperitoneal lymphadenopathies may cause chest or inferior vena cava thrombosis in the absence of any hemostatic abnormalities. However, there are also literatures suggesting that systemic rather than local factors play a predominant role [6]. There are case reports on different types of thrombosis in literature related to tuberculosis including extremity deep venous thrombosis, portal vein thrombosis, hepatic vein thrombosis and superior sagittal vein thrombosis [[10], [11], [12]]. Our patient presented with pulmonary vein thrombosis with a newly diagnosed tuberculosis. Pulmonary vein thrombosis is a rare condition. The incidence is unclear, as most of the literature includes case reports. The majority of cases are reported following lobectomy for malignancy, lung transplantation, radiofrequency catheter ablation for atrial fibrillation, sclerosing mediastinitis and following metastatic cancer, such as liposarcoma. Idiopathic cases of pulmonary vein thrombosis are also described in a literature. Most patients with PVT are commonly asymptomatic or have nonspecific symptoms such as cough, hemoptysis, and dyspnea from pulmonary edema or infarction. In majority of cases, pulmonary artery pressure increases concomitant with systemic hypotension and low cardiac output. Respiratory parameters also deteriorate, including worsening oxygenation, hypercapnia, and decreasing pulmonary compliance. Our patient presented with mild hemoptysis and shortness of breath but didn't have any hemodynamic abnormality other than a tachycardia of 106 beats per minute [8]. Our patient also didn't have an increase in pulmonary artery pressure. This can be explained by the partial nature of pulmonary vein obstruction seen in our patient. He was also having cough with yellowish sputum.\n\nThe coexistence of tuberculosis and pulmonary vein thrombosis in our patient will make it very difficult to say that a symptom is caused by TB or PVT as it could also be the other one causing the same symptom. One case report in literature described a presentation of tuberculosis with pulmonary vein thrombosis with atrial extension which we didn't see in our patient [13]. Post-operative, Malignancy and radiofrequency catheter ablation related pulmonary vein thromboses have a dramatic presentation with hemodynamic instability and it requires prompt diagnosis and intervention due to high mortality. The relatively stable presentation of our patient is due to the incomplete obstruction and the fact that the patient might have presented early, and this type of non-specific presentation needs a high index of suspicion for the condition and proper investigation and management to prevent further complications. Pulmonary vein thrombosis is difficult to diagnose clinically and requires a combination of conventional diagnostic modalities. Pulmonary venous phase of a contrast CT of the chest is used to diagnose pulmonary vein thrombosis and our patient was diagnosed while undergoing a contrast CT scan. In literature, a trans esophageal echocardiogram (TEE) can also be used to diagnose it and TEE may demonstrate extension of a thrombus into the atrium if it is present. In malignancy associated pulmonary vein thrombosis, Magnetic resonance imaging of the chest is a useful modality for diagnosis, because it is able to distinguish between a bland thrombus and a tumor thrombus in the pulmonary vein [[6], [7], [8]]. Treatment of PVT depends on the overall clinical condition and comorbidity of the patient. There are no consensus guidelines on optimal management of PVT, but anticoagulation is very important even if there is no preferred duration and type of anticoagulant. It was also noticed in literatures that treating the underlying pathology whether it was post-operative, tuberculosis, or malignancy may lead to favorable outcomes in the pulmonary vein thrombosis. In some cases of postoperative patients in whom anticoagulant was contraindicated, spontaneous lysis of small, untreated thrombi without sequelae was observed. Thrombectomy has been successfully performed when medical therapy fails. Lobectomy may be indicated when PVT is complicated with massive hemoptysis or pulmonary necrosis [6,8,14]. Our patient was started with treatment with anti-tuberculosis medications and systemic anticoagulation. He responded to the treatment very well but developed elevated liver enzymes secondary to the anti-TB medications. The medications were discontinued to be restarted one by one when the liver enzymes improve. Our patient was started with heparin and warfarin and once he was therapeutic (INR = 2–3), he was continued with warfarin.\n\nHe needed a higher daily dose of warfarin (10mg) because of the effect of rifampin on warfarin metabolism. Complications that can occur after PVT include pulmonary infarction, pulmonary edema and right ventricular failure. Peripheral embolism was also seen in literature including limb ischemia, stroke, and renal infarction. Because of these life and limb threatening complications, waiting for spontaneous lysis is very risky and it is suggested to put patients on systemic anticoagulation and monitoring of the thrombus size in the coming months [8].\n\n4 Conclusion\nTuberculosis, both pulmonary and extrapulmonary, has been suggested as an independent risk factor for thromboembolism due to a hypercoagulable state induced by changes in clotting factors, protein C and vascular endothelium. Pulmonary vein thrombosis can be seen in patients with tuberculosis, lung transplantation, malignancy and post radiofrequency catheter ablation. Presentation of patients is non-specific and needs a very high index of suspicion for proper diagnosis and management to prevent further complications. Contrast enhanced CT and trans esophageal echocardiogram are important for confirming the diagnosis and evaluate atrial extension. Pulmonary vein thrombosis is associated with limb and life-threatening complications and needs early detection and treatment to prevent these complications. Systemic anticoagulation, treatment of the predisposing pathology and monitoring of the thrombosis are parts of management of pulmonary vein thrombosis.\n\nConflict of interest\nThe authors have no conflict of interest.\n==== Refs\nReferences\n1 World Health Organization Global Tuberculosis Report 2017 \n2 Corbett E.L. Marston B. Churchyard G.J. De Cock K.M. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment Lancet 367 2006 926 16546541 \n3 Stewart R.J. Tsang C.A. Pratt R.H. Tuberculosis - United States, 2017 MMWR Morb. Mortal. Wkly. Rep. 67 2018 317 29565838 \n4 Dentan C. Epaulard O. Seynaeve D. Active tuberculosis and venous thromboembolism: association according to international classification of diseases, ninth revision hospital discharge diagnosis codes Clin. Infect. Dis. 58 2014 495 24280089 \n5 Heit J.A. Melton L.J. 3rd Lohse C.M. Incidence of venous thromboembolism in hospitalized patients vs community residents Mayo Clin. Proc. 76 2001 1102 11702898 \n6 Bansal S. Utpat K. Joshi J.M. Systemic thrombosis due to pulmonary tuberculosis Natl. Med. J. India 30 2017 201 202 29162752 \n7 Akiode O. Prakash G. Pulmonary vein thrombosis associated with metastatic carcinoma Fed. Pract. 31 2014 26 28 \n8 Chaaya G. Vishnubhotla P. Pulmonary vein thrombosis: a recent systematic review Muacevic A. Adler J.R. Cureus vol. 9 2017 e993 (1) \n9 Sharma A. Sharma V. Abdominal aortic thrombosis and tuberculosis: an uncommon association Gastroenterol. Rep. (Oxf.) 2 2014 311 312 24759354 \n10 Ambrosetti M. Ferrarese M. Codecasa L.R. Besozzi G. Sarassi A. Viggiani P. AIPO/SMIRA TB Study Group. Incidence of venous thromboembolism in tuberculosis patients Respiration 73 2006 396 16439829 \n11 Fiorot Júnior J.A. Felício A.C. Fukujima M.M. Rodrigues C.A. Morelli V.M. Lourenço D.M. Tuberculosis: an uncommon cause of cerebral venous thrombosis? Arq. Neuropsiquiatr. 63 3B 2005 852 854 16258669 \n12 Fullerton D.G. Shrivastava A. Munavvar M. Jain S. Howells J. Macdowall P. Pulmonary tuberculosis presenting with central retinal vein occlusion Br. J. Ophthalmol. 91 2007 1714 1715 18024819 \n13 Wu J.P. Wu Q. Yang Y. Du Z.Z. Sun H.F. Idiopathic pulmonary vein thrombosis extending to left atrium: a case report with a literature review Chin. Med. J. (Engl.) 125 2012 1197 1200 22613556 \n14 Alexander G.R. Reddi A. Reddy D. Idiopathic pulmonary vein thrombosis: a rare cause of massive hemoptysis Ann. Thorac. Surg. 88 2009 281 283 19559247\n\n",
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"title": "Pulmonary vein thrombosis secondary to tuberculosis in a non-HIV infected patient.",
"title_normalized": "pulmonary vein thrombosis secondary to tuberculosis in a non hiv infected patient"
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"abstract": "Gastrointestinal tract cancers are highly lethal malignancies with early metastatic dissemination. Chemotherapy is therefore of crucial importance in advanced cancer for obtaining palliation of symptoms and improving survival. However, there is no universal standard chemotherapy regimen for the treatment of gastroesophageal cancer. Also, complete remission is an uncommon outcome in advanced gastroesophageal cancers treated with chemotherapy; and where encountered, the response is not sustained. We present a 65 year-old patient who presented with advanced gastric adenocarcinoma. She had histopathologically proven liver metastases. She was treated with chemotherapy comprising of six cycles of Docetaxel, Oxaliplatin and Capecitabine (DOX). She showed complete remission with disappearance of local as well as liver lesions, and achieved disease free status for 9 months. This is the first known sustained Complete Response in a case of advanced gastric carcinoma with DOX combination regimen.",
"affiliations": "Department of Internal Medicine, Montefiore Medical Center, 600 E 233rd Street, Bronx, New York, 10470, USA. Email: gaugoel@hotmail.com.",
"authors": "Goel|Gaurav|G|",
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"fulltext": "\n==== Front\nWorld J OncolWorld J OncolElmer PressWorld Journal of Oncology1920-45311920-454XElmer Press 10.4021/wjon469wCase ReportLong Term Complete Remission in Advanced Gastric Adenocarcinoma With Docetaxel, Oxaliplatin and Capecitabine Combination Regimen Remission in Advanced Gastric AdenocarcinomaGoel Gaurav Department of Internal Medicine, Montefiore Medical Center, 600 E 233rd Street, Bronx, New York, 10470, USA. Email: gaugoel@hotmail.com6 2012 05 7 2012 3 3 124 126 14 2 2012 Copyright 2012, Goel2012This 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.Gastrointestinal tract cancers are highly lethal malignancies with early metastatic dissemination. Chemotherapy is therefore of crucial importance in advanced cancer for obtaining palliation of symptoms and improving survival. However, there is no universal standard chemotherapy regimen for the treatment of gastroesophageal cancer. Also, complete remission is an uncommon outcome in advanced gastroesophageal cancers treated with chemotherapy; and where encountered, the response is not sustained. We present a 65 year-old patient who presented with advanced gastric adenocarcinoma. She had histopathologically proven liver metastases. She was treated with chemotherapy comprising of six cycles of Docetaxel, Oxaliplatin and Capecitabine (DOX). She showed complete remission with disappearance of local as well as liver lesions, and achieved disease free status for 9 months. This is the first known sustained Complete Response in a case of advanced gastric carcinoma with DOX combination regimen.\n\nComplete remissionGastric cancerDocetaxelOxaliplatinCapecitabine\n==== Body\nIntroduction\nCancers of the upper gastrointestinal (GI) tract are highly lethal malignancies with propensity for early metastatic dissemination [1]. Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer death worldwide [2]. Chemotherapy is therefore of crucial importance in advanced gastroesophageal cancer patients in order to obtain palliation of symptoms and improve survival. Single agents with activity in advanced gastric cancer include 5-fluorouracil (5FU), cisplatin, the anthracyclines- doxorubicin and epirubicin, mitomycin C, etoposide; all associated with modest response rates of short duration and infrequent complete responses [3]. Various combinations of these agents have been tried to improve upon these results. However, no single regimen has proclaimed precedence over the others, and currently there is no universal standard regimen for the treatment of gastroesophageal cancer [4]. Data from several phase II trials suggest that complete remission (CR) is an uncommon outcome in advanced gastroesophageal cancers treated with chemotherapy. The V325 phase III trial of docetaxel, cisplatin and 5FU (DCF) in gastric cancer showed CR in 4 (2%) patients (n = 221) [5]. Moreover, in cases where CR is encountered, the response is not sustained. Thus, new treatment protocols are warranted to achieve better disease control. We document a sustained complete remission with docetaxel, oxaliplatin and capecitabine (DOX) combination regimen in a case of advanced gastric carcinoma.\n\nCase Report\nA 65-year-old postmenopausal woman presented in May 2007 with vomiting, early satiety and 20 lbs weight loss over last 2 months. There was no history of associated fever, cough, bleeding from any site, and the family history was also insignificant. On examination, pallor was present. However, no icterus, edema or lymphadenopathy was noted. Detailed systemic examination revealed no abnormality. Investigations revealed mild anemia (Hb 9.8 g/dL) and elevated alkaline phosphatase levels (310 U/L). Esophagogastroduodenoscopy (EGD) showed large ulcerated lesion at the fundus, extending into the esophagus. CECT abdomen showed mass lesion in gastric cardia extending to involve the gastroesophageal junction and fundus, with compression of fat planes and wall thickness of 44 mm. There were multiple space occupying lesions (SOLs) in the right lobe of liver, the largest measuring 4.3 x 3.1 cm (Fig. 1). Tissue specimens from endoscopic biopsy (gastric region) and CT guided FNAC of liver showed moderately differentiated adenocarcinoma. Hence, a diagnosis of gastric carcinoma with liver metastases was made. Tumor markers - CEA and CA 72.4 levels were 1.7ng/mL and 0.99 U/mL respectively. The patient was then started on chemotherapy regimen consisting of docetaxel, oxaliplatin and capecitabine (DOX). Docetaxel was administered as 25 mg/m2 followed by oxaliplatin 50 mg/m2 on days 1 and 8, with capecitabine 625 mg/m2 BID from days 1 to 14, in 21-day cycles. The protocol was well tolerated by the patient except for grade 2 hematologic toxicity, which responded to blood product transfusions, erythropoietin and G-CSF. Patient also experienced diarrhea, managed with supportive therapy. A thorough workup done was after 3 and 6 cycles of chemotherapy to evaluate the response. Investigations at the end of 6 cycles of chemotherapy (November 2007) showed decreased gastric lesion, with a wall thickness of 8 mm on CT abdomen (Fig. 2); the particular liver lesion also decreased in size to 1.3 x 1.1 cm. EGD revealed few small erosions in fundus near the gastroesophageal junction, no ulcer or growth was seen. CT abdomen done 3 months later (February 2008) showed complete absence of gastric and liver lesions (Fig. 3). This patient responded dramatically to the chemotherapy protocol, as evidenced by > 50% decrease in the size of gastric and liver lesions after 6 cycles of chemotherapy, and complete disappearance of the lesions after further 3 months. Hence the patient’s clinical response to chemotherapy was labeled as CR. The patient continued to maintain CR for about 9 months, since the initial response.\n\nFigure 1 Disease status at the time of diagnosis. Gastric cancer with gastric wall thickness of 44 mm (left), Liver metastases (right).\n\nFigure 2 Disease status after 6 cycles of chemotherapy. Gastric cancer with gastric wall thickness of 8 mm.\n\nFigure 3 Disease status at 9 months after diagnosis. Complete disappearance of gastric and liver lesions.\n\nDiscussion\nPalliative systemic chemotherapy is more beneficial as compared to supportive care alone for patients with advanced gastric cancer [6]. Cytotoxic chemotherapy can provide symptom palliation, improve quality of life, and prolong survival in these patients. Meta-analysis has shown that combination chemotherapy regimens provide higher response rates including CR than do single agents [7]. Despite a large number of randomized trials, there is no consensus as to the best regimen. The combination of cisplatin plus 5-FU has been one of the most commonly used regimens in both metastatic and localized gastric cancer due to its activity and well-established toxicity profile. The V325 trial showed that addition of docetaxel to cisplatin-5FU resulted in increases in the CR [5]. It established a role for docetaxel in the treatment of advanced gastroesophageal cancer. However, DCF has significant toxicity, tolerability issues and needs ambulatory infusion pump. Cunningham et al. in a randomized, phase 3 study showed that for advanced esophagogastric cancer, oral capecitabine and oxaliplatin are non-inferior to infused fluorouracil and cisplatin respectively [8].\n\nWith this background, we modified the efficacious, albeit toxic DCF regimen, by replacing cisplatin with oxaliplatin and 5FU with capecitabine, to make it more tolerable and easier to administer while maintaining efficacy. The rationale for combining docetaxel with capecitabine is the synergism between the two, as docetaxel upregulates thymidine phosphorylase enzyme in the tumor cells. This enzyme is responsible for conversion of capecitabine to its active metabolite, 5-FU that kills cancer cells [9]. DOX regimen therefore utilizes the promising activity of all 3 agents against gastroesophageal cancer. The Brown University Oncology Group has conducted a phase I trial to study this combination of DOX in patients with metastatic esophageal and gastric cancer [10]. Goel et al. have studied the DOX combination regimen in this patient population and demonstrated CR in 3 (14%) patients (n = 21) [11]. Our patient achieved CR post 6-cycles and continued to maintain remission for about 9 months. To conclude, the regimen of docetaxel, oxaliplatin, and capecitabine is a promising, well tolerated chemotherapy regimen in advanced gastroesophageal cancer, and merits further evaluation.\n==== Refs\nReferences\n1 Jemal A Siegel R Ward E Hao Y Xu J Thun MJ Cancer statistics, 2009 CA Cancer J Clin 2009 59 4 225 249 10.3322/caac.20006 19474385 \n2 Parkin DM Bray F Ferlay J Pisani P Global cancer statistics, 2002 CA Cancer J Clin 2005 55 2 74 108 10.3322/canjclin.55.2.74 15761078 \n3 Shah MA Schwartz GK Treatment of metastatic esophagus and gastric cancer Semin Oncol 2004 31 4 574 587 10.1053/j.seminoncol.2004.04.013 15297948 \n4 Ajani JA Evolving chemotherapy for advanced gastric cancer. Oncologist 2005 10 Suppl 3 49 58 16368871 \n5 Van Cutsem E Moiseyenko VM Tjulandin S Majlis A Constenla M Boni C Rodrigues A et al Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group J Clin Oncol 2006 24 31 4991 4997 10.1200/JCO.2006.06.8429 17075117 \n6 Glimelius B Ekstrom K Hoffman K Graf W Sjoden PO Haglund U Svensson C et al Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer Ann Oncol 1997 8 2 163 168 10.1023/A:1008243606668 9093725 \n7 Wagner AD Grothe W Haerting J Kleber G Grothey A Fleig WE Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data J Clin Oncol 2006 24 18 2903 2909 10.1200/JCO.2005.05.0245 16782930 \n8 Cunningham D Starling N Rao S Iveson T Nicolson M Coxon F Middleton G et al Capecitabine and oxaliplatin for advanced esophagogastric cancer N Engl J Med 2008 358 1 36 46 10.1056/NEJMoa073149 18172173 \n9 Park YH Ryoo BY Choi SJ Kim HT A phase II study of capecitabine and docetaxel combination chemotherapy in patients with advanced gastric cancer Br J Cancer 2004 90 7 1329 1333 10.1038/sj.bjc.6601724 15054450 \n10 Evans D Miner T Akerman P Millis R Jean M Kennedy T Safran H A phase I study of docetaxel, oxaliplatin, and capecitabine in patients with metastatic gastroesophageal cancer Am J Clin Oncol 2007 30 4 346 349 10.1097/COC.0b013e318042d582 17762433 \n11 Goel G Jauhri M Negi A Aggarwal S Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma Hematol Oncol Stem Cell Ther 2010 3 2 55 59 20543537\n\n",
"fulltext_license": "CC BY",
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"journal": "World journal of oncology",
"keywords": "Capecitabine; Complete remission; Docetaxel; Gastric cancer; Oxaliplatin",
"medline_ta": "World J Oncol",
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"pubdate": "2012-06",
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"title": "Long Term Complete Remission in Advanced Gastric Adenocarcinoma With Docetaxel, Oxaliplatin and Capecitabine Combination Regimen.",
"title_normalized": "long term complete remission in advanced gastric adenocarcinoma with docetaxel oxaliplatin and capecitabine combination regimen"
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